CN101448875A - 鬼臼毒素类的高分子量结合体 - Google Patents
鬼臼毒素类的高分子量结合体 Download PDFInfo
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- CN101448875A CN101448875A CNA2007800177809A CN200780017780A CN101448875A CN 101448875 A CN101448875 A CN 101448875A CN A2007800177809 A CNA2007800177809 A CN A2007800177809A CN 200780017780 A CN200780017780 A CN 200780017780A CN 101448875 A CN101448875 A CN 101448875A
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- podophillotoxines
- high molecular
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- group
- molecular combination
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Classifications
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Abstract
人们需要一种新颖的鬼臼毒素衍生物,其能够在无需依赖生物酶的条件下释放药物,能够预期其具有有效的疗效,而且可溶于水。提供了一种包含聚乙二醇结构单元以及两个或更多个琥珀酸单酰胺结构单元的聚合物,特别是鬼臼毒素的聚合物结合体,其中聚乙二醇/聚天冬氨酸共聚物的羧酸基团与鬼臼毒素的羟基通过酯键连接。
Description
技术领域
本发明涉及鬼臼毒素类的高分子量结合体,其中包含聚乙二醇部分以及两个或更多个琥珀酸单酰胺部分的聚合物的羧酸基团与鬼臼毒素类的羟基通过酯键而结合,本发明还涉及所述鬼臼毒素类的高分子量结合体的制备方法及其应用。
背景技术
鬼臼毒素是一种包含在美国盾叶鬼臼的根和茎的水提取物中的具有生理活性的物质,所述美国盾叶鬼臼是鬼臼属的一种多年生植物,已知鬼臼毒素及其衍生物具有抗癌活性。但是,这些化合物当中的许多水溶性差,因此为了进一步改进其效果,对鬼臼毒素类的水溶性高分子量衍生物等进行了研究。
例如,专利文献1描述了与聚乙二醇结合的鬼臼毒素类的高分子量衍生物。但是,在这些鬼臼毒素类的高分子量衍生物中,因为鬼臼毒素的结构,每个聚乙二醇分子仅与一个到两个鬼臼毒素分子相结合,因此为了给予有效量的药物,需要大量的聚合物。
专利文献2描述了一种分子,其中药物与聚乙二醇和聚天冬氨酸的嵌段共聚物结合,所述嵌段共聚物形成胶束,具有水溶性。专利文献3描述了一种聚合物载体,其中疏水性物质与聚乙二醇和聚(酸性氨基酸)的嵌段共聚物的侧链中的羧酸基团结合,所述嵌段共聚物起聚合物药物载体的作用。专利文献4描述了喜树碱的高分子量衍生物,其中聚乙二醇和聚谷氨酸的嵌段共聚物的侧链中的羧酸基团与喜树碱的酚羟基相结合。但是专利文献2-4没有描述鬼臼毒素类的结合体。
[专利文献1]日本专利申请公开(KOHYO)第10-513187号
[专利文献2]日本专利第2694923号
[专利文献3]日本专利第3268913号
[专利文献4]国际专利申请公开第WO 2004/39869号,小册子
发明内容
发明所要解决的问题。
专利文献1中所述聚乙二醇部分和药物之间的键可被体内的水解酶断裂开,由此可以对药物的递送和释放进行控制。但是,人们认为,不同物种之间,以及在相同物种的个体之间体内的水解酶会发生很大的变化。因此,人们存在一种担心,即当与药物连接的键的断裂取决于水解酶的时候,不同个体之间释放的药物的效果可能会有很大的不同。
对于专利文献2中所述的阿霉素结合体,其中嵌段共聚物通过酰胺键与阿霉素结合,其功效很成问题,因为酰胺键是化学稳定的键合形式,所以通过水解的药物释放相当缓慢。
依托泊苷和鬼臼噻吩苷之类的鬼臼毒素类是有效的抗癌药,因此人们需要水溶性和具有极佳的抗癌活性的新颖的衍生物。
解决问题的方法
为了解决上述问题,本发明人进行了深入而细致的研究,结果发现以下现象,当包含羟基的化合物通过酯键与琥珀酸单酰胺的游离羧酸结合的时候,由于所述琥珀酸单酰胺的结构改变为环状结构(琥珀酸酰亚胺),所述包含羟基的化合物可以很容易地释放。基于这一点,本发明人制备了鬼臼毒素类的高分子量结合体,其中包含聚乙二醇部分和琥珀酸单酰胺部分的聚合物能够与鬼臼毒素类的羟基通过酯键而结合,还发现如此制得的高分子量结合体能够在无需依赖水解酶的情况下释放鬼臼毒素类,从而完成了本发明。
具体来说,本发明涉及以下(1)至(10)项。
(1)一种鬼臼毒素类的高分子量结合体,其中包含聚乙二醇部分和两个或更多个琥珀酸单酰胺部分的聚合物的羧酸基团与所述鬼臼毒素的羟基通过酯键而结合。
