CN1761473A - 异双官能聚合生物共轭物 - Google Patents
异双官能聚合生物共轭物 Download PDFInfo
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- CN1761473A CN1761473A CNA2004800076734A CN200480007673A CN1761473A CN 1761473 A CN1761473 A CN 1761473A CN A2004800076734 A CNA2004800076734 A CN A2004800076734A CN 200480007673 A CN200480007673 A CN 200480007673A CN 1761473 A CN1761473 A CN 1761473A
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Abstract
本发明公开了异双官能聚合前体药物平台,用于递送生物学活性化合物,包括蛋白,单克隆抗体等。优选的化合物为式(I)。本发明还提供了制备以及应用本发明所述化合物以及共轭物的方法。
Description
技术领域
本发明涉及用于靶向以及递送治疗剂的高分子量异双官能聚合生物共轭物。本发明还公开了制备以及利用所述共轭物的方法。
发明背景
治疗学的靶向以及药物递送正在变得越来越重要,尤其是在治疗癌症中需要使用细胞毒素。多种方法已被用于利用治疗剂选择性靶向肿瘤治疗人类及其他动物的癌症。靶向部分诸如单克隆抗体(mAb)或者其片段通过它们的侧链官能团被共轭连接于线型聚合物。然而,这种方法通常由于抗体化学性质的改变或者由于将靶部分包埋再无规卷曲结构中的聚合物的折叠构型导致受体结合亲合性下降。理论上,新的共轭物将拥有靶向官能性以及治疗价值。
近来,在一端具有靶官能团并且在相对末端具有治疗部分(例如,化学治疗药物)的异双官能聚合共轭物已经公开在美国专利申请2002/0197261A1中。所使用的聚合共轭物具有结合到含多个侧链官能团的聚合载体的聚合间隔物,其可以在一端连接多个药物分子(例如聚(1-谷氨酸),聚合间隔物的另一端结合到靶部分。然而,聚合间隔物部分的分子量相当低。
制备较高分子量的异双官能聚合物构建体的方法公开在美国专利申请2002/0072573A1中。然而,这些的方法包括本身由于不合需要的聚合物分散性而不理想的单体聚合。其它先前的方法包括阴离子乙氧基化以及艰难的纯化步骤。试图利用以上技术获得高分子聚合物基质只导致所需产品质量较差并且产率较低。
由于现存方法的不足,需要存在生产高分子量异双官能聚合物基质的改进方法,所述改进方法可以获得高产率并且高纯度的基质同时保留低的聚合物分散度。也希望提供掺入异双官能聚合物作为靶向以及递送治疗用活性化合物工具的化合物。本发明满足了这些需要。
发明概述
在本发明的一个方面提供了式(I)的化合物:
其中:X1-X6独立地为0,S或NR1;
R44和R44’为独立地选择的聚环氧烷;
R1选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,芳烷基,以及C3-8取代的环烷基;
R40-43独立地选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,C3-8取代的环烷基,芳基,取代的芳基,芳烷基,C1-6杂烷基,取代的C1-6杂烷基,C1-6烷氧基,苯氧基以及C1-6杂烷氧基;
y和y’独立地为零或者正整数;
p和p’独立地为零或者一;
n和n’独立地为一或者正整数;
a和b独立地为零或者正整数,条件是a+b大于或等于2;
z为1或者正整数;
D1和D2独立地选自B,离去基团,活化基团,OH以及端基;并且
B选自生物学活性部分,诊断剂以及OH。
在优选实施方案中,X1-X6独立地为O或NR1,R1为氢,a和b为独立选择的1到约20的整数,y以及y’独立地为0,1或2,p以及p’各自为1,D1和D2独立地选自离去基团以及端基以及B,其中B为生物学活性部分诸如,药物,含氨基或羟基的残基,诊断剂诸如染料,螯合剂或同位素标记化合物,离去基团或活化基团。
对本发明来说,术语“残基”应该被理解为生物学活性化合物的一部分,在经历了连接前体药物载体的取代反应后仍然保留的部分。
对本发明来说,术语“烷基”应该理解为包括直链,支链,取代的C1-12烷基,C3-8环烷基或取代的环烷基等等。
本发明的一些主要优点包括能够增强天然的或未修改的分子的循环半衰期和溶解性的新的高分子量异双官能聚合共轭物以及构建这种共轭物的方法,其中无需层析步骤就可保持高纯度。本发明方法的另一个优点是随着聚合物共轭物分子量的增加依然保持低的聚合物分散度。本发明进一步的优点是可以使本领域技术人员设计可以在聚合物部分的两侧具有相同或者不同基团的药物共轭物。这些优点可以使本领域技术人员根据特定需要制备在同一共轭物内包含递送或靶向功能和治疗功能的化合物。
本发明还提供了生产和利用本发明描述的化合物和共轭物的方法。
附图说明
图1到9图示了在实施例中描述的制备本发明化合物的方法。
发明详述
A.式(I)
在本发明的一个方面提供了下式(I)的化合物:
其中:X1-X6独立地为O,S或NR1;
R44和R44’为独立选择的聚环氧烷;
R1选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,芳烷基,以及C3-8取代的环烷基;
R40-43独立地选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,C3-8取代的环烷基,芳基,取代的芳基,芳烷基,C1-6杂烷基,取代的C1-6杂烷基,C1-6烷氧基,苯氧基以及C1-6杂烷氧基;
y和y’独立地为零或者正整数;
p和p’独立地为零或者一;
n和n’独立地为一或者正整数;
a和b独立地为零或者正整数,条件是a+b大于或等于2;
z为1或者正整数;
D1和D2独立地选自B,离去基团,活化基团,OH以及端基;并且
B选自生物学活性部分,诊断剂以及OH。
在式(I)化合物的优选实施方案中:
X1-X6独立地为O或NR1;
R1选自氢,C1-6烷基,C1-6杂烷基,芳烷基,以及C1-6取代的烷基;
y和y’独立地是0或1和18之间的整数;
p和p’独立地为0或1;
n和n’为独立选择的0和100之间的整数;
a和b是独立选择的1和20之间的整数;
z是正整数。
更优选地,
X1-X4独立地为NR1;
X5-X6各自为O;
R44以及R44’各自为-(CH2-CH2-O)-;
R1为氢或甲基;
y以及y’各自为0,1或2;
p以及p’各自为1;
n以及n’为独立选择的70以及80之间的整数;
a和b为独立选择的5和10之间的整数;
z为正整数;
D1以及D2独立地选自OH,卤素,靶向剂,药物,酶,蛋白,治疗活性化合物,染料,螯合剂以及同位素标记化合物。
在式(1)化合物的另一优选实施方案中,D1和D2为独立选择的端基诸如:
其中:
Y1-6独立地为O或NR1;
R1′为氢或甲基;
R2-8独立地选自氢以及C1-6烷基;
Ar为形成多取代的芳烃或多取代的杂环基团的部分;
L1-2为独立选择的双功能接头;
e以及f’各自为一;
c,c’以及e’独立地为零或一;
d,f以及d’独立地为零或一;以及
B’选自离去基团,活化基团,OH,生物学活性部分以及诊断剂。
本发明的另一优选的方面,提供了式(Ia)的聚合物共轭物:
其中:
Y7-9独立地为O或NR1”;
R1”为氢或甲基;
R9-18独立地为氢或C1-6烷基;
L3-4为独立选择的双功能接头;
Q选自主动运输入靶细胞的部分,疏水部分,双功能的连接部分以及其组合;l,k,m以及o独立地为正整数;
j以及h独立地为零或一;
g,以及i各自为一;
q为零或一;
B’选自离去基团,活化基团,OH,生物学活性部分以及诊断剂;
D10以及D11选自限定D1的同一基团或一起形成下式的端基:
在本发明另一优选的方面,D1和D2为独立选择的端基,诸如:
其中D’为下式之一:
和
其中B’选自离去基团,活化基团,OH,生物学活性部分以及诊断剂。
B.接头部分L1-4
如上所述,本发明可以包括双功能连接部分L1-L4。优选地,L1-L4独立地选自:
