CN101098854A - 二价连接体及其轭合物 - Google Patents

二价连接体及其轭合物 Download PDF

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CN101098854A
CN101098854A CNA2005800314046A CN200580031404A CN101098854A CN 101098854 A CN101098854 A CN 101098854A CN A2005800314046 A CNA2005800314046 A CN A2005800314046A CN 200580031404 A CN200580031404 A CN 200580031404A CN 101098854 A CN101098854 A CN 101098854A
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I·R·弗拉霍夫
C·P·利蒙
A·萨泰亚姆
S·J·霍沃德
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Abstract

描述了包括在或用于制备维生素、药物、诊断试剂和/或显像剂的二价连接体，该连接体衍生自式(V)、(VI)和(VII)化合物，其中X1和X2为离去基团，其它变量的定义同权利要求书。

Description

二价连接体及其轭合物
相关申请的交叉参考
本申请要求2004年7月23日提交的美国临时专利申请顺序号60/590,580的35 U.S.C.§119(e)下的优先权，其内容通过引用整体结合到本文中。
发明领域
本发明涉及二价连接体及其合成和用途。本发明尤其涉及在制备维生素、药物、诊断试剂和/或显像剂轭合物中二价连接体的合成和用途。
背景
药物、维生素、诊断和显像剂轭合物已用于治疗、诊断和评价人和动物的各种疾病。在很多情况下，这些药物、维生素、诊断和显像剂轭合物包含插入连接体，这些连接体将例如靶向配体与药物、诊断试剂或显像剂分离。这些连接体包括各种二价片段，这些片段可用于分离或当连接在一起包含在轭合物中时，例如将药物、诊断试剂或显像剂与轭合物的其它部分例如维生素或其它靶向配体分开。当给予人或动物时，这些连接体也可对存在的代谢、生理或生物条件保持稳定，或者这些连接体可在此类条件下经历各种解离和/或断裂途径。对通常可用于药物、维生素、诊断和显像剂轭合物的二价连接体有不断的需求。
发明概述
例示性地，本发明包括二价连接体，这些连接体或者指可用于偶联、连接、结合、连结或缔合两个或多个化学实体的二价连接体。该偶联、连接、连结或缔合可用于形成此类化学实体的轭合物。那些化学实体包括靶向配体和受体-结合配体，例如维生素。那些化学实体还包括治疗各种疾病或疾病状态的药物，和用于诊断、检测或监测各种疾病或疾病状态的显像剂和诊断试剂。
在一个实施方案中，一个化学实体包含维生素受体-结合部分，另一个实体包含药物、显像剂、诊断试剂、另一种二价连接体或与药物、显像剂、诊断试剂轭合的另一种二价连接体。应认识到，可在两个或多个化学实体之间使用多种连接体以改变两个实体之间的距离，和/或改变由其制备的轭合物的物理化学性质。
在另一个实施方案中，所述化合物包含可被第一种亲核体置换的第一离去基团、连接体区域和可被第二种亲核体置换的第二离去基团，其中第一种亲核体是维生素受体结合部分，连接体区域包含一个或多个二价连接体单元，它们可相同或不同，第二种亲核体是药物、显像剂、诊断试剂或另一种二价连接体。
在另一个实施方案中，描述具有结构(V)的化合物
Figure A20058003140400051
其中n为1至约4的整数；Ra和Rb各自独立选自氢和烷基，包括低级烷基例如任选为支链的C1-C4烷基；或Ra和Rb与所连接的碳原子结合在一起形成碳环；且X1和X2为各自独立选择的离去基团。在一个方面，独立选择的离去基团X1和X2各自可被亲核体置换，该亲核体为例如药物、维生素、显像剂、诊断试剂或另一种二价连接体亲核体等。
在另一个实施方案中，通过用亲核体例如药物、维生素、显像剂、诊断试剂或另一种二价连接体亲核体等置换一个或多个离去基团X1和X2，由式(V)化合物形成轭合物。
在另一个实施方案中，描述具有结构(VI)的化合物
Figure A20058003140400061
