CN104448296B - 炔基多臂聚乙二醇衍生物 - Google Patents
炔基多臂聚乙二醇衍生物 Download PDFInfo
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Abstract
本发明提供一种具有通式Ⅰ或通式ⅩⅧ的结构的炔基多臂聚乙二醇衍生物。在该衍生物中,X1,X2,X3,X4是连接基团,F1,F2,F3,F4为端基基团,所述端基基团可以是相同的也可以是不同的,选自:羟基,羧基,酯基,氨基,炔基等,并且所述端基基团中至少有一个为炔基,PEG为相同或不同的‑(CH2CH2O)m‑,m为3‑250的整数,l为≥1的整数。多臂聚乙二醇具有多个分支,可以负载多个活性端基,同时还可以负载多种不同的活性端基,使所得到的多臂聚乙二醇衍生物具有更强的应用灵活性和更大的应用范围,在有机合成、药物合成及医疗器械等方面均有较好的应用前景。
Description
技术领域
本发明涉及一种聚乙二醇活性衍生物,尤其是涉及一种具有炔基端基的多臂聚乙二醇活性衍生物及其制备方法。
背景技术
聚乙二醇是一种用途极为广泛的聚醚高分子化合物,它可应用于医药、卫生、食品、化工等众多领域。聚乙二醇能够溶解于水和许多溶剂中,且该聚合物具有优异的生物相容性,在体内能溶于组织液中,能被机体迅速排出体外而不产生任何毒副作用。
在聚乙二醇的应用中,端基起着决定性的作用,不同端基的聚乙二醇具有不同的用途。聚乙二醇高分子链段不仅局限于端羟基,通过引入其他功能化端基,如氨基、羧基、醛基等所得到的聚乙二醇活性衍生物,可以极大地拓宽聚乙二醇的应用范围,使它在有机合成、多肽合成、高分子合成及药物的缓释控释、靶向施药等多方面均具有广阔的应用前景。
聚乙二醇活性衍生物在很多文献中均有报道。
专利文献US5672662描述了制备端基为丙酸和丁酸的线形聚乙二醇以及它们的N-羟基丁二酰亚胺酯。
专利文献US5643575描述了一种U形结构的聚乙二醇衍生物。
非专利文献“端炔基聚乙二醇的合成及固化”(火炸药学报,2010年12月,第33卷第6期)描述了一种端炔基聚乙二醇的合成方法,包括以聚乙二醇400和丙炔溴为原料,四氢呋喃为溶剂,在催化剂叔丁醇钾存在下反应得到产物,然而该方法制备得到的聚合物中为直链聚乙二醇,并且最多引入两个端炔基,无法引入其它活性基团。
专利WO2011075953A1描述一种由寡聚季戊四醇作为引发剂聚合环氧乙烷形成的新型的具有不同类型活性基团的多臂聚乙二醇,其端基活性集团选自:羟基、氨基、巯基、羧基、酯基、醛基、丙烯酸基和马来亚酰胺基,其未公开端基活性基团可以为炔基。
为克服现有技术中的缺陷,本发明提供了一种炔基多臂聚乙二醇活性衍生物及其制备方法。
发明内容
本发明一个目的是提供一种炔基多臂聚乙二醇活性衍生物,与直链型聚乙二醇相比,多臂聚乙二醇具有多个端基,进而具有多个功能基团的引入点、可以负载多个不同的活性端基,解决聚乙二醇端基炔基衍生物使用灵活性不佳、应用范围较小的问题。
本发明另一个目的是提供一种多臂聚乙二醇-炔基活性衍生物,能够与其它种类的聚合物反应,用于凝胶的制备,并能够降低反应形成的条件、缩短凝胶形成的时间。
本发明还一个目的是提供一系列不同结构的多臂聚乙二醇-炔基活性衍生物,解决了多臂聚乙二醇-炔基活性衍生物形成的凝胶时无法对活性成分释放速度进行控制的问题。
本发明的一方面提供了一种炔基多臂聚乙二醇活性衍生物,所述的多臂聚乙二醇衍生物具有通式Ⅰ的结构:
本发明的另一方面提供了一种炔基多臂聚乙二醇衍生物,所述的多臂聚乙二醇衍生物具有通式ⅩⅧ的结构:
其中:
PEG为相同或不同的-(CH2CH2O)m-,m是平均值为3-250的整数;
l为≧1的整数;
X1,X2,X3,X4是连接基团,可以相同或者不同,独立地选自由以下基团组成的组选自C1-12烷基、芳烷基、酯基、碳酸酯基、酰胺基、酰胺酯基、醚基、氨基甲酸酯基组成的组;
F1,F2,F3,F4是端基基团,可以相同或者不同,独立地选自由以下基团组成的组:
-NH2、-COOH、-OCH3、
并且F1,F2,F3,F4至少有一个为
在本发明所述的炔基多臂聚乙二醇衍生物通式Ⅰ或通式ⅩⅧ中,m平均值优选为18-150的整数,更优选为m平均值为18-75的整数。
在本发明所述的炔基多臂聚乙二醇衍生物通式Ⅰ或通式ⅩⅧ中,l优选为≥1且≤10的整数,更优选l为≥1且≤6的整数,尤其优选l为≥1且≤4的整数,在本发明的具体实施方式中,所述的l可以优选为1、2、3、4、5或6。
在本发明所述的炔基多臂聚乙二醇衍生物通式Ⅰ或通式ⅩⅧ中,X1,X2,X3,X4是连接基团,更为优选的,X1,X2,X3,X4独立地选自-(CH2)i-、-(CH2)iNHCO(CH2)j-、-(CH2)iCONH(CH2)j-、-(CH2)iNH-、-(CH2)iOCOO-、-(CH2)iOCONH-、-(CH2)iNHCOO-、-(CH2)iNHCONH-、-OC(CH2)iCOO-、-(CH2)iCOO-、-(CH2)iCONH-、-(CH2)iCOO-组成的组;最为优选的,X1,X2,X3,X4独立地选自-(CH2)i-、-(CH2)iNHCO(CH2)j-、-(CH2)iCONH(CH2)j-组成的组。
