CN1085987C - 杂远螯嵌段共聚物及其制备方法 - Google Patents

杂远螯嵌段共聚物及其制备方法 Download PDF

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CN1085987C
CN1085987C CN96194818A CN96194818A CN1085987C CN 1085987 C CN1085987 C CN 1085987C CN 96194818 A CN96194818 A CN 96194818A CN 96194818 A CN96194818 A CN 96194818A CN 1085987 C CN1085987 C CN 1085987C
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片冈一则
C·肖尔茨
饭岛道弘
沓名贵彦
长崎幸夫
加藤政雄
冈野光夫
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Abstract

公开了下式所示的杂远螯低聚物或聚合物，式中R1和R2是形成缩醛，或者合在一起形成氧代(＝O)的原子团，p、m、n和q是一定的数，L是形成酯的基团，Z是一定的官能团。而且，也公开了这些通过活性聚合制备的方法。这些低聚物或聚合物能在水基溶剂中形成稳定的高分子胶束，因而，例如，可用作药物的标的指向性载体。

Description

杂远螯嵌段共聚物及其制备方法
技术领域
本发明涉及两端有不同官能团的杂远螯嵌段共聚物及其制备方法，及其对高分子胶束的应用。更具体地说，本发明公开了两端有不同官能团、主链上有聚环氧乙烷作为亲水链段和聚酯作为疏水链段的聚合物。
此外，本发明中所谓聚合物这一术语，是以包含低聚物的概念使用的。
背景技术
聚环氧乙烷这样的亲水性高分子与其它疏水性高分子在分子水平上结合的亲水/疏水型嵌段共聚物所组成的高分子胶束或纳米球(nanosphere)，作为药物载带用载体等，日益引人瞩目。高分子胶束和纳米球的调整，是通过亲水性聚合物与疏水性聚合物在分子水平上结合的亲水/疏水型嵌段共聚物实现的。
然而，先有技术上亲水/疏水型嵌段共聚物的制备方法在导入其末端官能团方面是有限制的，已提出来的只不过是有甲氧基或羟基等所限定官能团的嵌段共聚物。具体地说，若能在胶束表面上成功地以任意比例导入任意反应性官能团，则将有可能提供可有利地用于医药等的活体内标的指向化的功能高分子胶束。
因此，本发明的目的，是提供两端有不同的官能团的嵌段共聚物，作为能形成高分子胶束的多功能高分子。
发明公开
本发明者等人发现，如果利用某种有醛基和羟基的亚烷基衍生物作为活性聚合的引发剂来使作为单体的环氧乙烷、丙交酯或内酯聚合，则可以容易地提供分子的一端为也可以有保护的醛基、而另一端为多种多样官能团的嵌段共聚物。
而且也确认，这样得到的嵌段共聚物在水基溶剂中形成极其稳定的高分子胶束。
因此，按照本发明，提供的是下述式(I)所示的、分子两末端有不同官能团的杂远螯嵌段共聚物，
式中R1和R2独立地表示C1-10烷氧基、芳氧基或芳基-C1-3烷氧基，或者R1与R2合在一起表示也可以有C1-6烷基取代的亚乙二氧基(-O-CH(R′)-CH-O-：其中R′表示氢原子或C1-6烷基)，或者R1与R2合在一起表示氧代(＝O)，L表示 或 其中R3和R4独立地表示氢原子、C1-10烷基、芳基或芳基-C1-3烷基，r是2～5的整数，
m是2～10,000的整数，
n是2～10,000的整数，
p是1～5的整数，
q是0或1～20的整数，而
Z当q为0时是氢原子、碱金属、乙酰基、丙烯酰基、甲基丙烯酰基、肉桂酰基、对甲苯磺酰基、2-巯基丙酰基或2-氨基丙酰基，或表示烯丙基或乙烯基苄基，而当q为1～20的整数时是C1-6烷氧羰基、羧基、巯基或氨基。