其中m为1至约4的整数；且X1和X2为各自独立选择的离去基团。在一个方面，独立选择的离去基团X1和X2各自可被亲核体置换，该亲核体为例如药物、维生素、显像剂、诊断试剂或另一种二价连接体亲核体等。
在另一个实施方案中，通过用亲核体例如药物、维生素、显像剂、诊断试剂或另一种二价连接体亲核体等置换一个或多个离去基团X1和X2，由式(VI)化合物形成轭合物。
在另一个实施方案中，描述具有结构(VII)的化合物
其中m为1至约4的整数；且X1和X2为各自独立选择的离去基团。在一个方面，独立选择的离去基团X1和X2各自可被亲核体置换，该亲核体为例如药物、维生素、显像剂、诊断试剂或另一种二价连接体亲核体等。
在另一个实施方案中，通过用亲核体例如药物、维生素、显像剂、诊断试剂或另一种二价连接体亲核体等置换一个或多个离去基团X1和X2，由式(VII)化合物形成轭合物。
在一个方面，轭合物具有以下结构(VIII)之一
Figure A20058003140400071
其中n为1至约4的整数；Ra和Rb各自独立选自氢和烷基，包括低级烷基例如任选为支链的C1-C4烷基；或Ra和Rb与所连接的碳原子结合在一起形成碳环；X1和X2为各自独立选择的离去基团；且L1和L2各自为独立选择的二价连接体。
在另一个实施方案中，轭合物具有以下结构(IX)之一
Figure A20058003140400072
其中m为1至约4的整数；X1和X2为各自独立选择的离去基团；且L1和L2各自为独立选择的二价连接体。
在另一个实施方案中，轭合物具有以下结构(X)之一
Figure A20058003140400081
其中m为1至约4的整数；X1和X2为各自独立选择的离去基团；且L1和L2各自为独立选择的二价连接体。
附图简述
图1a显示实施例1中化合物5的质谱；
图1b显示实施例1中化合物5的1H NMR图谱；
图2显示实施例3中化合物10的1H NMR图谱；和
图3显示实施例4中化合物12的1H NMR图谱。
详述
本文中描述了用于轭合物或用于制备轭合物的二价连接体。这些二价连接体可用于制备药物轭合物、显像剂轭合物和/或诊断试剂轭合物。药物轭合物包括靶向药物轭合物，例如美国专利申请公布号US-2005-0002942-A1中所述维生素受体-结合药物轭合物，和美国专利申请公布号US-2001-0031252-A1和US-2003-0086900-A1中所述其它药物轭合物。显像剂轭合物和诊断试剂轭合物包括美国专利申请公布号US-2004-0033195-A1和国际专利申请公布号WO03/097647中所述那些。前述专利申请公布的公开内容各自通过引用结合到本文中。
应认识到，可用本文中所述二价连接体制备药物类似物和衍生物的轭合物、维生素类似物和衍生物的轭合物、显像剂类似物和衍生物的轭合物和诊断试剂类似物和衍生物的轭合物。另外，除非另外说明，应理解术语药物包括其类似物和衍生物；应理解术语维生素包括其类似物和衍生物；应理解术语显像剂包括其类似物和衍生物；和应理解术语诊断试剂包括其类似物和衍生物。
本文中所述二价连接体可用作改变药物、维生素、显像剂或诊断试剂与它轭合的部分之间整个长度的间隔基。另外，本文中所述二价连接体可用于改变其中包含它们的药物、维生素、显像剂或诊断试剂轭合物的物理化学性质、溶解性和其它性质。
例示性地，本文中所述二价连接体可包含在用于制备式(I)维生素受体结合药物轭合物、维生素受体结合显像剂轭合物和维生素受体结合诊断试剂轭合物的连接体中
V-L-D
V-L-IA
V-L-DA
(I)
其中V为维生素受体-结合部分，包括其类似物或衍生物；L为连接体；D为药物，包括其类似物或衍生物；IA为显像剂，包括其类似物或衍生物；和DA为诊断试剂，包括其类似物或衍生物。连接体(L)可包含多种二价连接体，包括本文中所述二价连接体。
在一个实施方案中，本文中所述二价连接体是式(II)化合物
Figure A20058003140400101
其中n为选自1至约4的整数；Ra和Rb各自独立选自氢和烷基，包括低级烷基例如任选为支链的C1-C4烷基；或Ra和Rb与所连接的碳原子结合在一起形成碳环；R为任选取代的烷基、任选取代的酰基或适当选择的氮保护基团；和(*)表示轭合物的药物、维生素、显像剂、诊断试剂、其它二价连接体或其它部分的连接位点。
在另一个实施方案中，本文中所述二价连接体包括式(III)化合物
其中m为选自1至约4的整数；R为任选取代的烷基、任选取代的酰基或适当选择的氮保护基团；和(*)表示轭合物的药物、维生素、显像剂、诊断试剂、其它二价连接体或其它部分的连接位点。