-(CH2)3,
-(CH2)3NH-C(O),
-(CH2)3NH-,
-C(O)(CR34R35)a′O(CR36R37)b′
-NH(CH2CH2O)a′(CH2)b′NR38-,
-NH(CH2CH2O)a′-,
-NH(CR34R35)a′O-,
-C(O)(CR34R35)a′NHC(O)(CR36R37)b′NR38-,
-C(O)O(CH2)a′O-,
-C(O)(CR34R35)a′NR38-,
-C(O)NH(CH2CH2O)a′(CH2)b′NR38-,
-C(O)O-(CH2CH2O)a′NR38-,
-C(O)NH(CR34R35)a′O-,
-C(O)O(CR34R35)a′O-,
-C(O)NH(CH2CH2O)a′-,
其中:
R34-R38独立地选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,C3-8取代的环烷基,芳基,取代的芳基,芳烷基,C1-6杂烷基;取代的C1-6杂烷基,C1-6烷氧基,苯氧基和C1-6杂烷氧基;
R39选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,C3-8取代的环烷基,芳基,取代的芳基,芳烷基,C1-6杂烷基,取代的C1-6杂烷基,C1-6烷氧基,苯氧基,C1-6杂烷氧基,NO2,卤代烷基和卤素;a’和b’为独立选择的正整数。
C.Ar部分的描述
在本发明的某些方面,可见Ar部分为当包括在式(I)内时形成多取代的芳烃或多取代的杂环基团的部分。关键特征为Ar部分本质上为芳香烃。通常,作为芳香族化合物,π电子必须在环状分子平面上下方电子云的范围内共享。此外,π电子的数目必须满足休克尔规则(4n+2)。本领域技术人员将可以认识到无数的部分将满足式(1)芳香族部分的需要并因此适于本发明的应用。
一些尤其优选的芳族基包括:
其中R62-67独立地选自限定R2的相同基团。
其它优选的芳烃部分包括但不限于:
其中Z和E独立地为CR68或NR69;以及J为O,S或NR70其中R68-70选自限定R2或氰基,硝基,羧基,酰基,取代的酰基或羧基烷基的相同基团。5以及6元环的异构体为也包括在内,苯并以及二苯并-系统及其相关同系物也包括在内。本领域技术人员也应该认识到芳香环可以任选地用杂原子诸如O,S,NR1等取代,只要遵循休克尔规则。此外,芳香族或杂环构造可以任选地被卤素和/或侧链取代,同样为本领域技术人员所熟知。
D.聚环氧烷
参考式(I)可见R44为诸如聚环氧烷的聚合物部分。这种聚合物的适合的实例包括基本上无抗原性的聚乙二醇。同样有用的为诸如美国专利5,643,575描述的聚丙二醇。其它用于本发明方法的PEG描述在Shearwater Polymers,Inc的目录“聚乙二醇以及衍生物2001”中。每个公开在此处引入作为参考。
虽然PAO’s以及PEG’s可以基本上以平均分子量进行区分,优选地,在本发明大多数方面,R44具有从约2,000到约136,000Da的重量平均分子量。更优选地,R44具有从约3,400到约65,000Da的重量平均分子量,其中从约3,400到约20,000Da的重量平均分子量最优选。
本发明包括的聚合物优选在室温下为水溶性的。这种聚合物的非限制实例包括聚环氧烷均聚物诸如聚乙二醇(PEG)或聚丙二醇,聚氧乙烯化多元醇,其共聚物以及其嵌段共聚物,条件是嵌段共聚物的水溶性得以保持。
E.式(I)D1,D2B以及B’基团
1.离去基团
在式(I)中D1,D2为独立选择的离去基团,适合的部分包括但不限于诸如卤素,活化的碳酸酯诸如羟基琥珀酰亚氨基碳酸酯,羰基咪唑,环亚胺硫酮,异氰酸酯,N-对-硝基酚,N-羟基苯邻二甲酰亚胺,N-羟基苯并三唑基,咪唑,甲苯磺酸酯的基团,
其它适合的离去基团对本领域技术人员而言是显而易见的。
对本发明来说,离去基团可以被理解为能够与目标靶上发现的亲核试剂反应的基团,即生物学活性部分,双功能的间隔物,中间体等等。因此靶包含用于置换的基团,诸如在蛋白,肽,酶,天然或化学合成的治疗分子诸如阿霉素上发现的NH2基团。
2.活化基团
在式(1)中D1,D2,B以及B’独立地为活化基团。这种官能团的非限制实例包括马来酰亚氨基,乙烯基,乙烯基砜的残基,羟基,氨基,羧基,巯基,酰肼,肼基甲酸酯等等。一旦连接于聚合物共轭物,官能团,(例如,马来酰亚胺)可用于连接聚合物共轭物到靶诸如多肽的半胱氨酸残基,氨基酸或肽间隔物等等。
3.生物活性部分
在式(I)中D1,D2,B或B’为包含胺或羟基化合物的残基。这种适合的化合物的非限制性实例包括有机化合物,酶,蛋白,多肽等等的残基。有机化合物包括但不限于蒽环素化合物部分包括柔红霉素,阿霉素;p-氨基苯胺芥末黄,苯丙氨酸氮芥,Ara-C(阿糖胞苷)以及相关的抗代谢物化合物,例如吉西他汀(Gemcitabine)等等。或者,所述部分可以是含胺或者羟基的心血管剂,抗肿瘤剂诸如喜树碱以及紫杉醇(Paclitaxel),抗感染,抗真菌诸如制霉菌素,氟康唑(Fluconazole)以及两性霉素B,抗忧虑剂,肠胃病药,中枢神经系统-活性剂,止痛剂,妊娠促进药,避孕药,消炎剂,类固醇剂,药剂等等的残基。
除了上述的,生物学活性部分还可以为酶,蛋白,多肽,单链抗原结合蛋白,(SCA)单克隆抗体诸如CC49,其片段等等的残基。也包括SCA的单克隆抗体。适合的蛋白包括但是不限于多肽,酶,肽等等,具有至少一个基团可用于聚合物的连接,例如ε-氨基,胱氨酰硫基,N-末端氨基,包括具有生理或药物学活性的物质以及能够催化有机溶剂中反应的物质。
目标蛋白,多肽以及肽包括但是不局限于,血红素,血清蛋白诸如血液因子包括因子VII,VIII,以及IX;免疫球蛋白,细胞因子诸如白介素,即IL-1到IL-13,等等,α,β以及γ干扰素,集落刺激因子,包括粒细胞集落刺激因子,血小板衍生的生长因子以及磷脂酶-活化的蛋白(PLAP)。其他的生物学或治疗有用的蛋白包括胰岛素,植物蛋白诸如凝集素以及蓖麻毒,肿瘤坏死因子以及相关蛋白,生长因子诸如转化生长因于,诸如TGFα或TGFβ以及表皮生长因子,激素,促生长因子,红细胞生成素,含色素的激素,下丘脑释放因子,抗利尿激素,催乳激素,绒毛膜促性腺激素,促卵泡激素,促甲状腺激素,组织纤溶酶原激活物,等等。目标免疫球蛋白包括IgG,IgE,IgM,IgA,IgD以及其片段。
一些蛋白诸如白介素,干扰素以及集落刺激因子同样以非糖基化的形成存在,通常作为利用重组体技术的结果。非糖基化的形式同样包括在本发明的蛋白中。
目标酶包括碳水化合物特异性酶,蛋白水解酶,氧化还原酶,转移酶,水解酶,裂解酶,异构酶以及连接酶。非限制性的特定酶的例子包括天冬酰胺酶,精氨酸酶,精氨酸脱氨酶,腺苷脱氨酶,超氧化物歧化酶,内毒素酶,歧化酶,胰凝乳蛋白酶,脂肪酶,尿酸酶,二磷酸腺苷酶,酪氨酸酶以及胆红素氧化酶。目标碳水化合物特异性酶包括葡萄糖氧化酶,glucodase,,半乳糖苷酶,葡糖脑苷酯酶,葡糖醛酸糖苷酶等等。
本发明同样包括显示体内生物活性的生物聚合物的任一部分。包括氨基酸序列,核酸(DNA,RNA),肽核酸(PNA),抗体片段,单链结合蛋白,例如参见美国专利4,946,778,其内容在此处引入作为参考,结合分子,包括抗体或片段的融合,多克隆抗体,单克隆抗体以及催化抗体。
其蛋白或部分可以通过利用本领域技术人员公知的技术进行制备或者分离,诸如组织培养,从动物来源提取,或通过重组DNA的方法。转基因来源的蛋白,多肽,氨基酸序列等等同样包括在内。这种材料获自转基因动物,即小鼠,猪,牛等,其中蛋白表达在牛奶,血液或组织中。转基因的昆虫以及杆状病毒表达系统也同样作为来源。而且,蛋白的突变体形式,诸如突变体干扰素也同样包括在本发明的范围内。
目标其他的蛋白为过敏原蛋白诸如豚草,抗原E,蜜蜂毒液,螨过敏原等等。上述是用于本发明的示范性蛋白。应该理解和在这里列举的这些蛋白一样未具体提及但是具有合适的氨基的那些蛋白也包括在本发明的范围内。
在本发明优选的方面,含氨基或羟基化合物为适合于治疗动物,例如哺乳动物包括人类的药物或诊断应用的生物活性化合物,条件为这种治疗所需的条件。上述列举是可以被修饰的化合物的说明性而非限制性实例。本领域技术人员可以认识到其它的这种化合物/组合物可以被类似的修饰并且无需过多的试验。应该理解本发明中未具体提及但是具有合适的连接基团的那些生物学活性物质也包括在本发明的范围内。
