CN105307685B - 吡咯并苯并二氮杂卓和其结合物 - Google Patents
吡咯并苯并二氮杂卓和其结合物 Download PDFInfo
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- CN105307685B CN105307685B CN201480015244.5A CN201480015244A CN105307685B CN 105307685 B CN105307685 B CN 105307685B CN 201480015244 A CN201480015244 A CN 201480015244A CN 105307685 B CN105307685 B CN 105307685B
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Landscapes
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Abstract
式(A)的结合物化合物:其中:R2是,其中R36a和R36b独立地选自H、F、C1‑4饱和烷基、C2‑3烯基,该烷基和烯基基团被选自C1‑4烷基酰胺基和C1‑4烷基酯的基团可选取代;或,当R36a和R36b中的一个是H时,另一个选自腈和C1‑4烷基酯;R6和R9独立地选自H、R、OH、OR、SH、SR、NH2、NHR、NRR’、NO2、Me3Sn和卤素;R7独立地选自H、R、OH、OR、SH、SR、NH2、NHR、NRR’、NO2、Me3Sn和卤素;Y选自式A1、A2、A3、A4、A5和A6:L是连接至细胞结合剂的接头;CBA是细胞结合剂;n是选自0至48的范围内的整数;RA4是C1‑6亚烷基基团;要么(a)R10是H,和R11是OH、ORA,其中RA是C1‑4烷基;或(b)R10和R11形成它们键连的氮和碳原子之间的氮‑碳双键;或(c)R10是H和R11是OSOzM,其中z为2或3并且M是单价药用阳离子;R和R’各自独立地选自可选取代的C1‑12烷基、C3‑20杂环基和C5‑20芳基基团,并且可选地关联基团NRR’,R和R’连同它们连接的氮原子一起形成可选取代的4‑、5‑、6‑或7‑元杂环环;其中R16、R17、R19、R20、R21和R22是如分别对R6、R7、R9、R10、R11和R2所限定的;其中Z是CH或N;其中T和T’独立地选自单键或C1‑9亚烷基,该链可以被一个或多个杂原子例如O、S、N(H)、NMe中断,条件是X和X’之间的原子的最短链中的原子数是3至12个原子;和X和X’独立地选自O、S和N(H)。
Description
技术领域
本发明涉及吡咯并苯并二氮杂(吡咯并苯并二氮杂卓,pyrrolobenzodiazepines)(PBD),特别是具有连接至细胞结合剂的接头基团的吡咯并苯并二氮杂
背景技术
吡咯并苯并二氮杂
一些吡咯并苯并二氮杂(PBD)能够识别和结合于DNA的特定序列;优选的序列是PuGPu。于1965年发现第一PBD抗肿瘤抗生素,安曲霉素(anthramycin)(Leimgruber,etal.,J.Am.Chem.Soc.,87,5793-5795(1965);Leimgruber,et al.,J.Am.Chem.Soc.,87,5791-5793(1965))。其后,已报道许多自然存在的PBD,并且针对各种类似物已开发超过10种合成途径(Thurston,et al.,Chem.Rev.1994,433-465(1994);Antonow,D.andThurston,D.E.,Chem.Rev.2011111(4),2815-2864)。家族成员包括abbeymycin(Hochlowski,et al.,J.Antibiotics,40,145-148(1987))、奇卡霉素(chicamycin)(Konishi,et al.,J.Antibiotics,37,200-206(1984))、DC-81(日本专利58-180487;Thurston,et al.,Chem.Brit.,26,767-772(1990);Bose,et al.,Tetrahedron,48,751-758(1992))、甲基氨茴霉素(mazethramycin)(Kuminoto,et al.,J.Antibiotics,33,665-667(1980))、新丝拉霉素(neothramycin)A和B(Takeuchi,et al.,J.Antibiotics,29,93-96(1976))、porothramycin(Tsunakawa,et al.,J.Antibiotics,41,1366-1373(1988))、prothracarcin(Shimizu,et al,J.Antibiotics,29,2492-2503(1982);Langley andThurston,J.Org.Chem.,52,91-97(1987))、西班米星(sibanomicin)(DC-102)(Hara,etal.,J.Antibiotics,41,702-704(1988);Itoh,et al.,J.Antibiotics,41,1281-1284(1988))、西伯里亚霉素(sibiromycin)(Leber,et al.,J.Am.Chem.Soc.,110,2992-2993(1988))和托马霉素(tomamycin)(Arima,et al.,J.Antibiotics,25,437-444(1972))。PBD为以下一般结构:
它们的区别在于取代基的数量、类型和位置,在于它们的芳族A环和吡咯并C环两者,以及在于C环的饱和度。在B环中,在N10-C11位置(其是负责使DNA烷基化的亲电中心)处存在亚胺(N=C)、甲醇胺(carbinolamine)(NH-CH(OH))或甲醇胺甲醚(NH-CH(OMe))。所有已知的天然产物在手性C11a位置处具有(S)-构型,当从C环到A环观察时,该构型向它们提供右手扭转(right-handed twist)。这给予它们用于与B型DNA的小沟的等螺旋性(isohelicity)的适当的三维形状,获得在结合位点处的滑动配合(Kohn,In AntibioticsIII.Springer-Verlag,New York,pp.3-11(1975);Hurley and Needham-VanDevanter,Acc.Chem.Res.,19,230-237(1986))。它们在小沟中形成加合物的能力使得它们可以干扰DNA加工,因此它们可用作抗肿瘤剂。
由Gregson et al.作为化合物1(Chem.Commun.1999,797-798)以及由Gregson etal.作为化合物4a(J.Med.Chem.2001,44,1161-1174)描述了特别有利的吡咯并苯并二氮杂化合物。该化合物,也称为SJG-136,在以下示出:
其他二聚体PBD化合物,如WO 2005/085251中的包含C2芳基取代基的那些,也已经公开,实例有:
已经证明这些化合物是高度有用的细胞毒性剂。
抗体-药物结合物
已经建立用于患有癌症、免疫疾病和血管疾病患者的靶向治疗的抗体疗法(Carter,P.(2006)Nature Reviews Immunology 6:343-357)。癌症治疗中用于局部递送细胞毒性剂或细胞抑制剂(即,药物)以杀死或抑制肿瘤细胞的抗体-药物结合物(ADC)(即,免疫结合物)的使用靶向将药物部分递送至肿瘤,并且在其中细胞内积聚,而这些非结合药物试剂的全身给予可以导致对正常细胞以及设法去消除的肿瘤细胞不可接受的毒性水平(Xie et al(2006)Expert.Opin.Biol.Ther.6(3):281-291;Kovtun et al(2006)CancerRes.66(6):3214-3121;Law et al(2006)Cancer Res.66(4):2328-2337;Wu et al(2005)Nature Biotech.23(9):1137-1145;Lambert J.(2005)Current Opin.in Pharmacol.5:543-549;Hamann P.(2005)Expert Opin.Ther.Patents 15(9):1087-1103;Payne,G.(2003)Cancer Cell 3:207-212;Trail et al(2003)Cancer Immunol.Immunother.52:328-337;Syrigos and Epenetos(1999)Anticancer Research 19:605-614)。
由此观察到具有最小毒性的最大疗效。设计和改善ADC的努力集中在单克隆抗体(mAb)的选择性以及药物作用机制、药物连接、药物/抗体比值(负载)和药物释放性质上(Junutula,et al.,2008b Nature Biotech.,26(8):925-932;Dornan et al(2009)Blood114(13):2721-2729;US 7521541;US 7723485;WO2009/052249;McDonagh(2006)ProteinEng.Design&Sel.19(7):299-307;Doronina et al(2006)Bioconj.Chem.17:114-124;Erickson et al(2006)Cancer Res.66(8):1-8;Sanderson et al(2005)Clin.CancerRes.11:843-852;Jeffrey et al(2005)J.Med.Chem.48:1344-1358;Hamblett et al(2004)Clin.Cancer Res.10:7063-7070)。药物部分可以通过包括微管结合、DNA结合或拓扑异构酶抑制的机制赋予它们细胞毒性和细胞抑制作用。在结合至大抗体或蛋白质受体配体时,一些细胞毒性剂趋向于不活泼或较不活泼。
ADC中的PBD
已经公开二聚的PBD作为药物结合物中的药物。例如,在WO 2011/130598中,公开了具有连接到细胞结合剂如抗体的接头基团的二聚体PBD化合物,其中接头基团连接至可用的N10位置中的一个,并且一般由在接头基团上的酶作用而被切割。
与此相反,在WO 2011/130613和WO 2011/130616中,公开了具有用于连接到细胞结合剂如抗体的接头基团的二聚体PBD化合物,其中接头基团在C2位置之一处经由芳族基团连接,并且一般由在接头基团上的酶作用而被切割。这种抗体药物结合物也描述于文献Flygare,J.,et al,Chem.Biol.Drug Des.81:113-121(2013)中,其还描述了其他类型的抗体药物结合物。
另一种方法描述于WO2007/085930中,其中托马霉素样的二聚体具有用于连接至细胞结合剂如抗体的接头基团,其中接头基团被连接至托马霉素单元之间的系链(tether),并且一般由接头基团上的酶作用而被切割。
本发明人已经开发出了一种形成具有细胞结合剂的PBD结合物、并且特别是PBD抗体结合物的新方法。
发明内容
在一个一般方面中,本发明提供了包含具有用于连接至细胞结合剂的接头的PBD二聚化合物的结合物,其中接头具有连接至在连接两个PBD单体的桥中的亚苯基或亚吡啶基的三唑、哌嗪、亚丙炔基或肟基团。细胞结合剂优选是抗体。
在第一方面中,本发明提供了式(A)的新的结合物化合物:
其中:
R2是其中R36a和R36b独立地选自H、F、C1-4饱和烷基、C2-3烯基,该烷基和烯基基团被选自C1-4烷基酰胺基和C1-4烷基酯的基团可选取代;或者,当R36a和R36b中的一个是H时,另一个选自腈和C1-4烷基酯;
R6和R9独立地选自H、R、OH、OR、SH、SR、NH2、NHR、NRR’、NO2、Me3Sn和卤素;
R7独立地选自H、R、OH、OR、SH、SR、NH2、NHR、NRR’、NO2、Me3Sn和卤素;
Y选自式A1、A2、A3、A4、A5和A6:
L是连接至细胞结合剂的接头;
CBA是细胞结合剂;
n是在0至48范围内选择的整数;
RA4是C1-6亚烷基基团;
要么
(a)R10是H,并且R11是OH、ORA,其中RA是C1-4烷基;或
(b)R10和R11形成它们键连的氮和碳原子之间的氮-碳双键;或
(c)R10是H并且R11是OSOzM,其中z是2或3并且M是单价药用阳离子;
R和R’各自独立地选自可选取代的C1-12烷基、C3-20杂环基和C5-20芳基基团,并可选地关联基团NRR’,R和R’连同它们连接的氮原子一起形成可选取代的4-、5-、6-或7-元杂环环;
其中R16、R17、R19、R20、R21和R22如分别对R6、R7、R9、R10、R11和R2所限定的;
其中Z是CH或N;
其中T和T”独立地选自单键或C1-9亚烷基,其链可以被一个或多个杂原子例如O、S、N(H)、NMe中断,条件是X和X’之间的原子的最短链中的原子数是3至12个原子;和
X和X’独立地选自O、S和N(H)。
因此,取决于Y,式A选自下式A-I、A-II、A-III、A-IV、A-V和A-VI:
本发明的第二方面提供了式(B)的新的药物-接头化合物:
其中所有基团是如在本发明的第一方面中所限定的;和
YL选自式B1、B2、B3、B4、B5和B6的组中:
其中G是用于连接至细胞结合剂的反应性基团。
本发明的第三方面提供了可以用于制备本发明的化合物和结合物化合物的式(c)的化合物:
其中YC选自式C1、C2、C3、C4和C5的组中:
要么
(a)R30是H,并且R31是OH、ORA,其中RA是C1-4烷基;或
(b)R30和R31形成它们键连的氮和碳原子之间的氮-碳双键;或
(c)R30是H和R31是OSOzM,其中z为2或3并且M是单价药用阳离子;或
(d)R30是氮保护基团并且R31是OProtO,其中ProtO是羟基保护基团;和
R40和R41如分别对R30和R31所限定的;和
所有其余的基团如在本发明的第一方面中所限定的。
本发明第四方面提供了可以用于制备本发明的第二方面和第三方面的化合物的式(D)的化合物:
YD选自式D2、D3、D4和D6的组中:
而所有其余的基团是如在本发明的第三方面中所限定的。
本发明的第五方面提供了可以用于制备本发明第二方面、第三方面和第四方面的化合物的式(E)的化合物:
YE选自式E1、E2和E5的组中:
其中
RE1选自H和TMS;
RE2选自Br、Cl和I;和
所有其余的基团是如在本发明的第三方面中所限定的。
本发明的第六方面提供了本发明的第一方面的化合物在医学治疗中的用途。第四方面还提供了包含第一方面的化合物和药用赋形剂的药物组合物。
本发明的第七方面提供了适用于治疗增生性疾病的方法的本发明的第一方面的化合物或本发明第四方面的药物组合物。第四方面还提供了第一方面的化合物在生产治疗增生性疾病的药物的方法中的用途,以及治疗患有增生性疾病的哺乳动物的方法,包括给予有效量的第一方面的化合物或第四方面的药物组合物。
