CN114450324B - 具有肽连接子的异双官能单分散聚乙二醇 - Google Patents
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Abstract
本发明提供一种具有肽连接子被细胞内的酶分解而缓释药物且有效遮蔽药物疏水性的相邻的两条单分散聚乙二醇侧链的异双官能单分散聚乙二醇,以及使用异双官能单分散聚乙二醇使抗体与药物结合而成的抗体‑药物复合体。一种异双官能单分散聚乙二醇,其如式(1)所示:
Description
技术领域
本发明涉及一种具有肽连接子和两个不同的可化学反应的官能团的异双官能单分散聚乙二醇。更详细地,涉及一种具有肽连接子和两个不同的可化学反应的官能团的异双官能单分散聚乙二醇,其用于修饰生理活性蛋白、肽、抗体、核酸和低分子药物等生物功能分子、药物递送系统中的药物载体、诊断用材料或医疗器械等,特别是对修饰抗体药物很有用。
背景技术
抗体-药物复合体(Antibody-Drug Conjugate;ADC)是一种使抗体与药物结合的抗体药物,其目的在于利用抗体的抗原特异性将药物主动输送至患病部位,近年来,是癌症治疗领域中发展最快的技术之一。ADC由抗体、药物以及使抗体与药物结合的连接子的各部分构成。
用于ADC的药物多为疏水性,如果多个这些疏水性药物结合于抗体来制备ADC,则有因药物的疏水性导致发生凝聚或抗体在血液中的稳定性下降的问题。因此,每个抗体能加载的药物数量有限,结果有可能无法充分获得ADC的药效。
对于该问题,研究的解决方法之一是利用亲水性连接子。作为亲水性连接子,使用聚乙二醇、亲水性肽、糖链等,特别是由于聚乙二醇的抗原性低、生物适应性高,因此目前在临床试验和临床前试验阶段的多个ADC中得到采用。
ADC领域中,出于保证ADC的均一性,便于纯化、分析和药物审批申请的目的,使用含有90%以上的具有特定乙二醇链长的成分的化合物。这样的化合物称为单分散聚乙二醇。
在将单分散聚乙二醇用作ADC的连接子时,由于需要区别抗体与药物而结合,所以利用具有两个不同的可化学反应的官能团的异双官能单分散聚乙二醇。通常,使用在单分散聚乙二醇链的两末端具有互不相同的可化学反应的官能团的化合物来制备ADC。
然而,近年来,已报告了一种ADC,其不使用将单分散聚乙二醇作为连接抗体和药物的连接子主链,且在连接抗体和药物的分枝连接子引入单分散聚乙二醇作为侧链而成。
在非专利文献1中,报告了:使用单分散聚乙二醇作为连接抗体和药物的连接子主链的ADC与在连接抗体和药物的分枝连接子使用单分散聚乙二醇作为侧链的ADC的药物动力学和治疗效果相比较,后者的ADC对药物的疏水性遮蔽(masking)的效果高,表现出优异的药物动力学和治疗效果。
另外,在专利文献1和专利文献2中,公开了具有单分散聚乙二醇作为分枝连接子的侧链的各种类型的ADC,以及用于制备这些ADC的中间体。
另外,在专利文献3中,公开了一种在四分枝骨架中在季碳原子结合两条单分散聚乙二醇,在分枝中2个末端具有两种官能团的异双官能单分散聚乙二醇,以及使用该异双官能单分散聚乙二醇的ADC。
现有技术文献
专利文献
专利文献1:国际公开第2015/057699号单行本
专利文献2:国际公开第2016/063006号单行本
专利文献3:国际公开第2018/181059号单行本
非专利文献
非专利文献1:Nature Biotechnology,2015,33,733-735
发明内容
发明所要解决的课题
在专利文献1和专利文献2中,还公开了在分枝连接子的侧链具有两条以上的单分散聚乙二醇的ADC。但是,各自的单分散聚乙二醇侧链的结合位置分离,且作为具有多条聚乙二醇链的分枝型聚乙二醇的特征的“伞状(umbrella-like)”结构(Biomaterials 2001,22(5),405-417)所带来的疏水性药物的遮蔽效果较小,不能有效利用具有多条单分散聚乙二醇侧链的优点。
另外,在非专利文献1和专利文献3中,公开了在分枝连接子侧链中具有单分散聚乙二醇的分枝型单分散聚乙二醇和将其用于抗体与药物的结合的ADC。但是,该ADC被摄入到细胞内后,抗体被细胞内的酶分解,但形成该单分散聚乙二醇结合于药物的状态,药物活性可能会降低,因此不优选。
本发明涉及一种抗体和药物通过具有肽连接子和单分散聚乙二醇侧链的连接子连接而成的抗体-药物复合体。即,本发明的课题是提供一种具有肽连接子被细胞内的酶分解而缓释药物且有效遮蔽药物疏水性的相邻的两条单分散聚乙二醇侧链的异双官能单分散聚乙二醇,以及使用异双官能单分散聚乙二醇使抗体与药物结合而成的抗体-药物复合体。
用以解决课题的手段
为了解决上述问题,本发明人反复进行了深入研究,结果开发出一种具有被细胞内的酶分解的肽连接子、且两条单分散聚乙二醇侧链相邻而结合的异双官能化合物即异双官能单分散聚乙二醇,以及使用该异双官能单分散聚乙二醇使抗体与药物结合而成的抗体-药物复合体。
进一步地,本发明的异双官能单分散聚乙二醇由于两条单分散聚乙二醇侧链通过稳定的醚键结合于分枝部分的季碳原子,因此在该异双官能单分散聚乙二醇结构的化学转变过程中,具有难以分解为单链单分散聚乙二醇的特征。
另外,本发明的异双官能单分散聚乙二醇由于具有被细胞内的酶分解的肽连接子,因此能够使药物有效地缓释在细胞内,具有不会对细胞内的药物活性产生影响的特征。
即,本发明如下所示:
[1]一种异双官能单分散聚乙二醇,其如式(1)所示:
[化1]
(式(1)中,X1和Y1分别为至少含有与生物功能分子中存在的官能团反应而形成共价键的官能团的原子团,原子团X1所含的所述官能团与原子团Y1所含的所述官能团互不相同;
R1是碳原子数为1~7的烃基或氢原子;
n是3~72的整数;
A1表示-L1-(CH2)m1-L2-、-L1-(CH2)m1-L2-(CH2)m2-、酰胺键、氨基甲酸酯键、仲氨基或单键,m1和m2各自独立地表示1~5的整数;
B1表示-CH2-L3-、-CH2-L3-(CH2)m3-L4-或-CH2-L3-(CH2)m3-L4-(CH2)m4-,m3和m4各自独立地表示1~5的整数;
W是2~4个残基的寡肽;
Z是具有与肽的C末端结合的双官能对氨基苄醇基的间隔基;
a1和a2在a1=1时是a2=0,在a1=0时是a2=1;
b是0或1;
C1表示-L5-(CH2)m5-、-L5-(CH2)m5-L6-(CH2)m6-、酰胺键或单键,m5和m6各自独立地表示1~5的整数;
L1~L6各自独立地表示醚键、氨基甲酸酯键、酰胺键、仲氨基、羰基或单键。)
[2]根据[1]所述的异双官能单分散聚乙二醇,其中,W包含苯丙氨酸、亮氨酸、缬氨酸、异亮氨酸的疏水性中性氨基酸中的至少一种,且除此之外的氨基酸是由不包括半胱氨酸的中性氨基酸组成的2~4个残基的寡肽。
[3]根据[1]所述的异双官能单分散聚乙二醇,其中,W包含苯丙氨酸、亮氨酸、缬氨酸、异亮氨酸的疏水性中性氨基酸中的至少一种,且除此之外的氨基酸是具有丙氨酸、甘氨酸、瓜氨酸、脯氨酸、丝氨酸、天冬酰胺中的至少一种的2~4个残基的寡肽。
[4]根据[1]所述的异双官能单分散聚乙二醇,其中,W是C末端氨基酸为甘氨酸的寡肽。
[5]根据[1]所述的异双官能单分散聚乙二醇,其中,W是二肽。
[6]根据[1]~[5]中任一项所述的异双官能单分散聚乙二醇,其中,式(1)中的X1和Y1分别独立地选自式(a)、式(b1)、式(b2)、式(c)、式(d1)、式(d2)、式(e)、式(f)、式(g)、式(h)、式(i)、式(j)、式(k)、式(l)、式(m)、式(n)和式(o)构成的组:
[化2]
(式(d1)、(d2)中,R2是氢原子或碳原子数为1~5的烃基;式(e)中,R3是选自氯原子、溴原子和碘原子的卤素原子;以及,式(l)中,R4是氢原子或碳原子数为1~5的烃基。)
[7]一种含有异双官能单分散聚乙二醇而成的抗体-药物复合体,其如式(2)所示:
[化3]
(式(2)中,X2与Y2中的一个为抗体,另一个为药物;
R1是碳原子数为1~7的烃基或氢原子;
n是3~72的整数;
A2表示-L1-(CH2)m1-L7-、-L1-(CH2)m1-L8-、-L1-(CH2)m1-L2-(CH2)m2-L8-或-L8-,m1和m2各自独立地表示1~5的整数;
B2表示-CH2-L9-、-CH2-L9-(CH2)m3-L10-、-CH2-L9-(CH2)m3-L10-(CH2)m4-L11-、-CH2-L12-、-CH2-L9-(CH2)m3-L12-或-CH2-L9-(CH2)m3-L10-(CH2)m4-L12-,m3和m4各自独立地表示1~5的整数;
L1和L2各自独立地表示醚键、氨基甲酸酯键、酰胺键、仲氨基或单键;
L7、L9、L10和L11各自独立地表示醚键、氨基甲酸酯键、酰胺键、仲氨基或羰基;
L8和L12表示酰胺键、氨基甲酸酯键、马来酰亚胺与硫醇的键、硫醚键、二硫键、碳酸酯键、酯键、醚键、1H-1,2,3-三唑-1,4-二基结构、仲氨基、酰肼基、氧酰胺基或含有这些的烃基或单键;
W是2~4个残基的寡肽;
Z是具有与肽的C末端结合的双官能对氨基苄醇基的间隔基;
a3和a4在X2为药物时是a3=1且a4=0,在Y2为药物时是a3=0且a4=1;
b是0或1;以及
C2表示酰胺键、氨基甲酸酯键、马来酰亚胺与硫醇的键、硫醚键、二硫键、碳酸酯键、酯键、醚键、1H-1,2,3-三唑-1,4-二基结构、仲氨基、酰肼基、氧酰胺基或含有这些的烃基。)
[8]根据[7]所述的抗体-药物复合体,其中,W包含苯丙氨酸、亮氨酸、缬氨酸、异亮氨酸的疏水性中性氨基酸中的至少一种,且除此之外的氨基酸是由不包括半胱氨酸的中性氨基酸组成的2~4个残基的寡肽。
[9]根据[7]所述的抗体-药物复合体,其中,W包含苯丙氨酸、亮氨酸、缬氨酸、异亮氨酸的疏水性中性氨基酸中的至少一种,且除此之外的氨基酸是具有丙氨酸、甘氨酸、瓜氨酸、脯氨酸、丝氨酸、天冬酰胺中的至少一种的2~4个残基的寡肽。
[10]根据[7]所述的抗体-药物复合体,其中,W是C末端氨基酸为甘氨酸的寡肽。
[11]根据[7]所述的抗体-药物复合体,其中,W是二肽。
发明效果
本发明的异双官能单分散聚乙二醇由于两条单分散聚乙二醇侧链通过稳定的醚键结合于分枝部分的季碳原子,因此在化学转变过程中难以分解为单链单分散聚乙二醇。因此,通过使用该异双官能单分散聚乙二醇使抗体与药物结合,可以得到均质性高的抗体-药物复合体。
进一步地,该异双官能单分散聚乙二醇由于两条单分散聚乙二醇侧链相邻而结合,因此在制备抗体-药物复合体时,对疏水性药物的遮蔽效果很大,能够抑制因药物的疏水性导致发生凝聚、抗体在血液中的稳定性下降。
进一步,该异双官能单分散聚乙二醇由于含有被细胞内的酶分解的肽连接子,因此在细胞内从药物切断连接子部位,能够使药物有效缓释在细胞内。
附图说明
图1表示实施例10的式(20)的化合物的实施例37中的分解性试验前后的HPLC测定结果。
图2表示实施例37的分解性试验后的来自式(20)的化合物的分解物的质谱图。
图3表示比较例2的式(44)的化合物的实施例37中的分解性试验前后的HPLC测定结果。
图4表示实施例11的式(21)的化合物的实施例38中的分解性试验前后的HPLC测定结果。
图5表示实施例38的分解性试验后的来自式(21)的化合物的分解物的质谱图。
图6表示实施例16的式(26)的化合物的实施例38中的分解性试验前后的HPLC测定结果。
图7表示实施例30的式(40)的化合物的实施例39中的分解性试验前后的HPLC测定结果。
图8表示实施例39的分解性试验后的来自式(40)的化合物的分解物的质谱图。
图9表示比较例4的式(46)的化合物的实施例39中的分解性试验前后的HPLC测定结果。
图10表示实施例40的分解性试验后的来自式(42)的化合物的分解物的质谱图。
图11表示绘制使用式(40)和式(46)的药物-连接子化合物的实施例41的细胞毒性试验中的各样品浓度的细胞存活率的图表。
图12表示绘制使用式(42)和式(46)的药物-连接子化合物的实施例42的细胞毒性试验中的各样品浓度的细胞存活率的图表。
具体实施方式
下面,详细说明本发明。
本说明书中的“异双官能”是指具有两个不同的可化学反应的官能团,“单分散聚乙二醇”是指含有90%以上的具有特定乙二醇链长的成分的化合物,“连接子”是指使抗体与药物共价结合的或含碳链的化学位点。
本发明的异双官能单分散聚乙二醇如式(1)所示:
[化4]
本发明的式(1)中的R1是碳原子数为1~7的烃基或氢原子,作为具体的烃基,可举出:甲基、乙基、丙基、异丙基、叔丁基、苯基和苄基等。作为R1的优选的实施方式,是甲基或氢原子,进一步优选为甲基。
本发明的式(1)中的n表示单分散聚乙二醇的重复单元数,为3~72的整数,优选为4~48的整数,进一步优选为6~36的整数,特别优选为8~24的整数。
本说明书中,式(1)中的原子团X1和Y1互不相同,只要是至少含有与作为该异双官能单分散聚乙二醇的修饰对象的生物功能分子(生理活性蛋白、肽、抗体、核酸和低分子药物等)中存在的官能团反应而形成共价键的官能团的原子团,就没有特别限制。作为上述官能团的例子,可举出:“Hermanson,G.T.Bioconjugate Techniques,2nd ed.;AcademicPress:San Diego,CA,2008”、“Harris,J.M.Poly(Ethylene Glycol)Chemistry;PlenumPress:New York,1992”和“PEGylated Protein Drugs:Basic Science and ClinicalApplications;Veronese,F.M.,Ed.;Birkhauser:Basel,Switzerland,2009”等中记载的官能团。
其中,X1和Y1中所含的官能团各自独立地优选为能够在温和的反应条件且以高反应效率与在以蛋白质为代表的天然生物功能分子中存在的官能团(氨基、硫醇基、醛基、羧基等)或能够人工引入到上述生物功能分子中的官能团(马来酰亚胺基、酮基、叠氮基、炔基等)进行反应的官能团。更具体地,优选活性酯基、活性碳酸酯基、醛基、异氰酸酯基、异硫氰酸酯基、环氧基、马来酰亚胺基、乙烯基砜基、丙烯酰基、磺酰氧基、羧基、硫醇基、2-吡啶基二硫基、α-卤代乙酰基、羟基、炔基、烯丙基、乙烯基、氨基、氧氨基、酰肼基、叠氮基和二苯并环辛炔(DBCO)基,若进一步考虑到反应效率,则优选活性酯基、活性碳酸酯基、马来酰亚胺基、α-卤代乙酰基、炔基、叠氮基和二苯并环辛炔(DBCO)基,更优选活性酯基、活性碳酸酯基和马来酰亚胺基。
更具体地,在作为修饰对象的生物功能分子中存在的官能团为氨基时,X1和Y1中所含的官能团各自独立地是活性酯基、活性碳酸酯基、醛基、异氰酸酯基、异硫氰酸酯基、环氧基、马来酰亚胺基、乙烯基砜基、丙烯酰基、磺酰氧基或羧基,在作为修饰对象的生物功能分子中存在的官能团为硫醇基时,是活性酯基、活性碳酸酯基、醛基、异氰酸酯基、异硫氰酸酯基、环氧基、马来酰亚胺基、乙烯基砜基、丙烯酰基、磺酰氧基、羧基、硫醇基、2-吡啶基二硫基、α-卤代乙酰基、炔基、烯丙基或乙烯基,在作为修饰对象的生物功能分子中存在的官能团为醛基或羧基时,是硫醇基、羟基、氨基、氧氨基或酰肼基,在作为修饰对象的生物功能分子中存在的官能团为炔基时,是硫醇基或叠氮基,在作为修饰对象的生物功能分子中存在的官能团为叠氮基时,是炔基和二苯并环辛炔基,在作为修饰对象的生物功能分子中存在的官能团为卤代烷基、烷基磺酸酯或芳基磺酸酯时,是硫醇基、羟基或氨基。
此处,所谓“活性酯基”表示由式:-C(=O)-E表示的被活性化的羧基,E表示离去基团。作为由E表示的离去基团,可举出:琥珀酰亚胺基氧基、邻苯二甲酰亚胺基氧基、4-硝基苯氧基、1-咪唑基、五氟苯氧基、苯并三唑-1-基氧基和7-氮杂苯并三唑-1-基氧基等,优选琥珀酰亚胺基氧基和4-硝基苯氧基。所谓“活性碳酸酯基”表示由式:-O-C(=O)-E表示的被活性化的碳酸酯基,E表示与上述相同的离去基团。
在本发明的优选的实施方式中,X1和Y1各自独立地是组(I)、组(II)、组(III)、组(IV)、组(V)或组(VI)所示的基团。
组(I):能够与生物功能分子的氨基反应而形成共价键的官能团
下述的(a)、(b1)、(b2)、(c)、(d1)、(d2)、(e)和(f);
组(II):能够与生物功能分子的硫醇基反应而形成共价键的官能团
下述的(a)、(b1)、(b2)、(c)、(d1)、(d2)、(e)、(f)、(g)、(h)和(l);
组(III):能够与生物功能分子的醛基或羧基反应而形成共价键的官能团
下述的(g)、(i)、(j)、(k)和(o);
组(IV):能够与生物功能分子的炔基反应形成共价键的官能团
下述的(g)、(i)、(j)、(k)和(n);
组(V):能够与生物功能分子的叠氮基反应而形成共价键的官能团
下述的(l)和(m);
组(VI):能够与生物功能分子的卤代烷基、烷基磺酸酯或芳基磺酸酯反应形成共价键的官能团
下述的(g)、(i)和(o)。
[化5]
式中,R2、R4是氢原子或碳原子数为1~5的烃基,作为具体的烃基,可举出:甲基、乙基、丙基、异丙基、丁基、叔丁基和戊基等。R3是选自氯原子、溴原子和碘原子的卤素原子。
作为式(1)中的原子团X1和Y1中所含的官能团的优选组合,当X1中所含的官能团是活性酯基或活性碳酸酯基时,Y1中所含的官能团是选自马来酰亚胺基、乙烯基砜基、α-卤代乙酰基、炔基和叠氮基的基团;当X1中所含的官能团是醛基时,Y1中所含的官能团是选自马来酰亚胺基、乙烯基砜基、炔基和叠氮基的基团;当X1中所含的官能团是马来酰亚胺基、乙烯基砜基或α-卤代乙酰基时,Y1中所含的官能团是选自活性酯基、活性碳酸酯基、炔基、叠氮基的基团;当X1中所含的官能团是炔基或叠氮基时,Y1中所含的官能团是选自马来酰亚胺基、乙烯基砜基、α-卤代乙酰基、活性酯基、活性碳酸酯基、氨基、氧氨基和羟基的基团;当X1中所含的官能团是氨基或氧氨基时,Y1中所含的官能团是炔基、叠氮基、硫醇基、羟基或羧基;当X1中所含的官能团是硫醇基、2-吡啶基二硫基或羟基时,Y1是选自氨基、氧氨基、叠氮基和羧基的基团。更优选地,当X1中所含的官能团是活性酯基或活性碳酸酯基时,Y1中所含的官能团是选自马来酰亚胺基、α-卤代乙酰基、炔基和叠氮基的基团;当X1中所含的官能团是醛基时,Y1中所含的官能团是选自马来酰亚胺基、α-卤代乙酰基、炔基和叠氮基的基团;当X1中所含的官能团是马来酰亚胺基或α-卤代乙酰基时,Y1中所含的官能团是选自活性酯基、活性碳酸酯基、炔基、叠氮基的基团;当X1中所含的官能团是炔基或叠氮基时,Y1中所含的官能团是选自马来酰亚胺基、α-卤代乙酰基、活性酯基、活性碳酸酯基、氨基、氧氨基和羟基的基团;当X1中所含的官能团是氨基或氧氨基时,Y1中所含的官能团是炔基、叠氮基、羟基或硫醇基;当X1中所含的官能团是硫醇基、2-吡啶基二硫基或羟基时,Y1中所含的官能团是选自氨基、氧氨基和叠氮基的基团。
式(1)中的W是被细胞内的溶酶体酶特异性切断的分解性连接子。这样的连接子例如是以肽为基本的结构。溶酶体酶仅在细胞内的溶酶体的低pH环境下被活性化,因此分解性肽连接子通常具有良好的血液中稳定性。药物从抗体的释放通过溶酶体酶例如组织蛋白酶和质粒的作用而特异性发生。这些酶有时以高水平存在于某种肿瘤组织中。在某种实施方式中,连接子可以被溶酶体酶切断,作为该溶酶体酶的例子,可举出组织蛋白酶B等。
式(1)中的W只要是在生物体内的血液中稳定且被细胞内的酶分解的2~4个残基的寡肽,就没有特别限制,但为了在制备抗体-药物复合体时最大限度遮蔽药物的疏水性,抑制因药物的疏水性导致的凝聚,优选使用含有亲水性更高的氨基酸的寡肽。在某种实施方式中,由于更长的肽为疏水性,因此相比于更长的肽,更优选二肽。
另一方面,作为溶酶体酶的组织蛋白酶B具有有效地水解疏水性高的氨基酸的寡肽的性质(Vieira Portaro,F.C.et al.Biochem.J.2000,347:123-129、Cezari,M.H.S.etal.Biochem.J.2002,368:365-369)。因此,式(1)中的W是亲水性指数为2.5以上的疏水性中性氨基酸,具体地,优选为具有苯丙氨酸、亮氨酸、缬氨酸、异亮氨酸中的至少一种的2~4个残基的寡肽,进一步优选为具有缬氨酸或苯丙氨酸的2~4个残基的寡肽。由Kyte和Doolittle制作的定量表示氨基酸的疏水性的亲水性指数(hydropathy index),其值越大,越表示是疏水性的氨基酸(Kyte J&Doolittle RF,1982,J Mol Biol,157:105-132.)。