适合于本发明的对含氨基或羟基分子种类的唯一限制是至少一个(伯或仲)胺-或羟基-可以与聚合共轭物反应以及连接而且在前体药物系统释放以及再生母体化合物后基本上无生物活性的损失。
4.诊断剂
在式(1)中D1,D2,B和B’是诊断药剂,适合的药剂的非限制性实例包括染料,螯合剂,以及同位素标记的化合物及其他标记化合物诸如绿色荧光蛋白(GFP)。
F.Q部分及其功能
在本发明的一个方面,Q是L5-C(=Y10)其中L5是选自限定L1,L2,L3以及L4的基团的双功能接头:并且Y10选自限定Y1-9的相同基团。在本发明的这个方面,Q基团作为B’基团以及聚合共轭物的其余部分之间的键。
在本发明的其它方面,Q是主动运输入靶细胞的部分,疏水部分及其组合。虽然Q优选地是单价的,Q可以任选地为二价的或多价的,从而可以将超过一个的B’基团与聚合物共轭物连接。为了实现主动运输,Q可以包括氨基酸或肽残基,糖残基,脂肪酸残基,C6-18烷基,取代的芳基,杂芳基,-C(=O),-C(=S)或-C(=NR28),其中R28为氢,低级烷基等。
本发明的这个方面广泛基于如下原则:适合于掺入聚合物共轭物的生物学活性物质可能本身为从聚合物基质水解释放后不活化但是经历更进一步的化学加工/反应后活化的物质/化合物。在这个方案中,通过聚合物系统递送给血流的治疗或诊断剂,肽,多肽等将保持不活化直到进入或者主动运输到目标靶细胞,由此通过胞内化学作用,例如通过存在于组织或细胞内的酶或酶系统进行活化。
本发明这个方面的化合物的制备可以使基于聚合物的共轭物的体内水解切割共轭物以便向入细胞外流体中释放活化的生物材料(在这里称为B’),同时依然与Q部分相连。在本发明这个方面的生物活性物质优选地但不限于小分子治疗剂和/或诊断剂。例如,一个可能的Q-B’组合为亮氨酸-阿霉素,另一为氨基酸-连接的喜树碱或paclitaxel并且待治疗的组织为肿瘤组织。
不想受到有关本发明如何操作的任何理论或假设的限制,人们相信,根据选作运输改进剂的附加部分,生物学活性物质进入肿瘤细胞的输送率是由以保护和/或增强运输的形式将生物学活性物质递送入细胞外组织的速度决定的,所述细胞外组织例如为显示出EPR效果的组织。
进一步任选地,运输改进剂(Q)选自用于细胞膜运输系统的已知基质。简单地,例如,细胞已知主动运输某些养分以及内分泌因子,等等,并且这种养分,或其类似物可以方便用于增强生物学有效材料向靶细胞的主动运输。这些养分的实例包括氨基酸残基,肽,例如大小从约2到约10个或更多残基的短肽,单糖以及脂肪酸,内分泌因子等等。
短肽为上文所提及的例如从2到约10或更多氨基酸残基的肽。在本发明的这个实施方案中,人们相信这种肽运输改进剂无须疏水的,但是被认为是以其他方式起到增强吸收和/或保护全身血流中连接的小分子剂免于早期水解的功能。例如,肽运输改进剂,及其他类似分子量范围的运输改进剂被认为是空间上阻碍生物活性剂被基于血浆的水解酶切割,但是然后却在靶细胞内通过各种肽和/或蛋白酶,诸如capthesin切割。
在某些优选的方面,Q为疏水部分。不想受到有关疏水性如何促进效力的理论或假设的限制,人们相信疏水部分通过抑制存在于胞外组织间隙,例如血浆中的水解酶等的攻击抑制运输改进剂远离活性生物制剂的细胞外切割。因此,一些优选的运输改进剂包括,例如疏水的氨基酸诸如如上所述的丙氨酸,缬氨酸,亮氨酸,异亮氨酸,甲硫氨酸,脯氨酸,苯丙氨酸,酪氨酸以及色氨酸以及非天然存在的衍生物以及其类似物。
作为进一步的选择,运输改进剂为疏水的有机物部分。简单地例如,有机物部分为C6-18,或较大的烷基,芳基或杂芳基-取代的或非取代的。有机物部分运输改进剂也包括在内,并且包括有机官能团,包括例如-C(=S)和/或-C(=O)。
G.合成异双官能聚合共轭物
合成特异性异双官能聚合共轭物阐述在实施例中。参见为了说明目的的图1,一个优选的方法包括:
1)将胺保护的活化异双官能PEG聚合物与异双官能PEG聚合物在碱性偶联条件下反应获得第一中间体,以及
2)将第一中间体与适合的活化基团诸如NHS活化酯反应,
3)重复步骤1)的反应获得第二中间体,
4)对第二中间体去保护,以及
5)将活化的第一中间体与去保护的第二中间体在偶联条件下反应由此获得高分子量的异双官能PEG共轭物。
根据本发明制造聚合共轭物的进一步的方法包括:
a)将式(i)的化合物与式(ii)的化合物在足以形成下式(iii)的条件下进行反应:
式(i)中:
A1为活化基团;
T为保护基;
X1,X3以及X5独立地为O,S或NR1;
R44为聚环氧烷;
R1选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,芳烷基,以及C3-8取代的环烷基;
R40-41独立地选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,C3-8取代的环烷基,芳基,取代的芳基,芳烷基,C1-6杂烷基,取代的C1-6杂烷基,C1-6烷氧基,苯氧基以及C1-6杂烷氧基;
n为1或正整数;
y为零或正整数;
t为正整数;以及
p为零或一;
式(ii)中:
X2,X4以及X6独立地为O,S或NR1;
R44′为聚环氧烷;
R1选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,芳烷基,C1-6取代的烷基,以及C3-8取代的环烷基;
R42-43独立地选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,C3-8取代的环烷基,芳基,取代的芳基,芳烷基,C1-6杂烷基,取代的C1-6杂烷基,C1-6烷氧基,苯氧基以及C1-6杂烷氧基;
n’为正整数;
y’为零或正整数;
t’为正整数;以及
p’为零或一。
该方法还任选地进一步包括对(iii)去保护从而提供可用于进一步合成,活化和/或共轭连接药物等步骤的有用中间体。或者,该方法进一步包括:将式(iii)与活性剂在足以形成式(iv)化合物的条件下反应的步骤:
其中:A2为活化基团,并且所有的其它改变定义如上。
在更进一步的方面,该方法包括:将式(iv)的氨基保护基(T)在足以形成式(v)化合物的条件下转化成活化基团:
其中:A3为活化基团。
一旦形成式(v)的化合物,它可以与生物学活性部分,诊断剂或端基在形成式(vi)化合物的条件下反应:
其中D2为生物学活性部分,诊断剂或端基,并且所有其它的改变定义如上。
合适的偶联剂的非限制性实例包括1,3-二异丙基-碳二亚胺(DIPC),任一适合的二烷基碳二亚胺,2-卤代-1-烷基-吡啶卤化物(Mukaiyama试剂),1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDC),丙烷膦酸环酐(PPACA)以及苯基二氯磷酸酯等,其可获自例如商业来源,诸如Sigma-Aldrich Chemical,或利用已知的技术合成的偶联剂。
优选地,取代基在惰性溶剂中诸如四氢呋喃(THF),乙腈(CH3CN),二氯甲烷(DCM),氯仿(CHCl3),二甲基甲酰胺(DMF)或其混合物中反应。适合的碱包括二甲基氨基吡啶(DMAP),二异丙基乙胺,吡啶,三乙胺,KOH,叔丁醇钾以及NaOH等等。反应通常在从约0℃直至约22℃(室温)的温度下反应。
更具体地,高分子聚合物共轭物的形成方法包括:
1)将下式的胺保护的活化聚合物残基:
其中n为正整数,
与下式的异双官能聚合残基反应:
其中n为正整数,
形成下式的化合物:
2)将步骤1)的中间体与活化基团,生物学活性部分,诊断剂或端基反应形成下式的化合物:
其中D2为活化基团,生物学活性部分,诊断剂或端基诸如,例如丙氨酸-喜树碱:
3)对胺部分去保护并用诸如马来酰亚胺的部分活化形成下式的化合物:
4)其后,将马来酰亚胺中间体与生物学活性部分诸如单克隆抗体CC49(结合TAG-72)的单链抗原结合蛋白或上述任何一个的其它片段,在下文为了方便起见都称为“SCA”反应产生下式的SCA免疫共轭物:
其中n为正整数。
上述方法显示了产生具有氨基甲酸酯键的异双功能的活化碳酸酯。本领域技术人员可以认识到活化酯可被用于该方法的初始阶段从而形成酰胺键。