本发明的第八方面提供了一种合成本发明的第一方面的化合物的方法,包括将第二方面的药物-接头与细胞结合剂结合的步骤。
本发明还提供了由本发明第三方面、第四方面或第五方面的化合物通过将其与合适试剂反应而合成本发明第二方面的化合物。
具体实施方式
本发明的详细描述
本发明提供了包含通过二聚体桥接部分经由具体的接头连接至细胞结合剂的PBD二聚体的结合物。
本发明适用于向受试者内的优选位点提供PBD结合物。
氮保护基团
氮保护基团在本领域内是已知的。适用于本发明的优选氮保护基团是具有以下通式的氨基甲酸酯保护基团:
其中R’30是可选取代的烷基(例如C1-20烷基)、芳基(例如C5-20芳基)或杂芳基(例如C3-20杂环基)基团。
大量可能的氨基甲酸酯氮保护基团列于John Wiley&Sons,Inc.2007年的《有机合成中的格林氏保护基团》(Greene’s Protective Groups in Organic Synthesis)第4版(ISBN 978-0-471-69754-1)的第706至772页中,该书通过引用结合于此。
特别优选的保护基团包括Alloc、Troc、Teoc、BOC、TcBOC、Fmoc、1-Adoc和2-Adoc。
羟基保护基团
羟基保护基团在本领域内是众所周知的。大量的合适基团描述于John Wiley&Sons,Inc.2007年的《有机合成中格林氏保护基团》第4版(ISBN 978-0-471-69754-1)的第24至298页,该书通过引用结合于此。
特别感兴趣的类别包括甲硅烷基醚、甲基醚、烷基醚、苄基醚、酯、苯甲酸酯、碳酸酯和磺酸酯。特别优选的羟基保护基团包括THP。
优选内容
以下优选内容可以适用于如以上的本发明所有方面或可以涉及单个方面。这些优选内容可以按照任何组合进行合并。
R2
在一些实施方式中,R36a和R36b都是H。
在其他实施方式中,R36a和R36b都是甲基。
在进一步的实施方式中,R36a和R36b中的一个是H,而另一个选自C1-4饱和烷基、C2-3烯基,该烷基和烯基基团被可选取代。在一些这些进一步的实施方式中,不是H的基团可以选自甲基和乙基。
R22
以上对于R2的优选内容等同适用于R22。
R6
在一个实施方式中,R6独立地选自H、R、OH、OR、SH、SR、NH2、NHR、NRR’、NO2、Me3Sn-和卤素。
在一个实施方式中,R6独立地选自H、OH、OR、SH、NH2、NO2和卤素。
在一个实施方式中,R6独立地选自H和卤素。
在一个实施方式中,R6独立地是H。
在一个实施方式中,R6和R7一起形成基团-O-(CH2)p-O-,其中p为1或2。
这些实施方式也适用于R16。
R7
R7独立地选自H、R、OH、OR、SH、SR、NH2、NHR、NRR’、NO2、Me3Sn和卤素。
在一个实施方式中,R7独立地是OR。
在一个实施方式中,R7独立地是OR7A,其中R7A独立地是可选取代的C1-6烷基。
在一个实施方式中,R7A独立地是可选取代的饱和C1-6烷基。
在一个实施方式中,R7A独立地是可选取代的C2-4烯基。
在一个实施方式中,R7A独立地是Me。
在一个实施方式中,R7A独立地是CH2Ph。
在一个实施方式中,R7A独立地是烯丙基。
这些实施方式也适用于R17。
R9
在一个实施方式中,R9独立地选自H、R、OH、OR、SH、SR、NH2、NHR、NRR’、NO2、Me3Sn-和卤素。
在一个实施方式中,R9独立地是H。
在一个实施方式中,R9独立地是R或OR。
这些实施方式也适用于R19。
N10-C11
在一些实施方式中,R10是H,并且R11是OH、ORA,其中RA是C1-4烷基。在一些这些实施方式中,R11是OH。在其他的这些实施方式中,R11是ORA,其中RA是C1-4烷基。在一些这些实施方式中,RA是甲基。
在一些实施方式中,R10和R11形成它们键连的氮和碳原子之间的氮-碳双键。
在一些实施方式中,R10是H并且R11是OSOzM,其中z为2或3并且M是单价药用阳离子。在一些这些实施方式中,M是单价药用阳离子,并可以是Na+。另外,在一些实施方式中z为3。
以上优选内容同等适用于R20和R21。
在一些实施方式中,R30是H,并且R31是OH、ORA,其中RA是C1-4烷基。在一些这些实施方式中,R31是OH。在其他的这些实施方式中,R31是ORA,其中RA是C1-4烷基。在一些这些实施方式中,RA是甲基。
在一些实施方式中,R30和R31形成它们键连的氮和碳原子之间的氮-碳双键。
在一些实施方式中,R30是H并且R31是OSOzM,其中z为2或3并且M是单价药用阳离子。在一些这些实施方式中,M是单价药用阳离子,并可以是Na+。另外,在一些实施方式中z为3。
在一些实施方式中,R30是氮保护基团并且R31是OProtO,其中ProtO是羟基保护基团。
在一些这些实施方式中,氮保护基团可以选自Alloc、Troc、Teoc、BOC、TcBOC、Fmoc、1-Adoc和2-Adoc,并且更优选是Boc。
在一些这些实施方式中,氮保护基团可以是THP。
对于式D的化合物,优选的是R30和R31形成它们键连的氮和碳原子之间的氮-碳双键。
对于式E的化合物,优选的是R30是氮保护基团并且R31是OProtO,其中ProtO是羟基保护基团。
对于式C的化合物,其中YC是式C2、C3或C4,优选的是R30和R31形成它们键连的氮和碳原子之间的氮-碳双键。
对于式的化合物C,其中YC是式C1或C5,优选的是R30是氮保护基团并且R31是OProtO,其中ProtO是羟基保护基团。
以上优选内容同等适用于R40和R41。
T和T’
T和T’各自独立地选自单键或C1-9亚烷基基团,其链可以被一个或多个杂原子例如O、S、N(H)和/或NMe中断,条件是X和X’之间的原子的最短链中的原子数是3至12个原子。
在一个实施方式中,T和T’的每一个亚烷基基团可选地被一个或多个选自O,S的杂原子和NMe中断。
在一个实施方式中,T和T”中的每一个独立地选自单键和C1-9亚烷基基团。
在一个实施方式中,T选自单键、C1、C2、C3和C4亚烷基基团并且T’选自单键、C1、C2、C3和C4亚烷基基团。
在一个实施方式中,T选自单键、C1、和C2亚烷基基团并且T’选自单键、C1、和C2亚烷基基团。
在一个实施方式中,T选自单键和C1亚烷基基团并且T’选自单键和C1亚烷基基团。
在一个实施方式中,T是单键并且T’是单键。
在一个实施方式中,T是C1亚烷基基团并且T’是C1亚烷基基团。
在一些实施方式中,T和T’是相同的。
以上所列出的亚烷基基团可以可选地被一个或多个杂原子中断。
以上所列出的亚烷基基团可以是未取代的直链脂肪族亚烷基基团。
X
在一个实施方式中,X选自O、S或N(H)。
优选X是O。
二聚体
在一些实施方式中,基团R22、R16、R17、R19、R20和R21分别与基团R2、R6、R9、R7、R10和R11相同。在这些实施方式中,PBD单体单元具有相同的取代基。
本发明的第一方面的特别优选的化合物可以是式Ia的化合物:
其中
R10、R11、R20、R21和Y是如以上所限定的;
t1和t2独立选自0、1和2;
R7a和R17a独立地选自甲基和苯基。
本发明第二方面的特别优选的化合物可以是式IIa的化合物:
其中
R10、R11、R20、R21和YL是如以上所限定的;
t1和t2独立选自0、1和2;
R7a和R17a独立地选自甲基和苯基。
本发明的第三方面特别优选的化合物可以是式IIIa的化合物:
其中
R10、R11、R20、R21和YC是如以上所限定的;
t1和t2独立选自0、1和2;
R7a和R17a独立地选自甲基和苯基。
n(Y,YL)
在一些实施方式中,n(在Y或YL中)是0和24之间的整数。
在一些实施方式中,n(在Y或YL中)是0和12之间的整数。
在一些实施方式中,n(在Y或YL中)是0和8之间的整数。
在一些实施方式中,n(在Y或YL中)是0和6之间的整数。
在一些实施方式中,n(在Y或YL中)是0。
在一些实施方式中,n(在Y或YL中)是1。
在一些实施方式中,n(在Y或YL中)是2。
在一些实施方式中,n(在Y或YL中)是3。
在一些实施方式中,n(在Y或YL中)是4。
在一些实施方式中,n(在Y或YL中)是5。
在一些实施方式中,n(在Y或YL中)是6。
在一些实施方式中,n(在Y或YL中)是7。
在一些实施方式中,n(在Y或YL中)是8。
在一些实施方式中,n(在Y或YL中)是9。
在一些实施方式中,n(在Y或YL中)是10。
在一些实施方式中,n(在Y或YL中)是11。
在一些实施方式中,n(在Y或YL中)是12。
在一些实施方式中,n(在Y或YL中)是13。
在一些实施方式中,n(在Y或YL中)是14。
在一些实施方式中,n(在Y或YL中)是15。
在一些实施方式中当Y为A1或YL是B1,n可以选自3和6。
在一些实施方式中当Y为A2或YL是B2,n可以选自4和6。
在一些实施方式中当Y为A3或YL是B3,n可以是4。
在一些实施方式中当Y为A4或YL是B4,n可以是4。
在一些实施方式中当Y为A5或YL是B5,n可以是11。
在一些实施方式中当Y为A6或YL是B6,n可以是2。
L和G
L是结合物化合物中连接至细胞结合剂的接头。G是用于将PBD二聚体连接至细胞结合剂以形成结合物化合物的反应性基团。
优选地,接头/反应性基团包含用于与细胞结合剂上的亲核官能团反应的亲电官能团。抗体上的亲核基团包括,但不限于:(i)N-端氨基基团,(ii)侧链胺基基团,例如赖氨酸,(iii)侧链硫醇基团,例如半胱氨酸,和(iv)在抗体是糖基化的情况下的糖羟基或氨基。胺、硫醇和羟基基团是亲核的,并能够与接头部分和接头试剂上的亲电基团反应以形成共价键,接头部分和接头试剂包括:(i)马来酰亚胺基团(ii)活化的二硫化物,(iii)活性酯如NHS(N-羟基琥珀酰亚胺)酯、HOBt(N-羟基苯并三唑)酯、卤代甲酸酯和酰卤;(iv)烷基卤化物和苯甲酰卤如卤代乙酰胺;和(v)醛、酮、羧基,并且其中某些情况如下举例说明:
某些抗体具有可还原的链间二硫化物,即半胱氨酸桥。抗体可以通过用还原剂如DTT(二硫苏糖醇)处理而制备成具有与接头试剂发生结合的反应活性。因此,每个半胱氨酸桥理论上将形成两个反应活性的硫醇亲核体。能够通过赖氨酸与2-亚氨基硫烷(特劳特(Traut)试剂)导致胺成为硫醇的转化而将另外的亲核基团引入抗体。通过引入一个、两个、三个、四个或更多个半胱氨酸残基(例如,制备包含一个或多个非天然半胱氨酸氨基酸残基的突变抗体)而可以将反应性硫醇基团引入到抗体(或其片段)中。US 7521541教导了通过引入反应性半胱氨酸氨基酸而对抗体的改造设计。
在一些实施方式中,接头具有与抗体上存在的亲电基团具有反应活性的反应性亲核基团。抗体上有用的亲电基团包括,但不限于,醛和酮羰基基团。接头的亲核基团的杂原子能够与抗体上的亲电基团反应并且形成与抗体单元的共价键。接头上有用的亲核基团包括,但不限于,酰肼、肟、氨基、羟基、肼、缩氨基硫脲、肼羧酸酯和芳酰肼。抗体上的亲电基团提供了连接至接头的有利位点。
在一个实施方式中,基团L是:
其中星号表示与基团Y的其余部分的连接点,波浪线表示与细胞结合剂的连接点,而m是选自范围为0至6的整数。在一个实施方式中,m选自2,3,4和5。
在一个实施方式中,细胞结合剂和L之间的连接是通过细胞结合剂的硫醇残基和L的马来酰亚胺基团完成的。
在一个实施方式中,细胞结合剂和L之间的连接是:
其中星号表示与L基团的其余部分或Y基团的其余部分的连接点而波浪线表示与细胞结合剂其余部分的连接点,在该实施方式中,S原子通常衍生自细胞结合剂。
在以上的每一实施方式中,可替代的官能度可以用于代替如下所示的马来酰亚胺衍生的基团:
其中波浪线如前表示与细胞结合剂的连接点,并且星号表示与L基团的其余部分或Y基团的其余部分的连接点。
在一个实施方式中,用以下基团代替马来酰亚胺衍生的基团:
其中波浪线如前表示与细胞结合剂的连接点,并且星号表示与L基团的其余部分或Y基团的其余部分的连接点。
在一个实施方式中,用可选地连同细胞结合剂一起的选自以下基团的基团代替马来酰亚胺衍生的基团:
-C(=O)NH-、
-C(=O)O-、
-NHC(=O)-、
-OC(=O)-、
-OC(=O)O-、
-NHC(=O)O-、
-OC(=O)NH-、
-NHC(=O)NH-、
-NHC(=O)NH、
-C(=O)NHC(=O)-、
-S-、
-S-S-、
-CH2C(=O)-、
-C(=O)CH2-、
=N-NH-、和
-NH-N=。
在一个实施方式中,用可选地连同细胞结合剂一起的选自以下基团的基团代替马来酰亚胺衍生的基团:
其中波浪线表示与细胞结合剂的连接点或键连至L基团的其余部分或Y基团的其余部分的键,并且星号表示与细胞结合剂的连接点之外的其他连接点或键连至L基团的其余部分或Y基团的其余部分的键。
其他能够用作L用于将Y基团的其余部分连接至细胞结合剂的基团描述于WO2005/082023中。
因此,在本发明的实施方式中,L是下式:
-LA-(CH2)m- (L1)
其中m为0至6;和
LA选自:
其中Ar是C5-6亚芳基,例如亚苯基。
在L是L1的一些实施方式中,m可以是2、3或5。
在L是L1的一些实施方式中,LA可以是LA1-1。
在本发明的实施方式中,L是下式:
-LA-(CH2)m-O- (L2)
其中m为0至6;和
LA选自以上基团。
不期望受限于理论,这种基团可以从抗体上切割使得氨基甲酸酯基团产生末端胺。
在L是L2的一些实施方式中,LA可以是LA3-2。
在L是L2的一些实施方式中,m可以是1。
在本发明的实施方式中,L是下式:
-LA-(CH2)q-O-C(=O)-NH-(CH2)p- (L3)
其中q为1至3,并且p为1至3;和
LA选自以上基团。
不期望受限于理论,这种基团可以是可以从抗体上切割使得氨基甲酸酯基团产生基团:H2N-(CH2)p- (L3’)。
在L是L3的一些实施方式中,q可以是1,并且p可以是2。
在L是L3的一些实施方式中,LA可以选自LA7、LA8-1和LA8-2。
在本发明的实施方式中,L是下式:
其中m为0至6;
X1和X2是选自天然氨基酸的氨基酸基团,其可以是修饰的;
LA选自以上基团。
可以选择天然氨基酸使得二肽基团是组织蛋白酶易分解的。
在一个实施方式中,基团-X1-X2-选自:
-Phe-Lys-、
-Val-Ala-、
-Val-Lys-、
-Ala-Lys-、
-Val-Cit-、
-Phe-Cit-、
-Leu-Cit-、
-Ile-Cit-、
-Phe-Arg-、
-Trp-Cit-、
其中Cit是瓜氨酸。
优选地,基团-X1-X2-选自:
-Phe-Lys-、
-Val-Ala-、
-Val-Lys-、
-Ala-Lys-、
-Val-Cit-。
最优选地,基团-X1-X2-是-Phe-Lys-或-Val-Ala-。
在一些实施方式中,在L是L4的情况下,m可以是1。