(2)如上面(1)所述的鬼臼毒素类的高分子量结合体,其中所述包含聚乙二醇部分和两个或更多个琥珀酸单酰胺的聚合物是嵌段共聚物。
(3)如上面(2)所述的鬼臼毒素类的高分子量结合体,其中所述两个或更多个琥珀酸单酰胺部分构成聚天冬氨酸。
(4)如上面(3)所述的鬼臼毒素类的高分子量结合体,其由式(I)表示:
其中R1表示氢原子或(C1-C6)烷基;R2表示连接基团;R3表示氢原子或(C1-C6)酰基;R4表示鬼臼毒素类的羟基的残基;R5表示选自以下的基团:(C1-C30)烷氧基,(C7-C30)芳烷氧基,(C1-C30)烷基氨基,二(C1-C30)烷基氨基,以及带有保护的羧基的氨基酸,以及-N(R6)CONH(R7),其中R6和R7可以是相同或不同的,它们各自表示任选地被叔氨基取代的(C3-C6)环烷基或(C1-C5)烷基;t表示5-11,500的整数;d,e,f,g,h,i和j各自独立地表示0-200的整数,前提是d+e表示1-200的整数,d+e+f+g+h+i+j表示3-200的整数,相应的聚天冬氨酸的组成单元以任意的顺序结合。
(5)如上面(4)所述的鬼臼毒素类的高分子量结合体,其中R1是(C1-C6)烷基;R2是(C2-C6)亚烷基;R3是(C1-C6)酰基;t是8-2300的整数;d,e,f,g,h,i和j各自独立地是0-100的整数,前提是d+e是1-100的整数,d+e+f+g+h+i+j是6-100的整数。
(6)如上面(5)所述的鬼臼毒素类的高分子量结合体,其中R1是(C1-C3)烷基;R2是(C2-C4)亚烷基;R3是(C1-C3)酰基;t是100-300的整数;d,e,f,g,h,i和j各自独立地是0-90的整数,前提是d+e是1-90的整数,d+e+f+g+h+i+j是15-90的整数。
(7)如上面(1)-(6)中任一项所述的鬼臼毒素类的高分子量结合体,其中所述鬼臼毒素类是鬼臼毒素、依托泊苷或鬼臼噻吩苷。
(8)一种鬼臼毒素类的高分子量结合体,其通过在有机溶剂中使用脱水缩合剂,使包含聚乙二醇部分和两个或更多个琥珀酸单酰胺部分的聚合物的羧酸基团与所述鬼臼毒素的羟基通过酯键结合而制得。
(9)一种制备以上(1)至(7)中任一项所述的鬼臼毒素类的高分子量结合体的方法,该方法包括在有机溶剂中使用脱水缩合剂,使包含聚乙二醇部分和两个或更多个琥珀酸单酰胺部分的聚合物的羧酸基团与所述鬼臼毒素的羟基通过酯键而结合。
(10)一种抗癌药,包含上面(1)至(8)中任一项所述的鬼臼毒素类的高分子量结合体作为活性组分。
发明的效果
本发明的鬼臼毒素类的高分子量结合体能够在无需依赖体内的水解酶的情况下释放药物,几乎不会受到个体差异的影响,可预期具有高的疗效。
具体实施方式
本发明的鬼臼毒素类的高分子量结合体的特征是,包含聚乙二醇部分和两个或更多个琥珀酸单酰胺部分的聚合物的羧酸基团与所述鬼臼毒素类的羟基通过酯键而结合。
根据本发明,术语"琥珀酸单酰胺部分"表示以下结构:-HNCO-C-C-CO2H,例如其例子包括琥珀酸单酰胺(-HNCO-CH2-CH2-CO2H),天冬氨酸内的两个羧酸基团中的一个酰胺化的结构(-HNCO-CH(-NH-)-CH2-CO2H or-HNCO-CH2-CH(-NH-)-CO2H),等等。这些琥珀酸单酰胺部分可以构成聚合物主链,例如对于聚天冬氨酸就是这种情况,或者可以与由以下物质组成的主链聚合物的官能团结合:聚醇,例如葡聚糖,聚胺,例如聚赖氨酸,或者除了聚天冬氨酸以外的聚羧酸(例如聚乳酸等)。
包含聚乙二醇部分以及两个或更多个琥珀酸单酰胺部分的聚合物的例子包括接枝型聚合物,其中聚乙二醇部分和琥珀单酰胺部分以梳状形式从聚合物主链分支出来,还包括嵌段型聚合物(嵌段共聚物),其中包含聚乙二醇部分和琥珀酸单酰胺部分的聚合物串联排列,等等。
当所述两个或更多个琥珀酸单酰胺部分形成聚天冬氨酸的时候,所述接枝型聚合物还包括具有以下特征的聚合物:其中聚乙二醇部分是部分地与所述聚天冬氨酸主链结合,等等;而嵌段类聚合物包括具有以下特征的聚合物:其中聚天冬氨酸的末端与所述聚乙二醇部分的末端结合,等等。
本发明的鬼臼毒素类的高分子量结合体的聚合物中的聚乙二醇部分包括两个末端或者一个末端被改性的聚乙二醇。当两个末端都被改性的时候,所述改性基团可以是相同的或不同的。改性基团的例子包括任选包含取代基的(C1-C6)烷基。任选包含取代基的(C1-C6)烷基中烷基的例子包括以下的烷基,优选是(C1-C4)烷基,包括例如甲基、乙基、正丙基、正丁基等。任选包含取代基的(C1-C6)烷基中取代基的例子包括例如氨基、甲基氨基、二甲基氨基、乙基氨基、二乙基氨基等。
所述聚乙二醇部分的分子量约为300-500,000,优选约为500-100,000,更优选约为1000-50,000。
根据本发明包含聚乙二醇部分和两个或更多个琥珀酸单酰胺部分的聚合物的分子量约为500-600,000,优选约为600-110,000,更优选约为800-80,000。
根据本发明,术语“分子量”表示通过GPC法测定的重均分子量。