在本发明所述的炔基多臂聚乙二醇衍生物通式Ⅰ或通式ⅩⅧ,X1,X2,X3,X4中i为1-10的整数,优选为1-5的整数,更优选为1-3的整数,在本发明的具体实施方式中,所述的i为1、2、3、4或5。
在本发明所述的端基炔基多臂聚乙二醇衍生物通式Ⅰ或通式ⅩⅧ,X1,X2,X3,X4中j为1-10的整数,优选为1-5的整数,更优选为1-3的整数,在本发明的具体实施方式中,所述的j为1、2、3、4或5。
在本发明所述的端基炔基多臂聚乙二醇衍生物通式Ⅰ中,所述的F1,F2,F3,F4可以至少两个为在本发明的另一实施方式中,F1,F2,F3,F4至少三个为在本发明的另一实施方式中,F1,F2,F3,F4均为
在本发明所述的端基炔基多臂聚乙二醇衍生物通式ⅩⅧ中,所述的F1,F2,F4可以至少两个为在本发明的另一实施方式中,F1,F2,F4均为
在本发明所述的端基炔基多臂聚乙二醇衍生物通式Ⅰ或通式ⅩⅧ中,所述多臂聚乙二醇衍生物的分子量为1000-80000Da,在本发明优选的实施方案中,所述的多臂聚乙二醇的分子量为3000-20000Da,在本发明的更为优选的实施方案中,所述的多臂聚乙二醇的分子量为3000-10000Da,在本发明的最优选的实施方案中,所述的多臂聚乙二醇的分子量可以为3000Da、5000Da、10000Da、20000Da。
在一个具体实施方案中,所述的多臂聚乙二醇衍生物是具有以下通式Ⅱ结构的多臂聚乙二醇-炔基衍生物:
在一个具体实施方案中,所述通式Ⅱ结构的多臂聚乙二醇-炔基衍生物中,X1,X2,X3,X4独立地选自-(CH2)i-、-(CH2)iNHCO(CH2)j-、-(CH2)iCONH(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5。
在一个具体实施方案中,所述炔基多臂聚乙二醇衍生物是具有以下通式Ⅲ结构的多臂聚乙二醇单炔基-多酸衍生物:
其中所述PEG、l、X1同通式Ⅰ或通式ⅤⅢ中定义,所述k为1-10的整数。
在一个具体实施方案中,所述通式Ⅲ结构的炔基多臂聚乙二醇单炔基-多酸衍生物优选的,其中X1是-(CH2)i-或-(CH2)iNHCO(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;k优选为1-5的整数,更优选为为1、2、3、4或5。
在一个具体实施方案中,所述炔基多臂聚乙二醇衍生物是具有以下通式Ⅳ结构的多臂聚乙二醇多炔基-多酸衍生物:
其中所述PEG、l、X1同通式Ⅰ或通式ⅤⅢ中定义,所述k为1-10的整数。
在一个具体实施方案中,所述通式Ⅳ结构的多臂聚乙二醇多炔基-多酸衍生物优选的,其中X1是-(CH2)i-或-(CH2)iNHCO(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;k优选为1-5的整数,更优选为为1、2、3、4或5。
在一个具体实施方案中,所述炔基多臂聚乙二醇衍生物是具有以下通式Ⅴ结构的多臂聚乙二醇多炔基-单酸衍生物:
其中所述PEG、l、X1同通式Ⅰ或通式ⅤⅢ中定义,所述k为1-10的整数。
在一个具体实施方案中,所述通式Ⅴ结构的多臂聚乙二醇多炔基-单酸衍生物优选的,其中X1是-(CH2)i-或-(CH2)iNHCO(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;k优选为1-5的整数,更优选为为1、2、3、4或5。
在一个具体实施方案中,所述炔基多臂聚乙二醇衍生物是具有以下通式Ⅵ结构的多臂聚乙二醇单炔基-多酸活性NHS酯衍生物:
其中所述PEG、l、X1同通式Ⅰ或通式ⅤⅢ中定义,所述k为1-10的整数。
在一个具体实施方案中,所述通式Ⅵ结构的多臂聚乙二醇单炔基-多酸活性NHS酯衍生物优选的,其中X1是-(CH2)i-或-(CH2)iNHCO(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;k优选为1-5的整数,更优选为为1、2、3、4或5。
在一个具体实施方案中,所述炔基多臂聚乙二醇衍生物是具有以下通式Ⅶ结构的多臂聚乙二醇多炔基-多酸活性NHS酯衍生物:
其中所述PEG、l、X1同通式Ⅰ或通式ⅤⅢ中定义,所述k为1-10的整数。
在一个具体实施方案中,所述通式Ⅶ结构的多臂聚乙二醇多炔基-多酸活性NHS酯衍生物优选的,其中X1是-(CH2)i-或-(CH2)iNHCO(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;k优选为1-5的整数,更优选为为1、2、3、4或5。