在另一个实施方案中，本文中所述二价连接体包括式(IV)化合物
Figure A20058003140400111
其中m为选自1至约4的整数；R为任选取代的烷基、任选取代的酰基或适当选择的氮保护基团；和(*)表示轭合物的药物、维生素、显像剂、诊断试剂、其它二价连接体或其它部分的连接位点。
在另一个实施方案中，本文中所述二价连接体包括式(V)、(VI)和(VII)化合物
Figure A20058003140400112
其中n和m各自独立选自1至约4的整数；Ra和Rb各自独立选自氢和烷基，包括低级烷基例如任选为支链的C1-C4烷基；或Ra和Rb与所连接的碳原子结合在一起形成碳环；且X1和X2为各自独立选择的离去基团，这些离去基团可被轭合物的药物、维生素、显像剂、诊断试剂、另一种二价连接体或另外的部分亲核置换。
例示性地，可由本文中所述二价连接体形成的维生素-药物轭合物包括式(VIII)化合物
Figure A20058003140400121
其中V、D和n同本文中所述；n为1至约4的整数；Ra和Rb各自独立选自氢和烷基，包括低级烷基例如任选为支链的C1-C4烷基；或Ra和Rb与所连接的碳原子结合在一起形成碳环；且L1和L2各自为独立选择的用于制备轭合物的二价连接体。同样可以理解，对应于式(VIII)的维生素-显像剂和维生素-诊断试剂轭合物也可由本文中所述二价连接体形成。
例示性地，可由本文中所述二价连接体形成的维生素-药物轭合物包括式(IX)化合物
Figure A20058003140400122
其中V、D和n同本文中所述；m为1至约4的整数；且L1和L2各自为独立选择的用于完成轭合物的二价连接体。同样可以理解，对应于式(IX)的维生素-显像剂和维生素-诊断试剂轭合物也可由本文中所述二价连接体形成。
例示性地，可由本文中所述二价连接体形成的维生素-药物轭合物包括式(X)化合物
Figure A20058003140400131
其中V、D和n同本文中所述；m为1至约4的整数；且L1和L2各自为独立选择的用于完成轭合物的二价连接体。同样可以理解，对应于式(X)的维生素-显像剂和维生素-诊断试剂轭合物也可由本文中所述二价连接体形成。
还应理解，当任一V、L2和/或D与本文中所述二价连接体例如式(VIII)、(IX)和/或(X)的二价连接体的羰基连接时，通过杂原子例如氧、硫、任选取代的氮等进行该连接。
在另一示例性实施方案中，本文中描述了用于制备药物、维生素、显像剂或诊断试剂轭合物的中间体。此类中间体可随后与其它成分连接，形成维生素、显像剂或诊断试剂轭合物。本文中所述中间体包括式XI化合物
Figure A20058003140400141
其中V、D、L1、L2、X1和X2同本文中所述；且n为1至约4的整数。同样可以理解，对应于式(XI)的维生素-显像剂和维生素-诊断试剂轭合物也可由本文中所述二价连接体形成。
例示性地，可由本文中所述二价连接体形成的维生素-药物轭合物包括式(XII)化合物
Figure A20058003140400142
其中V、D、L1、L2、X1和X2同本文中所述；且m为1至约4的整数。同样可以理解，对应于式(XII)的维生素-显像剂和维生素-诊断试剂轭合物也可由本文中所述二价连接体形成。
例示性地，可由本文中所述二价连接体形成的维生素-药物轭合物包括式(XIII)化合物
Figure A20058003140400151
其中V、D、L1、L2、X1和X2同本文中所述；且m为1至约4的整数。同样可以理解，对应于式(XIII)的维生素-显像剂和维生素-诊断试剂轭合物也可由本文中所述二价连接体形成。
还应理解，当任一V、L2和/或D与本文中所述二价连接体例如式(XI)、(XII)和(XIII)的二价连接体的羰基连接时，通过杂原子例如氧、硫、任选取代的氮等进行该连接。
在一个示例性实施方案中，离去基团X1为芳硫基。在一个方面，芳硫基为杂芳硫基，且包括但不限于任选取代的2-吡啶硫基、任选取代的4-吡啶硫基等。在另一个示例性方面，取代基包括吸电子取代基，例如氰基、硝基、烷基磺酰基、芳基磺酰基、卤素、卤代烷基、酰基及其衍生物、羧基及其衍生物等及其组合。
在另一个示例性实施方案中，离去基团X2为芳氧基。在一个方面，芳氧基为任选取代的苯基。在另一个示例性方面，芳氧基为任选取代的杂芳氧基，且包括但不限于任选取代的苯并三唑等。在另一个示例性方面，取代基包括吸电子取代基，例如氰基、硝基、烷基磺酰基、芳基磺酰基、卤素、卤代烷基、酰基及其衍生物、羧基及其衍生物等及其组合。