作为可与上述的疏水性氨基酸组合的氨基酸,式(1)中的W优选是由XLogP3计算的LogP值小于-2.5的中性氨基酸,具体地,优选为具有丙氨酸、甘氨酸、瓜氨酸、脯氨酸、丝氨酸、天冬酰胺中的至少一种的2~4个残基的寡肽,进一步优选为具有丙氨酸、甘氨酸、瓜氨酸中的至少一种的2~4个残基的寡肽。此处,“LogP”是被定义为辛醇/水的分配系数的对数,是作为疏水性指标的值,其值越小越表示是亲水性。此外,“XlogP3”是指由Cheng等人制作的用于计算LogP值的方法(Cheng,T.et al.J Chem Inf Model.2007,47:2140-2148)。
而且,式(1)中的W优选为作为C末端氨基酸具有甘氨酸的2~4个残基的寡肽。在使C末端的羧基反应时,基本上需要用缩合剂等将C末端的羧基活性化。已知在该活性化工序中,在除甘氨酸之外的氨基酸中容易引起差向异构化,并复制立体异构体。通过将寡肽的C末端氨基酸作为非手性甘氨酸,能够得到不副产立体异构体的高纯度目的物。
另外,式(1)中的W优选为在侧链具有氨基或羧基的氨基酸,具体地为由不含赖氨酸、天冬酰胺酸、谷氨酸的氨基酸构成的2~4个残基的寡肽。在本发明的式(1)中的异双官能单分散聚乙二醇的合成中,在聚乙二醇部分引入寡肽时,将寡肽的N末端的氨基或C末端的羧基利用于反应。但是,如果在寡肽中含有在侧链具有氨基或羧基的氨基酸时,聚乙二醇部分不仅产生目标N末端的氨基或C末端的羧基,而且产生还被引入到侧链的氨基或羧基的杂质。该杂质难以通过通常的萃取或晶析等纯化工序除去,因此为了得到高纯度的目的物,理想的是使用由在侧链不具有氨基或羧基的氨基酸组成的寡肽。此处,所使用的氨基酸是α-氨基酸,而且基本上是L型。
进一步,作为中性氨基酸的半胱氨酸具有硫醇基,与其他硫醇基形成二硫键,因此式(1)中的W优选为由不包含半胱氨酸的氨基酸组成的寡肽。
式(1)中的W只要是在生物体内的血液中稳定且具有被细胞内的酶分解的性能、并由不包括半胱氨酸的中性氨基酸组成的2~4个残基的寡肽,就没有特别限制,作为具体的例子,是甘氨酸-苯丙氨酸-亮氨酸-甘氨酸、甘氨酸-甘氨酸-苯丙氨酸-甘氨酸、甘氨酸-苯丙氨酸-甘氨酸、甘氨酸-亮氨酸-甘氨酸、缬氨酸-瓜氨酸-甘氨酸、缬氨酸-丙氨酸-甘氨酸、缬氨酸-瓜氨酸、缬氨酸-丙氨酸、苯丙氨酸-甘氨酸等,优选为甘氨酸-苯丙氨酸-亮氨酸-甘氨酸、甘氨酸-甘氨酸-苯丙氨酸-甘氨酸、缬氨酸-瓜氨酸-甘氨酸、缬氨酸-丙氨酸-甘氨酸、缬氨酸-瓜氨酸、缬氨酸-丙氨酸、苯丙氨酸-甘氨酸,更优选为缬氨酸-瓜氨酸、缬氨酸-丙氨酸、或苯丙氨酸-甘氨酸,进一步更优选为缬氨酸-瓜氨酸。
式(1)中的Z是进一步从由W表示的肽连接子被酶切断的部位分离药物的自分解性间隔基。在药物与肽连接子直接结合时,在肽连接子切断时药物中残留有肽连接子部分,有可能导致药物活性降低。通过使用自分解性间隔基,可以在酰胺键水解时释放不含肽连接子的药物。
自分解性间隔基之一是双官能性的对氨基苄醇基,该基团经由氨基与肽连接而形成酰胺键,而具有氨基或羟基的药物经由氨基甲酸酯键或碳酸酯键,可与该连接子的苄醇基结合(产生对氨基苄基氨基甲酸酯或对氨基苄基碳酸酯)。得到的前药在肽-连接子间的酰胺键切断时被活性化,引起1,6-消除反应,释放不含肽连接子的药物、二氧化碳和连接子基的残余部分。此外,该基团仅在肽连接子的C末端侧的酰胺键被切断时引起消除反应,释放不含肽连接子的药物,因此肽连接子的C末端位于单分散聚乙二醇侧,如果肽连接子的C末端不在药物侧,则并不总是必要的。以下的方案图示了对酰胺苄基氨基甲酸酯或对酰胺苄基碳酸酯的片段化和药物的释放:
[化6]
(式中,X-D表示不含肽连接子的药物。)
式(1)的b为0或1。当b为0时,不含由式(1)中的Z表示的自分解性间隔基,当b为1时,包含由式(1)中的Z表示的自分解性间隔基。
本发明的式(1)中的A1是分枝部分的季碳原子与W或X1之间的2价间隔基,式(1)中的B1是分枝部分的季碳原子与W或Y1之间的2价间隔基,式(1)中的C1是Z与X1或Y1之间的2价间隔基,分别由共价键构成。
具体地,A1表示-L1-(CH2)m1-L2-、-L1-(CH2)m1-L2-(CH2)m2-、酰胺键、氨基甲酸酯键、仲氨基或单键,优选为-L1-(CH2)m1-L2-、-L1-(CH2)m1-L2-(CH2)m2-、酰胺键、仲氨基,进一步优选为-L1-(CH2)m1-L2-(CH2)m2-、酰胺键、仲氨基。式中的m1和m2分别独立地为1~5的整数。
另外,B1表示-CH2-L3-、-CH2-L3-(CH2)m3-L4-或-CH2-L3-(CH2)m3-L4-(CH2)m4-,优选为-CH2-L3-或-CH2-L3-(CH2)m3-L4-。式中的m3和m4分别独立地为1~5的整数。
进一步地,C1表示-L5-(CH2)m5-、-L5-(CH2)m5-L6-(CH2)m6-、酰胺键或单键,优选为单键。式中的m5和m6分别独立地为1~5的整数。
上式中的L1~L6分别独立地为2价间隔基,具体地为醚键、氨基甲酸酯键、酰胺键、仲氨基、羰基或单键。
进一步地,L1和L2分别独立地优选为氨基甲酸酯键、酰胺键或仲氨基,L3优选为醚键、氨基甲酸酯键或单键,L4优选为酰胺键、氨基甲酸酯键、仲氨基、羰基或单键,L5优选为氨基甲酸酯键,L6优选为酰胺键、氨基甲酸酯键或仲氨基。
本发明中的式(1)的a1和a2表示式(1)中有无由-W-(Z)b-C1-表示的间隔基部位,在某种实施方式中,在a1=1时是a2=0,在某种其他实施方式中,在a1=0时是a2=1。
以下说明本发明的优选的实施方式中的式(1)的异双官能单分散聚乙二醇的典型合成例子,但本发明并不限于这些合成例。
(A)本发明的优选的实施方式中的式(1)的异双官能单分散聚乙二醇,例如可以用以下的工序来制造。
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(式(3)中,P1为氨基的保护基团;以及P2为羟基的保护基团。)
在无水溶剂中在强碱存在下,使上式(3)所示的化合物与单甲基单分散聚乙二醇的烷基或芳基磺酸酯、或者单甲基单分散聚乙二醇的卤化物进行亲核取代反应,得到下式(4)所示的化合物。
此处,“保护基团”是指在某一反应条件下,防止或阻止分子中的特定官能团反应的成分。保护基团根据被保护的官能团的种类、所使用的条件和分子中的其他官能团或保护基团的存在而变化。保护基团的具体例子可以在很多普通书籍中找到,例如记载于“Wuts,P.G.M.;Greene,T.W.Protective Groups in Organic Synthesis,4th ed.;Wiley-Interscience:New York,2007”中。此外,被保护基团保护的官能团通过使用适于各个保护基团的反应条件进行脱保护、即进行化学反应,由此可以使原来的官能团再生。保护基团的代表性的脱保护条件记载于上述文献中。
作为被保护的官能团与保护基团的优选的组合,当被保护的官能团是氨基时,例如可举出酰基系保护基团和氨基甲酸酯系保护基团,具体地可举出:三氟乙酰基、9-芴基甲氧基羰基、叔丁基氧基羰基和2-(三甲基甲硅烷基)乙氧基羰基等。此外,当被保护的官能团是羟基时,例如可举出甲硅烷基系保护基团和酰基系保护基团,具体地可举出:叔丁基二苯基甲硅烷基、叔丁基二甲基甲硅烷基、三异丙基甲硅烷基、乙酰基和新戊酰基等。
当被保护的官能团是羧基时,例如可举出烷基酯系保护基团和甲硅烷基酯系保护基团,具体地可举出:甲基、9-芴甲基和叔丁基二甲基甲硅烷基等。当被保护的官能团是磺酰基时,例如可举出硫醚系保护基团、硫代碳酸酯系保护基团和二硫化物系保护基团,具体地可举出:S-2,4-二硝基苯基、S-9-芴基甲氧基羰基和S-叔丁基二硫化物基等。此外,可以使用能够同时保护同种或异种的两个官能团的双官能性的保护基团。作为被保护的官能团与保护基团的优选的组合,当被保护的官能团是两个羟基时,例如可举出环状缩醛系保护基团和环状甲硅烷基系保护基团,具体地可举出:2,2-二甲基-1,3-二氧戊环基、2,2-二甲基-1,3-二氧六环基、2-苯基-1,3-二氧戊环基、2-苯基-1,3-二氧六环基和二叔丁基亚甲硅烷基等。当被保护的官能团是氨基和羟基时,例如可举出噁唑啉保护基团,具体地可举出2-苯基噁唑啉基等。
保护基团的代表性的脱保护条件记载于上述文献中,可以选择适于各个保护基团的反应条件。然而,在结构中所含的官能团是即使未被保护基团保护也不抑制其他官能团的化学反应的官能团时,不需要使用保护基团。
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在将上式(4)所示化合物的保护基团P1脱保护后,在缩合剂存在下,使与N末端的氨基被保护基团P3保护的寡肽进行反应,得到下式(5)所示的化合物。此处,如果选择羟基不与氨基的反应试剂发生反应的反应条件,则也可与保护基团P1同时也使保护基团P2脱保护。此外,下式(5)中的肽是与上述W同义的寡肽。
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在将上式(5)所示化合物的保护基团P2脱保护后,在碱存在下,使用活性碳酸酯化试剂进行活性碳酸酯化,进一步通过活性碳酸酯与具有氨基的羧酸进行反应,得到下式(6)所示的化合物。
活性碳酸酯化试剂并没有特别限制,例如可举出对硝基氯甲酸苯酯或碳酸二(N-琥珀酰亚胺基)酯等。此外,下式(6)中的m3与上述同义。
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进一步地,通过使上式(6)所示的化合物的保护基团P3脱保护,得到下式(7)所示的化合物。
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另外,在本工序的优选的其他实施方式中,在将上式(5)所示的化合物的保护基团P2脱保护后,在强碱存在下,通过使羧酸被保护的丙烯酸酯进行反应,进一步使保护基团P3和羧酸的保护基团脱保护,得到下式(8)所示的化合物。此外,下式(8)中的m3与上述同义,只要反应中使用的丙烯酸酯是碳原子数满足m3的范围,没有特别限制,具体地,可使用丙烯酸叔丁酯等。
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(B)在本发明优选的其他实施方式中,式(1)的异双官能单分散聚乙二醇例如可以用以下的工序来制造。
在将上式(4)所示的化合物的保护基团P2脱保护后,在缩合剂存在下,通过使氨基被保护基团P4保护的羧酸进行反应,得到下式(9)所示的化合物。此外,下式(9)中的m1和m3与上述同义。
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在缩合剂存在下,通过使上式(9)所示的化合物与N末端的氨基无保护且在C末端缩合对氨基苄醇而成的寡肽衍生物进行反应后,使保护基团P4脱保护,得到下式(10)所示的化合物。此外,下式(10)中的肽与上述同义。
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上式(7)、(8)和(10)所示的化合物均具有1个氨基,利用该氨基能够转变为作为上述X1显示的官能团。
关于将上述异双官能单分散聚乙二醇末端的氨基转变为其他官能团的工序,没有特别限制,但基本上,通过使用具有可与氨基反应的活性酯基的化合物、或者酸酐、酰氯等通常的反应试剂,能够转变为各种官能团。
例如,在想要将上述异双官能单分散聚乙二醇末端的氨基转变为马来酰亚胺基的情况时,通过与以下的试剂进行反应,能够得到目的物。
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例如,在想要将上述异双官能单分散聚乙二醇末端的氨基转变为羧基的情况时,通过与琥珀酸酐或戊二酸酐进行反应,能够得到目的物。
例如,在想要将上述异双官能单分散聚乙二醇末端的氨基转变为羟基的情况时,通过与己内酯等环状酯的开环物进行缩合反应,能够得到目的物。
另外,上式(6)、(7)、(8)和(9)所示化合物均具有1个羧酸,上式(10)所示的化合物由于具有一个羟基,因此利用这些能够转变为作为上述Y1显示的官能团。
关于将上述异双官能单分散聚乙二醇末端的羧酸转变为其他官能团的工序,没有特别限制,例如,通过使可将羧酸转变为活性酯基的化合物、具体地为N-羟基丁二酰亚胺等试剂在缩合剂存在下进行反应,能够转变为各种官能团。
关于将上述异双官能单分散聚乙二醇末端的羟基转变为其他官能团的工序,没有特别限制,例如,通过使用可将羟基转变为活性碳酸酯基的化合物、具体地为对硝基氯甲酸苯酯或碳酸二(N-琥珀酰亚胺基)酯等活性碳酸酯化试剂,能够转变为各种官能团。
在本发明的另外一个方式中,提供一种含有异双官能单分散聚乙二醇而成的抗体-药物复合体,其如式(2)所示:
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本发明的式(2)中的R1是碳原子数为1~7的烃基或氢原子,作为具体的烃基,可举出甲基、乙基、丙基、异丙基、叔丁基、苯基和苄基等。作为R1的优选的实施方式,是甲基或氢原子,进一步优选为甲基。此外,式(2)中的R1与上述同义。
本发明的式(2)中的n表示单分散聚乙二醇的重复单元数,为3~72的整数,优选为4~48的整数,进一步优选为6~36的整数,特别优选为8~24的整数。此外,式(2)中的n与上述同义。
本说明书中,式(2)的X2和Y2中的一个为抗体,另一个为药物。
本发明的式(2)中的W、Z和b与上式(1)中的W、Z和b同义。
本发明的式(2)中的A2、B2和C2为二价间隔基,分别由共价键构成。
具体地,A2表示-L1-(CH2)m1-L7-、-L1-(CH2)m1-L8-、-L1-(CH2)m1-L2-(CH2)m2-L8-或-L8-,优选为-L1-(CH2)m1-L8-、-L1-(CH2)m1-L2-(CH2)m2-L8-或-L8-。此外,式中的L1、L2、m1和m2与上述同义。
另外,B2表示-CH2-L9-、-CH2-L9-(CH2)m3-L10-、-CH2-L9-(CH2)m3-L10-(CH2)m4-L11-、-CH2-L12-、-CH2-L9-(CH2)m3-L12-或-CH2-L9-(CH2)m3-L10-(CH2)m4-L12-,优选为-CH2-L9-(CH2)m3-L10-、-CH2-L9-(CH2)m3-L12-或-CH2-L9-(CH2)m3-L10-(CH2)m4-L12-,进一步优选为-CH2-L9-(CH2)m3-L10-或-CH2-L9-(CH2)m3-L12-。此外,式中的m3和m4与上述同义。
上式中的L7、L9、L10和L11分别独立地为醚键、氨基甲酸酯键、酰胺键、仲氨基或羰基。
进一步,L7和L11是在与上式(1)所示的W之间形成的键,分别独立地优选酰胺键或仲氨基,L9优选醚键或氨基甲酸酯键,L10优选氨基甲酸酯键、酰胺键或仲氨基。
另外,上式中的L8和L12分别在a3=0或a4=0时,是在上式(1)所示的异双官能单分散聚乙二醇的X1或Y1中所含的官能团与由X2或Y2表示的抗体中存在的官能团之间形成的原子团,具体地为酰胺键、氨基甲酸酯键、马来酰亚胺与硫醇的键、硫醚键、二硫键、碳酸酯键、酯键、醚键、1H-1,2,3-三唑-1,4-二基结构、仲氨基、酰肼基、氧酰胺基或含有这些的烃基或单键。
进一步地,C2在由W表示的肽连接子存在下,是在上式(1)所示的异双官能单分散聚乙二醇的X1或Y1中所含的官能团与抗体或药物中存在的官能团之间形成的原子团,具体地是酰胺键、氨基甲酸酯键、马来酰亚胺与硫醇的键、硫醚键、二硫键、碳酸酯键、酯键、醚键、1H-1,2,3-三唑-1,4-二基结构、仲氨基、酰肼基、氧酰胺基或含有这些的烃基。
本发明的式(2)中的a3和a4表示式(2)中有无由-W-(Z)b-C2-表示的间隔基部位,在X2为药物时是a3=1且a4=0,在Y2为药物时是a3=0且a4=1。
在本发明的具体的实施方式中,抗体-药物复合体(ADC)是由以下的式(I)表示的化合物或其盐,式中,Ab表示抗体,D表示药物,L表示由上式(1)所示的异双官能单分散聚乙二醇组成的连接子,k表示与抗体结合的连接子-药物偶联物(D-L)单元的数目。
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关于本发明中的抗体(Ab)、药物(D)、连接子(L)和连接子-药物偶联物(D-L)的结合方式,以及与ADC结合的药物数量的具体的实施方式,如下进行说明。
本说明书中使用的术语“抗体”是指以其最广泛的含义使用,具体地,只要表现出理想的生物学活性,就包括单克隆抗体、多克隆抗体、二聚体、多聚体、多特异性抗体(例如双特异性抗体)和抗体片段(Miller,K.et al.J.Immunol.2003,170,4854-4861)。
抗体可以是小鼠抗体、人抗体、人源化抗体、嵌合抗体或来源于其他物种。抗体是由免疫系统产生的蛋白,能够识别和结合特定抗原(Janeway,C.;Travers,P.;Walport,M.;Shlomchik,M.Immunobiology,5th ed.;Garlan Publishing:New York,2001)。靶抗原通常具有被位于多个抗体上的CDR识别的多个结合位点(也称为表位)。不同的表位特异性结合的抗体具有不同的结构。因此,某个抗原可以具有多于一个的对应抗体。抗体包括全长免疫球蛋白分子或全长免疫球蛋白分子的免疫学活性部分(即,包含与作为对象的抗原或其部分免疫特异性结合的抗原结合位点的分子)。作为这样的靶标,可举出:癌细胞或产生与自身免疫疾病相关的自身免疫抗体的细胞,但并不限定于这些。本说明书中公开的免疫球蛋白可以是任意的型(例如IgG、IgE、IgM、IgD和IgA)、类(例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或亚类的免疫球蛋白分子。上述免疫球蛋白可以来源于任意物种。但是,在一个方式中,上述免疫球蛋白是人源的、小鼠源的或兔源的。
多克隆抗体是来源于免疫化动物的血清等抗体分子的不均一集团。可以利用本领域中已知的各种步骤制作针对对象抗原的多克隆抗体。例如,为了制作多克隆抗体,可以通过注射对象抗原或其衍生物,对包括但不限于兔、小鼠、大鼠和豚鼠的各种宿主动物进行免疫。取决于宿主物种,可以使用包括但不限于弗氏(完全和不完全)佐剂、氢氧化铝等矿物凝胶、溶血卵磷脂等表面活性物质、普朗尼克(pluronic)多元醇、聚阴离子、肽、油乳化物、钥孔血蓝蛋白、二硝基苯酚和BCG(bacille Calmett-Guerin,卡介苗)和短小棒状杆菌(Corynebacteriumu parvum)等潜在有用的人佐剂的各种佐剂来增加免疫应答。这样的佐剂也是本领域所公知的。
单克隆抗体是针对特定的抗原决定基(例如细胞抗原(癌症或自身免疫细胞抗原)、病毒抗原、微生物抗原、蛋白质、肽、碳水化物、化学物质、核酸或它们的抗原结合片段)的抗体均一的集团。可以利用本领域中已知的任意技术制备针对对象抗原的单克隆抗体(mAb)。这些包括但不限于Kohler,G;Milstein,C.Nature 1975,256,495-497)最初记载的杂交瘤技术、人B细胞杂交瘤技术(Kozbor,D.et al.Immunol.Today 1983,4,72-79)和EBV-杂交瘤技术(Cole,S.P.C.et al.Monoclonal Antibodies and Cancer Therapy;AlanR.Liss:New York,1985,pp.77-96)。这样的抗体可以是包括IgG、IgM、IgE、IgA和IgD的任意免疫球蛋白的种类和它们的任意亚种。在本发明中产生单克隆抗体的杂交瘤可以在体外(in vitro)或体内(in vivo)培养。
单克隆抗体包括但不限于人单克隆抗体、人源化单克隆抗体、嵌合单克隆抗体和抗体片段。人单克隆抗体可以通过本领域已知的多种技术中的任意一种(例如参照Teng,N.N.et al.Proc.Natl.Acad.Sci.USA.1983,80,7308-7312、Kozbor,D.et al.ImmunologyToday 1983,4,72-79、Olsson,L.et al.Meth.Enzymol.1982,92,3-16和美国专利第5939598号说明书和第5770429号说明书)来制作。嵌合单克隆抗体和人源化单克隆抗体等重组抗体可以利用本领域已知的标准重组DNA技术来制作(例如参照美国专利第4816567号说明书、第4816397号说明书)。
也可以通过抗体的表面重塑(resurfacing)处理来降低抗体的免疫原性(参照美国专利第5225539号说明书、欧洲专利第0239400号说明书、第0519596号说明书、第0592106号说明书)。
在本发明的一实施方式中,抗体可以是双特异性抗体。用于制作双特异性抗体的方法在本领域中是已知的。既往的全长双特异性抗体的制作方法利用了在2个链具有不同的特异性时的2个免疫球蛋白重链-轻链对的同时表达(参照Milstein,C et al.Nature1983,305,537-539)。此外,作为其他方法,也可以通过使具有所期望的结合特异性(抗体-抗原结合位点)的抗体可变区与免疫球蛋白恒定区序列进行融合来制作双特异性抗体。