在本发明的鬼臼毒素类的高分子量结合体中,以羧酸基团的总数为基准计,与所述包含聚乙二醇部分和两个或更多个琥珀酸单酰胺部分的聚合物结合的鬼臼毒素类的量为1-100%,优选为1-90%,更优选为2-60%。
根据本发明,所述鬼臼毒素类并无特别限制,只要它们是具有羟基和抗肿瘤活性的鬼臼毒素类即可。鬼臼毒素类的例子包括以下式(II)表示的鬼臼毒素,以下式(III)表示的依托泊苷,以下式(IV)表示的鬼臼噻吩苷等。鬼臼毒素类的羟基的例子包括例如以下式(II)所示的醇羟基,糖部分上的醇羟基或者下式(III)或(IV)的苯环上的酚羟基,对羟基的取代位置没有限制。
本发明的鬼臼毒素类的高分子量结合体可包括通过鬼臼毒素类的醇羟基形成的结合体,或者通过鬼臼毒素类的酚羟基形成的结合体,或者它们的混合物。或者还可采用一种高分子量结合体,其中通过酚羟基结合的鬼臼毒素类以及通过酚酸性基团结合的鬼臼毒素类还可在一个分子上混合。
优选聚天冬氨酸作为根据本发明的两个或更多个琥珀酸单酰胺部分。
本发明优选的鬼臼毒素类的高分子量结合体包括上面通式(1)表示的化合物,其中R1表示氢原子或(C1-C6)烷基;R2表示连接基团;R3表示氢原子或(C1-C6)酰基;R4表示鬼臼毒素类的羟基的残基;R5表示选自以下的基团:(C1-C30)烷氧基,(C7-C30)芳烷氧基,(C1-C30)烷基氨基,二(C1-C30)烷基氨基,以及带有保护的羧基的氨基酸,以及-N(R6)CONH(R7),其中R6和R7可以是相同或不同的,它们各自表示任选地被叔氨基取代的(C3-C6)环烷基或(C1-C5)烷基;t表示5-11,500的整数;d,e,f,g,h,i和j各自独立地表示0-200的整数,前提是d+e表示1-200的整数,d+e+f+g+h+i+j表示3-200的整数,相应的聚天冬氨酸的组成单元以任意的顺序结合。
所述通式(1)中R1的(C1-C6)烷基的例子包括直链或支链的(C1-C6)烷基,包括例如甲基,乙基,正丙基,异丙基,正丁基,叔丁基,正戊基,异戊基,正己基等,优选的是直链或支链的(C1-C4)烷基,特别优选的是直链或支链的(C1-C3)烷基,包括例如甲基,乙基,正丙基,异丙基,更特别优选的是甲基。
通式(I)中R2表示的连接基团的例子包括但不特别限于(C2-C6)亚烷基。优选的是(C2-C4)亚烷基,包括例如亚乙基,1,3-亚丙基,亚丁基等,特别优选的是1,3-亚丙基。
通式(I)中R3的(C1-C6)酰基的例子包括但不特别限于甲酰基,乙酰基,丙酰基,新戊酰基等。优选的是(C1-C3)酰基,特别优选的是乙酰基。
对于通式(I)中R4的鬼臼毒素类的羟基的残基,鬼臼毒素类的例子包括上述鬼臼毒素类,它们没有特别的限制,只要所述鬼臼毒素类包括能够使用脱水缩合剂通过酯键与聚合物的羧酸部分结合的羟基,而且具有抗肿瘤活性即可。鬼臼毒素类的例子包括上面式(II)表示的鬼臼毒素,上面式(III)表示的依托泊苷,上面式(IV)表示的鬼臼噻吩苷等。
通式(I)中的R5表示选自以下的基团:(C1-C30)烷氧基,(C7-C30)芳烷氧基,(C1-C30)烷基氨基,二(C1-C30)烷基氨基,带有保护的羧酸的氨基酸,以及-N(R6)CONH(R7),其中R6和R7可以是相同或不同的,是任选地被叔氨基取代的(C3-C6)环烷基或者(C1-C5)烷基。通式(I)中的R5在一个分子中可以是相同或不同的,所述鬼臼毒素类的高分子量结合体中的聚合物可以包括单独种类或混合种类的R5。
(C1-C30)烷氧基的例子包括直链或支链的(C1-C30)烷氧基,优选的是直链或支链的(C1-C10)烷氧基,包括例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基等。(C7-C30)芳烷氧基的例子包括直链或支链的(C7-C12)芳烷氧基,优选的是直链或支链的(C1-C10)芳烷氧基,包括例如4-苯基丁氧基等。
(C1-C30)烷基氨基或二(C1-C30)烷基氨基的例子包括直链或支链的(C1-C30)烷基氨基或二(C1-C30)烷基氨基,优选是直链或支链的(C1-C20)烷基氨基或二(C1-C20)氨基氨基,包括例如甲基氨基,乙基氨基,正丙基氨基,异丙基氨基,正丁基氨基,叔丁基氨基,二甲基氨基,二乙基氨基,二(正丁基)氨基等。
带有保护的羧基的氨基酸的例子包括通常用于肽合成的其中羧基被保护的氨基酸,包括例如苯基丙氨酸苄酯等。
基团-N(R6)CONH(R7)[其中R6和R7可以是相同或不同的,为任选地被叔氨基取代的(C3-C6)环烷基或(C1-C5)烷基]包括但不特别限于,例如环己基氨基羰基环己基氨基,异丙基氨基羰基异丙基氨基等。
本发明的通式(I)表示的鬼臼毒素类的高分子量结合体中两个或更多个琥珀酸单酰胺组成的聚天冬氨酸包括α-氨基酸类、β-氨基酸类、环状种类的组成单元等。这些组成单元以任意的顺序结合,可以结合形成嵌段型或无规型的形式。