按照本发明，作为发明的另一个方面，也提供了上述式(I)的嵌段共聚物的制备方法。该方法包括如下步骤：
步骤(1)：
式(II)的聚合引发剂与环氧乙烷反应，生成式(III)所示化合物，
Figure C9619481800081
式中R1-1和R2-1独立地表示C1-10烷氧基，或者R1-1与R2-1合在一起表示也可以有C1-6取代的亚乙二氧基，p是1～5的整数，而M表示碱金属，
Figure C9619481800082
式中R1-1、R2-1、p和M均如对式(II)所定义的，而m是2～10,000的整数；
步骤(2)：
式(II)所示化合物与下式所示丙交酯或内酯反应，
Figure C9619481800083
式中R3和R4独立地表示氢原子、C1-10烷基、芳基或芳基-C1-3烷基，而r表示2～5的整数，生成下式所示的嵌段共聚物，式中L表示式 或
Figure C9619481800086
R1-1、R2-1、p、m、n和M均如上述所定义。
通过以上步骤，提供了本发明的活性聚合物(包含在式(I)聚合物中)，这也可以作为中间原料进一步用于使任何聚合物链段伸长。
步骤(3)：
(i)使式(IV)的碱金属醇盐基选择性水解，生成下式的嵌段共聚物，式中R1-1、R2-1、p、m、L和n均如以上所定义，或者
(ii)使式(IV)的嵌段共聚物完全水解，生成下式的嵌段共聚物，
Figure C9619481800092
式中p、m、n和L均如以上所定义。
在实施这些步骤时，可以得到在分子的α-末端有受保护醛基或醛基本身，在ω-末端有羟基的本发明嵌段共聚物。
步骤(4)：使式(V)的α-末端上有受保护醛基的嵌段共聚物
(i)与乙酸、丙烯酸、甲基丙烯酸、肉桂酸或对甲苯磺酸或其活泼衍生物反应，
(ii)与烯丙基卤或乙烯基苄基卤反应，或
(iii)与下式的卤化物反应，
Figure C9619481800093
式中X是氯、溴或碘，q′是1～20的整数，而Z′表示C1-6烷氧羰基、受保护氨基，
提供在分子的ω-末端有除羟基以外的各自对应官能团的本发明嵌段共聚物。
步骤(5)：步骤(4)的(i)得到的对甲苯磺酸酯通过酯交换等可以提供在ω-末端还有其它官能团(例如巯基、氨基)的嵌段共聚物，而通过以上步骤得到的有醛保护基或羧基保护基的嵌段共聚物还可以再借助于水解反应使任何一个保护基或全部保护基脱除，而提供本发明的嵌段共聚物。
按照本发明，作为发明的又一个方面，也提供利用式(I)所示嵌段共聚物可以得到的高分子胶束。
这样得到的本发明杂远螯聚合物的一部分可以作为前体物用于制备另一种聚合物，而且如同从其构成成分可以理解的，这些聚合物具有活体亲和性，而且可以预期其生物有效性高。因此，可以用于诸如活体内直接适用的材料，例如医药载带用载体材料等，而且，尤其按照本发明的第三方面，由于可以提供在水基溶剂中极其稳定的高分子胶束，因而也可用作活体内标的指向性医药载体。
附图简单说明
图1是缩醛α-末端/羟基ω-末端聚酯氧化物/聚丙交酯嵌段共聚物(实施例1的样品)的凝胶渗透色谱图。
操作条件：
柱：TSK-Gel(G4000HXL、G3000HXL、G2500HXL)
流出溶剂：THF(含2％三乙胺)
流速：1ml/分钟。
图2是缩醛α-末端/羟基ω-末端聚环氧乙烷/聚丙交酯嵌段共聚物(实施例1的样品)的质子核磁共振谱。
图3是缩醛α-末端/羟基ω-末端聚环氧乙烷/聚(δ-戊内酯)嵌段共聚物(实施例3的样品)的质子核磁共振谱。
图4是醛α-末端/羟基ω-末端聚环氧乙烷/聚丙交酯嵌段共聚物(实施例4的样品)的质子核磁共振谱。
图5是缩醛α-末端/甲基丙烯酰ω-末端聚环氧乙烷/聚丙交酯嵌段共聚物(实施例5的样品)的碳核磁共振谱。
图6是缩醛α-末端/烯丙基ω-末端聚环氧乙烷/聚丙交酯嵌段共聚物(实施例6的样品)的碳核磁共振谱。
图7是缩醛α-末端/对甲苯磺酰ω-末端聚环氧乙烷/聚丙交酯嵌段共聚物(实施例6的样品)的碳核磁共振谱。