其他有用的抗体包含抗体的片段,所述抗体包括但不限于以下:F(ab’)2片段、Fab’片段、Fab片段、Fvs、单链抗体(SCA)(例如记载于美国专利第4946778号说明书、Bird,R.E.et al.Science1988,242,423-442、Huston,J.S.et al.Proc.Natl.Acad.Sot USA1988,85,5879-5883和Ward,E.S.et al.Nature 1989,334,544-554)、scFv、sc-Fv-Fc、FvdsFv、微体(minibody)、双体抗体体(diabody)、三链抗体(triabody)、四链抗体(tetrabody)和CDR,具有与抗体相同的特异性的任意其他分子,例如可举出域抗体(domainantibody)等。
在本发明的优选的实施方式中,也可以使用用于治疗或预防癌症的已知的抗体。可以将包括表达与癌症、细胞增殖障碍或肿瘤在细胞上的表达有相关关系的任意靶蛋白在内的全部靶蛋白作为抗体的靶标。
在本发明的优选的实施方式中,抗体在癌症治疗方面有用。可用于癌症治疗的抗体的例子包括但不限于:美罗华(Rituxan)(注册商标)(Genentech Inc.),其为用于治疗患有非霍奇金淋巴瘤的患者的嵌合抗CD20单克隆抗体;OvaRex(AltaRex Corp.),其为用于治疗卵巢癌的小鼠抗体;Panorex(Glaxo Wellcome Inc.),其为用于治疗结肠直肠癌的小鼠IgG2a抗体;西妥昔单抗(cetuximab)爱必妥(ERBITUX)(ImClone Systems Inc.),其为用于治疗头颈癌等上皮细胞生长因子阳性癌的抗EGFR IgG嵌合抗体;Vitaxin(MedImmuneInc.),其为用于治疗肉瘤的人源化抗体;坎帕斯(Campath)I/H(Leukosite Inc.),其为用于治疗慢性淋巴细胞白血病(CLL)的人源化IgG1抗体;Smart M195(Protein Design LabsInc.),其为用于治疗急性骨髄性白血病(AML)的人源化抗CD33 IgG抗体;Lymphocide(Immunomedics Inc.),其为用于治疗非霍奇金淋巴瘤的人源化抗CD22 IgG抗体;SmartID10(Protein Design Labs Inc.),其为用于治疗非霍奇金淋巴瘤的人源化抗HLA-DR抗体;Oncolym(Techniclone Corp.),其为用于治疗非霍奇金淋巴瘤的放射性核素标记小鼠抗HLA-Dr10抗体;AlloMune(BioTransplant Inc.),其为用于治疗霍奇金病或非霍奇金淋巴瘤的人源化抗CD2 mAb;阿瓦斯汀(Avastin)(Genentech Inc.),其为用于治疗肺癌和结肠直肠癌的抗VEGF人源化抗体;Epratuzamab(Immunomedics Inc.和Amgen Inc.),其为用于治疗非霍奇金淋巴瘤的抗CD22抗体;以及CEAcide(Immunomedics Inc.),其为用于治疗结肠直肠癌的人源化抗CEA抗体。
在本发明的优选的实施方式中,抗体是针对以下抗原的抗体:CA125、CA15-3、CA19-9、L6、Lewis Y、Lewis X、甲胎蛋白、CA242、胎盘碱性磷酸酶、前列腺特异性膜抗原、EphB2、TMEFF2、前列腺酸性磷酸酶、表皮生长因子、MAGE-1、MAGE-2、MAGE-3、MAGE-4、抗转铁蛋白受体、p97、MUC1-KLH、CEA、gp100、MART1、前列腺特异性抗原、IL-2受体、CD20、CD52、CD33、CD22、人绒毛膜促性腺激素、CD38、CD40、粘蛋白、P21、MPG和Neu癌基因产物。一些特异性的有用的抗体包括但不限于:BR96 mAb(Trail,P.A.et al.Science 1993,261,212-215)、BR64(Trail,P.A.et al.Cancer Research 1997,57,100-105)、S2C6 mAb(Francisco,J.A.et al.Cancer Res.2000,60,3225-3231)等针对CD40抗原的mAb、或如美国专利申请公开第2003/0211100号说明书和第2002/0142358号说明书中公开的其他抗CD40抗体、1F6 mAb和2F2 mAb等针对CD70抗原的mAb和AC10(Bowen,M.A.etal.J.Immunol.1993,151,5896-5906、Wahl,A.F.et al.Cancer Res.2002,62(13),3736-42)或MDX-0060(美国专利申请公开第2004/0006215号说明书)等针对CD30抗原的mAb。
可以在本发明中使用的药物中包括化疗药。化疗药是在应对癌症中有用的化合物。化疗药的例子包括如下:烷基化剂,例如噻替派(thiotepa)和环磷酰胺(CYTOXAN(商标));烷基磺酸酯类,例如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶类(aziridines),例如苯佐替派(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);亚乙基亚胺类和甲基蜜胺类(methylamelamines),包括六甲蜜胺(altretamine)、三亚乙基蜜胺(triethylenemelamine)、三亚乙基磷酰胺(trietylenephosphoramide)、三亚乙基硫代磷酰胺(triethylenethiophosphoramide)和三甲蜜胺(trimethylolomelamine);番荔枝内酯类(acetogenins)(特别是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱(camptothecin)(包括作为合成类似物的托泊替康(topotecan));苔藓抑素(bryostatin);卡利司他汀(callystatin);CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);隐藻素类(cryptophycins)(特别是隐藻素1和隐藻素8);多拉司他汀(dolastatin);倍癌霉素(duocarmycin)(包括作为其合成类似物的KW-2189和CBI-TMI));艾榴塞洛素(eleutherobin);水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑制素(spongistatin);氮芥类,例如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、氯磷酰胺(cholophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、二氯甲基二乙胺(mechlorethamine)、二氯甲基二乙胺氧化物盐酸盐、美法仑(melphalan)、新恩比兴(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥;亚硝脲类(nitrosureas),例如卡莫司汀(carmustine)、吡葡亚硝脲(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine);抗生素,例如烯二炔类(enediyne)抗生素(例如加利车霉素(calicheamicin),特别是加利车霉素γ1和加利车霉素θI,例如参照Angew Chem Intl.Ed.Engl.33:183-186(1994);达内霉素(dynemicin),包括达内霉素A;埃斯培拉霉素(esperamicin);以及,新制癌菌素发色团(neocarzinostatin chromophore)和相关的色素蛋白质烯二炔类抗生素发色团类)、阿克拉霉类(aclacinomysins)、放线菌素(actinomycin)、安曲霉素(authramycin)、重氮丝氨酸(azaserine)、博来霉素类(bleomycins)、放线菌素C(cactinomycin)、卡拉比星(carabicin)、洋红霉素(carminomycin)、嗜癌菌素(carzinophilin);色霉素类(chromomycins)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-氧代-L-正亮氨酸、多柔比星(包括吗啉代多柔比星、氰基吗啉代-多柔比星、2-吡咯啉代多柔比星和脱氧多柔比星)、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、nitomycins、霉酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素类(olivomycins)、培洛霉素(peplomycin)、泊非霉素(potfiromycin)、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链脲霉素(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他汀(zinostatin)、佐柔比星(zorubicin);代谢拮抗剂,例如甲氨蝶呤(methotrexate)和5-氟尿嘧啶(5-FU);叶酸类似物,例如二甲叶酸(denopterin)、甲氨蝶呤、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,例如氟达拉滨(fludarabine)、6-巯基嘌呤、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物,例如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二脱氧尿苷(dideoxyuridine)、多西氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine)、5-FU;雄激素(androgen)类,例如卡鲁睾酮(calusterone)、屈他雄酮丙酸酯(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺素剂(anti-adrenals),例如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,例如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);安吖啶(amsacrine);阿莫司汀(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);地美可辛(demecolcine);亚丝醌(diaziquone);依氟鸟氨酸(elfomithine);依利醋铵(elliptinium acetate);埃博霉素(epothilone);依托格鲁(etoglucid);硝酸镓;羟基脲(hydroxyurea);香菇多糖(lentinan);氯尼达明(lonidamine);美登醇类,例如美登素(maytansine)和安丝菌素类(ansamitocins);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidamol);二胺硝吖啶(nitracrine);喷司他汀(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);鬼臼酸(podophyllinic acid);2-乙基酰肼;丙卡巴肼;PSK(注册商标);雷佐生(razoxane);根瘤菌素(rhizoxin);西佐喃(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2’,2”-三氯三乙胺;单端孢霉烯类(trichothecenes)、(特别是T-2毒素、疣孢菌素(verracurin)A、杆孢菌素(roridin)A和蛇行菌素(anguidine));脲烷(urethane);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);格塞图辛(gacytosine);阿糖胞苷(arabinoside)(“Ara-C”);环磷酰胺;噻替派;紫杉烷类(taxoids),例如紫杉醇(paclitaxel)(TAXOL(注册商标)、Bristol-Myers Squibb Oncology)和多西他赛(doxetaxel)(TAXOTERE(注册商标)、Rhone-Poulenc Rorer);苯丁酸氮芥;吉西他滨(gemcitabine);6-硫鸟嘌呤;巯基嘌呤;甲氨蝶呤(methotrexate);铂类似物,例如顺铂(cisplatin)和卡铂(carboplatin);长春花碱(vinblastine);铂;依托泊苷(etoposide)(VP-16);异环磷酰胺;丝裂霉素C(mitomycinC);米托蒽醌;长春新碱(vincristine);长春瑞滨(vinorelbine);诺维本(navelbine);诺肖林(novantrone);替尼泊苷(teniposide);道诺霉素(daunomycin);氨基蝶呤(aminopterin);希罗达(xeloda);伊班膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂RFS2000;二氟甲基鸟氨酸(difluoromethylomithine)(DMFO);视黄酸;卡培他滨(capecitabine);以及上述任意的药学上可接受的盐类、酸类或衍生物。以调节或抑制激素对肿瘤的作用而发挥作用的抗激素剂,例如在此定义中也包括如下物质:例如他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)、抑制芳香酶的4(5)-咪唑类、4-羟基他莫昔芬(tamoxifen)、曲沃昔芬(trioxifene)、盐酸雷洛昔芬(keoxifene)、LY117018、奥那司酮(onapristone)和托瑞米芬(toremifene)(包括法乐通(Fareston))的抗雄激素药;以及抗雄激素药,例如氟他米特(flutamide)、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、亮丙瑞林(leuprolide)和戈舍瑞林(goserelin);siRNA以及上述任意的药学上可接受的盐类、酸类或衍生物。可以在本发明中一起使用的其他化疗药公开于美国专利申请公开第2008/0171040号说明书或美国专利申请公开第2008/0305044号说明书中,直接引用这些内容。
在本发明的优选的实施方式中,化疗药是低分子药物。低分子药物具有优选为100~1500、更优选为120~1200、进一步优选为200~1000的分子量。典型地指具有分子量约小于1000的有机、无机、或有机金属化合物,而被广泛利用。此外,本发明的低分子药物包括具有分子量约小于1000的寡肽和其他生物体分子。低分子药物在本领域中,例如尤其在国际公开第05/058367号单行本、欧洲专利申请公开第85901495号说明书和第8590319号说明书中和美国专利第4,956,303号说明书中已很好地被表征,直接引用这些内容。
本发明的优选的低分子药物是可与抗体连接的低分子药物。本发明中包括已知的药物和具有要成为已知可能性的药物。特别优选的低分子药物中包括细胞毒性药物。
优选的细胞毒性药物是美登醇类、CC-1065类似物、吗啉代类(morpholinos)、多柔比星类、紫杉烷类(taxanes)、隐藻素类(cryptophycins)、埃博霉素类(epothilones)、加利车霉素类(calicheamicins)、澳瑞他汀类(auristatins)和吡咯并苯并二氮杂卓(pyrrolobenzodiazepine)二聚体类。
本发明的式(2)所示的含有异双官能单分散聚乙二醇而成的抗体-药物复合体,可以通过使用式(1)所示的异双官能单分散聚乙二醇使抗体与药物结合来制备。由上式(2)表示的抗体-药物复合体的制备方法可以在使上式(1)所示的异双官能单分散聚乙二醇与药物结合后再结合抗体来制备,也可以在使上式(1)所示的异双官能单分散聚乙二醇与抗体结合后再结合药物来制备均可。此外,可以在使抗体或药物中的任意一个结合后再进行纯化,也可以在使抗体与药物两者结合后再进行纯化均可。
使如上式(1)所示的异双官能单分散聚乙二醇与药物结合而成的化合物可以利用例如柱色谱、萃取、重结晶、吸附剂处理、再沉淀、超临界萃取等纯化方法进行纯化。此外,使上式(1)所示的异双官能单分散聚乙二醇与抗体结合而成的化合物和使抗体与药物两者结合而成的抗体-药物复合体,可以利用例如柱色谱、萃取、吸附剂处理等纯化方法进行纯化。
使上式(1)所示的异双官能单分散聚乙二醇结合药物而成的连接子-药物偶联物,可以利用本领域已知的标准偶联技术来制作(例如参照美国专利申请公开第8163888号说明书、第7659241号说明书、第7498298号说明书和国际公开第2011/023883号单行本、第2005/112919号单行本)。
由上式(1)所示的异双官能单分散聚乙二醇或该连接子和药物组成的连接子-药物偶联物与抗体的偶联物,可以在式(1)中的原子团X1或Y1中所含的官能团与抗体中的官能团反应形成共价键的条件下合成。此外,通常所使用的化学反应不能改变抗体的完整性,例如抗体的靶标结合能力。优选所偶联的抗体的结合特性与非偶联物抗体的结合特性类似。
使由上式(1)所示的异双官能单分散聚乙二醇或该连接子与药物组成的连接子-药物偶联物与抗体结合而成的偶联物可以利用本领域中已知的化学反应和技术来制作(例如参照“Arnon,R.et al.;Monoclonal antibodies as carriers for immunotargetingof drugs;Monoclonal antibodies for cancer detection and therapy.AcademicPress;Baldwin,R.W.et al.eds.;London,1985,367-382”、“Hellstrom,K.E.et al.;Antibodies for drug delivery.;Controlled Drug Delivery;Robinson,J.R.etal.eds.;Marcel Dekker,Inc.;New York;1987,623-653”、“Thorpe,P.E.etal.Monoclonal antibodies,1985,84:475-506”、“Order,S.E.;Analysis,results,andfuture prospective of the therapeutic use of radiolabeled antibody in cancertherapy;Monoclonal antibodies for cancer detection and therapy.AcademicPress;Baldwin,R.W.et al.eds.:London,1985”、“Thorpe,P.E et al.Immunol Rev.1982,62:119-158”和国际公开第89/12624号单行本)。
由上式(1)所示的异双官能单分散聚乙二醇或该连接子与药物组成的连接子-药物偶联物可以与抗体的氨基酸残基的侧链结合。例如是可利用的赖氨酸残基的伯氨基、或可利用的半胱氨酸残基的游离硫醇基。在本发明的一实施方式中,通过与抗体反应而形成的键是与抗体的氨基形成的键,例如是酰胺键、硫醚键和硫脲键,优选为酰胺键。此外,在某种实施方式中,通过与抗体反应而形成的键是与抗体的硫醇基形成的键,例如是酰胺键、马来酰亚胺与硫醇的键、硫醚键和硫脲键,优选为马来酰亚胺与硫醇的键和硫醚键。
在本发明的优选的实施方式中,本发明的异双官能单分散聚乙二醇或连接子-药物偶联物与抗体的结合是通过与抗体的链间半胱氨酸残基反应而产生的马来酰亚胺与硫醇的键或硫醚键。为了得到均一性更高的ADC,理想的是通过与抗体的4对链间二硫键还原而生成的半胱氨酸残基进行反应,由此每个抗体结合平均8个药物。
关于用于使由上式(1)所示的异双官能单分散聚乙二醇或该连接子与药物组成的连接子-药物偶联物与可利用的赖氨酸残基的伯氨基连接的官能团是公知的,没有特别限定,例如可举出:NHS-酯基、N-琥珀酰亚胺基碳酸酯基和p-硝基苯基碳酸酯基等。