通式(I)表示的鬼臼毒素类的高分子量结合体的聚天冬氨酸中天冬氨酸残基的总数用"d+e+f+g+h+i+j"表示,可以通过例如用来制备嵌段共聚物的天冬氨酸衍生物的量确定。天冬氨酸残基的数量(d+e+f+g+h+i+j)约为3-200,优选约为6-100,特别优选为15-90。
以天冬氨酸残基的总数(d+e+f+g+h+i+j)为基准计,与鬼臼毒素类结合的天冬氨酸残基的数量(d+e)所占的比例为1-100%,优选为3-90%,更优选为4-60%。另外,天冬氨酸残基的数量(d+e)约为1-200,优选约为1-100,特别优选为1-90。
与鬼臼毒素类结合的天冬氨酸残基的数量(d+e)可以通过例如下面实施例中所述,在有机溶剂中,进行脱水缩合反应,通过酯键连接鬼臼毒素类之后,反应液体中剩余的未反应的鬼臼毒素类的量来确定。
以天冬氨酸残基的总数(d+e+f+g+h+i+j)为基准计,α-氨基酸类的比例(d+f+h)为10-100%,优选为20-100%。β-氨基酸类(e+g+i)的比例为0-90%,优选为0-80%。例如可通过适当地选择聚天冬氨酸等中保护基团的去保护条件适当地改变所述比例。
在通式(I)中,t是约为5-11,500的整数,优选约为8-2,300的整数,更优选约为100-300的整数。
本发明的鬼臼毒素类的高分子量结合体可形成具有聚乙二醇部分的胶束作为处于水中的外壳。
本发明的鬼臼毒素类的高分子量结合体通过在有机溶剂中使用脱水缩合剂使包含聚乙二醇部分和两个或更多个琥珀酸单酰胺部分的聚合物的羧酸基团与鬼臼毒素的羟基通过酯键结合而制得,本发明还包括该制备方法;也就是说,例如在0-180℃、优选5-50℃的温度下,在有机溶剂中,使用脱水缩合剂,使通过专利文献2所述的方法制备的聚乙二醇部分-聚天冬氨酸的嵌段共聚物,和鬼臼毒素类发生反应,所述鬼臼毒素类中除了要反应的基团以外的官能团根据需要进行保护,所述脱水缩合剂包括例如二环己基碳二亚胺(DCC),二异丙基碳二亚胺(DIPC),盐酸1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(WSC)或者1-乙氧基羰基-2-乙氧基-1,2-二羟基喹啉酮(quinolinone)(EEDQ),所述有机溶剂能够溶解上述两种反应物质,优选是非质子极性溶剂,例如N,N-二甲基甲酰胺(DMF),1,3-二甲基-2-咪唑啉酮(DMI)或者N-甲基吡咯烷酮(NMP)。另外,在缩合反应中还可以使用反应助剂,例如N,N-二甲基氨基吡啶(DMAP)。缩合反应之后,根据需要进行去保护,可以采用常规的分离和纯化等操作,以制得鬼臼毒素类的高分子量结合体。
另外,其中R5是-N(R6)CONH(R7)基团(其中R6和R7可以是相同或不同的,各自是任选地被叔氨基取代的(C3-C6)环烷基或(C1-C5)烷基)的鬼臼毒素类的高分子量结合体还可通过使用上述碳二亚胺类作为缩合剂的反应制得。
作为用来将(C1-C30)烷氧基、(C7-C30)芳烷氧基、(C1-C30)烷基氨基、二(C1-C30)烷基氨基或者带有保护的羧基的氨基酸作为R5引入通式(I)的化合物中的方法,可提及:首先对聚合物的羧酸基团进行活化,然后在碱性条件下,与一定量的需要加入的相应的醇、相应的胺、或者带有保护的羧基的氨基酸等进行反应的方法;首先使得相应的醇、相应的胺、带有保护的羧基的氨基酸等活化,然后与聚合物反应的方法;等等。在对聚合物进行纯化之后,可以通过相同的反应对聚合物中任意未反应的羧酸基团进行再活化,所述再活化的羧酸基团可以与鬼臼毒素类的羟基缩合。或者,其他的醇、胺等可以重复地反应,以合成包含各种取代基作为R5的聚合物的混合物,然后鬼臼毒素类可以与该混合物缩合。另外,在使聚合物与鬼臼毒素类缩合之后,可以引入(C1-C30)烷氧基、(C7-C30)芳烷氧基,(C1-C30)烷基氨基,二(C1-C30)烷基氨基,带有保护的羧基的氨基酸等。
用来制备本发明的鬼臼毒素类的高分子量结合体的方法不限于上述方法。
本发明还包括包含本发明的鬼臼毒素类的高分子量结合体作为活性组分的抗癌药。所述高分子量结合体可以常用的剂型使用,包括例如注射剂、片剂、粉末等。在配制的过程中,可以使用药学上可接受的常用载体,例如粘合剂、润滑剂、崩解剂、溶剂、赋形剂、增溶剂、分散剂、稳定剂、悬浮剂、防腐剂、安慰剂、着色剂、香料等。其中优选以注射剂的形式使用,通常可以使用例如水、生理盐水、5%的葡萄糖或甘露醇溶液,水溶性有机溶剂(例如甘油、乙醇、二甲亚砜、N-甲基吡咯烷酮、聚乙二醇、克列莫佛(cremophor)等,以及它们的混合物),水和水溶性有机溶剂的混合物等。
当然,本发明的鬼臼毒素类的高分子量结合体的剂量可以根据患者的性别、年龄、生理条件、病理等因素变化,所述高分子量结合体胃肠道外给药,通常对于成年人每天的剂量(按活性组分)为0.01-500毫克/米2,优选0.1-250毫克/米2。注射给药通过静脉注射、动脉注射、作用位点(肿瘤位点)注射等进行。
实施例
下面,将结合实施例更详细地说明本发明,但是本发明不限于这些实施例。
实施例1