示例性离去基团X1包括式(XIV)化合物
Figure A20058003140400161
其中(*)表示本文中所述二价连接体的硫的连接位点。在一个方面，每个具有式(XIV)的离去基团X1可任选被一个或多个选自以下的取代基或另外的取代基取代：卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、硝基等。其它示例性离去基团包括烷基和芳基磺酰基离去基团，例如但不限于
Figure A20058003140400162
其中R为烷基或芳基，它们各自可任选被例如卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、硝基等取代；且其中(*)表示本文中所述二价连接体的硫的连接位点。
示例性离去基团X2包括式(XV)化合物
Figure A20058003140400171
其中(*)表示本文中所述二价连接体的羰基连接位点。在一个方面，每个具有式(XV)的离去基团X2可任选被一个或多个选自以下的取代基或另外的取代基取代：卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、硝基等。
包含离去基团例如式XIII、XIV和XV中所示那些的二价连接体可按本文中所述实施例中所述的相应合成方法制备。
在另一个示例性方面，本文中所述维生素受体结合药物传递轭合物中间体包括具有下式的化合物或其保护的衍生物：
Figure A20058003140400172
其中Ra和Rb各自独立选自氢和烷基，包括低级烷基例如任选为支链的C1-C4烷基；或Ra和Rb与所连接的碳原子结合在一起形成碳环；Y为氢或取代基，示例性地吸电子取代基包括但不限于硝基、氰基、卤素、烷基磺酰基、羧酸衍生物等；ls为键或另一种二价连接体；其中V定义同本文。应认识到，其它取代基例如长链和/或支链烷基、烷氧基、烷氧基烷基等可任选存在于这些药物传递轭合物的半胱氨酸或高半胱氨酸部分上。可以理解，这些药物传递轭合物的半胱氨酸部分可考虑环状形式。在一个方面，Ra为氢，且Rb为烷基例如甲基。在另一个方面，Ra和Rb均为烷基，它们相同或不同，例如均为甲基。在另一个方面，Ra和Rb与所连接的碳结合在一起形成螺环丙基。
在本文中所述维生素受体结合药物传递轭合物中间体的另一个示例性方面，该中间体包括具有下式的化合物或其保护的衍生物：
Figure A20058003140400181
其中V为维生素或其类似物或衍生物；AA为氨基酸，示例性地选自天然存在的氨基酸或其立体异构体；Ra和Rb各自独立选自氢和烷基，包括低级烷基，例如任选为支链的C1-C4烷基；或Ra和Rb与所连接的碳原子结合在一起形成碳环，Y为氢或取代基，示例性地吸电子取代基包括但不限于硝基、氰基、卤素、烷基磺酰基、羧酸衍生物等，n和m为独立选择的整数，例如1、2或3，且p为整数，例如1、2、3、4或5。应认识到，其它取代基例如长链和/或支链烷基、烷氧基、烷氧基烷基等可任选存在于这些药物传递轭合物的半胱氨酸或高半胱氨酸部分上。可以理解，这些药物传递轭合物的半胱氨酸部分可考虑环状形式。AA也可以是任何其它氨基酸，例如具有以下通式的任何氨基酸：
-N(R)-(CR′R″)q-C(O)-
其中R为氢、烷基、酰基或合适的氮保护基团，R′和R″为氢或取代基，每次出现时，它们各自独立选择，且q为整数，例如1、2、3、4或5。例示性地，R′和/或R″独立对应于但不限于存在于天然氨基酸中的氢或侧链，例如甲基、苄基、羟甲基、硫甲基、羧基、羧甲基、胍基丙基等，及其衍生物和保护的衍生物。上述式包括所有的立体异构体形式。例如，氨基酸可选自天冬酰胺、天冬氨酸、半胱氨酸、谷氨酸、赖氨酸、谷氨酰胺、精氨酸、丝氨酸、鸟氨酸(ornitine)、苏氨酸等。在本文中所述的维生素受体结合药物传递轭合物中间体的另一个示例性方面，所述药物或其类似物或衍生物包括烷基硫醇亲核体。
可认识到，本文中所述二价连接体在某些化学、环境或生理条件下可进行解离。尤其是，本文中所述二价连接体在生理条件下，例如通过谷胱甘肽介导的机制作用可进行解离。在此类实施方案中，那些连接体又可称为能释放的连接体。
本文中所述二价连接体的示例性解离机制包括以下1，4和1，6断裂机制
Figure A20058003140400191