关于用于使由上式(1)所示的异双官能单分散聚乙二醇或该连接子与药物组成的连接子-药物偶联物与可利用的半胱氨酸残基的游离硫醇基连接的官能团是公知的,没有特别限定,例如可举出:α-卤代乙酰基和马来酰亚胺基等。
但是,与由上式(1)所示的异双官能单分散聚乙二醇或该连接子与药物组成的连接子-药物偶联物发生反应的抗体的官能团,不限于天然存在的氨基酸的侧链基,通过使适当的低分子与抗体的氨基酸侧链反应,可以转变为其他有用的官能团。例如,如氨基这样的氨基酸的侧链通过使适当的低分子与氨基反应,可以转变为如羟基这样的其他有用的官能团。
另外,关于用于偶联的抗体的官能团,可以通过基因工程操作在抗体的任意位置引入氨基酸,所引入的氨基酸可以是天然型或非天然型的任意种。用于将氨基酸残基引入至抗体的基因工程学方法,例如记载于“Axup,J.Y.et al.Proc Natl Acad Sci.2012,109:16101-16106”和“Tian,F.et al.Proc Natl Acad Sci.2014,111:1766-1771”中。
由上式(1)所示的异双官能单分散聚乙二醇或该连接子与药物组成的连接子-药物偶联物,与抗体可以位点非特异性结合,也可以位点特异性结合,可以是任意种,但优选为位点特异性偶联。
本发明的式(2)所示的含有异双官能单分散聚乙二醇而成的抗体-药物复合体(ADC),可以通过与“Hamblett,K.J.et al.Clin.Cancer Res.2004,10:7063-7070”、“Doronina,S.O.et al.Nat Biotechnol.2003,21:778-784”、“Francisco,J.A.etal.Blood,2003,102:1458-1465”、“Chari,R.V.J.et al.Cancer Res.1992,52:127-131”和“Tumey,L.N.et al.ACS Med.Chem.Lett.2016,7:977-982”中记载的方法类似的标准法来制备。例如,抗体的链间半胱氨酸残基上结合本发明的连接子-药物偶联物且每个抗体具有8个药物的ADC,过量使用如二硫苏糖醇(DTT)或三(2-羧基乙基)膦(TCEP)这样的还原试剂,使抗体在37℃下部分还原1小时,随后加入过量的由上式(1)所示的异双官能单分散聚乙二醇与药物组成的连接子-药物偶联物,例如在20℃持续1小时加入15当量,然后通过进一步添加过量的N-乙酰基-L-半胱氨酸,例如50当量,从而使反应淬灭。此外,得到的ADC混合物可以通过使用经PBS平衡的NAP(注册商标)-5的凝胶过滤色谱法,进行脱盐,除去未反应的连接子-药物偶联物并进行纯化,可以通过尺寸排阻色谱法进一步进行纯化。随后,得到的ADC例如使用0.2μm过滤器进行灭菌过滤,并可以为了保管而进行冷冻干燥。
ADC中的每个抗体的药物数量例如可以通过紫外-可见分光法、质谱法、ELISA法、电泳、HPLC及将它们组合的方法等本领域技术人员公知的方法来确定(例如记载于“Chen,J.et al.Anal.Chem.2013,85:1699-1704”、“Valliere-Douglass,J.F.etal.Anal.Chem.2012,84:2843-2849”、“Birdsall,R.E.et al.mABs,2015,7:1036-1044”和“Zhao,R.Y.et al.J.Med.Chem.2011,54:3606-3623”)。在一实施方式中,ADC中的1个抗体的药物的平均数可以通过紫外-可见分光法进行计算。具体地,抗体-药物复合体水溶液可以通过测定不同的两个波长例如280nm和495nm处的UV吸光度,然后进行以下计算来算出。由于某一波长处的总吸光度与体系内存在的所有吸收化学物种的吸光度的总和相等[吸光度的加和性],因此假定在抗体与药物的偶联反应前后,抗体和药物的摩尔消光系数没有变化,则抗体-药物复合体中的抗体浓度和药物浓度以下述关系式表示。
A280=εD,280CD+εA,280CA式(i)
A495=εD,495CD+εA,495CA式(ii)
DAR=CD/CA式(iii)
A280表示抗体-药物复合体水溶液在280nm处的吸光度,A495表示抗体-药物复合体水溶液在495nm处的吸光度,εA,280表示抗体在280nm处的摩尔消光系数,εA,495表示抗体在495nm处的摩尔消光系数,εD,280表示在280nm处的连接子-药物偶联物的摩尔消光系数,εD,495表示在495nm处的连接子-药物偶联物的摩尔消光系数,CA表示抗体-药物复合体中的抗体浓度,CD表示抗体-药物复合体中的药物浓度。εA,280和εA,495可使用推定值,εA,495通常为0。εD,280和εD,495可以通过测定将连接子-药物偶联物溶解为任意摩尔浓度的溶液的吸光度,并利用朗伯-比尔定律(吸光度=摩尔浓度×摩尔消光系数×比色皿光路长度)而得到。可以通过测定抗体-药物复合体水溶液的A280和A495,并将这些值代入至式(i)和(ii)中解出联立方程式,求出CA和CD。进一步地,可以通过用CD除以CA来求出每个抗体的药物平均结合数。
表示为上式(I)中的k的经由本发明的式(1)所示的异双官能单分散聚乙二醇与抗体结合的药物的数量,例如由每个抗体的药物的平均数来定义。在本发明的式(1)所示的异双官能单分散聚乙二醇或连接子-药物偶联物与抗体的反应中,其结合数可由该连接子或连接子-药物偶联物所反应的抗体上的反应性部位的数量来确定。抗体上的反应性部位可以全部被封闭,与抗体结合的药物数量不同的偶联物也可以混合存在于制备后的ADC中。但是,通过控制或纯化反应性部位,也可以得到与抗体结合的药物数量单一的偶联物。因此,与1个抗体结合的药物数量可以是分布的平均值也可以是单一的值均可,由于分布少或无的ADC的物理性质更稳定,因此优选为单一的值。因此,上式(I)中的k表示具有非整数分布的某个数或整数。
在本发明中的实施方式中,与每个抗体结合的药物数量优选为1~20,更优选为2~16,进一步优选为3~12,特别优选为4~8,最优选为8。
本发明的异双官能单分散聚乙二醇要求具有可以在细胞内特异性分解、有效缓释药物的性能。为了适当评价其性能,例如可以进行以下所示的试验,评价上述异双官能单分散聚乙二醇在细胞内的分解性和结合有该连接子的药物在细胞内的活性。
关于用于评价上述异双官能单分散聚乙二醇利用细胞内的酶的分解性的试验方法,没有特别限制,例如可举出:使用作为细胞内的酶的溶酶体酶,确认结合有该连接子的模型化合物或药物分解的试验等。具体地,如果溶酶体酶是组织蛋白酶B,则向组织蛋白酶B中添加作为还原剂的DTT而制备组织蛋白酶B/DTT溶液,向其中添加含有结合上述异双官能单分散聚乙二醇而成的模型化合物或药物的溶液,在37℃孵育后,对取样的溶液进行HPLC测定,可以通过比较试验前后的图表来确定分解性。进一步地,如果是新峰,则通过确认质谱图,可以确认连接子的切断部位和游离的模型化合物或药物的结构。
关于试验中使用的模型化合物,没有特别限制,但由于当上述异双官能单分散聚乙二醇具有马来酰亚胺基作为官能团时,组织蛋白酶B的半胱氨酸残基与马来酰亚胺基反应而妨碍酶反应,因此优选使用与马来酰亚胺基反应的模型化合物,例如可举出具有硫醇基的化合物,具体地可举出谷胱甘肽等。
另外,试验中使用的药物,只要是上述所示的药物,就没有特别限制,例如可举出具有氨基的药物,具体地可举出多柔比星等。
进一步地,关于用于评价结合上述异双官能单分散聚乙二醇而成的药物-连接子化合物在细胞内的药理活性的试验方法,没有特别限制,例如可举出:通过使用含该药物-连接子化合物的培养基来培养细胞,来计算细胞存活率的细胞毒性试验等。
当被引入至本发明的异双官能单分散聚乙二醇中的肽连接子未在细胞内分解时,认为可能在细胞内与药物的结合未分解,药物活性降低。由于显示出细胞存活率越高则药物活性越低,因此通过本试验计算细胞存活率,并与不含肽连接子的对照的药物-连接子化合物比较细胞存活率,可以评价通过使用本发明的异双官能单分散聚乙二醇在细胞内的药物活性。
关于此处所使用的细胞或培养基,没有特别限制,具体地,将该药物-连接子化合物溶解于培养基RPMI-1640中,在37℃培养HeLa细胞后,使用活细胞数测定试剂盒进行显色反应,进一步进行吸光度测定,由此可以计算细胞存活率。细胞存活率通过将减去空白吸光度的样品吸光度除以不含样品的仅细胞的吸光度来计算。
另外,被引入至本发明的异双官能单分散聚乙二醇中的寡肽要求具有不会妨碍该连接子对疏水性药物的遮蔽效果且具有亲水性更高的性质。为了适当评价其性能,例如可以实施以下所示的试验,以评价上述异双官能单分散聚乙二醇的亲水性。
关于用于评价上述异双官能单分散聚乙二醇中的肽的亲水性的试验方法,没有特别限制,可以通过尺寸排阻色谱法(SEC)、离子交换色谱法(IEC)、反相(RP)色谱法和基于相互作用色谱法(HIC)的HPLC等本领域技术人员公知的方法进行评价(例如参照“Mant,C.T.et al.Methods Mol Biol.2007,386:3-55”)。在例示性的实施方式中,可以通过使用反相HPLC在相同条件下测定对象化合物,比较峰顶的保留时间来评价肽的亲水性。在反相HPLC时,对象化合物的亲水性越高,则越短地检测到保留时间。
实施例
下面,举出实施例更具体地说明本发明,但本发明并不限于这些实施例。
在1H-NMR分析中,使用日本电子DATUM株式会社制造的JNM-ECP400或JNM-ECA600。测定中使用管,氘代溶剂为CDCl3、CD2Cl2或DMSO-d6时,使用四甲基硅烷(TMS)作为内标物。
(实施例1化合物11的合成)
向配备有温度计、氮吹管、搅拌器、Dean-Stark管和冷却管的500mL四口烧瓶中装入三羟甲基氨基甲烷(30.3g,250mmol)、碳酸钠(5.30g,50mmol)、无水甲醇(237g)和苯甲腈(5.15g,50mmol),在65℃下反应24小时。进行过滤,减压蒸馏除去溶剂,然后加入异丙醇、二氯甲烷进行溶解,用10wt%食盐水洗涤。用无水硫酸钠干燥有机层,过滤后,减压蒸馏除去溶剂。将残渣溶于四氢呋喃中,加入己烷进行结晶化,通过过滤得到式(11)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):3.06(2H,brs,-OH),3.65-3.81(4H,dd,>C(CH 2OH)2),4.38(2H,s,-CNO-CH2 -),7.32-7.83(5H,m,arom. H)
[化18]
(实施例2化合物12的合成)
向配备有温度计、氮吹管、搅拌子、Dean-Stark管和冷却管的100mL三口烧瓶中装入十二乙二醇单甲醚(10.4g,18.5mmol)、甲苯(52.0g))三乙胺(2.44g,24.1mmol)、甲磺酰氯(2.34g,20.4mmol),在40℃下反应3小时。加入二氯甲烷进行稀释,然后进行水洗,并用无水硫酸镁干燥有机层。过滤后,减压蒸馏除去溶剂,得到式(12)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):3.08(3H,s,-O-SO2-CH3 ),3.38(3H,s,-O-CH3 ),3.45-3.85(46H,m,CH3-O-(CH2 CH2 O)11-CH2 CH2-O-SO2-CH3),4.38(2H,m,-CH2 -O-SO2-CH3)
[化19]
(实施例3化合物13的合成)
向配备有温度计、氮吹管、搅拌子、Dean-Stark管和冷却管的50mL三口烧瓶中装入式(11)的化合物(0.21g,1.01mmol)、脱水四氢呋喃(7.70g)、式(12)的化合物(2.46g,3.84mmol)、1M叔丁醇钾/四氢呋喃溶液(3.72g,4.04mmol),在50℃下反应4小时。加入二氯甲烷、25wt%食盐水进行水洗,用无水硫酸钠干燥有机层。过滤后,减压蒸馏除去溶剂,得到式(13)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):3.38(6H,s,-O-CH3 ),3.40-3.75(100H,m,>C(CH 2O)2-,-O-(CH2 CH 2O)12-,-CNO-CH2 -),4.36(2H,s,-CNO-CH2 -),7.37-7.94(5H,m,arom.H)
[化20]
(实施例4化合物14的合成)
向配备有温度计、氮吹管、搅拌子、Dean-Stark管和冷却管的100mL三口烧瓶中加入式(13)的化合物(1.13g,0.877mmol)、蒸馏水(31.1g)并进行溶解。加入85%磷酸(0.43ml)调节至pH 1.5,然后在50℃下反应3小时。随后边冷却边加入400g/L氢氧化钠水溶液(5.58ml)后,在50℃下反应6小时。接着,加入6N盐酸调节至pH 2.0,然后加入甲苯、氯仿进行洗涤。向水层中加入食盐至使成为25wt%食盐水,然后用400g/L氢氧化钠水溶液调节至pH 12.5。用甲苯进行萃取,用无水硫酸钠进行干燥。过滤后,减压蒸馏除去溶剂,得到式(14)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):3.08(1H,brs,-OH),3.38(6H,s,-O-CH3 ),3.40-3.80(102H,m,>C(CH 2O)2-,-O-(CH2 CH 2O)12-,>CNH2-CH2 -OH)
[化21]
(实施例5化合物15的合成)
向配备有温度计、氮吹管、搅拌子、Dean-Stark管和冷却管的50mL三口烧瓶中装入式(14)的化合物(1.80g,1.49mmol)、N末端被9-芴基甲氧基羰基(Fmoc基)保护的L-苯丙氨酸-甘氨酸(Fmoc-Phe-Gly)(0.862g,1.94mmol,渡边化学工业株式会社制造)、4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉盐酸盐(DMT-MM)(0.670g,1.94mmol)、乙腈(18.0g)、N,N-二异丙基乙胺(0.263g,2.04mmol),在25℃下反应7小时。加入5wt%磷酸二氢钠水溶液(10.8g),然后减压蒸馏除去乙腈,用甲苯、己烷洗涤水层。用甲苯、氯仿进行萃取,然后用5wt%磷酸二氢钠水溶液、含20wt%食盐的5wt%磷酸氢二钠水溶液进行水洗。进一步用20wt%食盐水洗涤有机层,然后用无水硫酸镁进行干燥,过滤后,减压蒸馏除去溶剂,得到式(15)的化合物。
1H-NMR(CD2Cl2,内标TMS);δ(ppm):2.99-3.26(2H,m,-CH-CH2 -phenyl),3.38(6H,s,-O-CH3 ),3.45-3.90(104H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,-CH-CH2-phenyl,>CCH2-NHCO-CH2 -NHCO-CH-,-NH-C(O)O-CH 2-Fmoc(1H))3.94-4.46(6H,m,>CNH-CH2 -OH,>CCH2-NHCO-CH2-NHCO-CH-,>CNH-CH2-OH,-NH-C(O)O-CH 2-Fmoc(1H),-NH-C(O)O-CH2-Fmoc(CH)),5.63(1H,d,-NH-C(O)O-CH2-Fmoc),6.74(1H,brs,>CCH2-NHCO-CH2-),7.09-7.76(13H,m,arom.H)
[化22]
(实施例6化合物16的合成)
向加入搅拌子的20mL螺口管中加入式(15)的化合物(1.80g,1.10mmol)、N-苯基吗啉(0.449g,3.85mmol)、对硝基氯甲酸苯酯(0.621g,3.08mmol)、二氯甲烷(17.9g),在25℃下反应2小时。进一步地,加入6.7wt%β丙氨酸水溶液(11.8g)进行稀释,然后减压蒸馏除去二氯甲烷,加入400g/L氢氧化钠水溶液(0.869g,6.60mmol),在25℃下反应1小时。用甲苯、二氯甲烷洗涤反应液,然后在水层中溶解食盐至使成为15wt%食盐水,用二氯甲烷进行萃取。有机层中添加乙腈,用含15wt%食盐的5wt%碳酸钠水溶液进行水洗,然后进一步用含20wt%食盐的0.2M盐酸进行水洗。用无水硫酸钠干燥有机层,过滤后,减压蒸馏除去溶剂,得到式(16)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):2.47-2.52(2H,m,>CNH-CH2-OC(O)-NH-CH2-CH2 -COOH),2.95-3.24(2H,m,-CH-CH2 -phenyl),3.38(6H,s,-O-CH3 ),3.45-3.90(106H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,-CH-CH2-phenyl,>CCH2-NHCO-CH2 -NHCO-CH-,-NH-C(O)O-CH 2-Fmoc(1H),>CNH-CH2-OC(O)-NH-CH2 -CH2-COOH),3.94-4.55(5H,m,>CNH-CH2 -OC(O)-NH-,-NH-C(O)O-CH2-Fmoc(CH),>CCH2-NHCO-CH2-NHCO-CH-,-NH-C(O)O-CH 2-Fmoc(1H)),5.72(1H,brs,>CNH-CH2-OC(O)-NH-CH2-CH2-COOH),5.81(1H,d,-NH-C(O)O-CH2-Fmoc),6.71(1H,brs,>CCH2-NHCO-CH2-),7.10-7.80(13H,m,arom.H)
[化23]
(实施例7化合物17的合成)
向加入搅拌子的50mL螺口管中加入式(16)的化合物(0.935g,0.535mmol)、哌啶(0.846g,10.7mmol)、氯仿(6.55g),在25℃下反应2小时。用含20wt%食盐的0.2M盐酸对反应液进行水洗,然后向有机层中加入甲苯进行稀释,用蒸馏水萃取至水层。对用400g/L氢氧化钠水溶液调节至pH10的水层用甲苯进行洗涤,然后用6N盐酸将水层pH调节至pH2.5。在水层中溶解食盐至使成为15wt%食盐水,用氯仿进行萃取。用无水硫酸钠干燥有机层,过滤后,减压蒸馏除去溶剂,得到式(17)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):2.58(2H,m,>CNH-CH2-OC(O)-NH-CH2-CH2 -COOH),3.15-3.30(1H,m,-NHCO-CH-NH2),3.38(6H,s,-O-CH3 ),3.45-3.90(106H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,-CH-CH2 -phenyl,>CCH2-NHCO-CH2 -NHCO-CH-,-OC(O)-NH-CH2 -CH2-COOH),4.20-4.50(2H,m,>CNH-CH2 -OC(O)-NH-),4.59(1H,s,>CCH2-NHCO-CH2-NHCO-CH-NH2),6.18(1H,brs,-OC(O)-NH-CH2-CH2-COOH),6.65(1H,brs,>CCH2-NHCO-CH2-),7.20-7.50(5H,m,arom.H),8.77(2H,s,-CH-NH2 )
[化24]
(实施例8化合物18的合成)
向加入搅拌子的30mL螺口管中加入式(17)的化合物(0.703g,0.450mmol)、4-(N-马来酰亚胺甲基)环己烷-1-羧酸N-琥珀酰亚胺基(0.181g,0.540mmol)、三乙胺(0.105g,1.04mmol)、2,6-二叔丁基对甲酚(0.21mg)、氯仿(13.4g),避光下,在25℃下反应13小时。用含20wt%食盐的0.2M柠檬酸磷酸缓冲液(pH2.4)对反应液进行水洗,然后浓缩有机层,将残渣溶解于0.2M柠檬酸磷酸缓冲液(pH3.0)中。用甲苯洗涤水层,然后用甲苯、氯仿萃取至有机层。用20wt%食盐水对有机层进行水洗,然后加入无水硫酸镁进行干燥,过滤后,减压蒸馏除去溶剂,得到式(18)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):0.89-2.09(10H,m,-cyclohexyl-),2.54(2H,brs,-OC(O)-NH-CH2-CH2 -COOH),2.93-3.20(2H,m,-cyclohexyl-CH2 -maleimide),3.38(6H,s,-O-CH3 ),3.33-3.95(106H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,-CH-CH2 -phenyl,>CCH2-NHCO-CH2 -NHCO-CH-,-OC(O)-NH-CH2 -CH2-COOH),4.28-4.45(2H,m,>CNH-CH2 -OC(O)-NH-),4.74-4.80(1H,m,-NHCO-CH-NHCO-cyclohexyl-),5.63(1H,brs,-OC(O)-NH-CH2-CH2-COOH),6.26(1H,d,>CCH2-NHCO-CH2-NHCO-CH-),6.64(1H,brs,>CCH2-NHCO-CH2-),6.69(2H,s,-maleimide),7.07(1H,brs,-NHCO-cyclohexyl-),7.16-7.26(5H,m,arom.H)