可以使用其他二肽组合,包括文献Dubowchik et al.,Bioconjugate Chemistry,2002,13,855-869中描述的那些,该文献通过引用结合于此。
在一个实施方式中,在合适的情况下氨基酸侧链被衍生化。例如,氨基酸侧链的氨基基团或羧基基团可以被衍生化。
在一个实施方式中,侧链氨基酸如赖氨酸的氨基基团NH2是选自由NHR和NRR’组成的组的衍生化形式。
在一个实施方式中,侧链氨基酸如天门冬氨酸的羧基基团COOH是选自由COOR、CONH2、CONHR和CONRR’组成的组的衍生化形式。
在一个实施方式中,氨基酸侧链在合适的情况下是化学保护的。侧链保护基团可以是如下对于基团RL进行讨论的基团。本发明人已确立受保护的氨基酸序列是酶可切割的。例如,已经确立的是,包含Boc侧链-保护的Lys残基的二肽序列是由组织蛋白酶可切解的。
用于氨基酸侧链的保护基团在本领域内是众所周知的,并描述于NovabiochemCatalog中。另外的保护基团策略记载于格林和伍兹的《有机合成中的保护基团》(Protective Groups in Organic Synthesis,Greene and Wuts)中。
对于具有反应性侧链官能度的那些氨基酸可能的侧链保护基团如下所示:
Arg:Z、Mtr、Tos;
Asn:Trt、Xan;
Asp:Bzl、t-Bu;
Cys:Acm、Bzl、Bzl-OMe、Bzl-Me、Trt;
Glu:Bzl、t-Bu;
Gln:Trt、Xan;
His:Boc、Dnp、Tos、Trt;
Lys:Boc、Z-Cl、Fmoc、Z、Alloc;
Ser:Bzl、TBDMS、TBDPS;
Thr:Bz;
Trp:Boc;
Tyr:Bzl、Z、Z-Br。
因此,在本发明的实施方式中,G是下式:
GA-(CH2)m- (G1)
其中m为0至6;和
GA选自:
其中Ar代表C5-6亚芳基基团,例如,亚苯基。
在G是G1的一些实施方式中,m可以是2、3或5。
在G是G1的一些实施方式中,GA可以是GA1-1。
在本发明的实施方式中,G是下式:
GA-(CH2)m-O- (G2)
其中m为0至6;和
GA选自以上基团。
在G是G2的一些实施方式中,GA可以是GA3-2。
在G是G2的一些实施方式中,m可以是1。
在本发明的实施方式中,G是下式:
GA-(CH2)q-O-C(=O)-NH-(CH2)p- (G3)
其中q为1至3,并且p为1至3;和
GA选自以上基团。
在G是G3的一些实施方式中,q可以是1,并且p可以是2。
在G是G3的一些实施方式中,GA可以选自GA7和GA8。
在本发明的实施方式中,G是下式:
其中m为0至6;
X1和X2如以上对于L4所限定的;
GA选自以上基团。
R和R’
在一个实施方式中,R独立地选自可选取代的C1-12烷基、C3-20杂环基和C5-20芳基基团。这些基团每一个都限定于以下取代基部分中。
在一个实施方式中,R独立地是可选取代的C1-12烷基。
在一个实施方式中,R独立地是可选取代的C3-20杂环基。
在一个实施方式中,R独立地是可选取代的C5-20芳基。
在一个实施方式中,R独立地是可选取代的C1-12烷基。
对于R的优选内容也适用于R’。
在本发明的一些实施方式中,提供了具有取代基-NRR’的化合物。在一个实施方式中,R和R’连同它们连接的氮原子一起形成可选取代的4-、5-、6-或7-元杂环环。环可以包含其他杂原子,例如N、O或S。
在一个实施方式中,杂环环自身取代有基团R。在存在另外的N杂原子的情况下,取代基可以处于N杂原子上。
RA4
在一个实施方式中,RA4是C2-4亚烷基基团。
在一个实施方式中,RA4是C2亚烷基基团。
在一个实施方式中,RA4是C3亚烷基基团。
在一个实施方式中,RA4是未取代的C1-6亚烷基基团。
在一个实施方式中,RA4是直链C1-6亚烷基基团。
在一个实施方式中,RA4选自由-CH2CH2-、-CH2CH2CH2-和-CH2CH2CH2CH2-组成的组。
细胞结合剂
细胞结合剂可以是任何类型,并且包括肽类和非肽类。这些能够包括包含至少一个结合位点的抗体或抗体片段、淋巴因子、激素、生长因子、营养素转运分子或任何其他细胞结合分子或物质。
本文的术语“抗体”是在最广义上使用并且具体地覆盖单克隆抗体、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,只要它们表现出期望的生物活性(Miller et al(2003)Jour.of Immunology 170:4854-4861)。抗体可以是鼠科动物抗体、人类抗体、人源化抗体、嵌合抗体或来自其他物种的抗体。抗体是能够识别和结合至特异性抗原的由免疫系统产生的蛋白质。(Janeway,C.,Travers,P.,Walport,M.,Shlomchik(2001)Immuno Biology,5th Ed.,Garland Publishing,New York)。靶抗原通常具有许多结合位点,也称为表位,其由在多种抗体上的CDR所识别。特异性结合至不同表位的每种抗体具有不同的结构。因此,一种抗原可以具有一种以上的对应抗体。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活性部分,即,包含免疫特异性结合感兴趣的靶的抗原或其部分的抗原结合位点的分子,这种靶包括但不限于癌细胞或产生与自身免疫病相关的自身免疫性抗体的细胞。免疫球蛋白可以是任何形式(例如,IgG、IgE、IgM、IgD和IgA)、类别(例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或子类别的免疫球蛋白分子。免疫球蛋白可以源自任何物种,包括人源、鼠源或兔源。
“抗体片段”包括全长抗体的一部分,通常是其抗原结合区或可变区。抗体片段的实例包括Fab、Fab'、F(ab')2和Fv片段;双体;线性抗体;由Fab表达文库产生的片段,抗独特型(抗Id)抗体,CDR(互补决定区),和任何以上免疫特异性结合至癌细胞抗原、病毒抗原或微生物抗原的表位结合片段,单链抗体分子,和由抗体片段形成的多特异性抗体。
如在本文中所使用的,术语“单克隆抗体”是指获自基本上同质抗体的群体的抗体,即,除可以以少量存在的可能的天然存在的突变之外,包括该群体的单个抗体是相同的。单克隆抗体针对单个抗原位点是高度特异性的。此外,相对于多克隆抗体制剂,其包括针对不同决定簇(表位)的不同抗体,每个单克隆抗体针对抗原上的单个决定簇。除它们的特异性以外,单克隆抗体是有利的,因为它们可以被合成而不被其他抗体污染。修饰语“单克隆”是指获自抗体的基本上同质群体的抗体的特性,并且不应当解释为需要通过任何特定方法来生产抗体。例如,通过Kohler et al(1975)Nature 256:495首次描述的杂交瘤方法可以制备,或可以通过DNA重组方法(参见US 4816567)制备根据本发明使用的单克隆抗体。也可以使用Clackson et al(1991)Nature,352:624-628;Marks et al(1991)J.Mol.Biol.,222:581-597中描述的技术从噬菌体抗体库分离单克隆抗体。
本文的单克隆抗体确切地包括“嵌合”抗体,其中,重链和/或轻链的部分与源自特定物种的抗体中的对应序列相同或同源或者属于特定特定抗体类别或子类别,而链的剩余部分与源自另一物种的抗体中的对应序列相同或同源或者属于另一抗体类别或子类别,以及这种抗体的片段,只要它们表现出期望的生物活性(US 4816567;和Morrison et al(1984)Proc.Natl.Acad.Sci.USA,81:6851-6855)。嵌合抗体包括包含源自非人类灵长类动物(例如,旧大陆猴或猿猴)的可变结构域抗原结合序列和人类恒定区域序列的“灵长类化的”抗体。
本文的“完整抗体”是包含VL结构域和VH结构域以及轻链恒定结构域(CL)和重链恒定结构域CH1、CH2和CH3的抗体。恒定结构域可以是天然的序列恒定结构域(例如,人类天然序列恒定结构域)或它的氨基酸序列变体。完整抗体可以具有一种或多种“效应子功能”,其是指由抗体的Fc区域(天然序列Fc区域或氨基酸序列变体Fc区域)引起的生物活性。抗体效应子功能的实例包括C1q结合;补体依赖的细胞毒性;Fc受体结合;抗体依赖的细胞介导的细胞毒性(ADCC);吞噬作用;和细胞表面受体(如B细胞受体和BCR)的下调。
取决于它们的重链的恒定结构域的氨基酸序列,可以将完整抗体分为不同“类别”。存在完整抗体的5种主要类别:IgA、IgD、IgE、IgG和IgM,并且这些中的一些可以进一步分为“子类别”(同种型),例如,IgG1、IgG2、IgG3、IgG4,IgA和IgA2。对应于抗体的不同类别的重链恒定结构域分别称为α、δ、ε、γ和μ。免疫球蛋白的不同类别的亚单位结构和三种尺寸构型是熟知的。
细胞结合剂的实例包括适用于WO 2007/085930中描述的那些结合剂,该专利结合于本文中。
细胞结合剂可以是或包括,多肽。多肽可以是环状多肽。细胞结合剂可以是抗体。因此,在一个实施方式中,本发明提供了一种抗体-药物结合物(ADC)。
载药量
载药量是每抗体PBD药物的平均数目。载药量可以在每抗体(Ab)1至8个药物(D)的范围内,即在这种情况下1、2、3、4、5、6、7和8个药物部分共价连接至抗体。ADC的组合物包括结合由从1至8的一定范围的药物的抗体的集合。在由结合反应制备ADC中,每抗体药物的平均数可以通过常规方法如质谱、ELISA分析测定法、电泳和HPLC进行表征。ADC依据p的定量分布也可以进行测定。通过ELISA,可以确定在特定的ADC的制备品中p的平均值(Hamblettet al(2004)Clin.Cancer Res.10:7063-7070;Sanderson et al(2005)Clin.CancerRes.11:843-852)。然而,通过抗体-抗原结合和ELISA的检测限,p(药物)值的分布是不可识别的。另外,用于检测抗体-药物结合物的ELISA测定不能确定药物部分在什么位置连接至抗体,如重链或轻链片段或特定的氨基酸残基。在某些情况下,可以通过如反相HPLC或电泳的方式来实现均相ADC(其中p是特定的值)与具有其他载药量的ADC的分离、纯化和表征。
对于某些抗体-药物结合物,p可以由抗体上连接位点的数目限制。例如,抗体可以具有仅一个或具有多个半胱氨酸硫醇基团,或可以具有仅一个或具有多个充分反应性的硫醇基团,通过该硫醇基团可以连接接头。较高的载药量,例如p>5,可以引起某些抗体-药物结合物的聚集、不溶、毒性或细胞通透性丧失。
通常,将少于理论最大量的药物部分通过结合反应结合至抗体。例如,抗体可以包含许多不与药物-接头中间产物(D-L)或接头试剂反应的赖氨酸残基。仅最具反应性的赖氨酸基团可以与胺反应性接头试剂反应。另外,仅最具反应性的半胱氨酸基团可以与硫醇反应性接头试剂反应。通常,抗体不包含许多(如果有的话)游离的和反应性的半胱氨酸硫醇基团,其可以连接至药物部分。化合物的抗体中的大多数半胱氨酸硫醇残基作为二硫桥存在,并且必须在部分或全部还原条件下用还原剂如二硫苏糖醇(DTT)或TCEP将其还原。可以以多种方式控制ADC的载药量(药物/抗体比),包括:(i)限制药物-接头中间产物(D-L)或接头试剂相对于抗体的摩尔过量,(ii)限制结合反应时间或温度,以及(iii)用于半胱氨酸硫醇修饰的部分或限制性还原条件。
可以在抗体中的反应位点处工程化半胱氨酸残基并且其不形成链内或分子内二硫键(Junutula,et al.,2008b Nature Biotech.,26(8):925-932;Dornan et al(2009)Blood 114(13):2721-2729;US 7521541;US 7723485;WO2009/052249,Shen et al(2012)Nature Biotech.,30(2):184-191;Junutula et al(2008)Jour of Immun.Methods 332:41-52)。工程化的半胱氨酸硫醇可以与具有硫醇反应活性的亲电基团如马来酰亚胺或α-卤代酰胺的接头试剂或本发明的药物-接头试剂反应以形成具有半胱氨酸工程化的抗体(ThioMabs)和PBD药物部分的ADC。因此,可以工程化、控制以及已知药物部分的位置。由于工程化的半胱氨酸硫醇基团通常以高产率与硫醇反应性接头试剂或药物-接头试剂反应,所有可以控制载药量。通过在重链或轻链的单一位点置换来设计IgG抗体以引入半胱氨酸氨基酸在对称抗体上产生两个新的半胱氨酸。能够实现载药量接近2和接近同质性的结合产物ADC。
当抗体的多于一个亲核或亲电基团与药物-接头中间产物或药物部分试剂之前的接头试剂反应时,那么得到的产物是具有连接至抗体的药物部分(例如,1、2、3个等)的分布的ADC化合物的混合物。液相色谱法,如聚合物反相(PLRP)和疏水相互作用可以通过载药量值分离混合物中的化合物。可以分离具有单一载药量值(p)的ADC的制备品,然而,这些单一载药量值ADC仍然可以是多种的混合物,因为药物部分可以经由接头连接在抗体的不同位点上。
因此,本发明的抗体-药物结合组合物包括抗体-药物结合化合物的混合物,其中,抗体具有一个或多个PBD药物部分,并且其中,药物部分可以在不同氨基酸残基处连接至抗体。
在一个实施方式中,每细胞结合剂的二聚体吡咯并苯并二氮杂基团的平均数目在1至20的范围内。在一些实施方式中,范围选自1至8、2至8、2至6、2至4和4至8。
在一些实施方式中,存在每细胞结合剂一个二聚体吡咯并苯并二氮杂基团。
肽
在一个实施方式中,细胞结合剂是包含4-20、优选6-20个邻接氨基酸残基的直链或环状肽。在该实施方式中,优选一个细胞结合剂连接至一个单体或二聚体吡咯并苯并二氮杂化合物。
在一个实施方式中,细胞结合剂包括结合整联蛋白ανβ6的肽。肽在XYS上针对ανβ6可以是选择性的。
在一个实施方式中,细胞结合剂包含A20FMDV-Cys多肽。A20FMDV-Cys具有序列:NAVPNLRGDLQVLAQKVARTC。可替代地,可以使用A20FMDV-Cys序列的变体,其中用另一氨基酸残基取代一、二、三、四、五、六、七、八、九或十个氨基酸残基。
在一个实施方式中,抗体是单克隆抗体;嵌合抗体;人源化抗体;完全人类抗体;或单链抗体。在一个实施方式中,抗体是具有生物活性的这些抗体之一的片段。这些片段的实例包括Fab、Fab'、F(ab')2和Fv片段。
在这些实施方式中,每一抗体可以连接至一个或几个二聚体吡咯并苯并二氮杂基团。吡咯并苯并二氮杂与细胞结合剂的优选比率如上所给出。
抗体可以是域抗体(DAB)。
在一个实施方式中,抗体是单克隆抗体。
本发明中使用的抗体包括在WO 2005/082023中描述的那些抗体,该专利结合于本文中。特别优选的是对于那些肿瘤相关抗原的抗体。本领域已知这些抗原的实例包括,但不限于,那些描述于WO 2005/082023的肿瘤相关的抗原,参见,例如,第41-55页。