其中X为外源性或内源性亲核体、谷胱甘肽或生物还原剂等，且Z或Z′中任一个为维生素或其类似物或衍生物，或药物或其类似物或衍生物，或与二价连接体的其它部分连接的维生素或药物部分。可以理解，尽管以上断裂机制描述为协同机制，但可能发生任何数目的不连续步骤，以实现二价连接体最终断裂为所示终产物。例如可以认识到，通过氨基甲酸酯部分的酸催化消除反应，也可发生键裂，它可通过由以上实例中举例说明的β硫芳基或二硫化物提供的稳定作用，得到邻位协助。在该实施方案中的那些变化形式中，能释放的连接体为氨基甲酸酯部分。或者，可通过对二硫化物基团进行亲核攻击引发断裂，导致解离形成硫醇盐。该硫醇盐可在分子间置换碳酸或氨基甲酸部分，并形成相应的硫杂环丙烷。在含苄基的二价连接体的情况，示例性二硫键断裂后，得到的苯基硫醇盐可通过形成共振稳定的中间体，进一步断裂释放碳酸或氨基甲酸部分。在任一此类情况下，可通过可能与存在的化学、代谢、生理或生物条件有关的任何机制，实现本文中所述示例性二价连接体的能释放性质。
通用二硫化物的形成
如流程1中所示，通常可通过使烷基或芳基磺酰基硫烷基衍生物，或相应的杂芳基二硫烷基衍生物例如吡啶-2-基二硫烷基衍生物等与亚烷基硫醇(alkylenethiol)衍生物反应，形成二硫化物基团。
流程1
Figure A20058003140400201
可用于该反应的溶剂包括THF、EtOAc、CH2Cl2、CHCl3、CCl4、DMF、DMSO等。该转化可采用的温度在0℃-80℃之间变化。可用本领域公认的方案，也可按照Ranasinghe and Fuchs，Synth.Commun.18(3)，227-32(1988)中的方法，其公开内容通过引用结合到本文中，制备需要的烷基或芳基磺酰基硫烷基衍生物。其它制备不对称二烷基二硫化物的方法基于不对称杂芳基-烷基二硫化物，例如2-硫基吡啶基、3-硝基-2-硫基吡啶基及类似的二硫化物与烷基硫醇的转硫醇作用，如WO 88/01622、欧洲专利申请号0116208A1和美国专利号4,691,024中所述，它们的公开内容通过引用结合到本文中。
通用碳酸酯硫代碳酸酯和氨基甲酸酯的形成
通常可按流程2中所示，通过使羟基-取代的化合物、硫基-取代的化合物或胺-取代的化合物分别与其中X为合适离去基团的活化烷氧基羰基衍生物反应，形成碳酸酯、硫代碳酸酯和氨基甲酸酯。
流程2
Figure A20058003140400211
其中Q为氧、硫、任选取代的氮、任选保护的氮等。可用于该反应的溶剂包括THF、EtOAc、CH2Cl2、CHCl3、CCl4、DMF、DMSO等。该转化采用的温度可在0℃-80℃之间变化。可使用任何碱性催化剂例如无机碱、胺碱、聚合物结合的碱等促进该反应。
实施例
实施例1：6-三氟甲基-1-[2-(2-吡啶基联硫基)乙氧基羰基氧基]苯并三唑
按流程3制备实施例1。
流程3
Figure A20058003140400221
(a)4-二甲基氨基吡啶(DMAP)，CH2Cl2；(b)Et2O；(c)CH3CH.
步骤(a)将4-(二甲基氨基)吡啶(3.0g；24.68mmol；1.03当量)的10mL无水甲醇溶液加入2-(2-吡啶基联硫基)乙醇盐酸盐(化合物(1a)；C7H9NS2O·HCl；5.4g；24mmol)的10ml无水甲醇悬浮液中，将混合物搅拌，形成澄清溶液。几分钟内，溶液变混浊，形成微粒悬浮液，使该悬浮液经闪层析(FC)纯化。用140g硅胶60和5％甲醇/CH2Cl2形成贮藏500ml溶剂的24cm×4.3cm硅胶床，进行FC。用20mLCH2Cl2将所述悬浮液上柱，柱用5％甲醇/CH2Cl2洗脱，按30mL组分进行标准收集，加上UV-检测。可通过TLC(1∶1的己烷∶EtOAc)，自组分2-9中测得产物化合物(1b)。
步骤(b)将1-羟基-6-(三氟甲基)苯并三唑(化合物(2)；C7H4F3N3O；2.3g；0.11mol；Aldrich)溶于770mL乙醚，将上清夜倾入2L RB烧瓶中。在室温下，在15分钟内，将氯甲酸三氯甲酯(化合物(3)；C2Cl4O2；107g；0.053mol；6.0mL)加入该澄清无色溶液中。将混合物温和加热至40-50℃，保持1小时，冷却至室温。将溶液过滤，将沉淀用乙醚(10×30mL)洗涤。沉淀为白色粉末，真空干燥，得到16.95g(74％收率)。其它合成细节见Ogura等在Synthesis，1987，557-560中描述，其公开内容通过引用结合到本文中。