[化25]
(实施例9化合物19的合成)
向加入搅拌子的4ml螺口管中加入式(18)的化合物(0.351g,0.201mmol)、N-羟基琥珀酰亚胺(0.058g,0.503mmol)、二甲基氨基丙基乙基碳二亚胺盐酸盐(0.123g,0.643mmol)、氯仿(2.08g),避光下,在25℃下反应4小时。用5wt%磷酸二氢钠水溶液对反应液进行水洗,然后加入无水硫酸镁进行干燥,过滤后,减压蒸馏除去溶剂,得到式(19)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):0.89-2.01(10H,m,-cyclohexyl-),2.81-2.90(6H,m,>CNH-CH2-OC(O)-NH-CH2-CH2 -COO-,-N-succinimidyl),2.90-3.25(2H,m,-cyclohexyl-CH2 -maleimide),3.38(6H,s,-O-CH3 ),3.33-3.95(106H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,-CH-CH2 -phenyl,>CCH2-NHCO-CH2 -NHCO-,-OC(O)-NH-CH2 -CH2-COO-),4.28-4.45(2H,m,>CNH-CH2 -OC(O)-NH-),4.65-4.70(1H,m,-NHCO-CH-NHCO-cyclohexyl-),5.84(1H,brs,-OC(O)-NH-CH2-CH2-COOH),6.16(1H,d,>CCH2-NHCO-CH2-NHCO-CH-),6.55(1H,brs,>CCH2-NHCO-CH2-),6.69(2H,s,-maleimide),6.91(1H,brs,-NHCO-cyclohexyl-),7.15-7.28(5H,m,arom.H)
[化26]
/>
(实施例10化合物18与谷胱甘肽的反应)
向加入搅拌子的4ml螺口管中装入式(18)的化合物(1mg),用乙酸调节至pH5的10mM谷胱甘肽/25mM乙酸钠/1mM乙二胺四乙酸二钠盐二水合物(EDTA)水溶液(1ml),避光下,在25℃下反应3小时,得到含有式(20)的化合物的水溶液。
[化27]
(实施例11化合物21的合成)
向加入搅拌子的30ml螺口管中装入式(14)的化合物(0.350g,0.290mmol)、N末端被9-芴基甲氧基羰基(Fmoc基)保护的L-缬氨酸-L-丙氨酸-甘氨酸(Fmoc-Val-Ala-Gly)(0.154g,0.363mmol,GenScript制造)、DMT-MM(0.130g,0.508mmol)、乙腈(3.50g)、N,N-二异丙基乙胺(0.073g,0.566mmol),在25℃下反应13小时。加入5wt%磷酸二氢钠水溶液(4.20g),然后减压蒸馏除去乙腈,用甲苯、己烷洗涤水层。用甲苯、氯仿进行萃取,然后用5wt%磷酸二氢钠水溶液、5wt%磷酸氢二钠水溶液进行水洗。进一步用20wt%食盐水洗涤有机层,然后用无水硫酸镁进行干燥,过滤后,减压蒸馏除去溶剂,得到式(21)的化合物。
1H-NMR(DMSO-d6,内标TMS);δ(ppm):0.78-0.93(6H,m,>CH-CH(CH3 )2),1.22(3H,d,>CH-CH3 ),1.93-2.04(1H,m,>CH-CH(CH3)2),3.24(6H,s,-O-CH3 ),3.38-3.76(102H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,>CNHCO-CH2 -NHCO-),3.83-3.94(1H,m,-CH2-Fmoc(CH)),4.16-4.42(6H,m,>CH-CH3,>CH-CH(CH3)2,-CH2 -Fmoc,>CNH-CH2 -OH),4.66(1H,t,>CNH-CH2-OH),7.09(1H,s,-NH-C(O)O-CH2-Fmoc),7.28-7.43(5H,m,arom.H,>CNHCO-CH2-NHCO-),7.70-7.92(4H,m,arom.H),8.00-8.11(2H,m,-NHCO-CH-NHCO-CH-,-NHCO-CH-NHCO-CH-)
[化28]
(实施例12化合物22的合成)
向加入搅拌子的6mL螺口管中加入式(21)的化合物(0.306g,0.185mmol)、N-苯基吗啉(0.106g,0.648mmol)、对硝基氯甲酸苯酯(0.104g,0.518mmol)、二氯甲烷(2.40g),在25℃下反应9小时。进一步,加入6.7wt%β丙氨酸水溶液(2.00g)进行稀释,然后减压蒸馏除去二氯甲烷,加入400g/L氢氧化钠水溶液(0.150g,1.11mmol),在25℃下反应1小时。用甲苯、二氯甲烷洗涤反应液,然后用二氯甲烷进行萃取。用含15wt%食盐的5wt%碳酸钠水溶液进行水洗,然后进一步用含20wt%食盐的0.2M盐酸进行水洗。用无水硫酸钠干燥有机层,过滤后,减压蒸馏除去溶剂,得到式(22)的化合物。
1H-NMR(DMSO-d6,内标TMS);δ(ppm):0.78-0.92(6H,m,>CH-CH(CH3 )2),1.22(3H,d,>CH-CH3 ),1.92-2.03(1H,m,>CH-CH(CH3)2),2.38(2H,t,>CCH2-OC(O)-NH-CH2-CH2 -COOH),3.12-3.21(2H,m,>CCH2-OC(O)-NH-CH2 -CH2-COOH),3.24(6H,s,-O-CH3 ),3.38-3.78(102H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,>CNHCO-CH2 -NHCO-),3.88(1H,t,-CH2-Fmoc(CH)),4.12-4.40(6H,m,>CH-CH3,>CH-CH(CH3)2,-CH2 -Fmoc,>CCH2 -OC(O)-NH-),7.09-7.28(2H,m,-NH-C(O)O-CH2-Fmoc,>CCH2-OC(O)-NH-),7.29-7.45(5H,m,arom.H,>CNHCO-CH2-NHCO-),7.70-7.94(4H,m,arom.H),7.96-8.10(2H,m,-NHCO-CH-NHCO-CH-,-NHCO-CH-NHCO-CH-)
[化29]
(实施例13化合物23的合成)
向加入搅拌子的9mL螺口管中加入式(22)的化合物(0.177g,0.100mmol)、哌啶(0.158g,2.00mmol)、氯仿(2.50g),在25℃下反应2小时。用含20wt%食盐的0.2M盐酸对反应液进行水洗,然后向有机层中加入甲苯进行稀释,用蒸馏水萃取至水层。对用400g/L氢氧化钠水溶液调节至pH10的水层用甲苯、氯仿进行洗涤,然后用6N盐酸将水层pH调节至pH2.5。在水层中溶解食盐至使成为10wt%食盐水,用氯仿进行萃取。用无水硫酸钠干燥有机层,过滤后,减压蒸馏除去溶剂,得到式(23)的化合物。
1H-NMR(DMSO-d6,内标TMS);δ(ppm):0.71-0.92(6H,m,>CH-CH(CH3 )2),1.13-1.31(3H,d,>CH-CH3 ),1.82-2.04(3H,m,>CH-CH(CH3)2,>CCH2-OC(O)-NH-CH2-CH2 -COOH),2.87-3.13(3H,m,>CCH2-OC(O)-NH-CH2 -CH2-COOH,>CH-CH(CH3)2),3.24(6H,s,-O-CH3 ),3.40-3.85(102H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,>CNHCO-CH2 -NHCO-),4.03-4.42(3H,m,>CH-CH3,>CCH 2 -OC(O)-NH-),6.64(1H,brs,>CCH2-OC(O)-NH-),6.95-7.32(3H,m,>CNHCO-CH2-NHCO-,-NHCO-CH-NHCO-CH-,-NHCO-CH-NHCO-CH-)
[化30]
/>
(实施例14化合物24的合成)
向加入搅拌子的9mL螺口管中加入式(23)的化合物(0.100g,0.0637mmol)、4-(N-马来酰亚胺甲基)环己烷-1-羧酸N-琥珀酰亚胺基(0.0788g,0.236mmol)、三乙胺(8.4mg,0.0828mmol)、2,6-二叔丁基对甲酚(0.03mg)、氯仿(1.90g),避光下,在25℃下反应17小时。用含20wt%食盐的0.2M柠檬酸磷酸缓冲液(pH2.4)对反应液进行水洗,然后浓缩有机层,将残渣溶解于0.2M柠檬酸磷酸缓冲液(pH3.0)中。用甲苯、氯仿洗涤水层,然后用甲苯、氯仿萃取至有机层。用20wt%食盐水对有机层进行水洗,然后加入无水硫酸镁进行干燥,过滤后,减压蒸馏除去溶剂,得到式(24)的化合物。
1H-NMR(CD2Cl2,内标TMS);δ(ppm):0.81-1.12(8H,m,>CH-CH(CH3 )2,-cyclohexyl-),1.31-1.48(5H,d,>CH-CH3 ,-cyclohexyl-),1.71-2.18(7H,m,>CH-CH(CH3)2,-cyclohexyl-),2.48-2.63(2H,m,>CCH2-OC(O)-NH-CH2-CH2 -COOH),3.34(6H,s,-O-CH3 ),3.38-3.95(106H,m,>C(CH 2 O)2-,-O-(CH2 CH2 O)12-,>CNHCO-CH2 -NHCO-,>CCH2-OC(O)-NH-CH2 -CH2-COOH,-cyclohexyl-CH2 -maleimide),4.16-4.38(2H,m,>CH-CH3,>CH-CH(CH3)2),4.42-4.52(2H,m,>CCH2 -OC(O)-NH-),6.17-6.32(2H,m,>CNHCO-CH2-NHCO-,>CCH2-OC(O)-NH-),6.50(1H,brs,>CNHCO-CH2-NHCO-CH-),6.68(2H,s,-maleimide),7.20-7.43(2H,m,>CNHCO-CH2-NHCO-CH-NHCO-CH-,-NHCO-cyclohexyl-)
[化31]
(实施例15化合物25的合成)
向加入搅拌子的4ml螺口管中加入式(24)的化合物(0.100g,0.0566mmol)、N-羟基琥珀酰亚胺(9.8mg,0.0849mmol)、二甲基氨基丙基乙基碳二亚胺盐酸盐(0.0228g,0.119mmol)、氯仿(0.800g),避光下,在25℃下反应4小时。用5wt%磷酸二氢钠水溶液对反应液进行水洗,然后加入无水硫酸镁进行干燥,过滤后,减压蒸馏除去溶剂,得到式(25)的化合物。
1H-NMR(DMSO-d6,内标TMS);δ(ppm):0.75-0.97(8H,m,>CH-CH(CH3 )2,-cyclohexyl-),1.17-1.33(5H,d,>CH-CH3 ,-cyclohexyl-),1.48-1.75(5H,m,-cyclohexyl-),1.93-2.02(1H,m,>CH-CH(CH3)2),2.17-2.27(1H,m,-cyclohexyl-),2.81(4H,s,-N-succinimidyl),2.83-2.88(2H,m,>CCH2-OC(O)-NH-CH2-CH2 -),3.23(6H,s,-O-CH3 ),3.42-3.75(106H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,>CNHCO-CH2 -NHCO-,>CCH2-OC(O)-NH-CH2 -CH2-,-cyclohexyl-CH2 -maleimide),4.08-4.33(4H,m,>CH-CH3,>CH-CH(CH3)2,>CCH2 -OC(O)-NH-),7.01(2H,s,-maleimide),7.26-7.35(2H,m,>CNHCO-CH2-NHCO-,>CCH2-OC(O)-NH-),7.62-7.72(1H,m,-NHCO-cyclohexyl-),7.90-8.05(2H,m,>CNHCO-CH2-NHCO-CH-,>CNHCO-CH2-NHCO-CH-NHCO-CH-)
[化32]
(实施例16化合物26的合成)
向加入搅拌子的50ml螺口管中装入式(14)的化合物(2.00g,1.66mmol)、Fmoc-β丙氨酸(0.568g,1.82mmol)、DMT-MM(0.631g,1.82mmol)、乙腈(18.0g)、N,N-二异丙基乙胺(0.279g,2.16mmol),在25℃下反应2小时。加入5wt%磷酸二氢钠水溶液(12.0g),然后减压蒸馏除去乙腈,用甲苯洗涤水层。以下,与实施例5相同地进行纯化,得到式(26)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):2.99-3.26(2H,m,>CCH2-NHCO-CH2 -CH2-NHCO-),3.38(6H,s,-O-CH3 ),3.45-3.90(104H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,>CNH-CH2 -OH,>CCH2-NHCO-CH2-CH2 -NHCO-),4.18-4.22(1H,m,>CNH-CH2-OH),4.34(1H,t,-NH-C(O)O-CH2-Fmoc (CH)),4.40(2H,d,-NH-C(O)O-CH 2-Fmoc),5.75-5.80(1H,m,-NH-C(O)O-CH2-Fmoc),6.34(1H,brs,>CCH2-NHCO-CH2-),7.28-7.78(8H,m,arom.H)
[化33]
(实施例17化合物27的合成)
向加入搅拌子的20mL螺口管中加入式(26)的化合物(2.00g,1.33mmol)、N-苯基吗啉(0.762g,4.00mmol)、对硝基氯甲酸苯酯(0.753g,3.20mmol)、二氯甲烷(19.3g),在25℃下反应6小时。进一步地,加入6.7wt%β丙氨酸水溶液(14.3g)进行稀释,然后减压蒸馏除去二氯甲烷,在25℃下反应1小时。用甲苯、二氯甲烷洗涤反应液,然后在水层中溶解食盐至使成为15wt%食盐水,用二氯甲烷进行萃取。有机层中添加乙腈,用含15wt%食盐的5wt%碳酸钠水溶液进行水洗,然后进一步用含20wt%食盐的0.2M盐酸进行水洗。用无水硫酸钠干燥有机层,过滤后,减压蒸馏除去溶剂,得到式(27)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):2.38(2H,brs,-OC(O)-NH-CH2-CH2 -COOH),2.51(2H,t,>CCH2-NHCO-CH2 -CH2-),3.38(6H,s,-O-CH3 ),3.40-3.90(104H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,>CCH2-NHCO-CH2-CH2 -NHCO-,-OC(O)-NH-CH2 -CH2-COOH),4.19-4.23(1H,m,-NH-C(O)O-CH2-Fmoc(CH)),4.45-4.50(4H,m,>CNH-CH2 -OC(O)-NH-,-NH-C(O)O-CH 2-Fmoc),5.56(1H,brs,>CNH-CH2-OC(O)-NH-),5.93(1H,brs,-NH-C(O)O-CH2-Fmoc),6.33(1H,brs,>CCH2-NHCO-CH2-),7.26-7.78(8H,m,arom.H)
[化34]
(实施例18化合物28的合成)
向加入搅拌子的20mL螺口管中装入式(27)的化合物(0.500g,0.310mmol)、C末端缩合对氨基苄醇(pAB)的L-苯丙氨酸-甘氨酸盐酸盐(H-Phe-Gly-pAB盐酸盐)(0.141g,0.387mmol,渡边化学工业株式会社制造)、DMT-MM(0.134g,0.387mmol)、乙腈(5.00g)、N,N-二异丙基乙胺(0.092g,0.712mmol),在25℃下反应3小时。加入5wt%磷酸二氢钠水溶液(3.00g),然后减压蒸馏除去乙腈,用甲苯、己烷洗涤水层。以下,与实施例5相同地进行纯化,得到式(28)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):2.20-2.45(4H,m,>CCH2-NHCO-CH2 -CH2-,-OC(O)-NH-CH2-CH2 -),3.38(6H,s,-O-CH3 ),2.60-3.80(108H,m,>C(CH2 O)2-,-O-(CH 2CH2 O)12-,-CH-CH2 -phenyl,CNH-CH2-OC(O)-NH-CH2 -CH2-,>CCH2-NHCO-CH2-CH2 -NHCO-,-CONH-CH2 -CONH-phenyl-CH2-OH),3.80-4.57(9H,-NH-C(O)O-CH2 -Fmoc,-CONH-phenyl-CH2 -OH,-CH2-Fmoc (CH),-(CH2)2-CONH-CH-CONH-CH2-,-CH2-OH,-(CH2)2-CONH-CH-CONH-CH2-,-(CH2)2-CONH-CH-CONH-CH2-),4.61(2H,>CNH-CH2 -OC(O)-NH-),6.02-6.15(2H,m,-NH-C(O)O-CH2-Fmoc,>CNH-CH2-OC(O)-NH-),6.53(1H,brs,>CCH2-NHCO-CH2-CH2-),7.11-7.84(17H,m,arom.H),8.89(1H,brs,-CONH-phenyl-CH2-OH)
[化35]
(实施例19化合物29的合成)
向加入搅拌子的6mL螺口管中加入式(28)的化合物(0.100g,0.052mmol)、哌啶(0.082g,1.04mmol)、氯仿(0.700g),在25℃下反应2小时。用含20wt%食盐的0.2M盐酸对反应液进行水洗,然后向有机层中加入甲苯进行稀释,用蒸馏水萃取至水层。对用400g/L氢氧化钠水溶液调节至pH10的水层用甲苯进行洗涤,然后用6N盐酸将水层pH调节至pH2.5。在水层中溶解食盐至使成为15wt%食盐水,用氯仿进行萃取。用无水硫酸钠干燥有机层,过滤后,减压蒸馏除去溶剂,得到式(29)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):2.20-2.55(6H,m,>CCH2-NHCO-CH2 -,-OC(O)-NH-CH2-CH2 -,-CH2 -NH2),3.38(6H,s,-O-CH3 ),2.90-3.80(106H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,-CH-CH2 -phenyl,>CNH-CH2-OC(O)-NH-CH2 -CH2-,-CONH-CH2 -CONH-phenyl-CH2-OH),3.80-4.57(6H,-CONH-phenyl-CH2 -OH,-(CH2)2-CONH-CH-CONH-CH2-,-(CH2)2-CONH-CH-CONH-CH2-,-(CH2)2-CONH-CH-CONH-CH2-,-CH2-OH),4.61(2H,>CNH-CH2 -OC(O)-NH-),6.01(1H,brs,>CNH-CH2-OC(O)-NH-),6.53(1H,brs,>CCH2-NHCO-CH2-CH2-),7.20-7.80(9H,m,arom.H),8.70(2H,brs,-CH2-NH2 ),8.87(1H,brs,-CONH-phenyl-CH2-OH)
[化36]
(实施例20化合物30的合成)