化合物1(依托泊苷和嵌段共聚物的结合体,所述嵌段共聚物是分子量为12000的甲氧基聚乙二醇部分以及聚合度为35的聚天冬氨酸部分的嵌段共聚物:通式(I),其中R1=Me(甲基),R2=1,3-亚丙基,R3=酰基(乙酰基),R4=依托泊苷残基,R5=异丙基氨基羰基异丙基氨基,d+e+f+g+h+i+j=35,t=273)的合成
将根据专利文献3所述方法制备的甲氧基聚乙二醇-聚天冬氨酸嵌段共聚物(天冬氨酸的聚合度:35,1.80克)以及市售的依托泊苷(700毫克)溶解在DMF(70毫升)中,向其中加入DMAP(72毫克)和DIPC(1.25毫升)。所述混合物在25℃下搅拌20小时。向反应液体中加入乙醇(105毫升)、乙酸乙酯(105毫升)和二异丙醚(840毫升),该混合物在室温下搅拌120分钟。然后通过过滤收集沉淀,用乙醇/二异丙醚(1/4(v/v),100毫升)洗涤。所得的沉淀溶解在乙腈/水(1/1(v/v),210毫升)中,然后使得溶液通过离子交换树脂柱(陶氏化学公司(DowChemical Company)制造,Dowex 50(H+),15毫升),用乙腈/水(1/1(v/v),30毫升)洗脱。将水(140毫升)加入由此制得的洗脱级分中,减压蒸馏掉乙腈,然后对残余物进行冷冻干燥,制得化合物1(2.06克)。
根据通过HPLC(高效液相色谱)测得的反应液中未反应的依托泊苷的量,确定化合物1中依托泊苷的含量为16.5%(w/w),确定(d+e)与(d+e+f+g+h+i+j)之比为15%。在化合物1中,未检测到游离的依托泊苷。
根据该方法,异丙基氨基羰基-异丙基氨基可以作为R5加入,基团的丰度比使用溶解在氘氧化钠(sodium deuteroxide)/氧化氘/氘代乙腈的化合物1通过1H-NMR(氢核磁共振谱)测定。化合物1的异丙基氨基羰基-异丙基氨基与聚天冬氨酸之比,即(f+g)与(d+e+f+g+h+i+j)之比为19.6%。剩余的天冬氨酸残基为游离羧酸(h+i)或环状结构(j)的形式。
实施例2
化合物2(鬼臼毒素和嵌段共聚物的结合体,所述嵌段共聚物是分子量为12000的甲氧基聚乙二醇部分以及聚合度为35的聚天冬氨酸部分的嵌段共聚物:通式(I),其中R1=Me(甲基),R2=1,3-亚丙基,R3=酰基(乙酰基),R4=鬼臼毒素残基,R5=异丙基氨基羰基异丙基氨基,d+e+f+g+h+i+j=35,t=273)的合成
将根据专利文献3所述方法制备的甲氧基聚乙二醇-聚天冬氨酸嵌段共聚物(天冬氨酸的聚合度:35,226毫克)以及市售的鬼臼毒素(106毫克)溶解在DMF(5毫升)中,向其中加入DMAP(12毫克)和DIPC(0.16毫升)。所述混合物在25℃下搅拌20小时。向反应液体中加入乙醇(15毫升)和二异丙醚(60毫升),该混合物在室温下搅拌120分钟。然后通过过滤收集沉淀,用乙醇/二异丙醚(1/4(v/v),10毫升)洗涤。所得的沉淀溶解在乙腈/水(1/1(v/v),10毫升)中,然后使得溶液通过离子交换树脂柱(陶氏化学公司(Dow Chemical Company)制造,Dowex 50(H+),2.5ml),用乙腈/水(1/1(v/v),5毫升)洗脱。将水(10毫升)加入由此制得的洗脱级分,然后减压蒸馏掉乙腈。然后对残余物冷冻干燥,制得化合物2(220毫克)。
根据通过HPLC(高效液相色谱)测得的反应液中未反应的鬼臼毒素的量,确定化合物2中鬼臼毒素的含量为10.6%(w/w),确定(d+e)与(d+e+f+g+h+i+j)之比为13.1%。在化合物2中,未检测到游离的鬼臼毒素。
根据该方法,异丙基氨基羰基-异丙基氨基可以作为R5加入,基团的丰度比使用溶解在氘氧化钠(sodium deuteroxide)/氧化氘/氘代乙腈的化合物2通过1H-NMR(氢核磁共振谱)测定。化合物2的异丙基氨基羰基-异丙基氨基与聚天冬氨酸之比,即(f+g)与(d+e+f+g+h+i+j)之比为15.2%。剩余的天冬氨酸残基为游离羧酸(h+i)或环状结构(j)的形式。
实施例3
化合物3(鬼臼毒素和嵌段共聚物的结合体,所述嵌段共聚物是分子量为12000的甲氧基聚乙二醇部分以及聚合度为33的聚天冬氨酸部分的嵌段共聚物:通式(I),其中R1=Me(甲基),R2=1,3-亚丙基,R3=酰基(乙酰基),R4=鬼臼毒素残基,R5=异丙基氨基羰基异丙基氨基或O-苄基-苯基丙氨酰基,d+e+f+g+h+i+j=33,t=273)的合成
将根据专利文献3所述方法制备的甲氧基聚乙二醇-聚天冬氨酸嵌段共聚物(天冬氨酸的聚合度:33,464.4毫克)以及市售的鬼臼毒素(100毫克)溶解在DMF(6毫升)中,向其中加入DMAP(12毫克)和DIPC(0.09毫升)。所述混合物在15℃下搅拌20小时。然后加入盐酸苯基丙氨酸苄酯(36.8毫克),三乙胺(0.02毫升)和DIPC(0.23毫升),该混合物在15℃搅拌20小时,然后在25℃再搅拌4小时。向反应液体中加入乙酸乙酯(10毫升)、乙醇(10毫升)和二异丙醚(80毫升),该混合物在室温下搅拌30分钟。然后通过过滤收集沉淀,用乙醇/二异丙醚(1/4(v/v),20毫升)洗涤。所得的沉淀溶解在乙腈/水(1/1(v/v),20毫升)中,然后使得溶液通过离子交换树脂柱(陶氏化学公司(Dow Chemical Company)制造,Dowex 50(H+),3ml),用乙腈/水(1/1(v/v),20毫升)洗脱。将水(25毫升)加入由此制得的洗脱级分中,减压蒸馏掉乙腈,然后对残余物进行冷冻干燥,制得化合物3(580毫克)。