本发明的结合物经过设计而经由其细胞表面抗原靶向肿瘤细胞。抗原通常是过度表达或异常倍数表达的正常细胞表面抗原。理想地,靶抗原仅仅表达于增生性细胞(优选肿瘤细胞)上,然而,这种情况很少在实践中观察到。因此,通常基于增生性和健康组织之间的差异表达选择靶抗原。
肿瘤相关的抗原(TAA)在本领域内是已知的,并能够制备用于使用本领域内众所周知的方法和信息产生抗体。在试图发现对癌诊断和治疗有效的细胞靶的努力中,研究人员正如相比于一种或多种正常的非癌细胞已设法识别特异性表达于一种或多种类型的癌细胞表面上的跨膜多肽或要不然是肿瘤相关的多肽。通常,这种肿瘤相关的多肽相比于非癌细胞的表面上更丰富地表达于癌细胞的表面上。识别这种肿瘤相关的细胞表面抗原多肽,已经产生了特异性靶向癌细胞而经由抗体-基疗法进行破坏的能力。
TAA的实例包括,但不限于,以下列出的TAA(1)-(36)。为方便起见,有关这些抗原的信息(其所有这些都是本领域中已知的)列于下面,并包括名称、替代名称、GenBank登录号和主参考文献、接着是“生物技术信息国家中心(National Center for BiotechnologyInformation)(NCBI)”的核酸和蛋白序列标识约定。能够在公共数据库如GenBank中获得对应于TAA(1)-(36)的核酸和蛋白序列。由抗体靶向的肿瘤相关抗原包括所有的氨基酸序列变体和同种型,其具有相对于所引用的参考文献中确定的序列至少约70%、80%、85%、90%或95%的序列同一性,或其表现出基本上与具有所引用的参考文献中找到的序列的TAA相同的生物学性质或特性。例如,具有变体序列的TAA一般能够特异性结合至特异性结合至具有所列出的相应序列的TAA的抗体。在本文中专门引用的参考文献中的序列和公开内容都明确通过引用结合于此。
肿瘤相关的抗原(1)-(36):
(1)BMPR1B(骨形态生成蛋白受体-IB型,GenBank登录号NM_001203)ten Dijke,P.,et al Science 264(5155):101-104(1994),Oncogene 14(11):1377-1382(1997));WO2004/063362(权利要求2);WO2003/042661(权利要求12);US2003/134790-A1(第38-39页);WO2002/102235(权利要求13;第296页);WO2003/055443(第91-92页);WO2002/99122(实施例2;第528-530页);WO2003/029421(权利要求6);WO2003/024392(权利要求2;图112);WO2002/98358(权利要求1;第183页);WO2002/54940(第100-101页);WO2002/59377(第349-350页);WO2002/30268(权利要求27;第376页);WO2001/48204(实施例;图4);NP_001194骨形态生成蛋白受体,IB型/pid=NP_001194.1.交叉引用:MIM:603248;NP_001194.1;AY065994。
(2)E16(LAT1、SLC7A5,GenBank登录号NM_003486)Biochem.Biophys.Res.Commun.255(2),283-288(1999),Nature 395(6699):288-291(1998),Gaugitsch,H.W.,et al(1992)J.Biol.Chem.267(16):11267-11273);WO2004/048938(实施例2);WO2004/032842(实施例IV);WO2003/042661(权利要求12);WO2003/016475(权利要求1);WO2002/78524(实施例2);WO2002/99074(权利要求19;第127-129页);WO2002/86443(权利要求27;第222,393页);WO2003/003906(权利要求10;第293页);WO2002/64798(权利要求33;第93-95页);WO2000/14228(权利要求5;第133-136页);US2003/224454(图3);WO2003/025138(权利要求12;第150页);NP_003477溶质载体家族7(阳离子氨基酸转运子,y+系统),成员5/pid=NP_003477.3-智人;交叉引用:MIM:600182;NP_003477.3;NM_015923;NM_003486_1。
(3)STEAP1(前列腺的六个跨膜上皮抗原,GenBank登录号NM_012449);CancerRes.61(15),5857-5860(2001),Hubert,R.S.,et al(1999)Proc.Natl.Acad.Sci.U.S.A.96(25):14523-14528);WO2004/065577(权利要求6);WO2004/027049(图1L);EP1394274(实施例11);WO2004/016225(权利要求2);WO2003/042661(权利要求12);US2003/157089(实施例5);US2003/185830(实施例5);US2003/064397(图2);WO2002/89747(实施例5;第618-619页);WO2003/022995(实施例9;图13A,实施例53;第173页,实施例2;图2A);NP_036581前列腺的六个跨膜上皮抗原;交叉引用:MIM:604415;NP_036581.1;NM_012449_1。
(4)0772P(CA125、MUC16,GenBank登录号AF361486);J.Biol.Chem.276(29):27371-27375(2001);WO2004/045553(权利要求14);WO2002/92836(权利要求6;图12);WO2002/83866(权利要求15;第116-121页);US2003/124140(实施例16);交叉引用:GI:34501467;AAK74120.3;AF361486_1。
(5)MPF(MPF、MSLN、SMR、巨核细胞增效因子、间皮素,GenBank登录号NM_005823)Yamaguchi,N.,et al Biol.Chem.269(2),805-808(1994),Proc.Natl.Acad.Sci.U.S.A.96(20):11531-11536(1999),Proc.Natl.Acad.Sci.U.S.A.93(1):136-140(1996),J.Biol.Chem.270(37):21984-21990(1995));WO2003/101283(权利要求14);(WO2002/102235(权利要求13;第287-288页);WO2002/101075(权利要求4;第308-309页);WO2002/71928(第320-321页);WO94/10312(第52-57页);交叉引用:MIM:601051;NP_005814.2;NM_005823_1。
(6)Napi3b(NAPI-3B、NaPi2B、NPTIIb、SLC34A2、溶质载体家族34(磷酸钠),成员2、II型钠依赖型磷酸盐转运蛋白3b,GenBank登录号NM_006424)J.Biol.Chem.277(22):19665-19672(2002),Genomics 62(2):281-284(1999),Feild,J.A.,et al(1999)Biochem.Biophys.Res.Commun.258(3):578-582);WO2004/022778(权利要求2);EP1394274(实施例11);WO2002/102235(权利要求13;第326页);EP0875569(权利要求1;第17-19页);WO2001/57188(权利要求20;第329页);WO2004/032842(实施例IV);WO2001/75177(权利要求24;第139-140页);交叉引用:MIM:604217;NP_006415.1;NM_006424_1。在某些实施方式中,本发明的结合物化合物包括抗NaPi2B抗体。在本发明的一个实施方式中,本发明的ADC的抗NaPi2B抗体包括(A)SEQ ID NO:1的CDR L1;(b)SEQ ID NO:2的CDR L2;(c)SEQ ID NO:3的CDR L3;(d)SEQ ID NO:4的CDR H1;(e)SEQ ID NO:5的CDR H2;(f)SEQ ID NO:6的CDRH3。在一个实施方式中,抗体分别包含SEQ ID NO:8和SEQ ID NO:7中的VH和VL序列,包括这些序列的翻译后修饰。在一个实施方式中,抗体分别包含SEQ ID NO:10和SEQ ID NO:9中的重链和轻链序列,包括这些序列的翻译后修饰。
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、臂板蛋白5b Hlog、sema域、七个钙结合糖蛋白重复体(1型和1型样)、跨膜域(TM)和短胞质域、(臂板蛋白)5B,GenBank登录号AB040878);Nagase T.,et al(2000)DNA Res.7(2):143-150);WO2004/000997(权利要求1);WO2003/003984(权利要求1);WO2002/06339(权利要求1;第50页);WO2001/88133(权利要求1;第41-43,48-58页);WO2003/054152(权利要求20);WO2003/101400(权利要求11);登录号:Q9P283;EMBL;AB040878;BAA95969.1.Genew;HGNC:10737。
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA 2700050C12、RIKENcDNA 2700050C12基因,GenBank登录号AY358628);Ross et al(2002)Cancer Res.62:2546-2553;US2003/129192(权利要求2);US2004/044180(权利要求12);US2004/044179(权利要求11);US2003/096961(权利要求11);US2003/232056(实施例5);WO2003/105758(权利要求12);US2003/206918(实施例5);EP1347046(权利要求1);WO2003/025148(权利要求20);交叉引用:GI:37182378;AAQ88991.1;AY358628_1。
(9)ETBR(内皮缩血管肽B型受体,GenBank登录号AY275463);Nakamuta M.,et alBiochem.Biophys.Res.Commun.177,34-39,1991;Ogawa Y.,et alBiochem.Biophys.Res.Commun.178,248-255,1991;Arai H.,et al Jpn.Circ.J.56,1303-1307,1992;Arai H.,et al J.Biol.Chem.268,3463-3470,1993;Sakamoto A.,YanagisawaM.,et al Biochem.Biophys.Res.Commun.178,656-663,1991;Elshourbagy N.A.,et alJ.Biol.Chem.268,3873-3879,1993;Haendler B.,et al J.Cardiovasc.Pharmacol.20,s1-S4,1992;Tsutsumi M.,et al Gene 228,43-49,1999;Strausberg R.L.,et alProc.Natl.Acad.Sci.U.S.A.99,16899-16903,2002;Bourgeois C.,et alJ.Clin.Endocrinol.Metab.82,3116-3123,1997;Okamoto Y.,et al Biol.Chem.272,21589-21596,1997;Verheij J.B.,et al Am.J.Med.Genet.108,223-225,2002;HofstraR.M.W.,et al Eur.J.Hum.Genet.5,180-185,1997;Puffenberger例如,et al Cell 79,1257-1266,1994;Attie T.,et al,Hum.Mol.Genet.4,2407-2409,1995;Auricchio A.,etal Hum.Mol.Genet.5:351-354,1996;Amiel J.,et al Hum.Mol.Genet.5,355-357,1996;Hofstra R.M.W.,et al Nat.Genet.12,445-447,1996;Svensson P.J.,et alHum.Genet.103,145-148,1998;Fuchs S.,et al Mol.Med.7,115-124,2001;Pingault V.,et al(2002)Hum.Genet.111,198-206;WO2004/045516(权利要求1);WO2004/048938(实施例2);WO2004/040000(权利要求151);WO2003/087768(权利要求1);WO2003/016475(权利要求1);WO2003/016475(权利要求1);WO2002/61087(图1);WO2003/016494(图6);WO2003/025138(权利要求12;第144页);WO2001/98351(权利要求1;第124-125页);EP0522868(权利要求8;图2);WO2001/77172(权利要求1;第297-299页);US2003/109676;US6518404(图3);US5773223(权利要求1a;第31-34列);WO2004/001004。
(10)MSG783(RNF124、假定蛋白FLJ20315,GenBank登录号NM_017763);WO2003/104275(权利要求1);WO2004/046342(实施例2);WO2003/042661(权利要求12);WO2003/083074(权利要求14;第61页);WO2003/018621(权利要求1);WO2003/024392(权利要求2;图93);WO2001/66689(实施例6);交叉引用:基因座ID:54894;NP_060233.2;NM_017763_1。
(11)STEAP2(HGNC_8639、IPCA-1、PCANAP1、STAMP1、STEAP2、STMP、前列腺癌相关的基因1、前列腺癌相关的蛋白1、前列腺的六个跨膜上皮抗原2、六个跨膜前列腺蛋白,GenBank登录号AF455138);Lab.Invest.82(11):1573-1582(2002));WO2003/087306;US2003/064397(权利要求1;图1);WO2002/72596(权利要求13;第54-55页);WO2001/72962(权利要求1;图4B);WO2003/104270(权利要求11);WO2003/104270(权利要求16);US2004/005598(权利要求22);WO2003/042661(权利要求12);US2003/060612(权利要求12;图10);WO2002/26822(权利要求23;图2);WO2002/16429(权利要求12;图10);交叉引用:GI:22655488;AAN04080.1;AF455138_1。