在一个具体实施方案中,所述炔基多臂聚乙二醇衍生物是具有以下通式Ⅷ结构的多臂聚乙二醇多炔基-单酸活性NHS酯衍生物:
其中所述PEG、l、X1同通式Ⅰ或通式ⅤⅢ中定义,所述k为1-10的整数。
在一个具体实施方案中,所述通式Ⅷ结构的多臂聚乙二醇多炔基-单酸衍生物优选的,其中X1是-(CH2)i-或-(CH2)iNHCO(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;k优选为1-5的整数,更优选为为1、2、3、4或5。
在一个具体实施方案中,所述炔基多臂聚乙二醇衍生物是具有以下通式Ⅸ结构的多臂聚乙二醇单炔基-多酸活性MAL衍生物:
其中所述PEG、l、X1同通式Ⅰ或通式ⅤⅢ中定义,所述k为1-10的整数。
在一个具体实施方案中,所述通式Ⅸ结构的多臂聚乙二醇单炔基-多酸活性MAL衍生物优选的,其中X1是-(CH2)i-或-(CH2)iNHCO(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;k优选为1-5的整数,更优选为为1、2、3、4或5。
在一个具体实施方案中,所述炔基多臂聚乙二醇衍生物是具有以下通式Ⅹ结构的多臂聚乙二醇多炔基-多酸活性MAL衍生物:
其中所述PEG、l、X1同通式Ⅰ或通式ⅤⅢ中定义,所述k为1-10的整数。
在一个具体实施方案中,所述通式Ⅹ结构的多臂聚乙二醇多炔基-多酸活性MAL衍生物优选的,其中X1是-(CH2)i-或-(CH2)iNHCO(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;k优选为1-5的整数,更优选为为1、2、3、4或5。
在一个具体实施方案中,所述炔基多臂聚乙二醇衍生物是具有以下通式Ⅺ结构的多臂聚乙二醇多炔基-单酸活性MAL衍生物:
其中所述PEG、l、X1同通式Ⅰ或通式ⅤⅢ中定义,所述k为1-10的整数。
在一个具体实施方案中,所述通式Ⅺ结构的多臂聚乙二醇多炔基-单酸活性MAL衍生物优选的,其中X1是-(CH2)i-或-(CH2)iNHCO(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;k优选为1-5的整数,更优选为为1、2、3、4或5。
在一个具体实施方案中,所述炔基多臂聚乙二醇衍生物是具有以下通式Ⅻ结构的多臂聚乙二醇单炔基-多胺基衍生物:
其中所述PEG、l、X1同通式Ⅰ或通式ⅤⅢ中定义,所述k为1-10的整数。
在一个具体实施方案中,所述通式Ⅻ结构的多臂聚乙二醇单炔基-多胺基衍生物优选的,其中X1是-(CH2)i-或-(CH2)iCONH(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;k优选为1-5的整数,更优选为为1、2、3、4或5。
在一个具体实施方案中,所述炔基多臂聚乙二醇衍生物是具有以下通式ⅩⅢ结构的多臂聚乙二醇多炔基-多胺基衍生物:
其中所述PEG、l、X1同通式Ⅰ或通式ⅤⅢ中定义,所述k为1-10的整数。
在一个具体实施方案中,所述通式ⅩⅢ结构的多臂聚乙二醇多炔基-多胺基衍生物优选的,其中X1是-(CH2)i-或-(CH2)iCONH(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;k优选为1-5的整数,更优选为为1、2、3、4或5。
在一个具体实施方案中,所述炔基多臂聚乙二醇衍生物是具有以下通式ⅩⅣ结构的多臂聚乙二醇多炔基-单胺基衍生物:
其中所述PEG、l、X1同通式Ⅰ或通式ⅤⅢ中定义,所述k为1-10的整数。
在一个具体实施方案中,所述通式ⅩⅢ结构的多臂聚乙二醇多炔基-单胺基衍生物优选的,其中X1是-(CH2)i-或-(CH2)iCONH(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;k优选为1-5的整数,更优选为为1、2、3、4或5。
在一个具体实施方案中,所述炔基多臂聚乙二醇衍生物是具有以下通式ⅩⅤ结构的多臂聚乙二醇单炔基-多胺基活性MAL衍生物:
其中所述PEG、l、X1同通式Ⅰ或通式ⅤⅢ中定义,所述k为1-10的整数。
在一个具体实施方案中,所述通式ⅩⅤ结构的多臂聚乙二醇单炔基-多胺基活性MAL衍生物优选的,其中X1是-(CH2)i-或-(CH2)iCONH(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;k为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5。
在一个具体实施方案中,所述炔基多臂聚乙二醇衍生物是具有以下通式ⅩⅥ结构的多臂聚乙二醇多炔基-多胺基活性MAL衍生物:
其中所述PEG、l、X1同通式Ⅰ或通式ⅤⅢ中定义,所述k为1-10的整数。
在一个具体实施方案中,所述通式ⅩⅥ结构的多臂聚乙二醇多炔基-多胺基活性MAL衍生物优选的,其中X1是-(CH2)i-或-(CH2)iCONH(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;k优选为1-5的整数,更优选为为1、2、3、4或5。
在一个具体实施方案中,所述炔基多臂聚乙二醇衍生物是具有以下通式ⅩⅦ结构的多臂聚乙二醇多炔基-单胺基活性MAL衍生物:
其中所述PEG、l、X1同通式Ⅰ或通式ⅤⅢ中定义,所述k为1-10的整数。
在一个具体实施方案中,所述通式ⅩⅦ结构的多臂聚乙二醇多炔基-单胺基衍生物优选的,其中X1是-(CH2)i-或-(CH2)iCONH(CH2)j-;i为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;j为1-10的整数,优选为1-5的整数,更优选为为1、2、3、4或5;k优选为1-5的整数,更优选为为1、2、3、4或5。
本发明另一方面还提供了一种炔基多臂聚乙二醇衍生物的制备方法,包括将多臂聚乙二醇溶于溶剂中,加入氢化钠室温反应后,加入溴丙炔和碘化钾反应,分离后得多臂聚乙二醇-丙炔。
本发明另一方面还提供了一种炔基多臂聚乙二醇衍生物的制备方法,包括将多臂聚乙二醇-端基乙酸和N-羟基琥珀酰亚胺(NHS)溶于溶剂中,加入N,N'-二环己基碳二亚胺(DCC)反应后,加入炔丙胺反应分离后得多臂聚乙二醇-丙炔乙酰胺。
本发明另一方面还提供了一种炔基多臂聚乙二醇衍生物的制备方法,包括将多臂聚乙二醇-端基羟基-端基乙酸甲酯溶于溶剂中,加入氢化钠室温反应后,加入溴丙炔和碘化钾反应,得到多臂聚乙二醇-丙炔-乙酸甲酯;将多臂聚乙二醇-丙炔-乙酸甲酯水解后,得到聚乙二醇-丙炔-乙酸衍生物。
进一步的,本发明另一方面还提供了一种炔基多臂聚乙二醇衍生物的制备方法,包括将多臂聚乙二醇-端基羟基-端基乙酸甲酯溶于溶剂中,加入氢化钠室温反应后,加入溴丙炔和碘化钾反应,得到多臂聚乙二醇-丙炔-乙酸甲酯;将多臂聚乙二醇-丙炔-乙酸甲酯水解后,得到聚乙二醇-丙炔-乙酸衍生物;将聚乙二醇-丙炔-乙酸衍生物溶于溶剂中,加入N-羟基琥珀酰亚胺(NHS)和N,N'-二环己基碳二亚胺(DCC),反应得多臂聚乙二醇-丙炔-乙酸NHS酯。
进一步的,本发明另一方面还提供了一种炔基多臂聚乙二醇衍生物的制备方法,包括将多臂聚乙二醇-端基羟基-端基乙酸甲酯溶于溶剂中,加入氢化钠室温反应后,加入溴丙炔和碘化钾反应,得到多臂聚乙二醇-丙炔-乙酸甲酯;将多臂聚乙二醇-丙炔-乙酸甲酯水解后,得到聚乙二醇-丙炔-乙酸衍生物;将聚乙二醇-丙炔-乙酸衍生物溶于溶剂中,加入N-羟基琥珀酰亚胺(NHS)和N,N'-二环己基碳二亚胺(DCC),反应后,再加入马来酰亚乙二胺反应,得多臂聚乙二醇-端基丙炔-端基乙酸MAL酯。
本发明另一方面还提供了一种炔基多臂聚乙二醇衍生物的制备方法,包括将多臂聚乙二醇-端基乙酸-端基乙胺溶于溶剂中,加入三乙胺和二碳酸二叔丁酯(Boc2O),反应得多臂聚乙二醇-乙酸-Boc酰胺;反应后将多臂聚乙二醇-乙酸-Boc酰胺和N-羟基琥珀酰亚胺(NHS)0.086g溶于溶剂中,加入N,N'-二环己基碳二亚胺(DCC)反应后,再加入炔丙胺反应,得到多臂聚乙二醇-炔基-Boc酰胺;将上述多臂聚乙二醇-炔基-Boc酰胺溶于溶剂中,加入三氟乙酸反应,得多臂聚乙二醇-端基炔基-端基乙胺。
进一步,本发明另一方面还提供了一种炔基多臂聚乙二醇衍生物的制备方法,包括将多臂聚乙二醇-端基乙酸-端基乙胺溶于溶剂中,加入三乙胺和二碳酸二叔丁酯(Boc2O),反应得多臂聚乙二醇-乙酸-Boc酰胺;反应后将多臂聚乙二醇-乙酸-Boc酰胺和N-羟基琥珀酰亚胺(NHS)溶于溶剂中,加入N,N'-二环己基碳二亚胺(DCC)反应后,再加入炔丙胺反应,得到多臂聚乙二醇-炔基-Boc酰胺;将上述多臂聚乙二醇-炔基-Boc酰胺溶于溶剂中,加入三氟乙酸反应,得多臂聚乙二醇-端基炔基-端基乙胺;将多臂聚乙二醇-端基炔基-端基乙胺溶于溶剂中,加入3-马来酰亚胺基丙酸羟基琥珀酰亚胺酯反应,得到多臂聚乙二醇-端基炔基-端基乙胺MAL。
本发明所述炔基多臂聚乙二醇衍生物的制备方法中,反应物多臂聚乙二醇、多臂聚乙二醇-端基乙酸、多臂聚乙二醇-端基羟基-端基乙酸甲酯、多臂聚乙二醇-端基乙酸-端基乙胺可由市售获得,或者通过专利CN102108119A中的方法制备得到。
本发明所述炔基多臂聚乙二醇衍生物的制备方法中,所述的溶剂可以使用本领域所述熟知适宜溶剂,选自甲醇、乙醇、氯仿、二氯甲烷、丙酮、乙醚、乙酸乙酯等。