根据通过HPLC(高效液相色谱)测得的反应液中未反应的鬼臼毒素的量,确定化合物3中鬼臼毒素的含量为13.7%(w/w),确定(d+e)与(d+e+f+g+h+i+j)之比为19%。在化合物3中,未检测到游离的鬼臼毒素。
作为R5之一引入的O-苄基-苯基丙氨酰基通过对40℃下在乙腈-氢氧化钠水溶液中使化合物3水解6小时释放出的苄醇的量进行定量而确定。O-苄基-苯基丙氨酰基与聚天冬氨酸之比,即计入(f+g)的O-苄基-苯基丙氨酰基与(d+e+f+g+h+i+j)之比为13%。
另外,异丙基氨基羰基-异丙基氨基也可以作为R5加入,基团的丰度比使用溶解在氘氧化钠(sodium deuteroxide)/氧化氘/氘代乙腈的化合物3通过1H-NMR(氢核磁共振谱)测定。异丙基氨基羰基异丙基氨基基团与聚天冬氨酸之比,即计入(f+g)的异丙基氨基羰基异丙基氨基与(d+e+f+g+h+i+j)之比为15%。结果,R5的总量与聚天冬氨酸之比,即(f+g)与(d+e+f+g+h+i+j)之比为28%。剩余的天冬氨酸残基为游离羧酸(h+i)或环状结构(j)的形式。
比较例1
比较化合物1(依托泊苷和嵌段共聚物的结合体,所述嵌段共聚物包含分子量为12000的甲氧基聚乙二醇部分以及聚合度为23的聚谷氨酸部分)的合成
将根据日本专利申请公开(公开)第5-955号所述的方法制备的甲氧基聚乙二醇-聚谷氨酸嵌段共聚物(21毫克)和市售的依托泊苷(9.6毫克)溶解在DMF(1毫升)中,将DMAP(0.6毫克)和DIPC(0.01毫升)加入其中。所述混合物在25℃下搅拌20小时。向反应液体中加入乙醇(1.5毫升)、乙酸乙酯(1.5毫升)和二异丙醚(12毫升),该混合物在室温下搅拌30分钟。然后通过过滤收集沉淀,用乙醇/二异丙醚(1/4(v/v),2毫升)洗涤。所得的沉淀溶解在乙腈/水(1/1(v/v),3毫升)中,然后使得溶液通过离子交换树脂柱(陶氏化学公司(Dow ChemicalCompany)制造,Dowex 50(H+),0.2毫升),用乙腈/水(1/1(v/v),1毫升)洗脱。将水(1毫升)加入由此制得的洗脱级分中,减压蒸馏掉乙腈,然后对残余物进行冷冻干燥,制得比较化合物1(28.0克)。
基于通过HPLC测得的反应液中未反应的依托泊苷的量,确定比较化合物1中依托泊苷的含量为23.8%(w/w)。在比较化合物1中,未检测到游离的依托泊苷。
比较例2
比较化合物2(鬼臼毒素和嵌段共聚物的结合体,所述嵌段共聚物包含分子量为12000的甲氧基聚乙二醇部分以及聚合度为23的聚谷氨酸部分)的合成
将根据日本专利申请公开(公开)第5-955号所述的方法制备的甲氧基聚乙二醇-聚谷氨酸嵌段共聚物(52毫克)和市售的鬼臼毒素(10毫克)溶解在DMF(1毫升)中,将DMAP(2毫克)和DIPC(0.03毫升)加入其中。所述混合物在25℃下搅拌20小时。向反应液体中加入乙醇(3毫升)和二异丙醚(12毫升),该混合物在室温下搅拌30分钟。然后通过过滤收集沉淀,用乙醇/二异丙醚(1/4(v/v),2毫升)洗涤。所得的沉淀溶解在乙腈/水(1/1(v/v),3毫升)中,然后使得溶液通过离子交换树脂柱(陶氏化学公司(Dow Chemical Company)制造,Dowex 50(H+),0.2毫升),用乙腈/水(1/1(v/v),1毫升)洗脱。将水(1毫升)加入由此制得的洗脱级分,然后减压蒸馏掉乙腈。然后对残余物冷冻干燥,制得比较化合物2(64.3毫克)。
基于通过HPLC测得的反应液中未反应的鬼臼毒素的量,比较化合物2中鬼臼毒素的含量为16.0%(w/w)。在比较化合物2中,未检测到游离的鬼臼毒素。
测试实施例1
在不存在酶的条件下药物从化合物1中释放
将化合物1或比较化合物1溶解在PBS(磷酸盐缓冲的生理盐水;pH=7.1)中,使得聚合物浓度为1毫克/毫升,该溶液在37℃培养。通过HPLC将从高分子量结合体释放的依托泊苷分离,并通过与标准曲线比较对其定量。图1显示了以由高分子量结合体的药物含量确定的总药物量为基准计的定量值的比例。
从图1可看出,本发明的高分子量结合体(化合物1)在不存在水解酶的条件下,在24小时内释放出了等于或大于85%的依托泊苷,而不含琥珀酸单酰胺部分的比较化合物1在24小时内实际上不释放依托泊苷。该结果表明本发明的依托泊苷的高分子量结合体在不存在酶的条件下具有极佳的药物释放性能。
测试实施例2
在不存在酶的条件下药物从化合物2和3释放
将化合物2或3,或者比较化合物2溶解在PBS(磷酸盐缓冲的生理盐水;pH=7.1)中,使得聚合物浓度为1毫克/毫升,该溶液在37℃培养。通过HPLC将高分子量结合体释放的鬼臼毒素分离,并通过与标准曲线比较对其定量。图2显示了以由高分子量结合体的药物含量确定的总药物量为基准计的定量值的比例。