步骤(c)在室温下，搅拌下将化合物(1b)(约7.5mmol)的10mL乙腈溶液在2分钟内加入化合物4(3.46g；8mmol)的300ml乙腈澄清溶液中。然后将混合物在室温下搅拌24小时。24小时后，用TLC分析混合物。将混合物再搅拌14小时，至搅拌总计38小时。将混合物浓缩，用50mL 1N当量NaHCO3和100mL乙酸乙酯洗涤。将有机层分离，再用1N当量NaHCO3(1×10mL)洗涤，干燥(Na2SO4)，过滤，得到白色固体粉末，真空干燥5小时，得到2.54g。
实施例2
按流程4制备实施例2。
流程4
Figure A20058003140400231
(a)吡啶，CH2Cl2
将2-(2-吡啶基联硫基)乙醇盐酸盐(化合物(1b)；8.8g；39.33mL)溶于78mL CH2Cl2中，且加入2当量吡啶(C5H5N；80.88mL)。将氯甲酸对硝基苯酯(化合物(6)；8.08g；40mmol)溶于80mL CH2Cl2，在15分钟内，将该溶液加入2-(2-吡啶基联硫基)乙醇盐酸盐和吡啶的混合物中。将得到的澄清溶液在室温下搅拌15小时。经15小时搅拌后，用TLC分析以上混合物，表明反应完全。然后将混合物过滤，除去盐酸吡啶沉淀。将浅黄色澄清滤液用去离子水(2×50mL)洗涤，除去溶解的盐酸吡啶，干燥(Na2SO4)，过滤，真空浓缩(13.8g)。用硅胶60(250g)的CH2Cl2浆形成储藏250mL溶剂的50cm×4.2cm硅胶床。将约13.8g产物化合物(7)溶于15mL(10mL+5mL)CH2Cl2，将该溶液上柱，按30mL/min速率洗脱，按30mL组分的标准收集，加上UV-检测，得到13.3g(96％收率)。
实施例3
按流程5制备实施例3。
流程5
Figure A20058003140400241
(a)无水CH2Cl2
将3-硝基-2-吡啶硫基氯(化合物(8))溶于15mL无水CH2Cl2。将溶液用冰浴冷却。将4-乙酰基苯硫酚(化合物(9))溶于10mL CH2Cl2，并加入滴液漏斗中，该漏斗连接在含3-硝基-2-吡啶硫基氯溶液的容器。在2-5分钟内，加入4-乙酰基苯硫酚溶液。4-乙酰基苯硫酚溶液加入后，将混合物升温至室温，然后搅拌2小时。在加入4-乙酰基苯硫酚时，形成沉淀。在室温下搅拌2小时后，将混合物超声5分钟，使沉淀溶解。TLC分析表明除3-硝基-2-吡啶硫基氯和4-乙酰基苯硫酚外，还有新的斑点形成。将反应混合物用饱和NaHCO3洗涤。向有机层中补加另外的100mL Ch2Cl2。将产物真空干燥3小时。
实施例4
按流程6制备实施例4。
流程6
Figure A20058003140400242
搅拌下，将化合物(10)(0.025g；0.085mmol)溶于无水CH2Cl2。搅拌下，将氯甲酸(cholorofomate)对硝基苯酯(化合物(11)；0.020g；1.2当量)和1当量三乙胺(TEA)一起加入溶液中。2小时后，TLC分析表明化合物(10)耗竭。将产物化合物(12)通过柱层析(7∶3的己烷∶EtOAc)分离。
实施例5：
制备含半胱氨酸二硫键化合物的通用方法
如流程7所示，使按Ranasinghe and Fuchs，Synth.Commun.18(3)，227-32(1988)(其公开内容通过引用结合到本文中)的方法制备的任一硫代磺酸酯(13)(1当量)与药物、药物类似物或药物衍生物(14)(1当量)反应，制备药物硫代磺酸酯(15)的甲醇溶液。
流程7
Figure A20058003140400251
参考流程7，R为烷基或芳基，L为合适的离去基团，例如卤素、五氟苯基等，n为1至约4的整数，且X为-O-、-NH-、-C(O)O-或-C(O)NH-。可通过TLC(硅胶；CHCl3/MeOH＝9/1)观察每种原料的消失情况，可方便地监控转化。最终收率为83％(从38.9mg总产量中取出产物的质量为32mg)。
如流程8所示，通过聚合物-载体的顺序方法，用Fmoc-策略，在对酸敏感的Fmoc-Cys(Trt)-Wang树脂(16)上制备含叶酸(folate)的肽基片段Pte-Glu-(AA)n-Cys-OH(18)。
流程8
Figure A20058003140400261
(a)20％哌啶/DMF；(b)Fmoc-AA-OH，PyBop，DIPEA，DMF；(c)Fmoc-Glu(O-t-Bu)-OH，PyBop，DIPEA，DMF；(d)1.N10(TFA)-Pte-OH；PyBop，DIPEA，DMSO；(e)TFAA，(CH2SH)2，i-Pr3SiH；(f)NH4OH，pH10.3.