本领域技术人员可以认识到根据本发明方法制备的共轭物可以增加单个或多个聚合物单位由此根据所选择的方法产生相同的或无规聚合物亚基的重复由此获得所需的共轭物。
不管选择的路径如何,由本发明描述的合成技术产生的一些优选的化合物包括:
其中B以及B’为离去基团,活性剂,生物活性剂,诊断剂等,并且SCA为单链抗体。
其它的优选的化合物包括:
治疗方法
本发明的另一方面提供了治疗哺乳动物各种病征的方法。该方法包括给需要这种治疗的哺乳动物施用如本发明所述制备的有效量的本发明的异双官能聚合组合物。该组合物可用于治疗哺乳动物的瘤性病,降低肿瘤重量,预防肿瘤的转移以及预防肿瘤生长的复发。
化合物的施用量将依赖于其中包含的母体分子,例如肽,多肽,蛋白,酶,小分子药物等。通常,用于该治疗方法的化合物的量为可以有效实现哺乳动物所希望治疗结果的量。天然地,各种化合物的剂量将根据母体化合物,体内水解的速率,聚合物的分子量等改变。本领域技术人员将根据临床经验以及治疗指标确定所选化合物的最佳剂量。实际的剂量对于技术人员而言无需过多试验就显而易见。
本发明的化合物可以包含在一或者多种适合的药物组合物中用于施用于哺乳动物。药物组合物可以根据本领域已知的方法制备成溶液,悬浮液,片剂,胶囊等的形式。同样施用这种组合物可以根据技术人员的需要通过口服和/或肠胃外路径进行。例如可以通过任一本领域已知的方法,例如静脉内,肌内,皮下注射等将组合物的溶液和/或悬浮液作为注射或者渗透组合物的载体介质。
这种施用也可以通过注入身体间隙或者空腔以及通过吸入和/或鼻内途径进行。然而,在本发明的优选方面,化合物通过肠胃外途径施用于需要的哺乳动物。
实施例
下列实施例用来提供对本发明更进一步的认识,但是并不意味着以任何方式限制本发明的有效范围。在实施例中加下划线以及黑体的数字对应于流程图1到9中显示的数字。
一般流程
所有的反应再干氮或者氩气的气体条件下进行。商业试剂的使用不经更进一步的纯化。所有的PEG化合物在真空下或者在使用之前从甲苯通过共沸蒸馏进行干燥。利用Varian Mercury300 NMR波谱仪获得NMR波谱并且将氘化氯仿作为溶剂,除非另作说明。化学位移(δ)用从四甲基硅烷(TMS)开始的向下场移动的百万分之一(ppm)表示。
HPLC法.通过具有多波长UV检测器,采用ZOBAX300 SB C-8反相柱(150×4.6mm)或者Phenomenex Jupiter300A C18反相柱(150×4.6mm)的Beckman Coulter System Gold高压液相色谱仪,利用30-90%乙腈的0.5%三氟乙酸(TFA)梯度,以1mL/min的流速监控反应混合物以及中间体和最终产品的纯度。
化合物3.在室温下搅拌1(0.623g,0.180mmol),2(0.623g,0.180mmol),和N,N-二甲基氨基吡啶(DMAP,0.110g,0.90mmol)的二氯甲烷(DCM,20mL)溶液12小时。用0.1N HCl(2×20mL)洗涤溶液,干燥(MgSO4),过滤,在减压下除去溶剂,并且从异丙醇(IPA,25mL)结晶产生3(0.910g,0.134mmol,74.3%)。13C NMR(67.8MHz,CDCl3)δ171.91,155.79,155.30,66.15,63.32,40.34,39.91,34.26,28.02。
化合物4.在室温下搅拌3(0.707g,0.104mmol)的DCM/三氟乙酸(TFA)(8mL∶4mL)溶液3.5小时。在减压下除去溶剂并用乙醚洗涤产生的固体产生4(0.707g).104mmol,约100%)。13C NMR(67.8MHz,CDCl3)δ172.18,155.94,66.62,66.32,63.49,40.49,39.71,34.46.
化合物5.向在0℃冷却15分钟的3(0.910g,0.134mmol),2-巯噻唑(2-MT,0.0319g,0.268mmol)以及DMAP(0.032.7g,0.268mmol)的DCM(15mL)的溶液中添加1-[3-(二甲基氨基)-丙基]-3-乙基碳二亚胺盐酸盐(EDC,0.0513g,0.268mmol)并且逐渐将反应溶液温热到室温然后搅拌12小时。用乙醚沉淀PEG衍生物,通过过滤收集,并从IPA(19mL)结晶产生5(0.820g,0.121mmol,90.0%)。13C NMR(67.8MHz,CDCl3)δ200.94,171.73,155.85,155.36,65.75,63.37,55.54,40.37,39.94,38.73,28.08.
化合物6.向4(0.668g,0.098mmol)的DCM(15mL)溶液中添加DMAP调节pH到7.0。添加化合物5(0.677g,0.098mmol)并在室温下搅拌反应混合物12小时。用0.1N HCl(2×20mL)洗涤溶液,干燥(MgSO4),过滤,在减压下除去溶剂并从异丙醇(IPA,25mL)结晶残余物产生6(1.053g,0.077mmol,79.0%)。13C NMR(67.8MHz,CDCl3)δ171.97,170.72,155.87,155.36,66.83,66.24,63.39,40.40,39.99,38.74,36.50,34.34,28.08.
化合物8.向在0℃冷却15分钟的6(0.616g,0.045mmol),20-(6)-喜树碱丙氨酸三氟乙酸盐(0.0706g,0.136mmol)以及DMAP(0.111g,0.906mmol)的DCM(10mL)溶液中添加EDC(0.026g,0.136mmol),并将反应溶液温热到室温。搅拌12小时后,用0.1N HCl(2×20mL)洗涤溶液,干燥(MgSO4),过滤,并在减压下除去溶剂,从异丙醇(IPA,13mL)结晶残余物产生8(0.536g,0.038,85.0%)。13C NMR(67.8MHz,CDCl3)δ171.09,170.83,170.63,166.48,156.82,155.99,151.82,148.46,146.01,144.98,130.77,130.12,129.40,128.06,127.77,127.58,119.72,95.58,66.97,66.77,63.57,49.74,47.56,40.55,40.14,38.90,36.70,36.41,31.48,28.22,17.58,7.40.
化合物9.在室温下搅拌8(0.536g,0.038mmol)的DCM/TFA(8mL∶4mL)的溶液2小时。在减压下除去溶剂并用乙醚洗涤残余物产生9(0.536g,0.038mmol,约100%)。13C NMR(67.8MHz,CDCl3)δ170.99,170.81,170.60,166.25,156.58,155.79,151.56,148.19,145.79,144.79,130.71,129.92,129.12,127.91,127.63,127.37,119.46,95.44,66.71,66.54,63.34,49.59,47.45,40.34,39.59,38,78,36.34,36.08,31.24,17.24,7.20.
化合物11.向9(0.818g,0.059mmol)的DCM(15mL)的溶液中添加DMAP调节pH到7.0,然后添加10并将溶液冷却到0℃。向反应中添加1,3-二异丙基碳二亚胺(DIPC,0.0554μL,0.354mmol)并将混合物温热到室温搅拌12小时。用0.1N HCl(2×20mL)洗涤溶液,干燥(MgSO4),过滤,在减压下除去溶剂,并且从异丙醇(IPA,16mL)结晶残余物产生11(0.65g,0.046mmol,78%)。13C NMR(67.8MHz,CDCl3)δ172.22,171.10,170.84,170.60,170.32,166.48,156.83,155.99,151.82,148.48,146.04,144.98,133.70,130.76,130.13,129.43,128.06,127.78,127.60,119.75,95.56,66.99,66.77,63.58,49.74,47.56,40.57,38.92,37.39,36.72,36.43,36.05,31.48,28.08,26.17,25.18,24.86,17.30,7.40.