从图2可看出,本发明的高分子量结合体(化合物2或3)在不存在水解酶的条件下,在24小时内释放出了10-60%或者更多的鬼臼毒素,而不含琥珀酸单酰胺部分的比较化合物2在24小时内实际上不释放鬼臼毒素。该结果表明本发明的鬼臼毒素的高分子量结合体在不存在酶的条件下具有极佳的药物释放性能。另外,表明药物释放性能可以自由控制。
测试实施例3
化合物1的抗肿瘤效果
通过在小鼠内的连续皮下继代培养保持的小鼠结肠癌,Colon 26,被切碎成约2-毫米见方的碎片,然后用套针将这些碎片皮下移植到雌性CDF1小鼠的背部。肿瘤移植七天之后,将本发明的高分子量结合体(化合物1)或者对照药物(依托泊苷,ETP)对小鼠的尾部静脉进行一次静脉给药。对照组表示没有给药的组。将化合物1溶解在5%的葡萄糖溶液中,供注射和使用。对于ETP,Rastet注射药(日本化药株式会社(Nippon Kayaku Co.,Ltd.)生产)用5%的葡萄糖溶液稀释,供注射和使用。给药之后,用卡尺测量肿瘤的主轴(L毫米)和次轴(W毫米),通过公式(L×W2)/2计算肿瘤体积。表1显示了以给药那天的肿瘤体积为基准计的相对肿瘤体积。表1中还显示了这段时间内体重的变化,以给药那天的体重为基准计的相对体重表示。
表1
表1表明本发明的高分子量结合体在造成体重减轻程度与ETP(90毫克/千克)相同的剂量下(450毫克/千克),具有优于后者的抗癌活性,因此可以作为抗癌药。
测试实施例4:化合物2和3的抗肿瘤作用
通过在小鼠内的连续皮下继代培养保持的小鼠结肠癌,Colon 26,被切碎成约2-毫米见方的碎片,然后用套针将这些碎片皮下移植到雌性CDF1小鼠的背部。肿瘤移植七天之后(表2,给药起始日),将本发明的高分子量结合体(化合物2和3)或者对照药物(鬼臼毒素,POD)对小鼠的尾部静脉进行一次静脉给药。化合物2和3溶解于5%的葡萄糖溶液,供一次性注射和给药。对照组表示没有给药的组。购自西格马-奥尔德里奇公司(Sigma-Aldrich Company)的POD用二甲亚砜和5%的葡萄糖溶液稀释,用来从给药起始日起连续给药5天。给药之后,用卡尺测量肿瘤的主轴(L毫米)和次轴(W毫米),通过公式(L×W2)/2计算肿瘤体积。表2显示了以给药起始日的肿瘤体积为基准计的相对肿瘤体积。表2中还显示了这段时间内体重的变化,以给药那天的体重为基准计的相对体重表示。
表2
表2表明本发明的高分子量结合体在造成体重减轻程度与POD(15毫克/千克/天,连续给药5天)相同的给药量下(75毫克/千克),尽管是单次给药,仍具有优于后者的抗癌活性,因此可以作为抗癌药。
附图简要说明
图1显示了以结合的依托泊苷的总量为基准计,在PBS溶液中(pH=7.1,37℃)从化合物1(高分子量衍生物,其中依托泊苷与嵌段共聚物的聚天冬氨酸结合)或者比较化合物1(高分子量衍生物,其中依托泊苷与嵌段共聚物的聚谷氨酸结合)释放的依托泊苷的量的百分数。在图1中,-●-表示从本发明的化合物1释放的量的百分数,-○-表示从比较化合物1释放的量的百分数。
图2显示了以结合的鬼臼毒素的总量为基准计,在PBS溶液中(pH=7.1,37℃)从本发明的化合物2或化合物3(高分子量衍生物,其中鬼臼毒素与嵌段共聚物的聚天冬氨酸结合)或者比较化合物2(高分子量衍生物,其中鬼臼毒素与嵌段共聚物的聚谷氨酸结合)释放的鬼臼毒素的量的百分数。在图2中,-◆-表示本发明的化合物2释放的量的百分数,-▲-表示化合物3释放的量的百分数,-◇-表示比较化合物2释放的量的百分数。
Claims (10)
1.一种鬼臼毒素类的高分子量结合体,其中,包含聚乙二醇部分和两个或更多个琥珀酸单酰胺部分的聚合物的羧酸基团与所述鬼臼毒素类的羟基通过酯键而结合。
2.如权利要求1所述的鬼臼毒素类的高分子量结合体,其特征在于,所述包含聚乙二醇部分和两个或更多个琥珀酸单酰胺部分的聚合物是嵌段共聚物。
3.如权利要求2所述的鬼臼毒素类的高分子量结合体,其特征在于,所述两个或更多个琥珀酸单酰胺部分构成聚天冬氨酸。
4.如权利要求3所述的鬼臼毒素类的高分子量结合体,其特征在于,该结合体由式(I)表示:
其中R1表示氢原子或(C1-C6)烷基;R2表示连接基团;R3表示氢原子或(C1-C6)酰基;R4表示鬼臼毒素类的羟基的残基;R5表示选自以下的基团:(C1-C30)烷氧基,(C7-C30)芳烷氧基,(C1-C30)烷基氨基,二(C1-C30)烷基氨基,以及带有保护的羧基的氨基酸,以及-N(R6)CONH(R7),其中R6和R7可以是相同或不同的,它们各自表示任选地被叔氨基取代的(C3-C6)环烷基或(C1-C5)烷基;t表示5-11,500的整数;d,e,f,g,h,i和j各自独立地表示0-200的整数,前提是d+e表示1-200的整数,d+e+f+g+h+i+j表示3-200的整数,相应的聚天冬氨酸的组成单元以任意的顺序结合。