本发明所述的炔基多臂聚乙二醇衍生物可以用于与蛋白质、肽、药物活性小分子相结合,提高靶向性和药物疗效,降低毒性。所述的蛋白质、肽、药物活性小分子包括但不限于:镇痛剂和消炎剂、抗酸剂、驱虫药、抗心律不齐药、抗菌剂、抗凝(血)剂、抗抑郁剂、抗糖尿病剂、止泻剂、抗癫痫药、防真菌剂、抗痛风药、抗高血压药、抗疟药、抗偏头痛药、抗毒蕈碱剂、抗瘤剂和免疫抑制剂、抗原虫药、抗风湿药、抗甲状腺剂、抗病毒剂、抗焦虑剂、镇静剂、安眼药和安定药、β-受体阻断剂、心脏收缩剂、皮质类甾醇、镇咳剂、细胞毒性剂、减充血剂、利尿剂、酶、抗帕金森氏症药、胃肠道药、组胺受体拮抗剂、油脂调节剂、局部麻醉剂、神经肌肉阻断剂、硝酸酯和抗心绞痛药、营养剂、麻醉性镇痛剂、口服疫苗、蛋白、肽和重组药物、性激素和避孕药、杀精子剂、和刺激剂。
本发明所述的炔基多臂聚乙二醇衍生物与蛋白质、肽、药物活性小分子结合方式,可以如专利CN102108119A所描述,通过其端基与药物分子所形成的结合物,优选通过-COOH或与蛋白质、肽、药物活性小分子相结合。
与直链型聚乙二醇相比,本发明所述的炔基多臂聚乙二醇衍生物具有多个分支,进而具有多个功能基团的引入点、可以负载多个活性端基。
同时,本发明提供的多臂聚乙二醇炔基衍生物能够明显提高炔基活性端基的负载率,还可以负载其他不同的活性端基,使所述多臂聚乙二醇衍生物具有更强的应用灵活性和更大的应用范围,在有机合成、药物合成及医疗器械等方面均有较好的应用前景。
另外,本发明提供的多臂聚乙二醇炔基衍生物能够与其它聚合物,特别是聚乙二醇叠氮衍生物发生反应形成凝胶,并且通过对多臂聚乙二醇炔基衍生物中分子量、分支数的改变能够实现对活性成分的释放速率控制。
具体实施方式
下面结合实施例描述本发明的衍生物及其制备方法,所述实施例不意图限制本发明,本发明的保护范围由本申请的权利要求书限定。
实施例1:四臂聚乙二醇(10000Da)-丙炔的制备
将四臂聚乙二醇(10000Da)10.0g溶于四氢呋喃150ml中,氮气保护下降温至0℃,加入氢化钠0.48g,室温反应0.5小时,加入溴丙炔(80%的甲苯溶液)22.4ml,加入碘化钾0.09g,避光加热回流2小时,降温,加入水100ml,旋出四氢呋喃,用二氯甲烷萃取三次,无水硫酸钠干燥,过滤,浓缩,45℃浓缩至黏稠,加入乙醚100ml沉淀,过滤收集沉淀真空干燥。得到四臂聚乙二醇-丙炔8.7g。
1H-NMR(DMSO)δ:3.08(s,-c≡CH,4H)
实施例2:八臂聚乙二醇(20000Da)-丙炔乙酰胺的制备
将八臂聚乙二醇(20000Da)-乙酸10.0g和N-羟基琥珀酰亚胺(NHS)0.69g溶于二氯甲烷100ml中,氮气保护下,加入N,N'-二环己基碳二亚胺(DCC)1.32g,反应4h,加入炔丙胺0.9ml,避光反应过夜,过滤,40℃浓缩,用异丙醇150ml加热溶解冰水浴沉淀,过滤,异丙醇洗涤滤饼2次,真空干燥得八臂聚乙二醇-丙炔乙酰胺9.0g。
1H-NMR(DMSO)δ:3.08(s,-C≡CH,4H),7.66(t,CONH,4H)
实施例3:四臂聚乙二醇(5000Da)-炔基-单乙酸的制备
将四臂聚乙二醇(5000Da)羟基-单乙酸甲酯10.0g溶于四氢呋喃150ml中,氮气保护下降温至0℃,加入氢化钠0.72g,室温反应0.5小时,加入溴丙炔(80%的甲苯溶液)33.6ml,加入碘化钾0.135g,避光加热回流2小时,降温,加入水100ml,旋出四氢呋喃,用二氯甲烷萃取三次,无水硫酸钠干燥,过滤,浓缩,45℃浓缩至黏稠,加入乙醚100ml沉淀,过滤收集沉淀真空干燥。得到四臂聚乙二醇丙炔-单乙酸甲酯8.2g。
将上述四臂聚乙二醇丙炔-单乙酸甲酯5.0g溶于50ml脱气水中,用0.5N氢氧化钠水溶液调节PH为12.0,室温下反应2-2.5小时,用1N盐酸水溶液调解PH为2-3,加入氯化钠6.0g,用二氯甲烷50ml萃取三次,合并有机相,无水硫酸钠干燥,过滤,45℃浓缩至黏稠,加入乙醚75ml沉淀,过滤收集沉淀真空干燥。得到四臂聚乙二醇-丙炔-单乙酸3.6g。
1H-NMR(DMSO)δ:3.08(s,-C≡CH,4H),4.01(s,CH2COOH,8H)
实施例4:四臂聚乙二醇(5000Da)-炔基-单乙酸活性NHS酯的制备
称取四臂聚乙二醇(5000Da)-丙炔-单乙酸1.0g和N-羟基琥珀酰亚胺(NHS)0.0276g,用二氯甲烷10ml溶解,氮气保护下,加入N,N'-二环己基碳二亚胺(DCC)0.0536g,密闭反应过夜,过滤,40℃浓缩至干,用异丙醇20ml加热溶解后冰水浴沉淀,过滤,异丙醇洗涤滤饼2次,真空干燥得四臂聚乙二醇-丙炔-单乙酸NHS酯。
1H-NMR(DMSO)δ:3.08(s,-C≡CH,3H),4.6(s,CH2CO,2H),2.8(s,CH2ring,4H)
实施例5:四臂聚乙二醇(5000Da)-炔基-单乙酸MAL的制备