图8是醛α-末端/羟基ω末端聚环氧乙烷/聚丙交酯嵌段共聚物(实施例4的样品)的水溶液中高分子胶束粒度分布的动态激光光散射测定结果示意图。
发明详细说明
本发明中所谓烷氧基的烷基部分和烷基，系指直链或枝链烷基。因此，式(II)、式(IIIa)中C1-10烷氧基的烷基部分或C1-10烷基，可以列举甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基、异戊基、己基、2-甲基戊基、3-甲基戊基、辛基、2-乙基己基、癸基或4-丙基戊基。这些当中，R1和R2中所谓烷氧基的烷基部分，较好的是C1-6烷基，尤其好的是C1-3烷基。
因此，R1和R2中所谓烷氧基，尤其好的可以列举甲氧基、乙氧基、丙氧基、异丙氧基。而R1和R2可以列举芳基、尤其苯基、或芳基C1-3烷基、尤其苄基或苯乙基，作为其较好者。这些基团可以相同也可以不同，但较好是相同基团。而且R1和R2合在一起，可以是也可以有C1-6烷基取代的亚乙二氧基(-OCH(R′)-CH2O-：式中R′是C1-6烷基)，较好是亚乙二氧基、亚丙二氧基、1，2-亚丁二氧基。
这些基团可以通过水解，方便地使R1和R2合在一起形成氧代(＝O)，即形成分子的α-末端有醛基的本发明嵌段共聚物。
式(I)的p表示1～5的整数，但式(I)的链段若考虑到其源于本发明制备方法中的聚合引发剂(参照式(II))，则这个链段作为整体，较好是选择R1、R2和p，使之能构成缩醛基，例如二甲氧甲氧基、2，2-二甲氧乙氧基、3，3-二甲氧丙氧基、4，4-二甲氧丁氧基、二乙氧甲氧基、2，2-二乙氧乙氧基、3，3-二乙氧丙氧基、4，4-二乙氧丁氧基、二丙氧甲氧基、2，2-二丙氧乙氧基、3，3-二丙氧丙氧基或4，4-二丙氧丁氧基等。
另一方面，R3和R4只要符合本发明之目的者，可以是氢原子、C1-10烷基、芳基或芳基-C1-3烷基中的任何一种，但从生物有效性的观点来看，较好是氢原子(源于戊二酸)和甲基(源于乳酸)。
式(I)中的m，按照本发明经由活性聚合的制备方法，通过调整环氧乙烷(单体)相对于聚合引发剂的数量比例，理论上可以达到任意的m值，但依照本发明之目的，m较好的是2～10,000之间的任何一个整数。这个链段能赋予本发明嵌段共聚物以亲水性的m，较好的是10以上的整数。而就易于在狭窄范围内调整这个链段的分子量分布和能提供生物有效性优异的嵌段共聚物而言，应选择得使m为500以下、较好为200以下的整数。
另一方面，定义式(I)中聚酯链段的分子量的n，可以从这个链段主要赋予本发明嵌段共聚物以疏水性这一点来理解，最佳n值要因R3和R4的基团性质而异。此外，在本发明的聚合方法中，例如，可以同聚环氧乙烷链段一样选取任意的n值。因此，n值是没有限定的，但通常是2～10,000。进而，就其与聚环氧乙烷链段的关系而言，为了较好地保持亲水性-疏水性的平衡，较好选取n为10～200的整数、尤其10～100的整数。式(I)的
Figure C9619481800121
链段主要规定本发明嵌段共聚物的ω-末端官能团(或活泼基团)。在q为0(即Z与聚酯链段的ω-位氧原子直接结合)的情况下，首先可以是碱金属。这种情况下的本发明聚合物可以是活性聚合物(living  polymers)。因此，这样的本发明聚合物可以进一步充当活性聚合(living polymerization)的引发剂，因而也可进一步用作各种聚合物的前体物。从这种观点来看，作为碱金属，可以列举钠、钾和铯。
而且，上述活性聚合物容易在醇化物部分发生水解，因而容易提供Z表示氢原子的化合物(ω末端是羟基)。进而，这种羟基还可以通过各种反应，例如酯化、醚化，而转化成其它官能团。因此，作为q为0情况下的Z，可以是乙酰基(-COCH3)、丙烯酰基(-COCH＝CH2)、甲基丙烯酰基(-COC(CH3)＝CH2)、肉桂酰基 和对甲苯磺酰基
Figure C9619481800123
，还可以是烯丙基(-CH2-CH＝CH2)和乙烯基苄基