化合物12.A.还原蛋白CC49:在37℃,向pH 7.8的28mg(2.79mg/ml)的CC49的100mM磷酸钠,2mM EDTA溶液中添加2mMDTT,并进行反应2小时。通过用100mM磷酸钠,pH 6.5,以及2mMEDTA的溶液平衡的脱盐柱除去DTT。还原蛋白的终浓度为0.39mg/ml(约23mg,约60ml,83%)。
B.PEGylation:将CC49以及11以1∶10摩尔比在100mM磷酸钠,pH 6.5,2mM EDTA的溶液中混合并在25℃反应2小时。
C.纯化CC49-PEG-CPT:用HOAc将反应溶液的pH值调节到5,并且添加水(约200mL)降低溶液的导电率到小于2mS并且以5mL/min将混合物上样到Poros HS柱上。通过1M NaCl的10mM磷酸钠溶液洗脱产品并且合并蛋白峰值的级分并且利用30k Centriplus离心管进行浓缩。用盐水透析浓缩的样品并且分析有效成分。碘染色试验发现在产品中无非蛋白共轭连接的PEG。
化合物13.在室温下搅拌6(4.50g,0.335mmol)的DCM/TFA(30mL∶15mL)的溶液3.5小时。然后在减压下除去溶剂并用乙醚洗涤产生的固体产生13(4.30g,0.320mmol,95.6%)。13CNMR(67.8MHz,CDCl3)δ171.59,155.58,66.36,65.89,63.02,40.05,39.36,38.61,35.85,33.96.
化合物14.向13(4.30g,0.320mmol)的DCM(50mL)的溶液中添加DMAP到pH 7.0。然后添加化合物5(2.20g,0.320mmol)并且在室温下搅拌反应混合物12小时。用0.1N HCl(2×30mL)洗涤溶液,干燥(MgSO4),过滤,在减压下除去溶剂,并且从异丙醇(IPA,25mL)结晶残余物产生14(5.30g,0.260mmol,81.2%)。13C NMR(67.8MHz,CDCl3)δ171.77,170.60,155.75,66.73,66.12,63.28,40.29,39.86,38.66,36.41,34.19,27.99.
化合物15.在室温下搅拌14(5.30g,0.260mmol)的DCM/TFA(30mL∶15mL)溶液3.5小时。然后在减压下除去溶剂并用乙醚洗涤产生的固体产生15(5.30g,0.260mmol,约100%)。13CNMR(67.8MHz,CDCl3)δ171.77,170.60,155.75,66.73,66.12,63.28,40.29,39.86,38.66,36.41,34.19.
化合物18.向冷却到0℃15分钟的若丹明B碱(1.00g,2.09mmol),甘氨酸叔丁基酯盐酸盐(0.670g,4.0mmol)以及DMAP(0.767g,8.0mmol)的DCM(30mL)溶液中添加EDC(0.767g,4.0mmol)。反应混合物温热到室温并搅拌12小时。用0.1N HCl(2×30mL)洗涤溶液,干燥(MgSO4),过滤,在减压下除去溶剂并且通过利用己烷和乙酸乙酯(3∶2,v/v)作为洗脱溶剂的硅胶柱层析纯化残余物产生18(0.937g,1.58mmol,76%)。13C NMR(67.8MHz,CDCl3)δ167.30,166.73,153.06,153.01,148.36,132.05,130.60,129.31,127.63,123.46,122.67,107.64,104.69,97.21,80.80,64.74,44.10,42.03,27.63,12.41.
化合物19.在室温下搅拌18(0.937g,1.58mmol)的DCM/TFA(16mL∶8mL)的溶液2小时。在减压下除去溶剂并通过乙醚洗涤产生的残余物产生19(0.930g,1.57mmol,约100%)。
13C NMR(67.8MHz,CDCl3)δ169.30,167.83,152.72,152.15,144.14,133.09,130.28,128.83,123.64,123.41,112.32,103.89,64.69,48.47,41.49,11.44.
化合物20.向在0℃冷却15分钟的19(0.421g,0.785mmol),2-MT(0.140g,1.18mmol)和DMAP(0.287g,2.30mmol)的DCM(15mL)的溶液中添加EDC(0.226g,1.18mmol)并且将反应溶液逐渐地温热到室温然后搅拌12小时。用0.1N HCl(2×20mL)洗涤溶液,干燥(MgSO4),过滤,在减压下除去溶剂产生20(0.450g,0.706mmol,90%)。13C NMR(67.8MHz,CDCl3)δ200.68,168.90,167.73,153.27,152.07,148.10,139.66,132.47,130.20,129.39,127.94,123.63,122.85,108.19,98.14,65.11,55.77,51.31,45.68,44.68,33.67,29.09,12.53.
化合物21.向15(2.7g,0.134mmol)的DCM溶液中添加DMAP将pH调节到7。添加化合物20(171mg,0.268mmol)并且在室温下搅拌反应混合物12小时。用0.1N HCl洗涤反应混合物,在减压下蒸发溶剂,并且从IPA结晶固体产生21(2.3g,0.112mmol,84%)。13CNMR(67.8MHz,CDCl3)δ201.00,170.78,167.73,155.88,152.86,148.80,132.51,129.86,128.06,127.87,123.59,122.53,108.14,98.09,66.86,63.45,55.57,44.37,43.99,40.43,38.80,38.54,36.57,34.32,28.10,12.18.
化合物22.向在0℃冷却的21(2.3,0.112mmol),2-MT(0.027g,0.224mmol)以及DMAP(0.027g,0.224mmol)的DCM(15mL)溶液中添加EDC(0.043g,0.224mmol)。将反应溶液逐渐温热到室温并搅拌12小时。用乙醚沉淀PEG衍生物,过滤并且从IPA结晶产生22(2.0g,0.097mmol,86%)。13C NMR(67.8MHz,CDCl3)δ200.00,171.70,170.64,167.96,167.68,155.79,152.86,148.24,132.38,129.86,127.84,127.72,123.55,122.38,104.12,97.47,66.80,63.37,55.51,44.91,40.37,38.72,38.44,36.50,28.08,12.26.
化合物23.回流22(2.0g,0.097mmol),3,5-二甲基-4-羟基苄基醇(0.059g,0.388mmol)以及DMAP(0.048g,0.388mmol)的DCM(10mL)溶液12小时。用乙醚沉淀PEG衍生物,过滤并且从IPA结晶产生23(1.9g,0.096mmol,99%)δ170.40,168.40,167.64,167.38,155.59,152.65,148.01,132.13,129.66,129.11,127.66,126.16,123.31,122.14,107.48,103.99,97.26,66.88,63.34,43.70,40.15,38.52,38.25,36.26,34.37,15.76,12.07.
化合物24.向冷却到0℃的23(1.9g,0.097mmol)以及N,N’-二琥珀酰亚氨基碳酸酯(0.199g,0.775mmol)DCM(20mL)以及DMF(2mL)溶液中添加吡啶(0.063μL,0.775mol)。将反应溶液逐渐温热到室温并搅拌12小时。用乙醚沉淀PEG衍生物,过滤并且从IPA结晶产生24(1.58g,0.075mmol,77%)。
13C NMR(67.8MHz,CDCl3)δ171.22,170.49,168.35,168.05,167.73,167.47,155.65,152.71,148.07,132.24,129.69,128.09,127.72,123.39,122.23,107.53,104.02,97.30,66.65,63.19,43.77,40.22,38.57,38.31,36.22,34.43,24.89,15.79,12.13.