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、瞬时受体电位阳离子通道,子家族M,成员4,GenBank登录号NM_017636);Xu,X.Z.,et al Proc.Natl.Acad.Sci.U.S.A.98(19):10692-10697(2001),Cell 109(3):397-407(2002),J.Biol.Chem.278(33):30813-30820(2003));US2003/143557(权利要求4);WO2000/40614(权利要求14;第100-103页);WO2002/10382(权利要求1;图9A);WO2003/042661(权利要求12);WO2002/30268(权利要求27;第391页);US2003/219806(权利要求4);WO2001/62794(权利要求14;图1A-D);交叉引用:MIM:606936;NP_060106.2;NM_017636_1。
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1、畸胎癌衍生的生长因子,GenBank登录号NP_003203或NM_003212);Ciccodicola,A.,et al EMBO J.8(7):1987-1991(1989),Am.J.Hum.Genet.49(3):555-565(1991));US2003/224411(权利要求1);WO2003/083041(实施例1);WO2003/034984(权利要求12);WO2002/88170(权利要求2;第52-53页);WO2003/024392(权利要求2;图58);WO2002/16413(权利要求1;第94-95,105页);WO2002/22808(权利要求2;图1);US5854399(实施例2;第17-18列);US5792616(图2);交叉引用:MIM:187395;NP_003203.1;NM_003212_1。
(14)CD21(CR2(补体受体2)或C3DR(C3d/爱泼斯坦巴尔病毒受体)或Hs.73792GenBank登录号M26004);Fujisaku et al(1989)J.Biol.Chem.264(4):2118-2125);Weis J.J.,et al J.Exp.Med.167,1047-1066,1988;Moore M.,et alProc.Natl.Acad.Sci.U.S.A.84,9194-9198,1987;Barel M.,et al Mol.Immunol.35,1025-1031,1998;Weis J.J.,et al Proc.Natl.Acad.Sci.U.S.A.83,5639-5643,1986;Sinha S.K.,et al(1993)J.Immunol.150,5311-5320;WO2004/045520(实施例4);US2004/005538(实施例1);WO2003/062401(权利要求9);WO2004/045520(实施例4);WO91/02536(图9.1-9.9);WO2004/020595(权利要求1);登录号:P20023;Q13866;Q14212;EMBL;M26004;AAA35786.1。
(15)CD79b(CD79B、CD79β、IGb(免疫球蛋白-相关的β)、B29、GenBank登录号NM_000626或11038674);Proc.Natl.Acad.Sci.U.S.A.(2003)100(7):4126-4131,Blood(2002)100(9):3068-3076,Muller et al(1992)Eur.J.Immunol.22(6):1621-1625);WO2004/016225(权利要求2,图140);WO2003/087768,US2004/101874(权利要求1,第102页);WO2003/062401(权利要求9);WO2002/78524(实施例2);US2002/150573(权利要求5,第15页);US5644033;WO2003/048202(权利要求1,第306和309页);WO 99/58658,US6534482(权利要求13,图17A/B);WO2000/55351(权利要求11,第1145-1146页);交叉引用:MIM:147245;NP_000617.1;NM_000626_1。
(16)FcRH2(IFGP4、IRTA4、SPAP1A(含SH2域磷酸酶锚链蛋白1a)、SPAP1B、SPAP1C,GenBank登录号NM_030764,AY358130);Genome Res.13(10):2265-2270(2003),Immunogenetics 54(2):87-95(2002),Blood 99(8):2662-2669(2002),Proc.Natl.Acad.Sci.U.S.A.98(17):9772-9777(2001),Xu,M.J.,et al(2001)Biochem.Biophys.Res.Commun.280(3):768-775;WO2004/016225(权利要求2);WO2003/077836;WO2001/38490(权利要求5;图18D-1-18D-2);WO2003/097803(权利要求12);WO2003/089624(权利要求25);交叉引用:MIM:606509;NP_110391.2;NM_030764_1。
(17)HER2(ErbB2,GenBank登录号M11730);Coussens L.,et al Science(1985)230(4730):1132-1139);Yamamoto T.,et al Nature 319,230-234,1986;Semba K.,et alProc.Natl.Acad.Sci.U.S.A.82,6497-6501,1985;Swiercz J.M.,et al J.CellBiol.165,869-880,2004;Kuhns J.J.,et al J.Biol.Chem.274,36422-36427,1999;ChoH.-S.,et al Nature 421,756-760,2003;Ehsani A.,et al(1993)Genomics 15,426-429;WO2004/048938(实施例2);WO2004/027049(图1I);WO2004/009622;WO2003/081210;WO2003/089904(权利要求9);WO2003/016475(权利要求1);US2003/118592;WO2003/008537(权利要求1);WO2003/055439(权利要求29;图1A-B);WO2003/025228(权利要求37;图5C);WO2002/22636(实施例13;第95-107页);WO2002/12341(权利要求68;图7);WO2002/13847(第71-74页);WO2002/14503(第114-117页);WO2001/53463(权利要求2;第41-46页);WO2001/41787(第15页);WO2000/44899(权利要求52;图7);WO2000/20579(权利要求3;图2);US5869445(权利要求3;第31-38列);WO9630514(权利要求2;第56-61页);EP1439393(权利要求7);WO2004/043361(权利要求7);WO2004/022709;WO2001/00244(实施例3;图4);登录号:P04626;EMBL;M11767;AAA35808.1.EMBL;M11761;AAA35808.1。在某些实施方式中,本发明的结合物化合物包含抗HER2抗体。在本发明的一个实施方式中,本发明的ADC的抗HER2抗体包含人源化的抗HER2抗体,例如,huMAb4D5-1,huMAb4D5-2,huMAb4D5-3,huMAb4D5-4,huMAb4D5-5,huMAb4D5-6,huMAb4D5-7和huMAb4D5-8,正如US 5821337的表3中。这些抗体包含具有结合至HER2的鼠抗体(4D5)的互补性决定区的人类框架区。人源化抗体huMAb4D5-8也称为曲妥珠单抗,市售的商品名为HERCEPTIN(赫塞汀)。在本发明的另一个实施方式中,本发明ADC的抗HER2抗体包括人源化抗HER2抗体,例如,人源化2C4,正如US 7862817中的描述。示例性人源化2C4抗体是帕妥珠单抗,以商品名PERJETA可商购获得。
(18)NCA(CEACAM6,GenBank登录号M18728);Barnett T.,et al Genomics 3,59-66,1988;Tawaragi Y.,et al Biochem.Biophys.Res.Commun.150,89-96,1988;Strausberg R.L.,et al Proc.Natl.Acad.Sci.U.S.A.99:16899-16903,2002;WO2004/063709;EP1439393(权利要求7);WO2004/044178(实施例4);WO2004/031238;WO2003/042661(权利要求12);WO2002/78524(实施例2);WO2002/86443(权利要求27;第427页);WO2002/60317(权利要求2);登录号:P40199;Q14920;EMBL;M29541;AAA59915.1.EMBL;M18728。
(19)MDP(DPEP1,GenBank登录号BC017023);Proc.Natl.Acad.Sci.U.S.A.99(26):16899-16903(2002));WO2003/016475(权利要求1);WO2002/64798(权利要求33;第85-87页);JP05003790(图6-8);WO99/46284(图9);交叉引用:MIM:179780;AAH17023.1;BC017023_1。
(20)IL20Rα(IL20Ra、ZCYTOR7,GenBank登录号AF184971);Clark H.F.,et alGenome Res.13,2265-2270,2003;Mungall A.J.,et al Nature 425,805-811,2003;Blumberg H.,et al Cell 104,9-19,2001;Dumoutier L.,et al J.Immunol.167,3545-3549,2001;Parrish-Novak J.,et al J.Biol.Chem.277,47517-47523,2002;Pletnev S.,et al(2003)Biochemistry 42:12617-12624;Sheikh F.,et al(2004)J.Immunol.172,2006-2010;EP1394274(实施例11);US2004/005320(实施例5);WO2003/029262(第74-75页);WO2003/002717(权利要求2;第63页);WO2002/22153(第45-47页);US2002/042366(第20-21页);WO2001/46261(第57-59页);WO2001/46232(第63-65页);WO98/37193(权利要求1;第55-59页);登录号:Q9UHF4;Q6UWA9;Q96SH8;EMBL;AF184971;AAF01320.1。
(21)短缩素(BCAN、BEHAB,GenBank登录号AF229053);Gary S.C.,et al Gene256,139-147,2000;Clark H.F.,et al Genome Res.13,2265-2270,2003;StrausbergR.L.,et al Proc.Natl.Acad.Sci.U.S.A.99,16899-16903,2002;US2003/186372(权利要求11);US2003/186373(权利要求11);US2003/119131(权利要求1;图52);US2003/119122(权利要求1;图52);US2003/119126(权利要求1);US2003/119121(权利要求1;图52);US2003/119129(权利要求1);US2003/119130(权利要求1);US2003/119128(权利要求1;图52);US2003/119125(权利要求1);WO2003/016475(权利要求1);WO2002/02634(权利要求1)。
(22)EphB2R(DRT、ERK、Hek5、EPHT3,Tyro5,GenBank登录号NM_004442);Chan,J.and Watt,V.M.,Oncogene 6(6),1057-1061(1991)Oncogene 10(5):897-905(1995),Annu.Rev.Neurosci.21:309-345(1998),Int.Rev.Cytol.196:177-244(2000));WO2003042661(权利要求12);WO200053216(权利要求1;第41页);WO2004065576(权利要求1);WO2004020583(权利要求9);WO2003004529(第128-132页);WO200053216(权利要求1;第42页);交叉引用:MIM:600997;NP_004433.2;NM_004442_1。
(23)ASLG659(B7h,GenBank登录号AX092328);US2004/0101899(权利要求2);WO2003104399(权利要求11);WO2004000221(图3);US2003/165504(权利要求1);US2003/124140(实施例2);US2003/065143(图60);WO2002/102235(权利要求13;第299页);US2003/091580(实施例2);WO2002/10187(权利要求6;图10);WO2001/94641(权利要求12;图7b);WO2002/02624(权利要求13;图1A-1B);US2002/034749(权利要求54;第45-46页);WO2002/06317(实施例2;第320-321页,权利要求34;第321-322页);WO2002/71928(第468-469页);WO2002/02587(实施例1;图1);WO2001/40269(实施例3;第190-192页);WO2000/36107(实施例2;第205-207页);WO2004/053079(权利要求12);WO2003/004989(权利要求1);WO2002/71928(第233-234,452-453页);WO 01/16318。