Figure C9619481800124
。在有这些官能团例如乙烯类不饱和键的情况下，可以利用它们衍生成侧链型聚合物。此外，在对甲苯磺酰基的情况下，通过酯交换等，还可以再用其本身已知的方法转化成其它官能团。因此，Z也可以是2-巯基丙酰基或2-氨基丙酰基。
在q为1～20的整数、较好1～4、尤其好的是2的整数的情况下，-(CH)qZ作为一个整体可以是C1-6烷氧基(例如甲氧基、乙氧基、丙氧基)羰基-甲基、-乙基或-丙基，或者是2-氨基乙基、羧-甲基、-乙基或-丙基。
以上各取代基(或链段)组合构成的本发明嵌段共聚物，可以列举下述表1中的实例。
             表1
               表1(续)
Figure C9619481800151
             表1(续)
Figure C9619481800161
*1)和*2)表示从数均分子量换算的值。
以上本发明提供的杂远螯嵌段共聚物可以用下述反应方案所示的本发明制备方法高效率地得到。反应方案
Figure C9619481800171
Figure C9619481800181
从(A)制备(B)：
使碱金属缩醛保护醇盐(A)与环氧乙烷反应，得到加成了聚环氧乙烷链段的化合物(B)。化合物(A)可以用金属化剂如钠或钾等碱金属，萘基钠、萘基钾、枯基钾、枯基铯等有机金属，氢化钠、氢化钾等金属氢化物等，处理缩醛保护醇来得到。
此外，上述从(A)变成(B)的反应可以在无溶剂下或较好在无水的非质子传递溶剂中，在广泛的温度例如-50℃～300℃、较好10℃～60℃、方便而好的是在室温(20～30℃)下进行。反应可以在加压下或减压下实施。使用的溶剂没有限定，但可以列举诸如苯、甲苯、二甲苯、四氢呋喃、二噁烷、乙腈等。反应容器没有特别限定，可以使用诸如圆底烧瓶、高压釜、耐压封管等。反应容器内较好能与外界大气隔断，若能充满惰性气体则更好。反应溶液的浓度较好是0.1～95％(重量)、更好的是1～80％(重量)、最好的是3～10％(重量)。
从(B)制备(C)：
含有(B)的反应混合物与丙交酯或内酯反应，得到聚酯链段通过聚环氧乙烷的ω末端羟基加成的活性嵌段共聚物(C)。其反应条件可以与上述(A)变成(B)的反应几乎完全一样。可以使用的丙交酯和内酯是能形成式(I)中L的R3和R4所定义的链者。丙交酯较好的虽没有限定，但可以是乳酸丙交酯和乙醇酸丙交酯。另一方面，可以使用的内酯是β-丙酸内酯、γ-丁酸内酯、δ-戊酸内酯和ε-己酸内酯。从反应容易性的观点来看，较好的是γ-丁酸内酯和δ-戊酸内酯。
以上各步骤中聚合引发剂与环氧乙烷或丙交酯或内酯的使用比例，以摩尔比计，较好分别为1∶1至1∶10,000，更好的是1∶5至1∶10,000，最好的是1∶10～200至1∶50～200。
按照本发明的方法，不仅各链段可以分别根据单体与引发剂的相对用量来调整分子量，而且可以提供所生成各链段的分子量分布非常狭窄、单分散性或一峰性嵌段共聚物。
这样得到的活性聚合物(C)本身也包含在本发明的聚合物范围内，但(C)的醇化物可以(i)在温和条件(只简单地加水)下部分水解而转化成聚合物(D)，或者(ii)在可以同时使缩醛水解的条件下处理(C)而转化成α-末端有醛基、ω-末端有羟基的聚合物(D′)。后者的水解可以使用三氟乙酸、盐酸、硫酸、硝酸、甲酸、氟化氢等酸类，氢氧化钠、氢氧化钾等碱类，必要时加热处理来进行。
从(D)制备(E)～(G)：
(i)在惰性有机溶剂中与乙酸、丙烯酸、甲基丙烯酸或对甲苯磺酸反应，生成ω-末端酰基化物，或
(ii)与下式的卤化物反应，提供ω-末端醚化物，
            halo-E            (V)式中halo与E对应于式(I)中-(CH2)q-Z除酰基以外的基团。
这些反应可以按照其本身已知的酯化或醚化法进行。此外，上述(i)的有机酸，方便的是使用各自的酸酐或酰卤等有机酸的活泼衍生物。