化合物25.以30∶1(PEG∶GFP)的摩尔比将活化的PEG接头24添加到GFP(2mg/ml)的0.05M HEPES,pH 7.8溶液中。在25℃,N2下搅拌溶液45分钟,通过添加pH 6.4,到50mM的终浓度的磷酸钠缓冲液降低溶液的pH。在Superdex 200Hiload 16/60柱(AmershamPharmacia Biotech,Piscataway,NJ)上利用Biocad灌注层析工作站除去游离的PEG。洗脱缓冲液由10mM磷酸钠,pH 6.8以及150mM NaCl组成。收集在280nm以及荧光段显示出吸光度的级分并利用ultrafree-15离心滤器装置用30k NMWL膜(Millipore Corp.,Bedford,MA)浓缩。通过在489nm的UV利用55,000cm-1M-1的消光系数确定PEG-GFP(25)的浓度。
化合物27.向6,26以及DMAP的DCM溶液中添加EDC并在室温下搅拌溶液12小时。在减压下除去溶剂并且从IPA结晶固体产生27。通过13C NMR确定27的结构。
化合物28.在室温下搅拌27的DCM/TFA溶液12小时。在减压下除去溶剂并且从IPA结晶固体产生28。通过13C NMR确定28的结构。
化合物29.向在0℃冷却15分钟的10,2-MT,以及DMAP的DCM溶液中添加EDC并且将反应溶液逐渐温热到室温然后搅拌2小时。通过0.1N HCI洗涤溶液,干燥(MgSO4),并在减压下除去溶剂产生29。通过13C NMR确定29的结构。
化合物30.在室温下搅拌28,29以及DMAP的DCM溶液12小时。在减压下除去溶剂并且从IPA结晶固体产生30。通过13C NMR确定30的结构。
化合物31.向在0℃冷却15分钟的30,7以及DMAP的DCM溶液中添加EDC并且将反应溶液温热到室温。搅拌12小时后,用0.1NHCl洗涤溶液,干燥(MgSO4),过滤,在减压下除去溶剂,并从IPA结晶残余物产生31。通过13C NMR确定31的结构。
Claims (39)
1.下式(I)的化合物:
其中:X1-X6独立地为O,S或NR1;
R44和R44’为独立地选择的聚环氧烷;
R1选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,芳烷基,以及C3-8取代的环烷基;
R40-43独立地选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,C3-8取代的环烷基,芳基,取代的芳基,芳烷基,C1-6杂烷基,取代的C1-6杂烷基,C1-6烷氧基,苯氧基以及C1-6杂烷氧基;
Y,p,y’和p’独立地为零或者正整数;
n和n’独立地为0或者正整数;
a和b独立地为零或者正整数,条件是a+b大于或等于2;
z为正整数;
D1和D2独立地选自B,OH,离去基团,活化基团以及端基;并且
B选自生物学活性部分,诊断剂以及OH。
2.权利要求1的化合物,其中所述端基选自:
其中:
Y1-6独立地选自O,S或NR1;
R1′选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,芳烷基,以及C3-8取代的环烷基;
R2-8独立地选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,C3-8取代的环烷基,芳基,取代的芳基,芳烷基,C1-6杂烷基,取代的C1-6杂烷基,C1-6烷氧基,苯氧基以及C1-6杂烷氧基;
Ar为形成多取代的芳烃或多取代的杂环基团的部分;
L1-2为独立选择的双功能接头;
e以及f’为独立选择的正整数;
c,c’以及e’独立地为零或正整数;
d,f以及d’独立地为零或一;以及
B’选自离去基团,活化基团,OH,生物学活性部分以及诊断剂。
4.权利要求1的化合物,其中:
X1-X4独立地为O或NR1;
X5-X6均为O;
R1选自氢,C1-6烷基,以及C16取代的烷基;
Y,p,y’和p’独立地为0或1和18之间的整数;
n以及n’独立地为1以及100之间的整数;以及
a和b为独立选择的1和20之间的整数。
5.权利要求1的化合物,其中:
X1-X4独立地为NR1;
X5-X6均为O;
R44以及R44’各自为-(CH2-CH2-O)-;
R1为氢或甲基;
y以及y’各自为0,1或2;
p以及p’各自为1;
n以及n’为独立选择的70以及80之间的整数;
a和b为独立选择的5和10之间的整数;以及
D1以及D2独立地选自OH,卤素,靶向剂,药物,酶,蛋白,治疗活性化合物,染料,螯合剂以及同位素标记的化合物。
7.权利要求6的化合物,其中所述离去基团选自卤素,N-羟基琥珀酰亚氨基;所述生物学活性部分选自靶向剂,药物,肽,蛋白,酶,寡核苷酸,类固醇,脂质;并且所述诊断剂选自绿色荧光蛋白(GFP),染料,螯合剂以及同位素标记的化合物。
8.权利要求1的化合物,其中n和n’为独立选择的正整数,从而使得重量平均分子量为从约4,000到约270,000Da。
9.权利要求1的化合物,其中n和n’为独立选择的正整数,从而使得重量平均分子量为从约6,800到约130,000Da。
10.权利要求1的化合物,其中n和n’为独立选择的正整数,从而使得重量平均分子量为从约6,800到约38,000Da。
11.权利要求1的化合物,其中所述离去基团选自卤素,活化的碳酸酯,羰基咪唑,环亚胺硫酮,异氰酸酯,N-羟基琥珀酰亚氨基,对-硝基酚,N-羟基苯邻二甲酰亚胺,N-羟基苯并三唑基,咪唑,甲苯磺酸酯。
12.权利要求2的化合物,其中B’选自马来酰亚胺以及含羟基或者含胺化合物的残基。
13.权利要求12的化合物,其中B’选自蒽环素,柔红霉素,阿霉素;p-羟基苯胺芥末黄,胞嘧啶,阿糖胞苷,吉西他汀,喜树碱,万古霉素,paullone,紫杉醇,顺氯氨铂,长春新碱,长春花碱。
16.权利要求1的化合物,选自:
17.权利要求1的化合物,包括下式:
其中:
Y7-9独立地为O或NR1”;
R1”为氢或甲基;
R9-18独立地为氢或C1-6烷基;
L3-4为独立选择的双功能接头;
Q选自主动运输进入靶细胞的部分,疏水部分,双功能的连接部分以及其组合;
l,k,m以及o为独立选择的正整数;
j以及h独立地为零或一;
g,以及i各自为一;
q为零或一;
B’选自离去基团,活化基团,OH,生物学活性部分以及诊断剂;
D10以及D11独立地选自OH,卤素,靶向剂,药物,酶,蛋白,治疗活性化合物,染料,螯合剂,同位素标记的化合物或者一起形成下式的端基:
其中:
Y7-9独立地选自O,S或NR1”;
R1”为氢或甲基;
R9-18独立地选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,C3-8取代的环烷基,芳基,取代的芳基,芳烷基,C1-6杂烷基,取代的C1-6杂烷基,C1-6烷氧基,苯氧基以及C1-6杂烷氧基;
L3-4为独立选择的双功能接头;
Q选自主动运输进入靶细胞的部分,疏水部分,双功能的连接部分以及其组合;
l,k,m以及o独立地为正整数;
j以及h独立地为零或正整数;
g,i以及q独立地为零或一;以及
B’选自离去基团,活化基团,OH,生物学活性部分以及诊断剂;
18.权利要求17的化合物,包括下式:
20.权利要求17的化合物,其中B′选自马来酰亚胺以及含羟基或含胺化合物的残基。
21.权利要求19的化合物,其中B′选自蒽环素,柔红霉素,阿霉素,p-羟基苯胺芥末黄,胞嘧啶,阿糖胞苷,吉西他汀,喜树碱,万古霉素,paullone,紫杉醇,顺氯氨铂,长春新碱,长春花碱。
22.制备聚合共轭物的方法,包括:
a)将式(i)的化合物与式(ii)的化合物在足以形成下式(iii)的条件下进行反应:
式(i)中:
A1为活化基团;
T为保护基;
X1,X3以及X5独立地为O,S或NR1;
R44为聚环氧烷;
R1选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,芳烷基,以及C3-8取代的环烷基;
R40-41独立地选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,C3-8取代的环烷基,芳基,取代的芳基,芳烷基,C1-6杂烷基,取代的C1-6杂烷基,C1-6烷氧基,苯氧基以及C1-6杂烷氧基;
n为1或正整数;
y为零或正整数;
t为正整数;以及
p为零或一;
在式(ii)中:
X4以及X2独立地为O,S或NR1;
R44′为聚环氧烷;
R1选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,芳烷基以及C3-8取代的环烷基;
R42-43独立地选自氢,C1-6烷基,C3-12支链烷基,C3-8环烷基,C1-6取代的烷基,C3-8取代的环烷基,芳基,取代的芳基,芳烷基,C1-6杂烷基,取代的C1-6杂烷基,C1-6烷氧基,苯氧基以及C1-6杂烷氧基;
n’为正整数;
y’为零或正整数;
t’为正整数;以及
p’为零或一。
23.权利要求22的方法,进一步包括对式(iii)的化合物去保护。
25.权利要求22的方法,其中t以及t′为独立选择的从1到约30的整数。
28.权利要求27的方法,其中D2为端基并且所述端基被进一步活化并且与生物学活性部分或诊断剂反应。
29.权利要求26的方法,其中活化基团A3与生物学活性部分,诊断剂或端基进一步反应。
30.权利要求26的方法,其中所述生物学活性部分选自靶向部分,药物,肽,蛋白,多肽,寡核苷酸,类固醇,脂质以及酶。
31.权利要求26的方法,其中所述诊断剂选自染料,螯合剂以及同位素标记的化合物。
32.权利要求27的方法,其中所述生物学活性部分选自靶向部分,药物,肽,蛋白,多肽,寡核苷酸,类固醇,脂质以及酶。
33.权利要求26的方法,其中所述诊断剂选自染料,螯合剂以及同位素标记的化合物。
34.权利要求28的方法,其中所述生物学活性部分选自靶向部分,药物,肽,蛋白,多肽,寡核苷酸,类固醇,脂质以及酶。
35.权利要求28的方法,其中所述诊断剂选自染料,螯合剂以及同位素标记的化合物。
36.权利要求27的方法,其中所述端基被进一步活化并且与生物学活性部分或诊断剂反应。
37.权利要求36的方法,其中所述生物学活性部分选自靶向部分,药物,肽,蛋白,多肽,寡核苷酸,类固醇,脂质以及酶。
38.权利要求36的方法,其中所述诊断剂选自染料,螯合剂以及同位素标记的化合物。
39.治疗哺乳动物的方法,包括给需要这种治疗的哺乳动物施用有效量的权利要求1的化合物,其中至少D1以及D2之一为B,并且B为生物学活性部分的残基。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107759671A (zh) * | 2017-09-11 | 2018-03-06 | 昆明理工大学 | 水相中合成万古霉素手性功能单体的方法 |
CN107805303A (zh) * | 2016-09-07 | 2018-03-16 | 四川大学 | 具有氧化还原敏感性的靶向聚合物及其载药胶束的制备方法和用途 |
Families Citing this family (72)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003037915A1 (en) * | 2001-10-31 | 2003-05-08 | Biopolymed Inc. | Biocompatible polymers including peptide spacer |
US7122189B2 (en) | 2002-08-13 | 2006-10-17 | Enzon, Inc. | Releasable polymeric conjugates based on aliphatic biodegradable linkers |
US7413738B2 (en) | 2002-08-13 | 2008-08-19 | Enzon Pharmaceuticals, Inc. | Releasable polymeric conjugates based on biodegradable linkers |
US7087229B2 (en) * | 2003-05-30 | 2006-08-08 | Enzon Pharmaceuticals, Inc. | Releasable polymeric conjugates based on aliphatic biodegradable linkers |
US7332164B2 (en) * | 2003-03-21 | 2008-02-19 | Enzon Pharmaceuticals, Inc. | Heterobifunctional polymeric bioconjugates |
ES2725808T3 (es) * | 2003-05-23 | 2019-09-27 | Nektar Therapeutics | Derivados de PEG que contienen dos cadenas de PEG |