向加入搅拌子的6ml螺口管中加入式(29)的化合物(0.100g,0.058mmol)、3-马来酰亚胺基丙酸(0.012g,0.072mmol)、DMT-MM(0.020g,0.072mmol)、三乙胺(0.013g,0.132mmol)、乙腈(1.00g),避光下,在25℃下反应2小时。加入0.2M柠檬酸磷酸缓冲液(pH3.0)(0.600g),然后减压蒸馏除去乙腈,用甲苯洗涤水层。用甲苯、氯仿进行萃取,然后用含20wt%食盐的0.2M柠檬酸磷酸缓冲液(pH2.4)、含20wt%食盐的0.2M柠檬酸磷酸缓冲液(pH6.5)进行水洗。进一步用20wt%食盐水洗涤有机层,然后用无水硫酸镁进行干燥,过滤后,减压蒸馏除去溶剂,得到式(30)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):2.13-2.57(6H,m,>CCH2-NHCO-CH2 -,-OC(O)-NH-CH2-CH2 -,-NHCO-CH2 -CH2-maleimide),3.38(6H,s,-O-CH3 ),2.90-3.80(111H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,-CH-CH2 -phenyl,>CNH-CH2-OC(O)-NH-CH2 -CH2-,-CONH-CH2 -CONH-phenyl-CH2-OH,-CH2 -maleimide,>CCH2-NHCO-CH2-CH2 -NHCO-,-CH-CH2-phenyl),3.80-4.57(6H,-CONH-phenyl-CH2 -OH,-(CH2)2-CONH-CH-CONH-CH2-,-(CH2)2-CONH-CH-CONH-CH2-,-(CH2)2-CONH-CH-CONH-CH2-,-CH2-OH),4.61(2H,>CNH-CH2 -OC(O)-NH-),6.01(1H,brs,>CNH-CH2-OC(O)-NH-),6.53(1H,brs,>CCH2-NHCO-CH2-CH2-),6.69(2H,s,-maleimide),7.20-7.80(9H,m,arom.H),8.87(1H,brs,-CONH-phenyl-CH2-OH)
[化37]
(实施例21化合物31的合成)
向加入搅拌子的6ml螺口管中装入式(30)的化合物(0.100g,0.054mmol)、碳酸二(N-琥珀酰亚胺基)酯(0.058g,0.227mmol)、三乙胺(0.025g,0.243mmol)、2,6-二叔丁基对甲酚(0.02mg),在25℃下反应2小时。用含15wt%食盐的0.2M柠檬酸磷酸缓冲液(pH2.4)对反应液进行水洗,然后装入乙腈、己烷、0.2M柠檬酸磷酸缓冲液(pH7.0)进行洗涤。进一步用含15wt%食盐的0.2M柠檬酸磷酸缓冲液(pH2.4)洗涤有机层,然后用无水硫酸钠进行干燥,过滤后,减压蒸馏除去溶剂,得到式(31)的化合物。
1H-NMR(DMSO-d6,内标TMS);δ(ppm):2.17-2.33(6H,m,>CNHCO-CH2 -CH2-,-NHCO-CH2 -CH2-maleimide,-OC(O)-NH-CH2-CH2 -),2.61(4H,s,-N-succinimidyl),2.75-2.83(1H,m,>CH-CH2-phenyl),3.04-3.18(4H,m,>CNHCO-CH2-CH2 -,>CNH-CH2-OC(O)-NH-CH2 -CH2-),3.24(6H,s,-O-CH3 ),3.41-3.70(104H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,-CONH-CH2 -CONH-phenyl-CH2-OC(O)-,-CH2 -maleimide),3.80-4.00(2H,m,>CH-CH2 -phenyl),4.14(2H,s,>CNH-CH2 -OC(O)-NH-),4.45-4.57(1H,m,>CCH2-NHCO-CH2-CH2-),4.94(2H,s,-CONH-phenyl-CH2 -OC(O)O-),6.99(2H,s,-maleimide),7.16-7.30(5H,m,arom.H),7.32(1H,brs,>CNH-CH2-OC(O)-NH-),7.40(2H,d,-CONH-phenyl-CH2-OC(O)O-),7.65(2H,d,-CONH-phenyl-CH2-OC(O)O-),7.83-7.92(1H,brs,-NHCO-CH2-CH2-maleimide),8.20-8.45(2H,m,-CONH-CH-CONH-CH2-,-CONH-CH-CONH-CH2-),9.91(1H,brs,-CONH-phenyl-CH2-OC(O)O-)
[化38]
(实施例22化合物32的合成)
向加入搅拌子的4ml螺口管中装入式(30)的化合物(0.100g,0.054mmol)、对硝基氯甲酸苯酯(0.026g,0.130mmol)、N-苯基吗啉(0.026g,0.227mmol)、二氯甲烷(0.716g),在25℃下反应12小时。加入蒸馏水(0.016g,0.0756mmol)、N-苯基吗啉(0.044g,0.270mmol)淬灭反应后,加入己烷进行稀释,用含20wt%食盐的0.2M盐酸进行洗涤。进一步用含10wt%食盐的0.15M硼酸缓冲液(pH10)、含10wt%食盐的5wt%磷酸二氢钠水溶液洗涤有机层,然后用无水硫酸钠进行干燥,过滤后,减压蒸馏除去溶剂。将残渣溶解于乙腈中,用己烷、叔丁醇洗涤,然后减压蒸馏除去溶剂,得到式(32)的化合物。
1H-NMR(DMSO-d6,内标TMS);δ(ppm):2.19-2.32(6H,m,>CNHCO-CH2 -CH2-,-NHCO-CH2 -CH2-maleimide,-OC(O)-NH-CH2-CH2 -),2.72-2.82(1H,m,>CH-CH2-phenyl),3.03-3.22(4H,m,>CNHCO-CH2-CH2 -,>CNH-CH2-OC(O)-NH-CH2 -CH2-),3.23(6H,s,-O-CH3 ),3.38-3.70(104H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,-CONH-CH2 -CONH-phenyl-CH2-OC(O)-,-CH2 -maleimide),3.80-3.96(2H,m,>CH-CH2 -phenyl),4.15(2H,s,>CNH-CH2 -OC(O)-NH-),4.45-4.56(1H,brs,>CNHCO-CH2-CH2-),5.25(2H,s,-CONH-phenyl-CH2 -OC(O)O-),6.99(2H,s,-maleimide),7.14-7.35(6H,m,arom.H,>CNH-CH2-OC(O)-NH-),7.42(2H,d,-CONH-phenyl-CH2-OC(O)O-),7.54-7.60(2H,m,arom.H(p-nitrophenyl)),7.64-7.72(2H,d,-CONH-phenyl-CH2-OC(O)O-),7.83-7.92(1H,m,-NHCO-CH2-CH2-maleimide),8.22-8.43(4H,m,-CONH-CH-CONH-CH2-,-CONH-CH-CONH-CH2-,arom.H(p-nitrophenyl)),9.90(1H,brs,-CONH-phenyl-CH2-OC(O)O-)
[化39]
(实施例23化合物33的合成)
向加入搅拌子的6ml螺口管中装入式(28)的化合物(0.100g,0.052mmol)、碳酸二(N-琥珀酰亚胺基)酯(0.056g,0.218mmol)、三乙胺(0.024g,0.234mmol)、2,6-二叔丁基对甲酚(0.02mg),在25℃下反应2小时。以下,与实施例16相同地进行纯化,得到式(33)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):2.20-2.45(4H,m,>CCH2-NHCO-CH2 -CH2-,-OC(O)-NH-CH2-CH2 -),2.82(4H,s,-N-succinimidyl),3.38(6H,s,-O-CH3 ),2.90-3.80(108H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,-CH-CH2 -phenyl,>CNH-CH2-OC(O)-NH-CH2 -CH2-,>CCH2-NHCO-CH2-CH2 -NHCO-,-CONH-CH2 -CONH-phenyl-CH2-),3.80-4.65(8H,-NH-C(O)O-CH2 -Fmoc,>CNH-CH2 -OC(O)-NH-,-CH2-Fmoc(CH),-(CH2)2-CONH-CH-CONH-CH2-,-(CH2)2-CONH-CH-CONH-CH2-,-(CH2)2-CONH-CH-CONH-CH2-),5.26(2H,s,-CONH-phenyl-CH2 -OC(O)O-),6.02-6.15(2H,m,-NH-C(O)O-CH2-Fmoc,>CNH-CH2-OC(O)-NH-),6.53(1H,brs,>CCH2-NHCO-CH2-CH2-),7.11-7.84(17H,m,arom.H),8.89(1H,brs,-CONH-phenyl-CH2-OC(O)O-)
[化40]
/>
(实施例24化合物34的合成)
向加入搅拌子的14mL螺口管中装入式(27)的化合物(0.300g,0.186mmol)、C末端缩合对氨基苄醇(pAB)的L-缬氨酸-瓜氨酸(H-Val-Cit-pAB)(0.088g,0.233mmol,渡边化学工业株式会社制造)、DMT-MM(0.080g,0.233mmol)、乙腈(3.00g)、N,N-二异丙基乙胺(0.031g,0.242mmol),在25℃下反应2小时。加入5wt%磷酸二氢钠水溶液(1.80g),然后减压蒸馏除去乙腈,用甲苯洗涤水层。以下,与实施例5相同地进行纯化,得到式(34)的化合物。
1H-NMR(DMSO-d6,内标TMS);δ(ppm):0.76-0.92(6H,m,>CH-CH(CH3 )2),1.30-1.48(2H,m,-CH2-CH2 -CH2-NHCO-NH2),1.55-1.78(2H,m,-CH2 -CH2-CH2-NHCO-NH2),1.92-2.04(1H,m,>CH-CH(CH3)2),2.22-2.44(4H,m,>CNHCO-CH2 -CH2-NHCO-,>CCH2-O-CONH-CH2-CH2 -),2.87-3.10(2H,m,-CH2-CH2-CH2 -NHCO-NH2),3.23(6H,s,-O-CH3 ),3.40-3.72(104H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,>CNHCO-CH2-CH2 -NHCO-,>CCH2-O-CONH-CH2 -CH2-),4.15(2H,brs,>CCH2 -O-CONH-),4.18-4.24(2H,m,-CH2-Fmoc(CH),>CH-CH(CH3)2),4.25-4.32(2H,m,-CH2 -Fmoc(CH)),4.36-4.42(1H,m,>CH-CH2-CH2-CH2-NHCO-NH2),4.42(2H,d,-CONH-phenyl-CH2 -OH),5.08(1H,t,-CONH-phenyl-CH2-OH),5.40(2H,brs,-CH2-CH2-CH2-NHCO-NH2 ),5.94-6.05(1H,m,-CH2-CH2-CH2-NHCO-NH2),7.02-7.10(1H,m,>CCH2-O-CONH-CH2-CH2-),7.16-7.28(3H,m,>CNHCO-CH2-CH2-NHCO-,-CONH-phenyl-CH2-OH),7.31-7.47(5H,m,>CNHCO-CH2-CH2-NHCO-,arom.H(Fmoc)),7.54(2H,d,-CONH-phenyl-CH2-OH),7.67(2H,d,arom.H(Fmoc)),7.83-8.16(4H,m,-(CH2)2-CONH-CH-CONH-CH-,-(CH2)2-CONH-CH-CONH-CH-,arom.H (Fmoc)),9.88(1H,brs,-CONH-phenyl-CH2-OH)
[化41]
(实施例25化合物35的合成)
向加入搅拌子的9mL螺口管中加入式(34)的化合物(0.150g,0.076mmol)、哌啶(0.120g,1.52mmol)、氯仿(1.34g),在25℃下反应3时间。用含20wt%食盐的0.2M盐酸对反应液进行水洗,然后向有机层中加入甲苯进行稀释,用蒸馏水萃取至水层。对用400g/L氢氧化钠水溶液调节至pH10的水层用甲苯、氯仿进行洗涤,然后在水层中溶解食盐至使成为15wt%食盐水,用氯仿进行萃取。用无水硫酸钠干燥有机层,过滤后,减压蒸馏除去溶剂,得到式(35)的化合物。
1H-NMR(DMSO-d6,内标TMS);δ(ppm):0.76-0.92(6H,m,>CH-CH(CH3 )2),1.30-1.50(2H,m,-CH2-CH2 -CH2-NHCO-NH2),1.52-1.75(2H,m,-CH2 -CH2-CH2-NHCO-NH2),1.92-2.02(1H,m,>CH-CH(CH3)2),2.13-2.43(4H,m,>CNHCO-CH2 -CH2-NH2,>CCH2-O-CONH-CH2-CH2 -),2.68-2.80(2H,m,>CNHCO-CH2-CH2 -NH2),2.87-3.08(2H,m,-CH2-CH2-CH2 -NHCO-NH2),3.24(6H,s,-O-CH3 ),3.15-3.70(102H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,>CCH2-O-CONH-CH2 -CH2-),4.16(2H,brs,>CCH2 -O-CONH-),4.20(1H,t,>CH-CH(CH3)2),4.36-4.41(1H,m,>CH-CH2-CH2-CH2-NHCO-NH2),4.42(2H,d,-CONH-phenyl-CH2 -OH),5.08(1H,brs,-CONH-phenyl-CH2-OH),5.41(2H,brs,-CH2-CH2-CH2-NHCO-NH2 ),6.00(1H,brs,-CH2-CH2-CH2-NHCO-NH2),7.04(1H,brs,>CCH2-O-CONH-CH2-CH2-),7.18-7.28(2H,m,-CONH-phenyl-CH2-OH),7.48-7.63(3H,m,-CONH-phenyl-CH2-OH,>CNHCO-CH2-CH2-NH2),7.89-8.20(2H,m,-(CH2)2-CONH-CH-CONH-CH-,-(CH2)2-CONH-CH-CONH-CH-),9.89(1H,brs,-CONH-phenyl-CH2-OH)
[化42]
(实施例26化合物36的合成)
向加入搅拌子的6ml螺口管中加入式(35)的化合物(0.100g,0.057mmol)、3-马来酰亚胺基丙酸(0.011g,0.063mmol)、DMT-MM(0.022g,0.063mmol)、三乙胺(6.9mg,0.068mmol)、乙腈(0.900g),避光下,在25℃下反应2小时。加入0.2M柠檬酸磷酸缓冲液(pH3.0)(1.20g),然后减压蒸馏除去乙腈,用甲苯洗涤水层。以下,与实施例20相同地进行纯化,得到式(36)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):0.76-0.92(6H,m,>CH-CH(CH3 )2),1.32-1.48(2H,m,-CH2-CH2 -CH2-NHCO-NH2),1.52-1.77(2H,m,-CH2 -CH2-CH2-NHCO-NH2),1.93-2.02(1H,m,>CH-CH(CH3)2),2.17-2.44(6H,m,>CNHCO-CH2 -CH2-NHCO-CH2-CH2-,>CNHCO-CH2-CH2-NHCO-CH2 -CH2-,>CCH2-O-CONH-CH2-CH2 -),2.87-3.08(2H,m,-CH2-CH2-CH2 -NHCO-NH2),3.24(6H,s,-O-CH3 ),3.13-3.74(106H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,>CNHCO-CH2-CH2 -NHCO-CH2-CH2-,>CNHCO-CH2-CH2-NHCO-CH2-CH2 -,>CCH2-O-CONH-CH2 -CH2-),4.15(2H,brs,>CCH2 -O-CONH-),4.16-4.23(1H,m,>CH-CH(CH3)2),4.34-4.41(1H,m,>CH-CH2-CH2-CH2-NHCO-NH2),4.42(2H,d,-CONH-phenyl-CH2 -OH),5.08(1H,t,-CONH-phenyl-CH2-OH),5.40(2H,brs,-CH2-CH2-CH2-NHCO-NH2 ),5.99(1H,brs,-CH2-CH2-CH2-NHCO-NH2),7.00(2H,s,-maleimide),7.04(1H,brs,>CCH2-O-CONH-CH2-CH2-),7.22-7.32(3H,m,-CONH-phenyl-CH2-OH,>CNHCO-CH2-CH2-),7.54(2H,d,-CONH-phenyl-CH2-OH),7.88-8.16(3H,m,>CNHCO-CH2-CH2-NHCO-,-(CH2)2-CONH-CH-CONH-CH-,-(CH2)2-CONH-CH-CONH-CH-),9.88(1H,brs,-CONH-phenyl-CH2-OH)
[化43]
(实施例27化合物37的合成)
向加入搅拌子的4ml螺口管中装入式(36)的化合物(0.100g,0.0483mmol)、碳酸双(4-硝基苯基)(0.029g,0.0966mmol)、N,N-二异丙基胺(0.0094g,0.0725mmol)、二氯甲烷(0.640g),在25℃下反应3小时。用含20wt%食盐的0.2M盐酸洗涤反应液。进一步用含10wt%食盐的0.15M硼酸缓冲液(pH10)、含20wt%食盐的5wt%磷酸二氢钠水溶液洗涤有机层,然后用无水硫酸钠进行干燥,过滤后,减压蒸馏除去溶剂。将残渣溶解于乙腈中,用己烷、叔丁醇洗涤,然后减压蒸馏除去溶剂,得到式(37)的化合物。
1H-NMR(DMSO-d6,内标TMS);δ(ppm):0.78-0.92(6H,m,>CH-CH(CH3 )2),1.32-1.52(2H,m,-CH2-CH2 -CH2-NHCO-NH2),1.54-1.80(2H,m,-CH2 -CH2-CH2-NHCO-NH2),1.93-2.02(1H,m,>CH-CH(CH3)2),2.16-2.42(6H,m,>CNHCO-CH2 -CH2-NHCO-,>CNHCO-CH2-CH2-NHCO-CH2 -CH2-,>CCH2-O-CONH-CH2-CH2 -),2.90-3.08(2H,m,-CH2-CH2-CH2 -NHCO-NH2),3.24(6H,s,-O-CH3 ),3.13-3.75(106H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,>CNHCO-CH2-CH2 -NHCO-,>CNHCO-CH2-CH2-NHCO-CH2-CH2 -,>CCH2-O-CONH-CH2 -CH2-),4.15(2H,brs,>CCH2 -O-CONH-),4.20(1H,t,>CH-CH(CH3)2),4.33-4.46(1H,m,>CH-CH2-CH2-CH2-NHCO-NH2),5.24(2H,brs,-CONH-phenyl-CH2 -O-),5.42(2H,brs,-CH2-CH2-CH2-NHCO-NH2 ),6.00(1H,brs,-CH2-CH2-CH2-NHCO-NH2),7.00(2H,s,-maleimide),7.05(1H,brs,>CCH2-O-CONH-CH2-CH2-),7.32(1H,brs,>CNHCO-CH2-CH2-NHCO-),7.37-7.47(2H,m,-CONH-phenyl-CH2-O-),7.57(2H,d,arom.H(p- nitrophenyl)),7.63-7.68(2H,m,-CONH-phenyl-CH2-O-),7.80-8.18(3H,m,>CNHCO-CH2-CH2-NHCO-,-(CH2)2-CONH-CH-CONH-CH-,-(CH2)2-CONH-CH-CONH-CH-),8.31(2H,d,arom.H (p-nitrophenyl)),10.1(1H,brs,-CONH-phenyl-CH2-O-)
[化44]
(实施例28化合物38的合成)