而且，当ω-末端导入巯基时，可以诸如使对甲苯磺酰化物(F)与亲电子试剂例如硫代乙酸钠、硫代乙酸钾、硫氢化钾等亲电子剂反应，从而在ω末端导入硫代酯基，然后，用碱或酸处理，得到(G)所示的聚合物。
当ω-末端导入氨基时，可以利用N-(2-溴乙基)邻苯二甲酰亚胺、N-(3-溴丙基)邻苯二甲酰亚胺、1-溴-2-(苯胺基)乙烷、N-(2-溴乙基)氨基甲酸苄酯等作为亲电子试剂进行(D)的水解，然后用碱或酸处理进行基团R1和R2的脱保护，同时进行ω-末端酰亚胺键的水解，得到ω-末端有氨基的聚合物。
聚合物(D)、(E)、(F)和(G)上基团R1和R2脱保护产生α-末端醛，可以按照上述从(C)向(D′)的转化那样进行。反应液中聚合物的回收，可以借助于其本身的溶剂沉淀法或凝胶渗透色谱法、渗析、超过滤等来进行。
这样，便可以得到本发明式(I)所示的各种杂远螯嵌段共聚物。所得到的聚合物(除活性聚合物外)可以在水基溶剂中形成极稳定的高分子胶束。
这种高分子胶束可以通过诸如对聚合物溶液或悬浮液以单独或组合方式进行加温处理、超声波照射处理、有机溶剂处理等来制备。加温处理，是使本发明嵌段共聚物中的1种或2种以上的混合物分散或溶解在水中，在30～100℃的温度、更好的是在30℃～50℃的温度调制。超声波照射处理，是使嵌段共聚物中的1种或2种以上的混合物分散在水中，在1W～20W的范围进行1秒～24小时，较好在1W～3W的范围进行3小时。
有机溶剂处理，是使嵌段共聚物中的1种或2种以上的混合物溶解在有机溶剂中，再将此溶液分散于水中，然后蒸发有机溶剂。作为有机溶剂，可以使用氯仿、苯、甲苯和二氯甲烷等。
此外，还可以通过溶解于甲醇、乙醇、四氢呋喃、二噁烷、二甲基亚砜、二甲基甲酰胺等中，然后对水基溶剂渗析，来制备本发明的高分子胶束。渗析中使用的渗析膜的分级分子量，其最佳值因作为处理对象的嵌段共聚物的分子量而异，因而没有予以限定，但一般可以使用1,000,000以下，较好5,000～20,000。
作为水基溶剂，可以使用水、缓冲溶液，渗析时，相对于所使用的上述有机溶剂而言，水基溶剂的使用比例一般是1～1000倍、较好是10～100倍。温度没有特别限定，但通常可以在5℃～25℃进行。
这样得到的本发明高分子胶束，一般来说，其临界胶束浓度极低，低达4～12mg/l，而且与作为药物载体广泛探讨的脂质体等低分子胶束相比，在水基溶剂中是显著稳定的。这意味着，例如，在本发明高分子胶束对血中给药的情况下，可以期待其在血中的半衰期显著增大，因而可以说本发明聚合物具备作为药物载体的优异特性。
以下列举具体例来更具体地说明本发明，但无意使本发明局限于这些实例。
实施例1
向反应容器中加入THF 20ml和3，3-二乙氧基丙醇0.15g，以及萘基钾0.5mol/升四氢呋喃溶液2ml，在氩气氛围下搅拌3分钟，生成3，3-二乙氧基丙醇的钾化物(3，3-二乙氧基丙醇钾)。
向此溶液中加入环氧乙烷8.8g，在一大气压和室温下进行搅拌。反应2天后，向此反应液中添加丙交酯7.2g，进一步搅拌1小时。将此溶液倾入冷丙醇中，使所生成的聚合物沉淀。离心分离得到的沉淀用苯冷冻干燥进行精制。其产率为15.0g(94％)。用凝胶渗透色谱法得到的聚合物是一峰性的，聚合物的数均分子量是约1600(参照图1)。
所得到的聚合物在氘代氯仿中的质子核磁共振谱证实，这种聚合物是有聚环氧乙烷(PEO)和聚丙交酯(PL)这两种单元、而且定量具有α-末端缩醛基和ω-末端羟基的杂远螯低聚物(参照图2)。从这种谱的积分比求出的嵌段共聚物各链段的数均分子量是PEO为约8800，PL为约7000。
实施例2
向反应容器中加入THF 20ml和3，3-二乙氧基丙醇0.15g，以及萘基钾0.5mol/升四氢呋喃溶液2ml，在氩气氛围下搅拌3分钟，生成3，3-二乙氧基丙醇的钾化物(3，3-二乙氧基丙醇钾)。