5.如权利要求4所述的鬼臼毒素类的高分子量结合体,其特征在于,R1是(C1-C6)烷基;R2是(C2-C6)亚烷基;R3是(C1-C6)酰基;t是8-2300的整数;d,e,f,g,h,i和j各自独立地是0-100的整数,前提是d+e是1-100的整数,d+e+f+g+h+i+j是6-100的整数。
6.如权利要求5所述的鬼臼毒素类的高分子量结合体,其特征在于,R1是(C1-C3)烷基;R2是(C2-C4)亚烷基;R3是(C1-C3)酰基;t是100-300的整数;d,e,f,g,h,i和j各自独立地是0-90的整数,前提是d+e是1-90的整数,d+e+f+g+h+i+j是15-90的整数。
7.如权利要求1-6中任一项所述的鬼臼毒素类的高分子量结合体,其特征在于,所述鬼臼毒素类是鬼臼毒素、依托泊苷或鬼臼噻吩苷。
8.一种鬼臼毒素类的高分子量结合体,其通过在有机溶剂中使用脱水缩合剂,使包含聚乙二醇部分和两个或更多个琥珀酸单酰胺部分的聚合物的羧酸基团与所述鬼臼毒素类的羟基通过酯键结合而制得。
9.一种制备以上权利要求1至7中任一项所述的鬼臼毒素类的高分子量结合体的方法,该方法包括在有机溶剂中使用脱水缩合剂,使包含聚乙二醇部分和两个或更多个琥珀酸单酰胺部分的聚合物的羧酸基团与所述鬼臼毒素类的羟基通过酯键而结合。
10.一种抗癌药,包含上面权利要求1至8中任一项所述的鬼臼毒素类的高分子量结合体作为活性组分。
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- 2007-05-16 JP JP2008516621A patent/JP5181347B2/ja not_active Expired - Fee Related
- 2007-05-16 KR KR1020087027893A patent/KR20090009241A/ko not_active Application Discontinuation
- 2007-05-16 WO PCT/JP2007/060026 patent/WO2007135910A1/ja active Application Filing
- 2007-05-16 EP EP07743461A patent/EP2019122A4/en not_active Withdrawn
- 2007-05-16 CN CNA2007800177809A patent/CN101448875A/zh active Pending
- 2007-05-16 AU AU2007252678A patent/AU2007252678A1/en not_active Abandoned
- 2007-05-16 RU RU2008149932/04A patent/RU2447095C2/ru not_active IP Right Cessation
- 2007-05-16 CA CA002652656A patent/CA2652656A1/en not_active Abandoned
- 2007-05-16 US US12/226,962 patent/US8940332B2/en not_active Expired - Fee Related
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113797351A (zh) * | 2021-09-30 | 2021-12-17 | 大连民族大学 | 一步法合成pH响应型的靶向透明质酸-鬼臼毒素前药胶束及其应用 |
CN113797351B (zh) * | 2021-09-30 | 2023-10-27 | 大连民族大学 | 一步法合成pH响应型的靶向透明质酸-鬼臼毒素前药胶束及其应用 |
Also Published As
Publication number | Publication date |
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RU2447095C2 (ru) | 2012-04-10 |
JPWO2007135910A1 (ja) | 2009-10-01 |
CA2652656A1 (en) | 2007-11-29 |
US20090162313A1 (en) | 2009-06-25 |
AU2007252678A1 (en) | 2007-11-29 |
EP2019122A1 (en) | 2009-01-28 |
EP2019122A4 (en) | 2009-07-01 |
WO2007135910A1 (ja) | 2007-11-29 |
US8940332B2 (en) | 2015-01-27 |
RU2008149932A (ru) | 2010-06-27 |
TW200811225A (en) | 2008-03-01 |
KR20090009241A (ko) | 2009-01-22 |
JP5181347B2 (ja) | 2013-04-10 |
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