向加入搅拌子的4ml螺口管中装入式(34)的化合物(0.100g,0.0506mmol)、碳酸双(4-硝基苯基)(0.031g,0.101mmol)、N,N-二异丙基胺(0.0098g,0.0759mmol)、二氯甲烷(0.671g),在25℃下反应3小时。用含20wt%食盐的0.2M盐酸洗涤反应液。进一步用含10wt%食盐的0.15M硼酸缓冲液(pH10)、含20wt%食盐的5wt%磷酸二氢钠水溶液洗涤有机层,然后用无水硫酸钠进行干燥,过滤后,减压蒸馏除去溶剂。将残渣溶解于乙腈中,用己烷、叔丁醇洗涤,然后减压蒸馏除去溶剂,得到式(38)的化合物。
1H-NMR(DMSO-d6,内标TMS);δ(ppm):0.77-0.90(6H,m,>CH-CH(CH3 )2),1.33-1.51(2H,m,-CH2-CH2 -CH2-NHCO-NH2),1.53-1.78(2H,m,-CH2 -CH2-CH2-NHCO-NH2),1.93-2.03(1H,m,>CH-CH(CH3)2),2.22-2.43(4H,m,>CNHCO-CH2 -CH2-NHCO-,>CCH2-O-CONH-CH2-CH2 -),2.87-3.15(2H,m,-CH2-CH2-CH2 -NHCO-NH2),3.23(6H,s,-O-CH3 ),3.13-3.70(104H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,>CNHCO-CH2-CH2 -NHCO-,>CCH2-O-CONH-CH2 -CH2-),4.13-4.23(4H,m,>CCH2 -O-CONH-,-CH2-Fmoc(CH),>CH-CH(CH3)2),4.24-4.29(2H,m,-CH2 -Fmoc(CH)),4.36-4.42(1H,m,>CH-CH2-CH2-CH2-NHCO-NH2),5.24(2H,brs,-CONH-phenyl-CH2 -OH),5.41(2H,brs,-CH2-CH2-CH2-NHCO-NH2 ),6.00(1H,brs,-CH2-CH2-CH2-NHCO-NH2),7.04(1H,brs,>CCH2-O-CONH-CH2-CH2-),7.19(1H,brs,>CNHCO-CH2-CH2-NHCO-),7.31-7.38(3H,m,>CNHCO-CH2-CH2-NHCO-,arom.H(Fmoc)),7.38-7.46(4H,m,-CONH-phenyl-CH2-OH,arom.H(Fmoc)),7.56-7.71(6H,m,-CONH-phenyl-CH2-OH,arom.H(Fmoc,p-nitrophenyl)),7.87-8.20(4H,m,-(CH2)2-CONH-CH-CONH-CH-,-(CH2)2-CONH-CH-CONH-CH-,arom.H(Fmoc)),8.28-8.33(2H,m,arom.H(p-nitrophenyl)),10.1(1H,brs,-CONH-phenyl-CH2-OH)
[化45]
(实施例29化合物31与多柔比星的偶联物)
向加入搅拌子的4ml螺口管中装入盐酸多柔比星盐(2.62mg,4.51μmol)、N,N-二异丙基胺(1.55mg,11.5μmol)、N,N-二甲基甲酰胺和式(31)的化合物(10.0mg,5.01μmol),在25℃下反应4小时。用二氯甲烷稀释反应液,然后用5wt%磷酸二氢钠水溶液、离子交换水进行水洗。用无水硫酸钠干燥有机层,过滤后,减压蒸馏除去溶剂,得到式(39)的药物-连接子化合物。
[化46]
(实施例30化合物33与多柔比星的偶联物)
向加入搅拌子的4ml螺口管中装入盐酸多柔比星盐(2.53mg,4.36μmol)、N,N-二异丙基胺(1.50mg,11.1μmol)、N,N-二甲基甲酰胺和式(33)的化合物(10.0mg,4.84μmol),在25℃下反应4小时。以下,与实施例29相同地进行纯化,得到式(40)的药物-连接子化合物。
[化47]
(实施例31化合物37与多柔比星的偶联物)
向加入搅拌子的4ml螺口管中装入盐酸多柔比星盐(2.62mg,4.51μmol)、N,N-二异丙基胺(1.55mg,11.5μmol)、N,N-二甲基甲酰胺和式(37)的化合物(10.4mg,5.01μmol),在25℃下反应4小时。用二氯甲烷稀释反应液,然后用5wt%磷酸二氢钠水溶液、5wt%磷酸氢二钠水溶液、离子交换水进行水洗。用无水硫酸钠干燥有机层,过滤后,减压蒸馏除去溶剂,得到式(41)的药物-连接子化合物。
[化48]
(实施例32化合物38与多柔比星的偶联物)
向加入搅拌子的4ml螺口管中装入盐酸多柔比星盐(2.53mg,4.36μmol)、N,N-二异丙基胺(1.50mg,11.1μmol)、N,N-二甲基甲酰胺和式(38)的化合物(10.4mg,4.84μmol),在25℃下反应4小时。以下,与实施例31相同地进行纯化,得到式(42)的药物-连接子化合物。
[化49]
(实施例33使用化合物39制备ADC)
将在小鼠中产生的单克隆抗白细胞介素-1β抗体(0.500mg,Sigma-Aldrich)溶解于磷酸缓冲食盐水(PBS,0.500mL)中。将该溶液0.048mL加入0.5mL的聚丙烯管中,向其中加入50.0mM的乙二胺四乙酸(EDTA,0.006mL)、0.800mM的三(2-羧甲基)膦盐酸盐(TCEP)水溶液(0.006mL;相对于抗体为15当量),将混合物在37℃振摇1小时。向上述溶液中添加式(39)的化合物的2.50mM N,N-二甲基乙酰胺溶液(0.007mL;相对于抗体为53当量),将混合物在20℃进一步振摇1小时。添加N-乙酰半胱氨酸的2.50mM水溶液(0.007mL;相对于抗体为53当量),将得到的混合物在20℃进一步振摇1小时。将上述中得到的溶液填充到经PBS(10mL)平衡的NAP-5柱(GE Healthcare Life Science)中,用PBS洗脱,从而分离出抗体组分。
(实施例34使用化合物41制备ADC)
将在小鼠中产生的单克隆抗白细胞介素-1β抗体(0.500mg,Sigma-Aldrich)溶解于磷酸缓冲食盐水(PBS,0.500mL)中。将该溶液0.048mL加入0.5mL的聚丙烯管中,向其中加入50.0mM的乙二胺四乙酸(EDTA,0.006mL)、0.800mM的三(2-羧甲基)膦盐酸盐(TCEP)水溶液(0.006mL;相对于抗体为15当量),将混合物在37℃振摇1小时。向上述溶液中添加式(41)的化合物的2.50mM N,N-二甲基乙酰胺溶液(0.007mL;相对于抗体为53当量),将混合物在20℃进一步振摇1小时。添加N-乙酰半胱氨酸的2.50mM水溶液(0.007mL;相对于抗体为53当量),将得到的混合物在20℃进一步振摇1小时。将上述中得到的溶液填充到用PBS(10mL)平衡的NAP-5柱(GE Healthcare Life Science)中,用PBS洗脱,从而分离出抗体组分。
(实施例35计算使用化合物39的ADC的每个抗体的药物平均结合数)
抗体-药物复合体中的每个抗体的平均结合数可以通过在测定抗体-药物复合体水溶液在280nm和495nm这两个波长处的UV吸光度之后,进行下述计算来进行计算。
由于某一波长处的总吸光度与体系内存在的所有吸收化学物种的吸光度的总和相等[吸光度的加和性],因此假定在抗体与药物的偶联反应前后,抗体和药物的摩尔消光系数没有变化,则抗体-药物复合体中的抗体浓度和药物浓度由下述关系式表示。
A280=AD,280+AA,280=εD,280CD+εA,280CA式(i)
A495=AD,495+AA,495=εD,495CD+εA,495CA式(ii)
此处,A280表示抗体-药物复合体水溶液在280nm处的吸光度,A495表示抗体-药物复合体水溶液在495nm处的吸光度,AA,280表示抗体在280nm处的吸光度,AA,495表示抗体在495nm处的吸光度,AD,280表示药物-连接子化合物在280nm处的吸光度,AD,495表示药物-连接子化合物在495nm处的吸光度,εA,280表示抗体在280nm处的摩尔消光系数,εA,495表示抗体在495nm处的摩尔消光系数,εD,280表示药物-连接子化合物在280nm处的摩尔消光系数,εD,495表示药物-连接子化合物在495nm处的摩尔消光系数,CA表示抗体-药物复合体中的抗体浓度,CD表示抗体-药物复合体中的药物浓度。
此处,εA,280、εA,495、εD,280、εD,495可使用预先准备的值(推定值或由化合物的UV测定获得的实测值)。εA,495通常为0。εD,280和εD,495可以通过测定以某一摩尔浓度溶解所使用的药物-连接子化合物而成的溶液的吸光度,并利用朗伯-比尔定律(吸光度=摩尔浓度×摩尔消光系数×比色皿光路长度)而得到。可以通过测定抗体-药物复合体水溶液的A280和A495,并将这些值代入式(i)和(ii)中解出联立方程式,求出CA和CD。进一步可以通过用CD除以CA来求出每个抗体的药物平均结合数。
使用摩尔消光系数εA,280=206,999(推定值)、εA,495=0、εD,280=10426(实测值)、εD,495=10339(实测值)解除上述的联立方程式,每个抗体的药物平均结合数为7.8。
(实施例36计算使用化合物41的ADC的每个抗体的药物平均结合数)
使用与实施例35相同的方法,使用摩尔消光系数εA,280=206,999(推定值)、εA,495=0、εD,280=9837(实测值)、εD,495=9785(实测值)进行计算,每个抗体的药物平均结合数为8.1。
(比较例1化合物43的合成)
向配备有温度计、氮吹管、搅拌子、Dean-Stark管和冷却管的50mL三口烧瓶中装入式(14)的化合物(0.800g,0.663mmol)、6-马来酰亚胺己酸(0.161g,0.762mmol)、DMT-MM(0.263g,0.762mmol)、乙腈(8.00g)、三乙胺(0.081g,0.796mmol),在25℃下反应7小时。加入pH 3.0柠檬酸磷酸缓冲液(pH3.0),然后用甲苯进行洗涤。用氯仿进行萃取,然后用10%食盐水洗涤有机层。用无水硫酸镁干燥有机层,过滤后,减压蒸馏除去溶剂,得到式(43)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):1.31(2H,m,-CH2 CH2CH2-CONH-),1.62(4H,m,-CH2 CH2CH2 CH2-CONH-),2.18(2H,t,-CH2 -CONH-),3.38(6H,s,-O-CH3 ),3.40-3.85(104H,m,>C(CH 2O)2-,-O-(CH2 CH 2O)12-,>CNH-CH2 -OH,-CH2 -maleimide),4.62(1H,t,-OH),6.23(1H,s,-CH2-CONH-),6.69(2H,s,-maleimide)
[化50]
(比较例2化合物43与谷胱甘肽的反应)
向加入搅拌子的4ml螺口管中装入式(43)的化合物(1mg)、用乙酸调节至pH5的10mM谷胱甘肽/25mM乙酸钠/1mM乙二胺四乙酸二钠盐二水合物(EDTA)水溶液(1ml),避光下,在25℃下反应3小时,得到含有式(44)的化合物的水溶液。
[化51]
(比较例3化合物45的合成)
向加入搅拌子的4ml螺口管中加入式(27)的化合物(0.100g,0.062mmol)、N-羟基琥珀酰亚胺(0.015g,0.133mmol)、二甲基氨基丙基乙基碳二亚胺盐酸盐(0.023g,0.121mmol)、氯仿(0.574g),在25℃下反应4小时。以下,与实施例9相同地进行纯化,得到式(45)的化合物。
1H-NMR(CDCl3,内标TMS);δ(ppm):2.28-2.43(2H,m,-OC(O)-NH-CH2-CH2 -COO-),2.75-2.92(6H,m,>CCH2-NHCO-CH2 -CH2-,-N-succinimidyl),3.38(6H,s,-O-CH3 ),3.35-3.90(104H,m,>C(CH2 O)2-,-O-(CH2 CH2 O)12-,>CCH2-NHCO-CH2-CH2 -NHCO-,-OC(O)-NH-CH2 -CH2-COO-),4.19-4.23(1H,m,-NH-C(O)O-CH2-Fmoc(CH)),4.35-4.50(4H,m,>CNH-CH2 -OC(O)-NH-,-NH-C(O)O-CH 2-Fmoc),5.62(1H,brs,>CNH-CH2-OC(O)-NH-),5.88(1H,brs,-NH-C(O)O-CH2-Fmoc),6.29(1H,brs,>CCH2-NHCO-CH2-),7.26-7.78(8H,m,arom.H)
[化52]
(比较例4化合物45与多柔比星的偶联物)
向加入搅拌子的4ml螺口管中装入盐酸多柔比星盐(3.05mg,4.36μmol)、N,N-二异丙基胺(1.82mg,13.4μmol)、N,N-二甲基甲酰胺和式(45)的化合物(10.0mg,5.84μmol),在25℃下反应4小时。以下,与实施例29相同地进行纯化,得到式(46)的药物-连接子化合物。
[化53]
(实施例37使用组织蛋白酶B的化合物20、44的分解性试验)
对于在实施例10中得到的(20)的化合物和在比较例2中得到的(44)的化合物,进行使用溶酶体内的蛋白分解酶即组织蛋白酶B的肽的分解性试验。在4ml螺口管中向人肝脏来源的组织蛋白酶B缓冲液(25μg,≧1500units/mg protein,Sigma-Aldrich公司制造)装入用乙酸调节至pH5的25mM乙酸钠/1mM EDTA水溶液(0.500ml),得到组织蛋白酶B稀释溶液。进一步地,向4ml螺口管中装入组织蛋白酶B稀释溶液(0.160ml)、调节至pH5的30mMDTT/25mM乙酸钠/15mM EDTA水溶液(0.320ml),在25℃静置15分钟后,混合预先加温至37℃的pH5的25mM乙酸钠/1mM EDTA水溶液(1.32ml)、含有式(20)或式(44)的化合物为0.1mg/ml的水溶液(0.200ml)。同时,混合加温至37℃的pH5的25mM乙酸钠/1mM EDTA水溶液(1.80ml)、含有式(20)或式(44)的化合物为0.1mg/ml的水溶液(0.200ml),制备不含组织蛋白酶B和DTT的对照水溶液。在37℃孵育所制备的水溶液(含有/不含有组织蛋白酶B),取样后,在下述测定条件下进行HPLC测定。测定结果的图表如图1~3所示。
作为结果,本发明中的式(20)的化合物在图1的图表中在保留时间12.9分钟处被检测到,但在利用组织蛋白酶B的试验后,在保留时间10.9分钟和7.7分钟处检测到新的峰,根据图2的质谱图结果,新峰的分子量与在式(20)的化合物的甘氨酸的C末端分解的片段一致。另一方面,作为比较例的式(44)的化合物在图3的图表中,在保留时间11.9分钟处被检测,在利用组织蛋白酶B的试验后也未检测到新的峰。因此,仅具有肽连接子的式(20)的化合物被组织蛋白酶B特异性切断,由此可知本发明的异双官能单分散聚乙二醇的肽连接子部分被细胞内的酶依赖性地切断。
·HPLC装置:Alliance(Waters)
·色谱柱:Sun Shell C18(3.0×150mm,2.6μm;株式会社ChromaNikTechnologies)
·流速:0.6mL/分
·分析时间:30分
·柱温度:40℃
·注入量:5μL
·检测器:质谱仪(离子化:ESI)
·流动相A:0.1M甲酸/水
·流动相B:0.1M甲酸/乙腈
·梯度程序:10%-50%(0分钟-20分钟)、50%-95%(20分钟-25分钟)、95%-10%(25分钟-30分钟)
(实施例38使用组织蛋白酶B的化合物21、26的分解性试验)
对于在实施例11中得到的(21)的化合物和在实施例16中得到的(26)的化合物,进行使用溶酶体内的蛋白分解酶即组织蛋白酶B的肽的分解性试验。以下,在与实施例37相同的条件下进行分解性试验和HPLC测定。测定结果的图表如图4~6所示。
作为结果,本发明中的式(21)的化合物在图4的图表中在保留时间13.8分钟处被检测到,但在利用组织蛋白酶B的试验后,在保留时间13.6分钟和7.5分钟处检测到新的峰,根据图5的质谱图结果,新峰的分子量与在式(21)的化合物的甘氨酸的C末端分解的片段一致。另一方面,式(26)的化合物在图6的图表中,在保留时间13.5分钟处被检测,在利用组织蛋白酶B的试验后也未检测到新的峰。因此,仅具有肽连接子的式(21)的化合物被组织蛋白酶B特异性切断,由此可知本发明的异双官能单分散聚乙二醇的肽连接子部分被细胞内的酶依赖性地切断。
(实施例39使用组织蛋白酶B的药物-连接子化合物40和46的分解性试验)
对于在实施例30中得到的(40)的药物-连接子化合物和在比较例4中得到的(46)的药物-连接子化合物,进行使用溶酶体内的蛋白分解酶即组织蛋白酶B的肽的分解性试验。以下,与实施例37相同地进行试验,在下述测定条件下进行HPLC测定。测定结果的图表如图7~9所示。
作为结果,本发明中的式(40)的药物-连接子化合物在图7的图表中在保留时间16.8分钟处被检测到,但在利用组织蛋白酶B的试验后,在保留时间6.8分钟处检测到新的峰。根据图8的质谱图结果,新峰与多柔比星一致。另一方面,作为比较例的式(46)的药物-连接子化合物在图9的图表中在保留时间14.7分钟处被检测,在利用组织蛋白酶B的试验后也未观察到新的峰。因此可知,本发明的异双官能单分散聚乙二醇在肽的C末端具有对氨基苄醇基时,通过肽连接子被切断,对氨基苄醇基也脱去,能够以未经化学修饰的结构使药物游离。
·HPLC装置:Alliance(Waters)
·色谱柱:Sun Shell C18(3.0×150mm,2.6μm;株式会社ChromaNikTechnologies)
·流速:0.6mL/分
·分析时间:30分
·柱温度:40℃
·注入量:5μL
·检测器:质谱仪(离子化:ESI),光电二极管阵列(PDA)(波长:480nm)
·流动相A:0.1M甲酸/水
·流动相B:0.1M甲酸/乙腈
·梯度程序:10%-80%(0分钟-20分钟)、80%-95%(20分钟-25分钟)、95%-10%(25分钟-30分钟)
(实施例40使用组织蛋白酶B的药物-连接子化合物42和46的分解性试验)
对于在实施例32中得到的(42)的药物-连接子化合物和在比较例4中得到的(46)的药物-连接子化合物,进行使用溶酶体内的蛋白分解酶即组织蛋白酶B的肽的分解性试验。以下,在与实施例39相同的条件下进行分解性试验和HPLC测定。测定结果的图表如图10所示。
作为结果,本发明中的式(42)的药物-连接子化合物中,与实施例39相同地在利用组织蛋白酶B的试验后在保留时间6.8分钟处检测到新的峰,根据质谱图结果,新峰与多柔比星一致。另一方面,作为比较例的式(46)的药物-连接子化合物中,在利用组织蛋白酶B的试验后也未观察到新的峰。因此可知,本发明的异双官能单分散聚乙二醇在肽的C末端具有对氨基苄醇基时,通过肽连接子被切断,对氨基苄醇基也脱去,能够以未经化学修饰的结构使药物游离。
(实施例41使用药物-连接子化合物40和46的细胞毒性试验)
使用培养基RPMI-1640(10%FBS Pn/St)10mL、HeLa细胞的80%融合细胞,制备为5000细胞/孔的细胞悬液,向96孔微孔板的各板中分注细胞悬液。在二氧化碳培养箱内培养24小时,然后更换培养基,添加以各种浓度溶解有在实施例30中得到的(40)的药物-连接子化合物或在比较例4中得到的(46)的化合物的培养基,在37℃培养24小时。向微孔板的各孔中添加细胞计数试剂盒-8(Cell Counting Kit-8)溶液(株式会社同仁化学制造),在二氧化碳培养箱内进行显色反应2小时。用酶标仪测定450nm处的吸光度,通过下式计算细胞存活率,并评价药物的细胞毒性。各浓度下的细胞存活率示于图11中。
细胞存活率(%)=[(A样品-A空白)/(A细胞-A空白)]×100
A样品:样品的吸光度、
A细胞:仅不含样品的细胞的吸光度、
A空白:不含细胞的空白的吸光度
作为结果,本发明中的式(40)的药物-连接子化合物由于样品浓度依赖性地细胞存活率下降,显示出细胞毒性。另一方面,作为比较例的式(46)的化合物,即使在样品浓度高的条件下,细胞存活率也高,未显示出细胞毒性。因此可知:使用本发明的异双官能单分散聚乙二醇的药物-连接子化合物,与不含肽连接子的比较例的药物-连接子化合物相比,细胞毒性高,能够使药物游离在细胞内。
(实施例42使用药物-连接子化合物42和46的细胞毒性试验)