称取四臂聚乙二醇(5000Da)-丙炔-单乙酸1.0g和N-羟基琥珀酰亚胺(NHS)0.035g,用二氯甲烷10ml溶解,氮气保护下,加入N,N'-二环己基碳二亚胺(DCC)0.066g溶于二氯甲烷10ml中,反应4h,加入马来酰亚乙二胺0.115g,避光反应过夜,40℃浓缩至干,用异丙醇20ml加热溶解后冰水浴沉淀,过滤,异丙醇洗涤滤饼2次,真空干燥得四臂聚乙二醇-炔基-单乙酸MAL。
1H-NMR(DMSO)δ:3.08(s,-C≡CH,3H),2.32(t,CH2N,2H),7.0(s,CH ring,2H)
实施例6:四臂聚乙二醇(20000Da)-二炔基-二乙胺的制备
将四臂聚乙二醇-二乙酸-二乙胺基(分子量为20000)10.0g溶于二氯甲烷100ml中,加入三乙胺0.15ml,搅拌10分钟,加入二碳酸二叔丁酯(Boc2O)0.3ml,室温反应过夜,45℃浓缩,用100ml乙醚沉淀,过滤,真空干燥得四臂聚乙二醇-二乙酸-二Boc酰胺9.7g。
将四臂聚乙二醇-二乙酸-二Boc酰胺5g和N-羟基琥珀酰亚胺(NHS)0.086g,用二氯甲烷50ml溶解,氮气保护下,加入N,N'-二环己基碳二亚胺(DCC)0.165g,反应4h,加入炔丙胺0.11ml,密闭反应过夜,过滤,40℃浓缩至干,用异丙醇75ml加热溶解后冰水浴沉淀,过滤,异丙醇洗涤滤饼2次,真空干燥得四臂聚乙二醇-二炔基-二Boc酰胺4.3g。
将上述四臂聚乙二醇-二炔基-二Boc酰胺3.0g溶于二氯甲烷21ml中,加入三氟乙酸9ml,反应3小时,45℃浓缩,60ml乙醚沉淀,过滤,真空干燥得四臂聚乙二醇-二炔基-二乙胺2.3g。
1H-NMR(DMSO)δ:3.08(s,-C≡CH,2H),3.0(m,CH2N,4H)
实施例7:四臂聚乙二醇(20000Da)-二炔基-二乙胺MAL的制备
将四臂聚乙二醇(20000Da)-二炔基-二乙胺1.0g溶于二氯甲烷10ml中,加入3-马来酰亚胺基丙酸羟基琥珀酰亚胺酯0.035g,避光反应过夜,40℃浓缩至干,用异丙醇20ml加热溶解后冰水浴沉淀,过滤,异丙醇洗涤滤饼2次,真空干燥得四臂聚乙二醇-二炔基-二乙胺MAL。
1H-NMR(DMSO)δ:3.08(s,-C≡CH,2H),2.32(t,CH2N,4H),7.0(s,CH ring,4H)
实施例8:八臂聚乙二醇(10000Da)-单炔基–七乙酸的制备
将4-炔丁酸14.7g溶于二氯甲烷100ml中,加入N-羟基琥珀酰亚胺(NHS)1.89g,氮气保护下,加入N,N'-二环己基碳二亚胺(DCC)3.75g,室温密闭反应过夜,将八臂聚乙二醇(10000Da)-单羟基-七乙酸甲酯10g溶于二氯甲烷100ml中,将上述溶液加入反应瓶中,反应4h,过滤,40℃浓缩至干,用异丙醇200ml加热溶解后冰水浴沉淀,过滤,异丙醇洗涤滤饼2次,真空干燥得到八臂聚乙二醇-炔基-七乙酸甲酯8.3g。
将上述八臂聚乙二醇-炔基-七乙酸甲酯5.0g溶于50ml脱气水中,用0.5N氢氧化钠水溶液调节PH为12.0,室温下反应2-2.5小时,用1N盐酸水溶液调解PH为2-3,加入氯化钠6.0g,用二氯甲烷50ml萃取三次,合并有机相,无水硫酸钠干燥,过滤,45℃浓缩至黏稠,加入乙醚75ml沉淀,过滤收集沉淀真空干燥。得到八臂聚乙二醇-炔基-七乙酸3.3g。
1H-NMR(DMSO)δ:3.08(s,-C≡CH,1H),4.01(s,CH2COOH,14H)
实施例9:八臂聚乙二醇(10000Da)-炔基-七乙酸NHS酯的制备
将八臂聚乙二醇(10000Da)-单炔基–七乙酸1.0g和N-羟基琥珀酰亚胺(NHS)0.12g,用二氯甲烷10ml溶解,氮气保护下,加入N,N'-二环己基碳二亚胺(DCC)0.23g,密闭反应过夜,过滤,40℃浓缩至干,用异丙醇20ml加热溶解后冰水浴沉淀,过滤,异丙醇洗涤滤饼2次,真空干燥得八臂聚乙二醇-单炔基-七乙酸NHS酯。
1H-NMR(DMSO)δ:3.08(s,-C≡CH,1H),4.6(s,CH2CO,14H),2.8(s,CH2ring,28H)
实施例10:八臂聚乙二醇(10000Da)-炔基-七乙酸MAL的制备
称取八臂聚乙二醇(10000Da)-单炔基–七乙酸1.0g和N-羟基琥珀酰亚胺(NHS)0.12g,用二氯甲烷10ml溶解,氮气保护下,加入N,N'-二环己基碳二亚胺(DCC)0.23g,反应4h,加入马来酰亚乙二胺0.35g,避光反应过夜,40℃浓缩至干,用异丙醇20ml加热溶解后冰水浴沉淀,过滤,异丙醇洗涤滤饼2次,真空干燥得八臂聚乙二醇(10000Da)-单炔基–七乙酸MAL。
1H-NMR(DMSO)δ:3.08(s,-C≡CH,1H),2.32(t,CH2N,14H),7.0(s,CH ring,14H)实施例11:八臂聚乙二醇(20000Da)-七炔基-单乙胺的制备
将八臂聚乙二醇(20000Da)-七羟基-单乙胺10.0g溶于二氯甲烷100ml中,加入三乙胺0.077ml,搅拌10分钟,加入二碳酸二叔丁酯(Boc2O)0.15ml,室温反应过夜,45℃浓缩,用100ml乙醚沉淀,过滤,真空干燥得八臂聚乙二醇(20000Da)-七羟基-单Boc酰胺9.5g。