向此溶液中加入环氧乙烷5.7g，在一大气压和室温下进行搅拌。反应2天后，向此溶液加入丙交酯7.2g，进一步搅拌1小时。将此溶液倾入冷丙醇中，使所生成的聚合物沉淀。离心分离得到的沉淀用苯冷冻干燥进行精制。其收率是12.4g(95％)。凝胶渗透色谱法得到的聚合物是一峰性的，聚合物数均分子量是约1200。
所得到的聚合物在氘代氯仿中的质子核磁共振谱证实，这种聚合物是有聚环氧乙烷(PEO)和聚丙交酯(PL)这两种单元、而且定量地具有α-末端缩醛基和ω-末端羟基的杂远螯低聚物。从这种谱的积分比求出的嵌段共聚物各链段的数均分子量是PEO为约5400，PL为约6600。
实施例3
向反应容器中加入THF 20ml和3，3-二乙氧基丙醇0.15g，以及萘基钾0.5mol/升四氢呋喃溶液2ml，在氩气氛围下搅拌3分钟，生成3，3-二乙氧基丙醇的钾化物(3，3-二乙氧基丙醇钾)。
向此溶液中加入环氧乙烷8.8g，在一大气压和室温下进行搅拌。反应2天后，向此溶液中添加δ-戊内酯5.0g，进一步搅拌1小时。将此溶液倾入冷丙醇中，使生成的聚合物沉淀。离心分离得到的沉淀用苯冷冻干燥进行精制。其收率为13.5g(97％)。凝胶渗透色谱法得到的聚合物是一峰性的，聚合物的数均分子量为约1400。
所得到的聚合物在氘代氯仿中的质子核磁共振谱证实，这种聚合物是有聚环氧乙烷(PEO)和聚-δ-戊内酯(PVL)这两种单元、定量地具有α-末端缩醛基和ω-末端羟基的杂远螯低聚物(参照图3)。从这种谱的积分比求出的嵌段聚合物各链段的数均分子量是PEO为约8800，PVL为约5200。
实施例4
向溶解了实施例2得到的嵌段共聚物样品1.0g的甲醇50毫升中添加2.0mol/L HCl 50ml，在室温搅拌1小时。此溶液用NaOH水溶液中和后，对20倍量的水进行4小时渗析(分级分子量1000)，用冷冻干燥法精制。其收率为0.85g(85％)。凝胶渗透色谱法得到的聚合物分子量与反应前相比，可以认为没有变化。
所得到的聚合物在氘代氯仿中的质子核磁共振谱证实，这种聚合物的α-末端缩醛基消失，取而代之的是出现由醛产生的峰，是定量地具有α-末端醛基和ω-末端羟基的杂远螯PEO/PL低聚物(参照图4)。
实施例5
向溶解了实施例2得到的嵌段共聚物样品1.0g的氯仿20毫升中添加吡啶20毫升和甲基丙烯酸酐1.0g，在室温搅拌24小时。此溶液用盐酸水溶液中和、洗涤。将氯仿相注入冷丙醇中，使聚合物沉淀。离心分离得到的沉淀用苯冷冻干燥进行精制。其收率为0.8g(80％)。凝胶渗透色谱法得到的聚合物分子量与反应前相比，可以认为没有变化。
所得到的聚合物在氘代氟仿中的碳核磁共振谱证实，这种聚合物的ω-末端羟基所产生的峰完全消失，取而代之的是出现由甲基丙烯酰基产生的峰，是定量地具有α-末端缩醛基和ω-末端甲基丙烯酰基的杂远螯PEO/PL低聚物(参照图5)。
实施例6
向溶解了实施例2得到的嵌段共聚物样品1.0g的四氢呋喃溶液20毫升中添加萘基钾0.5摩尔/升四氢呋喃溶液2毫升和烯丙基溴5毫升，在室温搅拌4小时。所得到的反应物倾入冷丙醇中，使聚合物沉淀。离心分离得到的沉淀用苯冷冻干燥进行精制。其收率为0.98g(98％)。凝胶渗透色谱法得到的聚合物分子量与反应前相比，可以认为没有变化。
所得到的聚合物在氘代氯仿中的碳核磁共振谱证实，这种聚合物的ω-末端羟基所产生的峰完全消失，取而代之的是出现烯丙基所产生的峰，是定量地具有α-末端缩醛基和ω-末端烯丙基的杂远螯PEO/PL低聚物(参照图6)。
实施例7
向溶解了实施例4得到的嵌段共聚物样品1.0g的四氢呋喃20毫升中添加萘基钾0.5mol/L-四氢呋喃溶液2ml和对甲苯磺酰氯5g，在室温搅拌4小时。所得到的反应物倾入冷丙醇中，使聚合物沉淀。离心分离得到的沉淀用苯冷冻干燥进行精制。其收率为0.95g(95％)。凝胶渗透色谱法得到的聚合物分子量与反应前相比，可以认为没有变化。
所得到的聚合物在氘代氯仿中的碳核磁共振谱证实，这种聚合物的ω-末端羟基所产生的峰完全消失，取而代之的是出现对甲苯磺酰基产生的峰，是定量地具有α-末端缩醛基和ω-末端对甲苯磺酰基的杂远螯PEO/PL低聚物(参照图7)。