US7947261B2 (en) | 2003-05-23 | 2011-05-24 | Nektar Therapeutics | Conjugates formed from polymer derivatives having particular atom arrangements |
JP2006282653A (ja) * | 2005-03-10 | 2006-10-19 | Kyoto Univ | 標的部位で選択的に活性化される新規化合物およびその利用 |
GB2427360A (en) * | 2005-06-22 | 2006-12-27 | Complex Biosystems Gmbh | Aliphatic prodrug linker |
US7601798B2 (en) * | 2005-10-04 | 2009-10-13 | Enzon Pharmaceuticals, Inc. | Methods of preparing polymers having terminal amine groups using protected amine salts |
CN101534643A (zh) * | 2006-09-15 | 2009-09-16 | 安佐制药股份有限公司 | 用于递送寡核苷酸的基于位阻酯的生物可降解连接体 |
JP2010503705A (ja) * | 2006-09-15 | 2010-02-04 | エンゾン ファーマスーティカルズ インコーポレイテッド | ヒンダードエステル系の生分解性リンカーを有するポリアルキレンオキサイド |
EP2164524B1 (en) * | 2007-05-30 | 2013-08-07 | Children's Medical Center Corporation | Fluorine-18 labeled rhodamine derivatives for myocardial perfusion imaging with positron emission tomography |
WO2009012288A2 (en) * | 2007-07-17 | 2009-01-22 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Trifunctional imaging agent for monoclonal antibody tumor-targeted imaging |
JP5731385B2 (ja) * | 2008-08-22 | 2015-06-10 | バクスター・インターナショナル・インコーポレイテッドBaxter International Incorp0Rated | ポリマーベンジルカルボネート誘導体 |
CN103079598B (zh) | 2010-04-02 | 2015-12-16 | 药物影像股份有限公司 | 罗丹明(rhodamine)染料的单一同分异构结合物 |
CN102212191B (zh) * | 2011-04-19 | 2012-08-22 | 复旦大学 | 一种端氨基聚醚及其连续化制备方法 |
US9283279B2 (en) | 2011-05-11 | 2016-03-15 | Ramot At Tel-Aviv University Ltd. | Targeted polymeric conjugates and uses thereof |
DE102011118029A1 (de) | 2011-06-20 | 2012-12-20 | Universität Leipzig | Modifizierte antibiotische Peptide mit variabler systemischer Freisetzung |
JP6482471B2 (ja) | 2012-12-21 | 2019-03-13 | バイオアライアンス コマンディテール フェンノートシャップ | 親水性の自壊性リンカー及びそのコンジュゲート |
CN103923310B (zh) * | 2013-01-11 | 2018-03-02 | 张雅珍 | 一种接枝蒽环类抗生素的树枝状聚合物的制备和用途 |
MY174813A (en) | 2013-03-15 | 2020-05-16 | Zymeworks Inc | Cytotoxic and anti-mitotic compounds, and methods of using the same |
US11103593B2 (en) | 2013-10-15 | 2021-08-31 | Seagen Inc. | Pegylated drug-linkers for improved ligand-drug conjugate pharmacokinetics |
CA2935077C (en) | 2013-12-27 | 2022-03-15 | Geoffrey C. Winters | Sulfonamide-containing linkage systems for drug conjugates |
US9950077B2 (en) | 2014-06-20 | 2018-04-24 | Bioalliance C.V. | Anti-folate receptor alpha (FRA) antibody-drug conjugates and methods of using thereof |
DK3194421T3 (da) | 2014-09-17 | 2022-02-14 | Zymeworks Inc | Cytotoksiske og antimitotiske forbindelser samt fremgangsmåder til anvendelse heraf |
AU2016363013B2 (en) | 2015-12-04 | 2022-03-10 | Seagen Inc. | Conjugates of quaternized tubulysin compounds |
US11793880B2 (en) | 2015-12-04 | 2023-10-24 | Seagen Inc. | Conjugates of quaternized tubulysin compounds |
PL3400019T3 (pl) | 2016-01-08 | 2023-01-23 | Ascendis Pharma Growth Disorders A/S | Proleki cnp z przyłączeniem nośnika w ugrupowaniu pierścieniowy |
WO2017118707A1 (en) | 2016-01-08 | 2017-07-13 | Ascendis Pharma Growth Disorders A/S | Controlled-release cnp agonists with reduced side-effects |
EP3400020A1 (en) | 2016-01-08 | 2018-11-14 | Ascendis Pharma Growth Disorders A/S | Cnp prodrugs with large carrier moieties |
CA3007982C (en) | 2016-01-08 | 2023-12-19 | Ascendis Pharma Growth Disorders A/S | Controlled-release cnp agonists with low initial npr-b activity |
US10472422B2 (en) | 2016-01-08 | 2019-11-12 | Abgenomics International Inc. | Tetravalent anti-PSGL-1 antibodies and uses thereof |
SG11201805026SA (en) | 2016-01-08 | 2018-07-30 | Ascendis Pharma Growth Disorders As | Controlled-release cnp agonists with low npr-c binding |
IL293979B1 (en) | 2016-01-08 | 2024-04-01 | Ascendis Pharma Growth Disorders As | Controlled-release CNP agonists with increased NEP stability |
SG11201806092TA (en) | 2016-03-01 | 2018-08-30 | Ascendis Pharma Bone Diseases As | Pth prodrugs |
AU2017237186A1 (en) | 2016-03-25 | 2018-11-01 | Seagen Inc. | Process for the preparation of PEGylated drug-linkers and intermediates thereof |
EP3484523A1 (en) | 2016-07-13 | 2019-05-22 | Ascendis Pharma A/S | Conjugation method for carrier-linked prodrugs |
MA46428A (fr) | 2016-09-29 | 2019-08-07 | Ascendis Pharma Bone Diseases As | Schéma posologique incrémentiel dans des composés de pth à libération contrôlée |
SG10202111952PA (en) | 2016-09-29 | 2021-12-30 | Ascendis Pharma Growth Disorders As | Combination therapy with controlled-release cnp agonists |
US11590207B2 (en) | 2016-09-29 | 2023-02-28 | Ascendis Pharma Bone Diseases A/S | Dosage regimen for a controlled-release PTH compound |
KR102611820B1 (ko) | 2016-09-29 | 2023-12-07 | 아센디스 파마 본 디지즈 에이/에스 | 낮은 피크 대 트로프 비를 가진 pth 화합물 |
SG10202107829YA (en) | 2017-03-22 | 2021-08-30 | Genentech Inc | Hydrogel cross-linked hyaluronic acid prodrug compositions and methods |
US11730822B2 (en) | 2017-03-24 | 2023-08-22 | Seagen Inc. | Process for the preparation of glucuronide drug-linkers and intermediates thereof |
AU2019246390A1 (en) | 2018-03-28 | 2020-08-06 | Ascendis Pharma A/S | Conjugates |
JP2021519336A (ja) | 2018-03-28 | 2021-08-10 | アセンディス ファーマ オンコロジー ディヴィジョン エー/エス | Il−2コンジュゲート |
MX2020012179A (es) | 2018-05-18 | 2021-01-29 | Ascendis Pharma Bone Diseases As | Dosis inicial de conjugados de hormona paratiroidea (pth). |
AU2019350376A1 (en) | 2018-09-26 | 2021-03-18 | Ascendis Pharma A/S | Treatment of infections |
MX2021003184A (es) | 2018-09-26 | 2021-08-11 | Ascendis Pharma As | Hidrogeles de acido hialuronico degradables. |
SG11202101971XA (en) | 2018-09-26 | 2021-03-30 | Ascendis Pharma As | Novel hydrogel conjugates |
US20220062273A1 (en) | 2019-01-04 | 2022-03-03 | Ascendis Pharma Oncology Division A/S | Conjugates of pattern recognition receptor agonists |