将八臂聚乙二醇(20000Da)-七羟基-单Boc酰胺5.0g溶于四氢呋喃100ml中,氮气保护下降温至0℃,加入氢化钠0.024g,室温反应0.5小时,加入溴丙炔(80%的甲苯溶液)1.12ml,加入碘化钾0.0045g,避光加热回流2小时,降温,加入水50ml,旋出四氢呋喃,用二氯甲烷萃取三次,无水硫酸钠干燥,过滤,浓缩,45℃浓缩至黏稠,加入乙醚100ml沉淀,过滤收集沉淀真空干燥。得到八臂聚乙二醇(20000Da)-七丙炔-单Boc酰胺3.9g。
将八臂聚乙二醇(20000Da)-七丙炔-单Boc酰胺3.0g溶于二氯甲烷21ml中,加入三氟乙酸9ml,反应3小时,45℃浓缩,60ml乙醚沉淀,过滤,真空干燥得八臂聚乙二醇(20000Da)-七炔基-单乙胺2.3g。
1H-NMR(DMSO)δ:3.08(s,-C≡CH,7H),3.0(m,CH2N,2H)
实施例12:八臂聚乙二醇(20000Da)-七炔基-单乙胺MAL的制备
将八臂聚乙二醇(20000Da)-七炔基-单乙胺1.0g溶于二氯甲烷10ml中,加入3-马来酰亚胺基丙酸羟基琥珀酰亚胺酯0.017g,避光反应过夜,40℃浓缩至干,用异丙醇20ml加热溶解后冰水浴沉淀,过滤,异丙醇洗涤滤饼2次,真空干燥得八臂聚乙二醇(20000Da)-七炔基-单乙胺MAL。
1H-NMR(DMSO)δ:3.08(s,-C≡CH,7H),2.32(t,CH2N,2H),7.0(s,CH ring,2H)
实施例13:四臂聚乙二醇-炔基(分子量为5000)凝胶的制备及其体外释药实验
将四臂聚乙二醇-炔基(分子量为5000)0.25g、聚乙二醇-叠氮衍生物(分子量为5000)0.25g以及伊立替康-甘氨酸盐酸盐0.05g溶于水5ml,加入抗坏血酸钠0.008g、醋酸铜0.004g,室温下搅拌25分钟形成凝胶。
将以上凝胶放入透析袋(节流分子量5000)中,以水20ml洗涤三次,至水溶液用高效液相色谱检测紫外无吸收,放入玻璃瓶中,加入水20ml,于40℃恒温振荡器中振摇。在30min、2h、4h分别取样,以0.0025g/ml的伊立替康-甘氨酸盐酸盐的水溶液作为参比样品,高效液相色谱测定凝胶在各时间点的释放量。
伊立替康-甘氨酸的释放比例为:0.5小时21%,2小时36%,4小时42%。
实施例14:四臂聚乙二醇-炔基(分子量为10000)凝胶的制备及其体外释药实验
将四臂聚乙二醇-炔基(分子量为10000)0.25g、聚乙二醇-叠氮衍生物(分子量为10000)0.25g以及伊立替康-甘氨酸盐酸盐0.05g溶于水5ml,加入抗坏血酸钠0.004g、醋酸铜0.002g,室温下搅拌1小时形成凝胶。
将以上凝胶放入透析袋(节流分子量5000)中,以水20ml洗涤三次,至水溶液用高效液相色谱检测紫外无吸收,放入玻璃瓶中,加入水20ml,于40℃恒温振荡器中振摇。在30min、2h、4h分别取样,以0.0025g/ml的伊立替康-甘氨酸盐酸盐的水溶液作为参比样品,高效液相色谱测定凝胶在各时间点的释放量。
伊立替康-甘氨酸的释放比例为:0.5小时35%,2小时54%,4小时69%。
实施例15:八臂聚乙二醇-炔基(分子量为10000)凝胶的制备及其体外释药实验
将八臂聚乙二醇-炔基(分子量为10000)0.25g、聚乙二醇-叠氮衍生物(分子量为10000)0.25g以及伊立替康-甘氨酸盐酸盐0.05g溶于水5ml,加入抗坏血酸钠0.008g、醋酸铜0.004g,室温下搅拌10分钟形成凝胶。
将以上凝胶放入透析袋(节流分子量5000)中,以水20ml洗涤三次,至水溶液用高效液相色谱检测紫外无吸收,放入玻璃瓶中,加入水20ml,于40℃恒温振荡器中振摇。在30min、2h、4h分别取样,以0.0025g/ml的伊立替康-甘氨酸盐酸盐的水溶液作为参比样品,高效液相色谱测定凝胶在各时间点的释放量。
伊立替康-甘氨酸的释放比例为:0.5小时24%,2小时48%,4小时60%。
由实施例13-15可见,在多臂聚乙二醇-炔基衍生物与其它聚乙二醇衍生物形成凝胶的制备中,分子量与聚二乙醇分支数均可以用来影响或控制凝胶的形成时间,分子量越小,分支数越多,凝胶的形成时间越短,而且增加聚乙二醇的分支数量可以更有效地提高凝胶的形成速度。同时,分子量与分支数对体外释药时间同样有显著地影响,因此,制备不同的多臂聚乙二醇-炔基衍生物也可以用于控制药物缓释过程。
实施例16:四臂聚乙二醇-三炔基-多巴胺及凝胶的制备
将四臂聚乙二醇-丙炔-单乙酸NHS活性酯(分子量为5000)3.0g溶于二氯甲烷30ml中,加入多巴胺0.12g、三乙胺0.11ml,避光室温反应过夜,40℃浓缩,用异丙醇60ml加热溶解,冰水浴沉淀,过滤,异丙醇洗涤滤饼2次,真空干燥得四臂聚乙二醇-三丙炔-多巴胺。