参考流程8，R1为Fmoc，R2为三苯甲基，DIPEA为二异丙基乙胺。为确保有效偶联，用PyBop作活化试剂。在标准条件下，在每个偶联步骤后，将Fmoc保护基团除去。按流程8中所述，使用适当保护的氨基酸构件例如Fmoc-Glu-OtBu、N10-TFA-Pte-OH等，并在步骤(b)中由Fmoc-AA-OH代表。因此，AA是指适当保护的任何氨基酸原料。
将涉及Fmoc-AA-OH的偶联顺序(步骤(a)和(b))进行″n″次，以便制备固体承载的肽(17)，其中n为整数，且可等于0至约100。在最后偶联步骤后，将剩余的Fmoc基团除去，并将肽顺序偶联至谷氨酸酯衍生物(步骤(c))，脱保护，并偶联至TFA-保护的蝶酸(步骤(d))。然后用三氟乙酸、乙二硫醇和三异丙基硅烷处理，使肽从聚合物载体解离(步骤(e))。这些反应条件导致同时除去t-Bu、t-Boc和Trt保护基团。用碱处理后，将TFA保护基团除去(步骤(f))，得到含叶酸的含Cys的肽基片段(18)。
在氩气下，通过使叶酸衍生物(18)(0.9-0.95当量)与药物硫代磺酸酯(15)的去离子水溶液(0.04M，用0.1N NaHCO3将pH调至7)反应约30分钟，形成二硫键，来制备药物轭合物。将甲醇真空蒸发后，可通过制备HPLC(Prep Novapak HR C18 19×300mM柱；流动相(A)-1.0mM磷酸盐缓冲液，pH＝6；有机相(B)-乙腈；条件-99％A和1％B至50％A和50％B的梯度，洗脱30分钟，流速＝15mL/分钟)，来纯化轭合物。
实施例6a-6f
按照以下通用方法制备实施例6a-6f。在氩气下，充分搅拌下，向相应的具有-OH的药物溶液(1当量的无水CH2Cl2或无水THF溶液)中加入碳酸6-(三氟甲基)苯并三唑基2-(2′-吡啶基联硫基乙基酯(1.3当量)和N，N-二甲基氨基吡啶(1.5当量)。将反应混合物搅拌3h，并使该吡啶基联硫基-衍生化药物经硅胶层析分离(每个实施例＞65％)。将按照本文中所述方法和或者通过常规方法，例如在美国专利申请公布号US-2005-0002942-A1中所述那些方法制备的相应肽基片段(0.5当量)溶于DMSO。向得到的澄清黄色溶液中加入吡啶基-联硫基衍生化药物。30min后反应完成，轭合物经HPLC纯化。在实施例6e的情况，先将肽基片段Pte-Glu-Asp-Arg-Asp-Asp-Cys-OH溶于水，用0.1N HCl将溶液的pH调至2.5，使肽基片段沉淀。将肽基片段离心收集，干燥，并溶于DMSO用于随后与吡啶基联硫基-衍生化药物反应。
实施例6a
Figure A20058003140400271
1H NMR(DMSO-d6)δ4.7(d，1H)，4.95(t，1H)，6.7(d，4H)，6.9(t，1H)，7.95(d，2H)，8.1(d，2H)，8.2(m，1H)，8.3(s，1H)，8.4(s，1H)，8.7(s，1H)，10.2(s，1H)，11.8(d，2H).
实施例6b
Figure A20058003140400281
ES MS(m-H)-1436.4，(m+H)+1438.3.
实施例6c
Figure A20058003140400282
1H NMR(DMSO-d6/D2O)δ1.0(s，1H)，1.1(s，1H)，1.6(s，1H)，1.8(s，1H)，2.1(s，1H)，2.25(s，3H)，2.65(dd，2H)，3.7(d，1H)，4.4(t，1H)，4.55(q，2H)，4.6(d，2H)，4.95(d，1H)，5.9(t，1H)，6.15(s，1H)，6.6(d，2H)，7.85(d，2H)，7.95(d，2H)，8.6(s，1H)，8.95(d，1H).
实施例6d
Figure A20058003140400283
1H NMR(DMSO-d6/D2O)δ1.0(s，1H)，1.1(s，1H)，1.65(s，1H)，2.1(s，1H)，2.25(s，3H)，2.6(dd，2H)，3.25(dd，1H)，3.6(t，2H)，3.7(d，1H)，4.4(t，1H)，4.6(d，1H)，4.95(d，1H)，5.9(t，1H)，6.2(s，1H)，6.6(d，2H)，7.7(t，1H)，7.9(d，2H)，7.95(d，2H)，8.6(s，1H)，9.1(d，2H).