(24)PSCA(前列腺干细胞抗原前体,GenBank登录号AJ297436);Reiter R.E.,etal Proc.Natl.Acad.Sci.U.S.A.95,1735-1740,1998;Gu Z.,et al Oncogene 19,1288-1296,2000;Biochem.Biophys.Res.Commun.(2000)275(3):783-788;WO2004/022709;EP1394274(实施例11);US2004/018553(权利要求17);WO2003/008537(权利要求1);WO2002/81646(权利要求1;第164页);WO2003/003906(权利要求10;第288页);WO2001/40309(实施例1;图17);US2001/055751(实施例1;图1b);WO2000/32752(权利要求18;图1);WO98/51805(权利要求17;第97页);WO98/51824(权利要求10;第94页);WO98/40403(权利要求2;图1B);登录号:O43653;EMBL;AF043498;AAC39607.1。
(25)GEDA(GenBank登录号AY260763);AAP14954脂肪瘤HMGIC类融合配对体的蛋白/pid=AAP14954.1-智人(人类);WO2003/054152(权利要求20);WO2003/000842(权利要求1);WO2003/023013(实施例3,权利要求20);US2003/194704(权利要求45);交叉引用:GI:30102449;AAP14954.1;AY260763_1。
(26)BAFF-R(B细胞-活化因子受体、BLyS受体3、BR3,GenBank登录号AF116456);BAFF受体/pid=NP_443177.1-智人:Thompson,J.S.,et al Science 293(5537),2108-2111(2001);WO2004/058309;WO2004/011611;WO2003/045422(实施例;第32-33页);WO2003/014294(权利要求35;图6B);WO2003/035846(权利要求70;第615-616页);WO2002/94852(第136-137列);WO2002/38766(权利要求3;第133页);WO2002/24909(实施例3;图3);交叉引用:MIM:606269;NP_443177.1;NM_052945_1;AF132600。
(27)CD22(B-细胞受体CD22-B同种型、BL-CAM、Lyb-8、Lyb8、SIGLEC-2、FLJ22814,GenBank登录号AK026467);Wilson et al(1991)J.Exp.Med.173:137-146;WO2003/072036(权利要求1;图1);交叉引用:MIM:107266;NP_001762.1;NM_001771_1。在某些实施方式中,本发明的结合物化合物包含抗CD22抗体。在本发明的一个实施方式中,根据US 8226945,本发明ADC的抗CD22抗体包含含有三个轻链超变量区(HVR-L1、HVR-L2和HVR-L3)和三个重链超变量区(HVR-H1、HVR-H2和HVR-H3):
(28)CD79a(CD79A、CD79α、免疫球蛋白相关的α,与Igβ(CD79B)共价相互作用并在与Ig M分子在表面上形成配合物的B细胞特异性的蛋白,转导涉及于B-细胞分化的信号),pI:4.84,MW:25028TM:2[P]基因染色体:19q13.2,GenBank登录号NP_001774.10);WO2003/088808,US2003/0228319;WO2003/062401(权利要求9);US2002/150573(权利要求4,第13-14页);WO99/58658(权利要求13,图16);WO92/07574(图1);US5644033;Ha et al(1992)J.Immunol.148(5):1526-1531;Müller et al(1992)Eur.J.Immunol..22:1621-1625;Hashimoto et al(1994)Immunogenetics 40(4):287-295;Preud’homme et al(1992)Clin.Exp.Immunol.90(1):141-146;Yu et al(1992)J.Immunol.148(2)633-637;Sakaguchi et al(1988)EMBO J.7(11):3457-3464。
(29)CXCR5(伯基特(Burkitt)淋巴瘤受体1,通过CXCL13趋化因子活化,在淋巴细胞迁移和体液防御中发挥功能,在HIV-2感染中扮演一定角色而或许发展AIDS,淋巴瘤,骨髓瘤和白血病的G蛋白-偶联受体);372aa,pI:8.54MW:41959TM:7[P]基因染色体:11q23.3,GenBank登录号NP_001707.1);WO2004/040000;WO2004/015426;US2003/105292(实施例2);US6555339(实施例2);WO2002/61087(图1);WO2001/57188(权利要求20,第269页);WO2001/72830(第12-13页);WO2000/22129(实施例1,第152-153页,实施例2,第254-256页);WO99/28468(权利要求1,第38页);US5440021(实施例2,第49-52列);WO94/28931(第56-58页);WO92/17497(权利要求7,图5);Dobner et al(1992)Eur.J.Immunol.22:2795-2799;Barella et al(1995)Biochem.J.309:773-779。
(30)HLA-DOB(结合肽并将其呈递于CD4+T淋巴细胞的MHC II类分子的β亚单位(Ia抗原));273aa,pI:6.56,MW:30820.TM:1[P]基因染色体:6p21.3,GenBank登录号NP_002111.1);Tonnelle et al(1985)EMBO J.4(11):2839-2847;Jonsson et al(1989)Immunogenetics 29(6):411-413;Beck et al(1992)J.Mol.Biol.228:433-441;Strausberg et al(2002)Proc.Natl.Acad.Sci USA 99:16899-16903;Servenius et al(1987)J.Biol.Chem.262:8759-8766;Beck et al(1996)J.Mol.Biol.255:1-13;Naruse etal(2002)Tissue Antigen 59:512-519;WO99/58658(权利要求13,图15);US6153408(第35-38列);US5976551(第168-170列);US6011146(第145-146列);Kasahara et al(1989)Immunogenetics 30(1):66-68;Larhammar et al(1985)J.Biol.Chem.260(26):14111-14119。
(31)P2X5(嘌啉能受体P2X配体门控离子通道5,由胞外ATP门控的离子通道,可以参与突触传递和神经发生,缺乏可能有助于特发性逼尿肌不稳定的病理生理学);422aa),pI:7.63,MW:47206TM:1[P]基因染色体:17p13.3,GenBank登录号NP_002552.2);Le et al(1997)FEBS Lett.418(1-2):195-199;WO2004/047749;WO2003/072035(权利要求10);Touchman et al(2000)Genome Res.10:165-173;WO2002/22660(权利要求20);WO2003/093444(权利要求1);WO2003/087768(权利要求1);WO2003/029277(第82页)。
(32)CD72(B-细胞分化抗原CD72,Lyb-2);359aa,pI:8.66,MW:40225,TM:1[P]基因染色体:9p13.3,GenBank登录号NP_001773.1);WO2004042346(权利要求65);WO2003/026493(第51-52,57-58页);WO2000/75655(第105-106页);Von Hoegen et al(1990)J.Immunol.144(12):4870-4877;Strausberg et al(2002)Proc.Natl.Acad.Sci USA 99:16899-16903。
(33)LY64(淋巴细胞抗原64(RP105),富亮氨酸重复(LRR)家族的I型膜蛋白,调节B-细胞活化和细胞凋亡,功能缺失与患有系统性红斑狼疮的患者中疾病活性增长有关);661aa,pI:6.20,MW:74147TM:1[P]基因染色体:5q12,GenBank登录号NP_005573.1);US2002/193567;WO97/07198(权利要求11,第39-42页);Miura et al(1996)Genomics 38(3):299-304;Miura et al(1998)Blood 92:2815-2822;WO2003/083047;WO97/44452(权利要求8,第57-61页);WO2000/12130(第24-26页)。
(34)FcRH1(Fc受体样蛋白1,包含C2型类Ig和ITAM域的免疫球蛋白Fc域的推定受体,在B-淋巴细胞分化中可能具有一定作用);429aa,pI:5.28,MW:46925TM:1[P]基因染色体:1q21-1q22,GenBank登录号NP_443170.1);WO2003/077836;WO2001/38490(权利要求6,图18E-1-18-E-2);Davis et al(2001)Proc.Natl.Acad.Sci USA 98(17):9772-9777;WO2003/089624(权利要求8);EP1347046(权利要求1);WO2003/089624(权利要求7)。
(35)IRTA2(免疫球蛋白超家族受体易位相关的2,在B-细胞发展和淋巴瘤形成中具有可能作用的推定免疫受体;通过易位的基因异常出现在某些B细胞恶性肿瘤中);977aa,pI:6.88,MW:106468,TM:1[P]基因染色体:1q21,GenBank登录号人类:AF343662、AF343663、AF343664、AF343665、AF369794、AF397453、AK090423、AK090475、AL834187、AY358085;鼠:AK089756、AY158090、AY506558;NP_112571.1;WO2003/024392(权利要求2,图97);Nakayama et al(2000)Biochem.Biophys.Res.Commun.277(1):124-127;WO2003/077836;WO2001/38490(权利要求3,图18B-1-18B-2)。
(36)TENB2(TMEFF2,肿瘤抑癌蛋白,TPEF,HPP1,TR,推定跨膜蛋白聚糖,相关于生长因子的EGF/人神经调节蛋白家族和卵泡抑素);374aa,NCBI登录号:AAD55776,AAF91397,AAG49451,NCBI RefSeq:NP_057276;NCBI基因:23671;OMIM:605734;SwissProt Q9UIK5;GenBank登录号AF179274;AY358907,CAF85723,CQ782436;WO2004/074320;JP2004113151;WO2003/042661;WO2003/009814;EP1295944(第69-70页);WO2002/30268(第329页);WO2001/90304;US2004/249130;US2004/022727;WO2004/063355;US2004/197325;US2003/232350;US2004/005563;US2003/124579;Horie et al(2000)Genomics 67:146-152;Uchida et al(1999)Biochem.Biophys.Res.Commun.266:593-602;Liang et al(2000)Cancer Res.60:4907-12;Glynne-Jones et al(2001)Int J Cancer.Oct 15;94(2):178-84。
(37)CD33(CD33分子,SIGLEC-3,SIGLEC3,p67;CD33抗原(gp67);gp67;髓细胞表面抗原CD33;结合唾液酸的Ig样凝集素3;结合唾液酸的Ig样凝集素);核苷酸:GenBank登录号M_23197;GenBank版本号NM_23197.1GI:180097;GenBank记录更新日期:1月23日,201008:47AM;多肽:GenBank登录号AAA51948;GenBank版本号AAA51948.1GI:188098;GenBank记录更新日期:1月23日,201008:47AM;Simmons D.,et al J.Immunol.141(8),2797-2800(1988);Antibodies:H195(Lintuzumab)-Raza A.,et al Leuk Lymphoma.2009Aug;50(8):1336-44;US6,759,045(Seattle genetics/Immunomedics);mAb OKT9:Sutherland,D.R.etal.Proc Natl Acad Sci USA 78(7):4515-45191981,Schneider,C.,et al J Biol Chem257,8516-8522(1982);mAb E6:Hoogenboom,H.R.,et al J Immunol 144,3211-3217(1990);US6,590,088(Human Genome Sciences)-例如,SEQ ID NO:1和2和ATCC登录号97521;US7,557,189(Immunogen)-f例如,抗体或及其片段包含含有三个具有SEQ ID NO:1-3的氨基酸序列的CDR的重链可变区和包含三个具有SEQ ID NO:4-6的氨基酸序列的CDR的轻链可变区。
在一些实施方式中,抗CD33抗体包含(A)含有SEQ ID NO:20的氨基酸序列的HVR-H1;(b)含有SEQ ID NO:21的氨基酸序列的HVR-H2;(c)含有SEQ ID NO:22的氨基酸序列的HVR-H3;(d)含有SEQ ID NO:17的氨基酸序列的HVR-L1;(e)含有SEQ ID NO:18的氨基酸序列的HVR-L2;和(f)含有SEQ ID NO:19的氨基酸序列的HVR-L3。