1H-NMR(DMSO)δ:3.08(s,-C≡CH,3H),6.4(m,ring,1H),6.6(m,ring,2H),8.6(s,OH,1H),8.7(s,OH,1H)
将四臂聚乙二醇-三丙炔-多巴胺(分子量为5000)0.33g、聚乙二醇-叠氮衍生物(分子量为5000)0.25g溶于水6ml,加入抗坏血酸钠0.008g、醋酸铜0.004g,室温下搅拌30分钟形成凝胶。
Claims (9)
1.一种炔基多臂聚乙二醇活性衍生物的制备方法,其特征在于,包括:
将多臂聚乙二醇-端基羟基-端基乙酸甲酯溶于溶剂中,加入氢化钠室温反应后,加入溴丙炔和碘化钾反应,得到多臂聚乙二醇-丙炔-乙酸甲酯;将多臂聚乙二醇-丙炔-乙酸甲酯水解后,得到聚乙二醇-丙炔-乙酸衍生物;
或者,将多臂聚乙二醇-端基羟基-端基乙酸甲酯溶于溶剂中,加入氢化钠室温反应后,加入溴丙炔和碘化钾反应,得到多臂聚乙二醇-丙炔-乙酸甲酯;将多臂聚乙二醇-丙炔-乙酸甲酯水解后,得到聚乙二醇-丙炔-乙酸衍生物;将聚乙二醇-丙炔-乙酸衍生物溶于溶剂中,加入N-羟基琥珀酰亚胺和N,N'-二环己基碳二亚胺,反应得多臂聚乙二醇-丙炔-乙酸NHS酯;
或者,将多臂聚乙二醇-端基羟基-端基乙酸甲酯溶于溶剂中,加入氢化钠室温反应后,加入溴丙炔和碘化钾反应,得到多臂聚乙二醇-丙炔-乙酸甲酯;将多臂聚乙二醇-丙炔-乙酸甲酯水解后,得到聚乙二醇-丙炔-乙酸衍生物;将聚乙二醇-丙炔-乙酸衍生物溶于溶剂中,加入N-羟基琥珀酰亚胺和N,N'-二环己基碳二亚胺,反应后,再加入马来酰亚乙二胺反应,得多臂聚乙二醇-端基丙炔-端基乙酸MAL酯;
或者,将多臂聚乙二醇-端基乙酸-端基乙胺溶于溶剂中,加入三乙胺和二碳酸二叔丁酯,反应得多臂聚乙二醇-乙酸- Boc酰胺;反应后将多臂聚乙二醇-乙酸- Boc酰胺和N-羟基琥珀酰亚胺溶于溶剂中,加入N,N'-二环己基碳二亚胺反应后,再加入炔丙胺反应,得到多臂聚乙二醇-炔基- Boc酰胺;将上述多臂聚乙二醇-炔基- Boc酰胺溶于溶剂中,加入三氟乙酸反应,得多臂聚乙二醇-端基炔基-端基乙胺;
或者,将多臂聚乙二醇-端基乙酸-端基乙胺溶于溶剂中,加入三乙胺和二碳酸二叔丁酯,反应得多臂聚乙二醇-乙酸- Boc酰胺;反应后将多臂聚乙二醇-乙酸- Boc酰胺和N-羟基琥珀酰亚胺溶于溶剂中,加入N,N'-二环己基碳二亚胺反应后,再加入炔丙胺反应,得到多臂聚乙二醇-炔基- Boc酰胺;将上述多臂聚乙二醇-炔基- Boc酰胺溶于溶剂中,加入三氟乙酸反应,得多臂聚乙二醇-端基炔基-端基乙胺;将多臂聚乙二醇-端基炔基-端基乙胺溶于溶剂中,加入3-马来酰亚胺基丙酸羟基琥珀酰亚胺酯反应,得到多臂聚乙二醇-端基炔基-端基乙胺MAL;
所述炔基多臂聚乙二醇活性衍生物具有如下通式结构:
Ⅲ,
或者Ⅳ,
或者Ⅴ,
或者Ⅵ,
或者Ⅶ,
或者Ⅷ,
或者Ⅸ,
或者Ⅹ,
或者Ⅺ,
或者Ⅻ,
或者ⅩⅢ,
或者ⅩⅣ,
或者ⅩⅤ,
或者ⅩⅥ,
或者ⅩⅦ,
其中:
PEG为相同或不同的-(CH2CH2O)m-;m是平均值为3-250的整数
l为≧1的整数;
X1选自-(CH2)i-、-(CH2)iNHCO(CH2)j-、-(CH2)iCONH(CH2)j-、-(CH2)iNH-、-(CH2)iOCOO-、-(CH2)iOCONH-、-(CH2)iNHCOO-、-(CH2)iNHCONH-、-OC(CH2)iCOO-、-(CH2)iCOO-、-(CH2)iCONH-、-(CH2)iCOO-组成的组;X1中i为1-10的整数,j为1-10的整数;
k为1-10的整数。
2.如权利要求1所述的制备方法,其特征在于,所述X1选自-(CH2)i-、-(CH2)iNHCO(CH2)j-、-(CH2)iCONH(CH2)j-组成的组;X1中i为1、2、3、4或5,j为1、2、3、4或5。
3.如权利要求1或2所述的制备方法,其特征在于,所述的炔基多臂聚乙二醇活性衍生物中k为1、2、3、4或5。
4.如权利要求1或2所述的制备方法,其特征在于,所述的炔基多臂聚乙二醇活性衍生物中l为1、2、3、4、5或6。
5.如权利要求1所述的制备方法,其特征在于,所述炔基多臂聚乙二醇活性衍生物的分子量为1000-80000Da。
6.如权利要求5所述的制备方法,其特征在于,所述炔基多臂聚乙二醇活性衍生物的分子量为3000-20000Da。
7.如权利要求6所述的制备方法,其特征在于,所述炔基多臂聚乙二醇活性衍生物的分子量为3000-10000Da。
8.如权利要求6所述的制备方法,其特征在于,所述炔基多臂聚乙二醇活性衍生物的分子量为3000Da、5000Da、10000Da、20000Da。
9.如权利要求1所述的制备方法,其特征在于,所述溶剂选自甲醇、乙醇、氯仿、二氯甲烷、丙酮、乙醚和乙酸乙酯。
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