实施例8
将实施例2得到的嵌段共聚物样品50mg溶解在水或适当缓冲溶液中，使其浓度为0.01～0.1％(重量/体积)。当通过动态光散射粒度分布测定确认这些溶液中的胶束形成时，可以确认形成了平均粒径30nm的单一好分子胶束(参照图8)。这种高分子胶束的临界胶束浓度是10mg/L。
实施例9
向反应容器中加入THF 30毫升和3，3-二乙氧基丙醇0.13g以及萘基钾0.5mol/L-四氢呋喃溶液2ml，在氩气氛围下搅拌3分钟，生成3，3-二乙氧基丙醇的钾化物(3，3-二乙氧基丙醇钾)。
向此溶液中添加环氧乙烷7.0g，在一大气压、室温下进行搅拌。反应2天后，向此反应液中添加乳酸丙交酯7.2g，进一步搅拌一小时。将此溶液倾入冷丙醇中，使所生成的聚合物沉淀。离心分离得到的沉淀用苯冷冻干燥进行精制。其收率为11.5g(79％)。凝胶渗透色谱法得到的聚合物是一峰性的，聚合物的数均分子量为11000。
所得到的聚合物在氘代氯仿中的质子核磁共振谱证实，这种聚合物是有聚环氧乙烷(PEO)和聚丙交酯(PL)这两种单元、定量地具有α-末端缩醛基、ω-末端羟基的杂远螯低聚物。从这种光谱的积分比求出的嵌段共聚物各链段的数均分子量是PEO为5800，PL为5100。
所得到的嵌段聚合物200mg溶解在二甲基乙酰胺40ml中，用分级分子量12000～14000的渗析膜对水进行24小时渗析(2、5、8小时后水交换各2升)。所得到的溶液的动态光散射测定表明精制了平均粒径40nm的高分子胶束。其临界胶束浓度是5mg/L。
实施例10
实施例9得到的胶束溶液10ml中滴加0.1N盐酸，调节至pH＝2，在室温下搅拌2小时。用0.1N氢氧化钠水溶液中和，用分级分子量12000～14000的渗析膜对水渗析24小时(2、5、8小时后水交换各2升)。所得到的溶液的动态光散射测定表明精制了平均粒径40nm的高分子胶束。其临界胶束浓度为5mg/L。
此胶束溶液冷冻干燥，溶解在氘代二甲基亚砜中之后进行NMR测定时，1.2ppm和4.6ppm的缩醛基产生的信号几乎完全消失，并出现了2.7ppm(t)和9.8ppm(s)分别为羰基亚甲基和醛氢产生的信号。信号的面积比表明，缩醛的95％水解成醛。
实施例11
同实施例1一样合成的PEO/PAL嵌段聚合物(数均链段的数均分子量PEO为4500，PLA为13000)200mg溶解在二甲基乙酰胺40ml中，用分级分子量12000～14000的渗析膜对水渗析24小时(2、5、8小时后水交换各2升)。所得到的溶液的动态光散射测定表明，精制了平均粒径30nm的高分子胶束。其临界胶束浓度为4mg/L。
产业上利用的可能性
按照本发明，提供了分子两末端有不同官能团、且主链上有亲水性链段和疏水性链段的杂远螯低聚物或聚合物。这些低聚物或聚合物，从其构成成分可以预期是生物有效性优异的。此外，这些低聚物或聚合物在水基溶剂中可以形成极稳定的高分子胶束。
因此，在适用于生物体，例如制造和/或使用药物标的指向性载体的技术领域，可以利用的可能性高。

Claims (13)

1.下述式(I)所示的、分子两末端有不同官能团的杂远螯嵌段共聚物，
式中R1和R2独立地表示C1-10烷氧基、芳氧基或芳基-C1-3烷氧基，或者R1与R2合在一起表示也可以有C1-6烷基取代的亚乙二氧基-O-CHR′-CH2-O-：其中R′表示氢原子或C1-6烷基，或者R1与R2合在一起表示氧代＝O，
Figure C9619481800022
其中R3和R4独立地表示氢原子、C1-10烷基、芳基或芳基-C1-3烷基，r是2～5的整数，
m是2～10,000的整数，
n是2～10,000的整数，
p是1～5的整数，
q是0或1～20的整数，而
Z当q为0时是氢原子、碱金属、乙酰基、丙烯酰基、甲基丙烯酰基、肉桂酰基、对甲苯磺酰基、2-巯基丙酰基或2-氨基丙酰基，或表示烯丙基或乙烯基苄基，而当q为1～20的整数时是C1-6烷氧羰基、羧基、巯基或氨基。