在一些实施方式中,抗CD33抗体分别含有SEQ ID NO:24和SEQ ID NO:23中的VH和VL序列,包括这些序列的翻译后修饰。
在一些实施方式中,抗CD33抗体包含(A)含有SEQ ID NO:28的氨基酸序列的HVR-H1;(b)含有SEQ ID NO:29的氨基酸序列的HVR-H2;(c)含有SEQ ID NO:30的氨基酸序列的HVR-H3;(d)含有SEQ ID NO:25的氨基酸序列的HVR-L1;(e)含有SEQ ID NO:26的氨基酸序列的HVR-L2;和(f)含有SEQ ID NO:27的氨基酸序列的HVR-L3。
在一些实施方式中,抗CD33抗体分别包含SEQ ID NO:32和SEQ ID NO:31中的VH和VL序列,包括这些序列的翻译后修饰。在一些实施方式中,抗CD33抗体分别包含SEQ ID NO:34和SEQ ID NO:33中的VH和VL序列,包括这些序列的翻译后修饰。在一些实施方式中,抗CD33抗体分别包含SEQ ID NO:36和SEQ ID NO:35中的VH和VL序列,包括这些序列的翻译后修饰。在一个实施方式中,在一些实施方式中,抗CD33抗体分别包含SEQ ID NO:38和SEQ IDNO:37中的VH和VL序列,包括这些序列的翻译后修饰。
(38)LGR5/GPR49;核苷酸:GenBank登录号NM_003667;GenBank版本号NM_003667.2GI:24475886;GenBank记录更新日期:2012年7月22日,03:38PM;多肽:GenBank登录号NP_003658;GenBank版本号NP_003658.1GI:4504379;GenBank记录更新日期:2012年7月22日,03:38PM。
在一些实施方式中,抗LGR5抗体包含(A)含有SEQ ID NO:46的氨基酸序列的HVR-H1;(b)含有SEQ ID NO:47的氨基酸序列的HVR-H2;(c)含有SEQ ID NO:48的氨基酸序列的HVR-H3;(d)含有SEQ ID NO:43的氨基酸序列的HVR-L1;(e)含有SEQ ID NO:44的氨基酸序列的HVR-L2;和(f)含有SEQ ID NO:45的氨基酸序列的HVR-L3。
在一个实施方式中,抗体分别包含SEQ ID NO:40和SEQ ID NO:39中的VH和VL序列,包括这些序列的翻译后修饰。
在一些实施方式中,抗LGR5包含(A)含有SEQ ID NO:52的氨基酸序列的HVR-H1;(b)含有SEQ ID NO:53的氨基酸序列的HVR-H2;(c)含有SEQ ID NO:54的氨基酸序列的HVR-H3;(d)含有SEQ ID NO:49的氨基酸序列的HVR-L1;(e)含有SEQ ID NO:50的氨基酸序列的HVR-L2;和(f)含有选自SEQ ID NO:51的氨基酸序列的HVR-L3。
在一些实施方式中,抗LgR5抗体包含如以上提供的任何实施方式中的VH,和如以上提供的任何实施方式中的VL。在一个实施方式中,抗体分别包含SEQ ID NO:42和SEQ IDNO:41中的VH和VL序列,包括这些序列的翻译后修饰。
亲本抗体也可以是包含白蛋白结合肽(ABP)序列的融合蛋白(Dennis et al.(2002)“Albumin Binding As A General Strategy For Improving ThePharmacokinetics Of Proteins”J Biol Chem.277:35035-35043;WO 01/45746)。本发明的抗体包括具有由以下文献教导的ABP序列的融合蛋白:(i)Dennis et al(2002)J BiolChem.277:35035-35043表III和IV,p 35038;(ii)US 2004/0001827在[0076]行;和(iii)WO01/45746第12-13页,而所有这些都通过引用结合于此。
在一个实施方式中,抗体已经提出特异性靶向肿瘤相关的抗原ανβ6。
可以在作为结合物或作为结合物的部分引入之前进行标记细胞结合剂,例如,以辅助试剂的检测和纯化。标记可以是生物素标记。在另一实施方式中,可以用放射同位素标记细胞结合剂。
取代基
如在本文中所使用的,短语“可选取代”涉及其可以是未取代的或其可以是取代的母基团。
除非另有规定,如在本文中所使用的,术语“取代”涉及其带有一个或多个取代基的母基团。术语“取代基”在本文中是在常规意义上使用并且是指这样的化学部分,其共价连接于,或者如果合适的话,稠合于母基团。各种的取代基是众所周知的,并且用于它们的形成和引入至各种的母基团的方法也是众所周知的。
在优选的实施方式中,本文描述的取代基(其包括可选的取代基)仅限于那些对细胞结合剂没有反应活性的基团。对本发明情况下与细胞结合剂的连接由两个PBD部分之间的桥接通过与细胞结合剂的接头基团形成。位于PBD结构的其他部位上的反应活性官能团可能能够形成与细胞结合剂的另外的键(这可以称之为交联)。这些另外的键可能改变结合物的运输和生物活性。因此,在一些实施方式中,其他取代基仅限于缺少反应活性官能度的那些。
在一个实施方式中,取代基选自由R、OR、SR、NRR’、NO2、卤素、CO2R、COR、CONH2、CONHR和CONRR’组成的组。
在一个实施方式中,取代基选自由R、OR、SR、NRR’、NO2、CO2R、COR、CONH2、CONHR和CONRR’组成的组。
在一个实施方式中,取代基选自由R、OR、SR、NRR’、NO2和卤素组成的组。
在一个实施方式中,取代基选自由R、OR、SR、NRR’和NO2组成的组。
以上提及的实施方式中任何一个可以适用于本文中的取代基中任何一个。可替代地,取代基可以选自以下所列的一种或多种基团。
在下文更详细描述取代基的实例。
C1-12烷基:如在本文中所使用的,术语“C1-12烷基”涉及通过从具有1至12个碳原子的烃化合物的碳原子去除氢原子所获得的单价部分,其可以是脂族或脂环族,并且其可以是饱和或不饱和的(例如部分不饱和的、完全不饱和的)。因此,术语“烷基”包括下文讨论的亚类:烯基、炔基、环烷基等。
饱和烷基的实例包括但不限于甲基(C1)、乙基(C2)、丙基(C3)、丁基(C4)、戊基(C5)、己基(C6)和庚基(C7)。
饱和线性烷基的实例包括但不限于甲基(C1)、乙基(C2)、正丙基(C3)、正丁基(C4)、正戊基(戊基)(C5)、正己基(C6)和正庚基(C7)。
饱和支链烷基的实例包括异丙基(C3)、异丁基(C4)、仲丁基(C4)、叔丁基(C4)、异戊基(C5)和新戊基(C5)。
饱和烷基的实例包括但不限于甲基(C1)、乙基(C2)、丙基(C3)、丁基(C4)、戊基(C5)、己基(C6)和庚基(C7)。
饱和线性烷基的实例包括但不限于甲基(C1)、乙基(C2)、正丙基(C3)、正丁基(C4)、正戊基(戊基)(C5)、正己基(C6)和正庚基(C7)。
饱和支链烷基的实例包括异丙基(C3)、异丁基(C4)、仲丁基(C4)、叔丁基(C4)、异戊基(C5)和新戊基(C5)。
烷基基团可以可选地被一个或多个选自O、N(H)和S的杂原子中断。这种基团可以称为“杂烷基”。
C2-12杂烷基:如本文中所使用的,术语“C2-12杂烷基”,涉及通过从具有2至12个碳原子和一个或多个选自O、N(H)和S,优选O和S的杂原子的烃化合物的碳原子除去一个氢原子的单价部分。
杂烷基基团的实例包括,但不限于包含一个或多个类型-(OCH2CH2)-的乙二醇单元的那些。杂烷基基团的末端可以是杂原子的原形(primary form),例如-OH、-SH或-NH2。在优选的实施方式中,末端是-CH3。
C2-12烯基:如在本文中所使用的,术语“C2-12烯基”涉及具有一个或多个碳-碳双键的烷基。
不饱和烯基的实例包括但不限于乙烯基(ethenyl)(乙烯基,vinyl,-CH=CH2)、1-丙烯基(-CH=CH-CH3)、2-丙烯基(烯丙基,-CH-CH=CH2)、异丙烯基(1-甲基乙烯基,-C(CH3)=CH2)、丁烯基(C4)、戊烯基(C5)和己烯基(C6)。
C2-12炔基:如在本文中所使用的,术语“C2-12炔基”涉及具有一个或多个碳-碳三键的烷基。
不饱和炔基的实例包括但不限于乙炔基(-C≡CH)和2-丙炔基(2-propynyl)(炔丙基(propargyl),-CH2-C≡CH)。
C3-12环烷基:如在本文中所使用的,术语“C3-12环烷基”涉及也是环基的烷基;即,通过从环烃(碳环)化合物的脂环原子去除氢原子所获得的单价部分,该单价部分具有3至7个碳原子,包括3至7个环原子。
环烷基的实例包括但不限于那些环烷基,其源自:
饱和单环烃化合物;
环丙烷(C3)、环丁烷(C4)、环戊烷(C5)、环己烷(C6)、环庚烷(C7)、甲基环丙烷(C4)、二甲基环丙烷(C5)、甲基环丁烷(C5)、二甲基环丁烷(C6)、甲基环戊烷(C6)、二甲基环戊烷(C7)和甲基环己烷(C7);
不饱和单环烃化合物;
环丙烯(C3)、环丁烯(C4)、环戊烯(C5)、环己烯(C6)、甲基环丙烯(C4)、二甲基环丙烯(C5)、甲基环丁烯(C5)、二甲基环丁烯(C6)、甲基环戊烯(C6)、二甲基环戊烯(C7)和甲基环己烯(C7);以及
饱和多环烃化合物:
降蒈烷(norcarane)(C7)、降蒎烷(norpinane)(C7)、降莰烷(降冰片烷,norbornane)(C7)。
C3-20杂环基:如在本文中所使用的,术语“C3-20杂环基”涉及通过从杂环化合物的环原子去除氢原子所获得的单价部分,该部分具有3至20个环原子,其中1至10个是环杂原子。优选地,每个环具有3至7个环原子,其中1至4个是环杂原子。
在此上下文中,前缀(例如C3-20、C3-7、C5-6,等)表示环原子的数目或环原子的数目的范围,而不管是碳原子或杂原子。例如,如在本文中所使用的,术语“C5-6杂环基”涉及具有5或6个环原子的杂环基。
单环杂环基的实例包括但不限于源自以下的那些单环杂环基:
N1:氮丙啶(C3)、氮杂环丁烷(C4)、吡咯烷(四氢吡咯)(C5)、吡咯啉(例如,3-吡咯啉、2,5-二氢吡咯)(C5)、2H-吡咯或3H-吡咯(异吡咯,异噁唑)(C5)、哌啶(C6)、二氢吡啶(C6)、四氢吡啶(C6)、氮杂(C7);
O1:氧杂环丙烷(oxirane)(C3)、氧杂环丁烷(oxetane)(C4)、氧杂环戊烷(四氢呋喃)(C5)、氧杂环戊二烯(氧杂茂,oxole)(二氢呋喃)(C5)、氧杂环己烷(exane)(四氢吡喃)(C6)、二氢吡喃(C6)、吡喃(C6)、氧杂(噁庚,oxepin)(C7);
S1:硫杂环丙烷(C3)、硫杂环丁烷(C4)、硫杂环戊烷(四氢噻吩)(C5)、硫杂环己烷(四氢噻喃)(C6)、硫杂环庚烷(thiepane)(C7);
O2:二氧杂环戊烷(C5)、二氧杂环已烷(C6)和二氧杂环庚烷(dioxepane)(C7);
O3:三氧杂环己烷(C6);
N2:咪唑烷(C5)、吡唑烷(二偶氮烷)(C5)、咪唑啉(C5)、吡唑啉(二氢吡唑)(C5)、哌嗪(C6);
N1O1:四氢噁唑(C5)、二氢噁唑(C5)、四氢异噁唑(C5)、二氢异噁唑(C5)、吗啉(C6)、四氢噁嗪(C6)、二氢噁嗪(C6)、噁嗪(C6);
N1S1:噻唑啉(C5)、噻唑烷(C5)、硫代吗啉(C6);
N2O1:噁二嗪(C6);
O1S1:氧硫杂环戊二烯(噁噻吩,oxathiole)(C5)和氧硫杂环己烷(噻噁烷)(C6);以及
N1O1S1:噁噻嗪(C6)。
取代的单环杂环基的实例包括那些取代的单环杂环基,其源自环形式的糖类,例如,呋喃糖(C5),如阿拉伯呋喃糖、来苏呋喃糖(lyxofuranose)、呋喃核糖和呋喃木糖(xylofuranse),以及吡喃糖(C6),如别吡喃糖(allopyranose)、吡喃阿卓糖、吡喃葡萄糖、吡喃甘露糖、吡喃古洛糖(gulopyranose)、吡喃艾杜糖(idopyranose)、吡喃半乳糖和吡喃塔罗糖(talopyranose)。
C5-20芳基:如在本文中所使用的,术语“C5-20芳基”涉及通过从芳族化合物的芳环原子去除氢原子所获得的单价部分,其具有3至20个环原子。优选地,每个环具有5至7个环原子。
在此上下文中,前缀(例如C3-20、C5-7、C5-6等)表示环原子(碳原子或杂原子)的数目或环原子的数目的范围。例如,如在本文中所使用的,术语“C5-6芳基”涉及具有5或6个环原子的芳基。
环原子可以都是碳原子,如在“碳芳基”中。
碳芳基的实例包括但不限于源自以下的那些碳芳基:苯(即苯基)(C6)、萘(C10)、薁(甘菊环)(C10)、蒽(C14)、菲(C14)、萘并萘(C18)和芘(C16)。
包含稠环(其至少之一是芳环)的芳基的实例包括但不限于源自以下的基团:茚满(例如2,3-二氢-1H-茚)(C9)、茚(C9)、异茚(C9)、四氢化萘(1,2,3,4-四氢萘(C10)、苊(C12)、芴(C13)、非那烯(C13)、醋菲(C15)和醋蒽(C16)。
可替换地,环原子可以包括一个或多个杂原子,如在“杂芳基”中。单环杂芳基的实例包括但不限于源自以下的那些:
N1:吡咯(Pyrrole)(唑,azole)(C5)、吡啶(吖嗪)(C6);
O1:呋喃(氧杂茂,oxole)(C5);
S1:噻吩(thiophene)(噻吩,thiole)(C5);
N1O1:噁唑(C5)、异噁唑(C5)、异噁嗪(C6);
N2O1:噁二唑(呋咱)(C5);
N3O1:噁三唑(C5);
N1S1:噻唑(C5)、异噻唑(C5);
N2:咪唑(1,3-二唑)(C5)、吡唑(1,2-二唑)(C5)、哒嗪(1,2-二嗪)(C6)、嘧啶(1,3-二嗪)(C6)(例如,胞嘧啶、胸腺嘧啶、尿嘧啶)、吡嗪(1,4-二嗪)(C6);
N3:三唑(C5)、三嗪(C6);以及
N4:四唑(C5)。
包含稠环的杂芳基的实例包括但不限于:
源自以下的C9(具有2个稠环):苯并呋喃(O1)、异苯并呋喃(O1)、吲哚(N1)、异吲哚(N1)、氮茚(N1)、吲哚啉(N1)、异吲哚啉(N1)、嘌呤(N4)(例如,腺嘌呤、鸟嘌呤)、苯并咪唑(N2)、吲唑(N2)、苯并噁唑(N1O1)、苯并异噁唑(N1O1)、苯并二氧杂环戊二烯(苯并二噁茂)(O2)、苯并呋咱(N2O1)、苯并三唑(N3)、苯并噻吩(S1)、苯并噻唑(N1S1)、苯并噻二唑(N2S);
源自以下的C10(具有2个稠环):色烯(O1)、异色烯(O1)、色满(chroman)(O1)、异色满(O1)、苯并二噁烷(O2)、喹啉(N1)、异喹啉(N1)、喹嗪(N1)、苯并噁嗪(N1O1)、苯并二嗪(N2)、吡啶并吡啶(N2)、喹喔啉(N2)、喹唑啉(N2)、噌啉(N2)、酞嗪(phthalazine)(N2)、萘啶(二氮杂萘,naphthyridine)(N2)、蝶啶(N4);