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WO2020165087A1 (en) | 2019-02-11 | 2020-08-20 | Ascendis Pharma Bone Diseases A/S | Liquid pharmaceutical formulations of pth conjugates |
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WO2020254617A1 (en) | 2019-06-21 | 2020-12-24 | Ascendis Pharma Oncology Division A/S | Anti-ctla4 compounds with localized pk properties |
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AU2020295725A1 (en) | 2019-06-21 | 2021-12-02 | Ascendis Pharma Oncology Division A/S | Anti-CTLA4 conjugates |
WO2020254613A1 (en) | 2019-06-21 | 2020-12-24 | Ascendis Pharma Oncology Division A/S | Controlled-release tyrosine kinase inhibitor compounds with localized pk properties |
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JP2023527919A (ja) | 2020-06-03 | 2023-06-30 | アセンディス ファーマ オンコロジー ディヴィジョン エー/エス | Il-2配列及びその使用 |
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AU2022246997A1 (en) | 2021-04-01 | 2023-09-28 | Ascendis Pharma A/S | Use of long-acting growth hormone for treating inflammation-induced diseases |
CA3230895A1 (en) | 2021-09-22 | 2023-03-30 | Kennett Sprogoe | Long-acting pth compound treatments |
WO2023110727A2 (en) | 2021-12-13 | 2023-06-22 | Ascendis Pharma Oncology Division A/S | Novel cancer treatments with tlr7/8 agonists |
WO2023110758A1 (en) | 2021-12-13 | 2023-06-22 | Ascendis Pharma Growth Disorders A/S | Effective doses of cnp conjugates |
WO2023227505A1 (en) | 2022-05-23 | 2023-11-30 | Ascendis Pharma Growth Disorders A/S | Liquid pharmaceutical formulations of cnp compounds |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU4272793A (en) * | 1993-04-24 | 1994-11-21 | Korea Research Institute Of Chemical Technology | Novel quinolone carboxylic acid derivatives and process for preparing the same |
US5919455A (en) | 1993-10-27 | 1999-07-06 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
KR19990029749A (ko) * | 1997-09-17 | 1999-04-26 | 미우라 아끼라 | 2가 반응성 수용성 고분자 유도체 및 이들을 함유하는 복합체 |
US6448369B1 (en) | 1997-11-06 | 2002-09-10 | Shearwater Corporation | Heterobifunctional poly(ethylene glycol) derivatives and methods for their preparation |
EP1040151A4 (en) | 1997-12-12 | 2003-05-21 | Macromed Inc | HETEROFUNCTIONALIZED STAR POLYETHYLENEGLYCOLS USED TO MODIFY A PROTEIN |
JP4465109B2 (ja) * | 1997-12-17 | 2010-05-19 | エンゾン ファーマシューティカルズ,インコーポレーテッド | アミノ及びヒドロキシル含有生物活性剤のポリマープロドラッグ |
US6180095B1 (en) * | 1997-12-17 | 2001-01-30 | Enzon, Inc. | Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents |
EP1041976B1 (en) * | 1997-12-23 | 2006-04-05 | Inex Pharmaceuticals Corp. | Polyamide oligomers |
US6320017B1 (en) | 1997-12-23 | 2001-11-20 | Inex Pharmaceuticals Corp. | Polyamide oligomers |
US6251382B1 (en) | 1998-04-17 | 2001-06-26 | Enzon, Inc. | Biodegradable high molecular weight polymeric linkers and their conjugates |
JP2000302864A (ja) * | 1999-02-19 | 2000-10-31 | Hokushin Ind Inc | アミドエステルアルコール、ポリアミド組成物及びその製造方法 |
US6669951B2 (en) * | 1999-08-24 | 2003-12-30 | Cellgate, Inc. | Compositions and methods for enhancing drug delivery across and into epithelial tissues |
US6629995B1 (en) * | 2000-03-31 | 2003-10-07 | Super Gen, Inc. | Camptothecin conjugates |
TW593427B (en) | 2000-12-18 | 2004-06-21 | Nektar Therapeutics Al Corp | Synthesis of high molecular weight non-peptidic polymer derivatives |
US20020161052A1 (en) * | 2001-02-20 | 2002-10-31 | Choe Yun Hwang | Terminally-branched polymeric linkers and polymeric conjugates containing the same |
DK1362053T3 (da) * | 2001-02-20 | 2008-03-10 | Enzon Inc | Terminalt forgrenede polymere linkere og polymere konjugater indeholdende disse |
DK1379257T3 (da) * | 2001-03-23 | 2009-12-14 | Enzon Inc | Anticancer-profarmakon anvendende substituerede aromatiske syrer |
US20030003048A1 (en) | 2001-04-26 | 2003-01-02 | Chun Li | Diagnostic imaging compositions, their methods of synthesis and use |
US7087229B2 (en) * | 2003-05-30 | 2006-08-08 | Enzon Pharmaceuticals, Inc. | Releasable polymeric conjugates based on aliphatic biodegradable linkers |
US7122189B2 (en) * | 2002-08-13 | 2006-10-17 | Enzon, Inc. | Releasable polymeric conjugates based on aliphatic biodegradable linkers |
WO2004044222A2 (en) * | 2002-11-12 | 2004-05-27 | Enzon Pharmaceuticals, Inc. | Polymeric prodrugs of vancomycin |
AU2003295432A1 (en) * | 2002-11-12 | 2004-06-03 | Enzon Pharmaceuticals, Inc. | Prodrugs of vancomycin with hydrolysis resistant polymer linkers |
US7332164B2 (en) * | 2003-03-21 | 2008-02-19 | Enzon Pharmaceuticals, Inc. | Heterobifunctional polymeric bioconjugates |
SG170618A1 (en) * | 2003-04-13 | 2011-05-30 | Enzon Pharmaceuticals Inc | Polymeric oligonucleotide prodrugs |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107805303A (zh) * | 2016-09-07 | 2018-03-16 | 四川大学 | 具有氧化还原敏感性的靶向聚合物及其载药胶束的制备方法和用途 |
CN107805303B (zh) * | 2016-09-07 | 2020-04-14 | 四川大学 | 具有氧化还原敏感性的靶向聚合物及其载药胶束的制备方法和用途 |
CN107759671A (zh) * | 2017-09-11 | 2018-03-06 | 昆明理工大学 | 水相中合成万古霉素手性功能单体的方法 |
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RU2361596C2 (ru) | 2009-07-20 |
US7332164B2 (en) | 2008-02-19 |
RU2005132471A (ru) | 2006-03-10 |
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AU2004223952B2 (en) | 2009-07-02 |
JP2006523256A (ja) | 2006-10-12 |
KR20050109595A (ko) | 2005-11-21 |
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CA2517459C (en) | 2012-10-02 |
MXPA05010118A (es) | 2006-03-08 |
NZ542138A (en) | 2009-01-31 |
CA2517459A1 (en) | 2004-10-07 |
TW200501941A (en) | 2005-01-16 |
EP1605953A2 (en) | 2005-12-21 |
JP5350586B2 (ja) | 2013-11-27 |
US20080076792A1 (en) | 2008-03-27 |
FI20050932A0 (fi) | 2005-09-19 |
WO2004085386A3 (en) | 2004-12-23 |
US8618124B2 (en) | 2013-12-31 |
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