2.权利要求1所述的杂远螯嵌段共聚物，其中R1和R2合在一起表示氧代。
3.权利要求1所述的杂远螯嵌段共聚物，其中R1和R2独立地表示C1-6烷氧基、苯氧基、苄氧基，或者R1和R2合在一起表示也可以有C1-3烷基取代的亚乙二氧基。
4.权利要求1所述的杂远螯嵌段共聚物，其中R1和R2合在一起表示氧代，L中的R3和R4都是氢或甲基或者r是整数4，而q是0或1～3的整数。
5.权利要求1所述的杂远螯嵌段共聚物，其中R1和R2独立地是C1-6烷氧基，L中的R3和R4都是氢或甲基或者r是整数4，而q是0或1～3的整数。
6.权利要求1所述的杂远螯嵌段共聚物，其中m表示10～200的整数，n表示10～200的整数。
7.权利要求1所述的杂远螯嵌段共聚物，其中R1和R2合在一起表示氧代，L中的R3和R4都是氢或甲基或者r是整数4，q是0，而Z是氢原子、乙酰基、丙烯酰基、甲基丙烯酰基、肉桂酰基或对甲苯磺酰基，或者是烯丙基或乙烯基苄基。
8.权利要求1所述的杂远螯嵌段共聚物，其中R1和R2独立地是C1-6烷氧基，L中的R3和R4都是甲基或者r是整数4，q是0，而Z是氢原子或钠、钾或铯。
9.权利要求1所述的杂远螯嵌段共聚物，其中R1和R2合在一起表示氧代，L中的R3和R4都是甲基或者r是整数4，q是1～3的整数，而Z是C1-6烷氧羰基、羧基、巯基或氨基。
10.权利要求1所述的式(I)所示杂远螯嵌段共聚物的制备方法，所述方法包括下列步骤：
步骤(1)：
式(II)的聚合引发剂与环氧乙烷反应，生成式(III)所示化合物，
Figure C9619481800031
式中R1-1和R2-1独立地表示C1-10烷氧基，或者R1-1与R2-1合在一起表示也可以有C1-6取代的亚乙二氧基，p是1～5的整数，而M表示碱金属，
Figure C9619481800032
式中R1-1、R2-1、p和M均如对式(II)所定义的，而m是2～10,000的整数；
步骤(2)：
式(II)所示化合物与下式所示丙交酯或内酯反应，
Figure C9619481800041
式中R3和R4独立地表示氢原子、C1-10烷基、芳基或芳基-C1-3烷基，而r表示2～5的整数，生成下式所示的嵌段共聚物，
Figure C9619481800042
式中L表示式
Figure C9619481800043
或
Figure C9619481800044
R1-1、R2-1、p、m、n和M均如上述所定义；
步骤(3)：因情况而异，
(i)使式(IV)的碱金属醇盐基选择性水解，生成下式的嵌段共聚物，式中R1-1、R2-1、p、m、L和n均如以上所定义，或者
(ii)使式(IV)的嵌段共聚物完全水解，生成下式的嵌段共聚物，式中p、m、n和L均如以上所定义；以及
步骤(4)：使式(V)的α-末端上有受保护醛基的嵌段共聚物
(i)与乙酸、丙烯酸、甲基丙烯酸、肉桂酸或对甲苯磺酸或其活泼衍生物反应，
(ii)与烯丙基卤或乙烯基苄基卤反应，或
(iii)与下式的卤化物反应，
Figure C9619481800051
式中X是氯、溴或碘，q′是1～20的整数，而Z′表示C1-6烷氧羰基、受保护氨基；
步骤(5)：因情况而异，使步骤(4)的(i)生成的对甲苯磺酸酯发生酯交换，或者使步骤(4)的(i)、(ii)或(iii)得到的衍生物发生水解反应。
11.高分子胶束，其中含有权利要求1所述杂远螯嵌段共聚物作为水基溶剂中的活性成分。
12.权利要求9所述的高分子胶束，其中权利要求1所述杂远螯嵌段共聚物是式(I)的Z表示碱金属以外的基团者。
13.权利要求9所述的高分子胶束，其中权利要求1所述杂远螯嵌段共聚物是式(I)的Z为碱金属以外的基团、而R1与R2合在一起表示氧者。
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