使用培养基RPMI-1640(10%FBS Pn/St)10mL、HeLa细胞的80%融合细胞,制备为5000细胞/孔的细胞悬液,向96孔微孔板的各板中分注细胞悬液。在二氧化碳培养箱内培养24小时,然后更换培养基,添加以各种浓度溶解有在实施例32中得到的(42)的药物-连接子化合物或在比较例4中得到的(46)的化合物的培养基,在37℃培养24小时。向微孔板的各孔中添加细胞计数试剂盒-8(Cell Counting Kit-8)溶液(株式会社同仁化学制造),在二氧化碳培养箱内进行显色反应2小时。用酶标仪测定450nm处的吸光度,通过下式计算细胞存活率,并评价药物的细胞毒性。各浓度下的细胞存活率示于图12中。
细胞存活率(%)=[(A样品-A空白)/(A细胞-A空白)]×100
A样品:样品的吸光度、
A细胞:仅不含样品的细胞的吸光度、
A空白:不含细胞的空白的吸光度
作为结果,细胞存活率的趋势与实施例41相同,可知:使用本发明的异双官能单分散聚乙二醇的药物-连接子化合物,与不含肽连接子的比较例的药物-连接子化合物相比,细胞毒性高,能够使药物游离在细胞内。
(实施例43各种连接子的亲水性评价)
对于在实施例5、11、18和24中得到的(15)、(21)、(28)和(34)的化合物,在下述测定条件下进行HPLC测定,各种连接子的峰保留时间如下表所示。
作为结果,包含缬氨酸-瓜氨酸的连接子的保留时间最短,接着包含缬氨酸-丙氨酸、苯丙氨酸-甘氨酸的连接子依次保留时间较短。因此可知:在本发明的异双官能单分散聚乙二醇中,包含缬氨酸-瓜氨酸的连接子可以进一步提高亲水性。
·HPLC装置:Thermo Fisher Ultimate3000
·色谱柱:Sun Shell C18(3.0×150mm,2.6μm;株式会社ChromaNikTechnologies)
·流速:0.6mL/分
·分析时间:80分
·柱温度:40℃
·注入量:10μL
·检测器:Corona电喷雾检测器(CAD)
·流动相A:0.1M甲酸/水
·流动相B:0.1M甲酸/乙腈
·梯度程序:20%-95%(0分钟-75分钟)、95%-95%(75分钟-80分钟)
[表1]
化合物编号(肽) | 保留时间(分钟) |
化合物15(苯丙氨酸甘氨酸) | 29.8 |
化合物21(缬氨酸-丙氨酸甘氨酸) | 26.4 |
化合物28(缬氨酸-丙氨酸甘氨酸) | 27.3 |
化合物34(缬氨酸-瓜氨酸) | 23.4 |
本发明的异双官能单分散聚乙二醇通过在细胞内被酶切断而从药物中游离出来,从而抑制了以连接子结合的状态存在而引起的药理活性降低。
产业上的可利用性
本发明的异双官能单分散聚乙二醇由于具有肽连接子被细胞内的酶分解而缓释药物且有效遮蔽药物疏水性的相邻的两条单分散聚乙二醇侧链,因此对生理活性蛋白、肽、抗体、核酸和低分子药物等生物功能分子、药物递送系统中的药物载体、或诊断用材料或医疗器械等的修饰很有用。
本申请以在日本提出申请的日本专利特愿2019-176066为基础,其全部内容包含在本说明书中。
Claims (11)
1.一种异双官能单分散聚乙二醇,其如式(1)所示:
式(1)中,X1和Y1分别为至少含有与生物功能分子中存在的官能团反应而形成共价键的官能团的原子团,原子团X1所含的所述官能团与原子团Y1所含的所述官能团互不相同;
R1是碳原子数为1~7的烃基或氢原子;
n是3~72的整数;
A1表示-L1-(CH2)m1-L2-、-L1-(CH2)m1-L2-(CH2)m2-、酰胺键、氨基甲酸酯键、仲氨基或单键,m1和m2各自独立地表示1~5的整数;
B1表示-CH2-L3-、-CH2-L3-(CH2)m3-L4-或-CH2-L3-(CH2)m3-L4-(CH2)m4-,m3和m4各自独立地表示1~5的整数;
W是具有苯丙氨酸、亮氨酸、缬氨酸、异亮氨酸中的至少一种的2~4个残基的寡肽;
Z是具有与肽的C末端结合的双官能对氨基苄醇基的间隔基;
a1和a2在a1=1时是a2=0,在a1=0时是a2=1;
b是0或1;
C1表示-L5-(CH2)m5-、-L5-(CH2)m5-L6-(CH2)m6-、酰胺键或单键,m5和m6各自独立地表示1~5的整数;
L1~L6各自独立地表示醚键、氨基甲酸酯键、酰胺键、仲氨基、羰基或单键。
2.根据权利要求1所述的异双官能单分散聚乙二醇,其中,W包含苯丙氨酸、亮氨酸、缬氨酸、异亮氨酸的疏水性中性氨基酸中的至少一种,且除此之外的氨基酸是由不包括半胱氨酸的中性氨基酸组成的2~4个残基的寡肽。
3.根据权利要求1所述的异双官能单分散聚乙二醇,其中,W包含苯丙氨酸、亮氨酸、缬氨酸、异亮氨酸的疏水性中性氨基酸中的至少一种,且除此之外的氨基酸是具有丙氨酸、甘氨酸、瓜氨酸、脯氨酸、丝氨酸、天冬酰胺中的至少一种的2~4个残基的寡肽。
4.根据权利要求1所述的异双官能单分散聚乙二醇,其中,W是C末端氨基酸为甘氨酸的寡肽。
5.根据权利要求1所述的异双官能单分散聚乙二醇,其中,W是二肽。
6.根据权利要求1~5中任一项所述的异双官能单分散聚乙二醇,其中,式(1)中的X1和Y1分别独立地选自式(a)、式(b1)、式(b2)、式(c)、式(d1)、式(d2)、式(e)、式(f)、式(g)、式(h)、式(i)、式(j)、式(k)、式(l)、式(m)、式(n)和式(o)构成的组:
-COOH(f) -SH(g)-NH2(i)-O-NH2(j)/>-C≡C-R4(I)/>-N3(n)-OH(O)
式(d1)、(d2)中,R2是氢原子或碳原子数为1~5的烃基;式(e)中,R3是选自氯原子、溴原子和碘原子的卤素原子;以及,式(l)中,R4是氢原子或碳原子数为1~5的烃基。
7.一种含有异双官能单分散聚乙二醇而成的抗体-药物复合体,其如式(2)所示:
式(2)中,X2与Y2中的一个为抗体,另一个为药物;
R1是碳原子数为1~7的烃基或氢原子;
n是3~72的整数;
A2表示-L1-(CH2)m1-L7-、-L1-(CH2)m1-L8-、-L1-(CH2)m1-L2-(CH2)m2-L8-或-L8-,m1和m2各自独立地表示1~5的整数;
B2表示-CH2-L9-、-CH2-L9-(CH2)m3-L10-、-CH2-L9-(CH2)m3-L10-(CH2)m4-L11-、-CH2-L12-、-CH2-L9-(CH2)m3-L12-或-CH2-L9-(CH2)m3-L10-(CH2)m4-L12-,m3和m4各自独立地表示1~5的整数;
L1和L2各自独立地表示醚键、氨基甲酸酯键、酰胺键、仲氨基或单键;
L7、L9、L10和L11各自独立地表示醚键、氨基甲酸酯键、酰胺键、仲氨基或羰基;
L8和L12表示酰胺键、氨基甲酸酯键、马来酰亚胺与硫醇的键、硫醚键、二硫键、碳酸酯键、酯键、醚键、1H-1,2,3-三唑-1,4-二基结构、仲氨基、酰肼基、氧酰胺基或含有这些的烃基或单键;
W是具有苯丙氨酸、亮氨酸、缬氨酸、异亮氨酸中的至少一种的2~4个残基的寡肽;
Z是具有与肽的C末端结合的双官能对氨基苄醇基的间隔基;
a3和a4在X2为药物时是a3=1且a4=0,在Y2为药物时是a3=0且a4=1;
b是0或1;以及
C2表示酰胺键、氨基甲酸酯键、马来酰亚胺与硫醇的键、硫醚键、二硫键、碳酸酯键、酯键、醚键、1H-1,2,3-三唑-1,4-二基结构、仲氨基、酰肼基、氧酰胺基或含有这些的烃基。
8.根据权利要求7所述的抗体-药物复合体,其中,W包含苯丙氨酸、亮氨酸、缬氨酸、异亮氨酸的疏水性中性氨基酸中的至少一种,且除此之外的氨基酸是由不包括半胱氨酸的中性氨基酸组成的2~4个残基的寡肽。
9.根据权利要求7所述的抗体-药物复合体,其中,W包含苯丙氨酸、亮氨酸、缬氨酸、异亮氨酸的疏水性中性氨基酸中的至少一种,且除此之外的氨基酸是具有丙氨酸、甘氨酸、瓜氨酸、脯氨酸、丝氨酸、天冬酰胺中的至少一种的2~4个残基的寡肽。
10.根据权利要求7所述的抗体-药物复合体,其中,W是C末端氨基酸为甘氨酸的寡肽。
11.根据权利要求7所述的抗体-药物复合体,其中,W是二肽。
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1706865A (zh) * | 2004-06-11 | 2005-12-14 | 北京键凯科技有限公司 | 多叉分支的聚乙二醇-氨基酸寡肽及其活性衍生物和药物结合物 |
CN101168594A (zh) * | 2006-10-24 | 2008-04-30 | 北京键凯科技有限公司 | 寡肽为骨架的聚乙二醇活性衍生物、其制备方法及与药物分子的结合物 |
CN102985462A (zh) * | 2010-06-25 | 2013-03-20 | 日油株式会社 | 支链异聚乙二醇和中间体 |
CN104109235A (zh) * | 2014-05-30 | 2014-10-22 | 厦门赛诺邦格生物科技有限公司 | 一种具有氮原子支化中心的单一官能化聚乙二醇、制备方法及其生物相关物质 |
WO2014177042A1 (zh) * | 2013-04-28 | 2014-11-06 | Qin Gang | 一种新型的连接子及其制备方法和用途 |
CN104448295A (zh) * | 2013-12-02 | 2015-03-25 | 北京键凯科技有限公司 | 聚乙二醇-多爪寡肽键合的雷帕霉素衍生物 |
CN108530617A (zh) * | 2017-03-05 | 2018-09-14 | 厦门赛诺邦格生物科技股份有限公司 | 一种支化聚乙二醇异双官能化衍生物、其制备方法及其双组份生物相关物质缀合物 |
WO2019176875A1 (ja) * | 2018-03-13 | 2019-09-19 | 日油株式会社 | 主鎖および側鎖に単分散ポリエチレングリコールを有するヘテロ二官能性化合物 |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8308235D0 (en) | 1983-03-25 | 1983-05-05 | Celltech Ltd | Polypeptides |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
GB8607679D0 (en) | 1986-03-27 | 1986-04-30 | Winter G P | Recombinant dna product |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
EP0247730A3 (en) | 1986-04-28 | 1989-04-12 | Antibody Technology Limited | Antibodies, their preparation and use and products containing them |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
DE68921982T4 (de) | 1988-06-14 | 1996-04-25 | Cetus Oncology Corp | Kupplungsmittel und sterisch gehinderte, mit disulfid gebundene konjugate daraus. |
JP3068180B2 (ja) | 1990-01-12 | 2000-07-24 | アブジェニックス インコーポレイテッド | 異種抗体の生成 |
US5770429A (en) | 1990-08-29 | 1998-06-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
EP0519596B1 (en) | 1991-05-17 | 2005-02-23 | Merck & Co. Inc. | A method for reducing the immunogenicity of antibody variable domains |
US5639641A (en) | 1992-09-09 | 1997-06-17 | Immunogen Inc. | Resurfacing of rodent antibodies |
US7063845B2 (en) | 2000-04-28 | 2006-06-20 | Gemini Science, Inc. | Human anti-CD40 antibodies |
AR039067A1 (es) | 2001-11-09 | 2005-02-09 | Pfizer Prod Inc | Anticuerpos para cd40 |
NZ534174A (en) | 2002-01-09 | 2007-03-30 | Medarex Inc | An isolated human monoclonal antibody which binds to human CD30 |
ES2544527T3 (es) | 2002-07-31 | 2015-09-01 | Seattle Genetics, Inc. | Conjugados de fármacos y su uso para tratar el cáncer, una enfermedad autoinmune o una enfermedad infecciosa |
US8088387B2 (en) | 2003-10-10 | 2012-01-03 | Immunogen Inc. | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
ZA200603619B (en) | 2003-11-06 | 2008-10-29 | Seattle Genetics Inc | Monomethylvaline compounds capable of conjugation to ligands |
WO2005058367A2 (en) | 2003-12-16 | 2005-06-30 | Nektar Therapeutics Al, Corporation | Pegylated small molecules |
US8562965B2 (en) * | 2004-05-03 | 2013-10-22 | Nektar Therapeutics | Polymer derivatives comprising an acetal or ketal branching point |
NZ550934A (en) | 2004-05-19 | 2010-05-28 | Medarex Inc | Chemical linkers and conjugates thereof |
KR20120064120A (ko) | 2004-06-01 | 2012-06-18 | 제넨테크, 인크. | 항체 약물 접합체 및 방법 |
AU2005254736B2 (en) * | 2004-06-18 | 2011-08-18 | Ipf Pharmaceuticals Gmbh | Oligomeric peptides and their use for the treatment of HIV infections |
JP2008521828A (ja) | 2004-11-29 | 2008-06-26 | シアトル ジェネティックス, インコーポレイテッド | 操作された抗体およびイムノコンジュゲート |
WO2006088248A1 (ja) * | 2005-02-18 | 2006-08-24 | Nof Corporation | ポリオキシアルキレン誘導体 |
FR2949469A1 (fr) | 2009-08-25 | 2011-03-04 | Sanofi Aventis | Derives anticancereux, leur preparation et leur application en therapeutique |
DE102009050170B4 (de) | 2009-10-21 | 2013-08-01 | Diehl Ako Stiftung & Co. Kg | Hausautomatisierungs- und Hausinformationssystem |
AU2012301793A1 (en) * | 2011-08-30 | 2014-03-20 | Quanta Biodesign, Ltd. | Branched discrette PEG constructs |
JP6248875B2 (ja) | 2014-09-17 | 2017-12-20 | トヨタ紡織株式会社 | 柱状集合体 |
CN110475802B (zh) * | 2017-03-30 | 2022-03-08 | 日油株式会社 | 异双官能性单分散聚乙二醇以及使用该异双官能性单分散聚乙二醇的缀合物 |
JP6630390B2 (ja) | 2018-03-29 | 2020-01-15 | アオイ電子株式会社 | 半導体装置 |
-
2020
- 2020-09-25 WO PCT/JP2020/036195 patent/WO2021060439A1/ja unknown
- 2020-09-25 KR KR1020227013431A patent/KR20220069989A/ko unknown
- 2020-09-25 US US17/762,719 patent/US20220362397A1/en active Pending
- 2020-09-25 CN CN202080067753.8A patent/CN114450324B/zh active Active
- 2020-09-25 JP JP2021549023A patent/JPWO2021060439A1/ja active Pending
- 2020-09-25 CA CA3156027A patent/CA3156027A1/en active Pending
- 2020-09-25 EP EP20868583.4A patent/EP4036149A4/en active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1706865A (zh) * | 2004-06-11 | 2005-12-14 | 北京键凯科技有限公司 | 多叉分支的聚乙二醇-氨基酸寡肽及其活性衍生物和药物结合物 |
CN101168594A (zh) * | 2006-10-24 | 2008-04-30 | 北京键凯科技有限公司 | 寡肽为骨架的聚乙二醇活性衍生物、其制备方法及与药物分子的结合物 |
CN102985462A (zh) * | 2010-06-25 | 2013-03-20 | 日油株式会社 | 支链异聚乙二醇和中间体 |
WO2014177042A1 (zh) * | 2013-04-28 | 2014-11-06 | Qin Gang | 一种新型的连接子及其制备方法和用途 |
CN104448295A (zh) * | 2013-12-02 | 2015-03-25 | 北京键凯科技有限公司 | 聚乙二醇-多爪寡肽键合的雷帕霉素衍生物 |
CN104109235A (zh) * | 2014-05-30 | 2014-10-22 | 厦门赛诺邦格生物科技有限公司 | 一种具有氮原子支化中心的单一官能化聚乙二醇、制备方法及其生物相关物质 |
CN108530617A (zh) * | 2017-03-05 | 2018-09-14 | 厦门赛诺邦格生物科技股份有限公司 | 一种支化聚乙二醇异双官能化衍生物、其制备方法及其双组份生物相关物质缀合物 |
WO2019176875A1 (ja) * | 2018-03-13 | 2019-09-19 | 日油株式会社 | 主鎖および側鎖に単分散ポリエチレングリコールを有するヘテロ二官能性化合物 |
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US20220362397A1 (en) | 2022-11-17 |
WO2021060439A1 (ja) | 2021-04-01 |
EP4036149A1 (en) | 2022-08-03 |
KR20220069989A (ko) | 2022-05-27 |
JPWO2021060439A1 (zh) | 2021-04-01 |
EP4036149A4 (en) | 2023-10-25 |
CN114450324A (zh) | 2022-05-06 |
CA3156027A1 (en) | 2021-04-01 |
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