实施例6e
1H NMR(DMSO-d6/D2O)δ10.85(d，2H)，1.05(d，2H)，1.2(d，2H)，1.7(d，2H)，3.95(d，1H)，4.05(dd，1H)，5.4(dd，1H)，5.7(dd，1H)，6.65(d，2H)，7.6(d，2H)，7.95(s，1H)，8.65(s，1H).
实施例6f
Figure A20058003140400292
ES MS(m+H)+1487.23；1H NMR(DMSO-d6/D2O)δ0.9(t，2H)，1.3(t，2H)，2.15(t，2H)，3.2(dd，1H)，4.0(t，1H)，4.15(q，1H)，5.3(s，2H)，5.5(s，2H)，6.6(d，2H)，7.0(s，1H)，7.4(m，2H)，7.55(d，2H)，8.0(d，2H)，8.6(s，1H).
实施例7
Figure A20058003140400293
按照P.Senter等，J.Org.Chem.1990，55，2875所述方法(其公开内容通过引用结合到本文中)，制备SN 38(10-羟基-7-乙基喜树碱)的中间体碳酸4-(2-吡啶基联硫基)苄酯。将按本文中所述制备的肽基片段Pte-Glu-Asp-Arg-Asp-Cys-OH溶于DMSO，并向得到的澄清黄色溶液中加入吡啶基-联硫基衍生化药物。30min后反应完成，轭合物经HPLC纯化；
ES MS(m+H)+1425.38；1HNMR(DMSO-d6/D2O)δ0.9(t)，1.15(t)，3.9(t)，4.0(t)，4.25(t)，5.1(m)，5.2(s)，5.4(s)，6.55(d)，7.25(d)，7.35(d)，7.5(d)，7.9(d)，8.55(s).
实施例8
Figure A20058003140400301
由按照本文中所述方法和或者通过常规方法，例如在美国专利申请公布号US-2005-0002942-A1中所述那些方法制备的肽基片段Pte-Glu-Asp-Arg-Asp-Asp-Cys-OH，制备实施例8化合物。也可使肽基片段与硫代磺酸酯或吡啶基联硫基-活化的长春碱反应，形成实施例8化合物。用本文中所述方法制备其它实施例的吡啶基联硫基-活化的长春碱中间体。
实施例9-13
按照本文中一般描述的方法，制备实施例9-13化合物，并通过电喷雾质谱(ES MS)，和包括1D和2D NMR以及UV在内的其它光谱技术进行表征，本文中描述了其说明性结果。
实施例9
Figure A20058003140400311
UV(nm)233(max)，255，280；1H NMR(D2O，NaOD，CD3CN)δ1.15(d，3H)，2.3(s，3H)，3.6(s，1H)，3.85(s，3H)，4.9(s，1H)，5.3(s，1H)，6.5(d，2H)，7.3(m，1H)，7.5(d，2H)，7.65(d，2H)，8.4(s，1H).
实施例10
Figure A20058003140400312
ES MS(m+H)+1382.3，(m+Na)+1405.4.
实施例11
Figure A20058003140400313
实施例12
Figure A20058003140400314
实施例13
Figure A20058003140400315
前述示例性实施方案将用于举例说明本发明，不应以任何方式解释和视为限定本文中所述的本发明。例如，通常由以下示例性维生素-药物轭合物代表的化合物将包括在本文中所述的本发明中。
Figure A20058003140400321
其中R1和R2各自独立为氢或烷基，例如甲基；且lH为杂原子，例如氧、硫、任选取代的氮或任选保护的氮等。

Claims (6)

1.一种下式化合物
Figure A2005800314040002C1
其中
n为1至约4的整数；
Ra和Rb各自独立选自氢和烷基，包括低级烷基例如任选为支链的C1-C4烷基；或Ra和Rb与所连接的碳原子结合在一起形成碳环；且
X1和X2为各自独立选择的离去基团，其中所述离去基团各自可被独立选择的亲核体置换。
2.权利要求1的化合物，其中所述亲核体是药物、维生素、显像剂、诊断试剂或另一种二价连接体。
3.一种下式化合物
Figure A2005800314040002C2
其中
m为1至约4的整数；且
X1和X2为各自独立选择的离去基团，其中所述离去基团各自可被独立选择的亲核体置换。
4.权利要求4的化合物，其中所述亲核体是药物、维生素、显像剂、诊断试剂或另一种二价连接体。
5.一种下式化合物
Figure A2005800314040003C1
其中
m为1至约4的整数；且
X1和X2为各自独立选择的离去基团，其中所述离去基团各自可被独立选择的亲核体置换。
6.权利要求5的化合物，其中所述亲核体是药物、维生素、显像剂、诊断试剂或另一种二价连接体。
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