源自以下的C11(具有2个稠环):苯并二氮杂(N2);
源自以下的C13(具有3个稠环):咔唑(N1)、二苯并呋喃(O1)、二苯并噻吩(S1)、咔啉(N2)、呸啶(萘嵌间二氮杂苯,perimidine)(N2)、吡啶并吲哚(N2);以及
源自以下的C14(具有3个稠环):吖啶(N1)、呫吨(xanthene)(O1)、噻吨(S1)、噁蒽(oxanthrene)(O2)、吩噁噻(phenoxathiin)(O1S1)、吩嗪(N2)、吩噁嗪(N1O1)、吩噻嗪(N1S1)、噻蒽(S2)、菲啶(N1)、菲咯啉(N2)、吩嗪(N2)。
上述基团,无论单独地或是另一取代基的一部分,可以本身可选地被选自它们本身和以下列出的另外的取代基的一个或多个基团取代。
卤素:-F、-Cl、-Br和-I。
羟基:-OH。
醚:-OR,其中R是醚取代基,例如,C1-7烷基(还被称为C1-7烷氧基,下文讨论的)、C3-20杂环基(还被称为C3-20杂环氧基)或C5-20芳基(还被称为C5-20芳氧基),优选C1-7烷基。
烷氧基:-OR,其中R是烷基,例如,C1-7烷基。C1-7烷氧基的实例包括但不限于-OMe(甲氧基)、-OEt(乙氧基)、-O(nPr)(正丙氧基)、-O(iPr)(异丙氧基)、-O(nBu)(正丁氧基)、-O(sBu)(仲丁氧基)、-O(iBu)(异丁氧基)和-O(tBu)(叔丁氧基)。
缩醛:-CH(OR1)(OR2),其中R1和R2独立地是缩醛取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基,或者,在“环状”缩醛基团的情况下,R1和R2连同它们所连接的两个氧原子和它们所连接的碳原子一起形成具有4至8个环原子的杂环。缩醛基团的实例包括但不限于-CH(OMe)2、-CH(OEt)2和-CH(OMe)(OEt)。
半缩醛:-CH(OH)(OR1),其中R1是半缩醛取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。半缩醛基团的实例包括但不限于-CH(OH)(OMe)和-CH(OH)(OEt)。
缩酮:-CR(OR1)(OR2),其中R1和R2是如针对缩醛所限定的,以及R是除氢以外的缩酮取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。缩酮基团的实例包括但不限于-C(Me)(OMe)2、-C(Me)(OEt)2、-C(Me)(OMe)(OEt)、-C(Et)(OMe)2、-C(Et)(OEt)2和-C(Et)(OMe)(OEt)。
半缩酮:-CR(OH)(OR1),其中R1是如针对半缩醛所限定,并且R是除氢以外的半缩酮取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。半缩醛基团的实例包括但不限于-C(Me)(OH)(OMe)、-C(Et)(OH)(OMe)、-C(Me)(OH)(OEt)和-C(Et)(OH)(OEt)。
氧代(酮基、-酮):=O。
硫酮(Thione)(硫代酮,thioketone):=S。
亚氨基(亚胺):=NR,其中R是亚氨基取代基,例如,氢、C1-7烷基、C3-20杂环基或C5-20芳基,优选氢或C1-7烷基。酯基的实例包括但不限于=NH、=NMe、=Net和=NPh。
甲酰基(甲醛,carbaldehyde,carboxaldehyde):-C(=O)H。
酰基(酮基):-C(=O)R,其中R是酰基取代基,例如,C1-7烷基(还被称为C1-7烷酰基)、C3-20杂环基(还被称为C3-20杂环酰基)或C5-20芳基(还被称为C5-20芳酰基),优选C1-7烷基。酰基的实例包括但不限于-C(=O)CH3(乙酰基)、-C(=O)CH2CH3(丙酰基)、-C(=O)C(CH3)3(叔丁酰基)和-C(=O)Ph(苯甲酰基,苯酮)。
羧基(羧酸):-C(=O)OH。
硫代羧基(硫代羧酸):-C(=S)SH。
巯基代羧基(硫醇羧基,Thiolocarboxy)(巯基代羧酸(硫醇羧酸),thiolocarboxylic acid):-C(=O)SH。
硫羰羧基(硫羰羧酸):-C(=S)OH。
亚胺酸(Imidic acid):-C(=NH)OH。
异羟肟酸:-C(=NOH)OH。
酯(羧酸酯(carboxylate,carboxylic acid ester),氧基羰基(oxycarbonyl)):-C(=O)OR,其中R是酯取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。酯基的实例包括但不限于-C(=O)OCH3、-C(=O)OCH2CH3、-C(=O)OC(CH3)3和-C(=O)Oph。
酰氧基(反向酯):-OC(=O)R,其中R是酰氧基取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。酰氧基的实例包括但不限于-OC(=O)CH3(乙酰氧基)、-OC(=O)CH2CH3、-OC(=O)C(CH3)3、-OC(=O)Ph、和-OC(=O)CH2Ph。
氧基羰氧基(Oxycarboyloxy):-OC(=O)OR,其中R是酯取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。酯基的实例包括但不限于-OC(=O)OCH3、-OC(=O)OCH2CH3、-OC(=O)OC(CH3)3和-OC(=O)Oph。
氨基:-NR1R2,其中R1和R2独立地是氨基取代基,例如,氢、C1-7烷基(还被称为C1-7烷基氨基或二C1-7烷基氨基)、C3-20杂环基或C5-20芳基,优选H或C1-7烷基,或者,在“环状”氨基的情况下,R1和R2连同它们所连接的氮原子一起形成具有4至8个环原子的杂环。氨基可以是伯氨基(-NH2)、仲氨基(-NHR1)或叔氨基(-NHR1R2),以及在阳离子形式中,可以是季氨基(-+NR1R2R3)。氨基的实例包括但不限于-NH2、-NHCH3、-NHC(CH3)2、-N(CH3)2、-N(CH2CH3)2和-NHPh。环状氨基的实例包括但不限于氮丙啶基、氮杂环丁烷基、吡咯烷并、哌啶子基(piperidino)、哌嗪子基(piperazino)、吗啉代和硫代吗啉代。
酰氨基(氨基甲酰基,氨基甲酰,氨基羰基,甲酰胺):-C(=O)NR1R2,其中R1和R2独立地是氨基取代基,如针对氨基所限定的。酰氨基的实例包括但不限于-C(=O)NH2、-C(=O)NHCH3、-C(=O)N(CH3)2、-C(=O)NHCH2CH3和-C(=O)N(CH2CH3)2,以及酰氨基,其中R1和R2连同它们所连接的氮原子一起形成杂环结构,如在,例如,哌啶子基羰基、吗啉代羰基、硫代吗啉代羰基和哌嗪子基羰基中。
硫代酰氨基(硫代氨基甲酰基):-C(=S)NR1R2,其中R1和R2独立地是氨基取代基,如针对氨基所限定的。酰氨基的实例包括但不限于-C(=S)NH2、-C(=S)NHCH3、-C(=S)N(CH3)2和-C(=S)NHCH2CH3。
酰基酰氨基(酰氨基):-NR1C(=O)R2,其中R1是酰胺取代基,例如,氢、C1-7烷基、C3-20杂环基或C5-20芳基,优选氢或C1-7烷基,以及R2是酰基取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选氢或C1-7烷基。酰胺基团的实例包括但不限于-NHC(=O)CH3、-NHC(=O)CH2CH3和-NHC(=O)Ph。R1和R2可以一起形成环状结构,如在,例如,琥珀酰亚胺基、马来酰亚胺基和苯邻二甲酰亚胺基中:
氨基羰氧基:-OC(=O)NR1R2,其中R1和R2独立地是氨基取代基,如针对氨基所限定的。氨基羰氧基的实例包括但不限于-OC(=O)NH2、-OC(=O)NHMe、-OC(=O)NMe2和-OC(=O)NEt2。
脲基:-N(R1)CONR2R3,其中R2和R3独立地是氨基取代基,如针对氨基所限定的,以及R1是脲基取代基,例如,氢、C1-7烷基、C3-20杂环基或C5-20芳基,优选氢或C1-7烷基。脲基的实例包括但不限于-NHCONH2、-NHCONHMe、-NHCONHEt、-NHCONMe2、-NHCONEt2、-NMeCONH2、-NMeCONHMe、-NMeCONHEt、-NMeCONMe2和-NMeCONEt2。
胍基:-NH-C(=NH)NH2。
四唑基:具有4个氮原子和一个碳原子的五元芳环,
亚氨基:=NR,其中R是亚氨基取代基,例如,氢、C1-7烷基、C3-20杂环基或C5-20芳基,优选H或C1-7烷基。亚氨基的实例包括但不限于=NH、=NMe和=NEt。
脒(脒基):-C(=NR)NR2,其中每个R是脒取代基,例如,氢、C1-7烷基、C3-20杂环基或C5-20芳基,优选H或C1-7烷基。脒基团的实例包括但不限于-C(=NH)NH2、-C(=NH)NMe2和-C(=NMe)NMe2。
硝基:-NO2。
亚硝基:-NO。
叠氮基:-N3。
氰基(腈,nitrile,carbonitrile):-CN。
异氰基:-NC。
氰酰基(Cyanato):-OCN。
异氰酰基:-NCO。
硫氰基(Thiocyano)(硫氰基):-SCN。
异硫氰基(isothiocyano)(异硫氰基,isothiocyanato):-NCS。
巯基(Sulfhydryl)(硫醇,thiol;巯基,mercapto):-SH。
硫醚(硫化物):-SR,其中R是硫醚取代基,例如,C1-7烷基(还被称为C1-7烷硫基)、C3-20杂环基或C5-20芳基,优选C1-7烷基。C1-7烷硫基的实例包括但不限于-SCH3和-SCH2CH3。
二硫化物:-SS-R,其中R是二硫化物取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基(在本文中还称为C1-7烷基二硫化物)。C1-7烷基二硫化物基团的实例包括但不限于-SSCH3和-SSCH2CH3。
硫肟基(锍化物,sulfine)(亚硫酰基,亚砜):-S(=O)R,其中R是硫肟基取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。硫肟基基团的实例包括但不限于-S(=O)CH3和-S(=O)CH2CH3。
砜(磺酰基):-S(=O)2R,其中R是砜取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基,包括,例如,氟化或全氟化C1-7烷基。砜基团的实例包括但不限于-S(=O)2CH3(甲磺酰基)、-S(=O)2CF3(三氟甲磺酰基,triflyl)、-S(=O)2CH2CH3(乙磺酰基,esyl)、-S(=O)2C4F9(九氟丁磺酰基,nonaflyl)、-S(=O)2CH2CF3(三氟乙磺酰基,tresyl)、-S(=O)2CH2CH2NH2(牛磺酰基,tauryl)、-S(=O)2Ph(苯磺酰,苯磺酰基(besyl))、4-甲基苯磺酰(甲苯磺酰基(tosyl))、4-氯苯磺酰(氯苯磺酰基(closyl))、4-溴苯磺酰(溴苯磺酰基(brosyl))、4-硝基苯基(硝基苯磺酰基(nosyl))、2-萘磺酸酯(萘磺酰基,napsyl)和5-二甲基氨基-萘-1-基磺酸酯(丹磺酰基(dansyl))。
亚磺酸(亚磺基):-S(=O)OH、-SO2H。
磺酸(磺基):-S(=O)2OH、-SO3H。
亚磺酸酯(sulfinate)(亚磺酸酯,sulfinic acid ester):-S(=O)OR;其中R是亚磺酸酯取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。亚磺酸酯基团的实例包括但不限于-S(=O)OCH3(甲氧基亚硫酰基;亚磺酸甲酯)和-S(=O)OCH2CH3(乙氧基亚硫酰基;亚磺酸乙酯)。
磺酸酯(sulfonate)(磺酸酯,sulfonic acid ester):-S(=O)2OR,其中R是磺酸酯取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。磺酸酯基团的实例包括但不限于-S(=O)2OCH3(甲氧基磺酰基;磺酸甲酯)和-S(=O)2OCH2CH3(乙氧基磺酰基;磺酸乙酯)。
亚磺酰氧基:-OS(=O)R,其中R是亚硫酰氧基取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。亚硫酰氧基的实例包括但不限于-OS(=O)CH3和-OS(=O)CH2CH3。
磺酰氧基:-OS(=O)2R,其中R是磺酰氧基取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。磺酰氧基的实例包括但不限于-OS(=O)2CH3(甲磺酸酯)和-OS(=O)2CH2CH3(乙磺酸酯)。
硫酸酯:-OS(=O)2OR;其中R是硫酸酯取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。硫酸酯基团的实例包括但不限于-OS(=O)2OCH3和-SO(=O)2OCH2CH3。
氨磺酰(sulfamyl)(氨磺酰(sulfamoyl);亚磺酸酰胺;亚磺酰胺):-S(=O)NR1R2,其中R1和R2独立地是氨基取代基,如针对氨基所限定的。氨磺酰的实例包括但不限于-S(=O)NH2、-S(=O)NH(CH3)、-S(=O)N(CH3)2、-S(=O)NH(CH2CH3)、-S(=O)N(CH2CH3)2和-S(=O)NHPh。
亚磺酰氨基(亚氨磺酰基;磺酸酰胺;氨磺酰):-S(=O)2NR1R2,其中R1和R2独立地是氨基取代基,如针对氨基所限定的。亚磺酰氨基的实例包括但不限于-S(=O)2NH2、-S(=O)2NH(CH3)、-S(=O)2N(CH3)2、-S(=O)2NH(CH2CH3)、-S(=O)2N(CH2CH3)2和-S(=O)2NHPh。
磺氨基:-NR1S(=O)2OH,其中R1是氨基取代基,如针对氨基所限定的。磺氨基的实例包括但不限于-NHS(=O)2OH和-N(CH3)S(=O)2OH。
磺酰氨基(Sulfonamino):-NR1S(=O)2R,其中R1是氨基取代基,如针对氨基所限定的,以及R是磺酰氨基取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。磺酰氨基的实例包括但不限于-NHS(=O)2CH3和-N(CH3)S(=O)2C6H5。
亚磺酰氨基(Sulfinamino):-NR1S(=O)R,其中R1是氨基取代基,如针对氨基所限定的,并且R是亚磺酰氨基取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。亚磺酰氨基的实例包括但不限于-NHS(=O)CH3和-N(CH3)S(=O)C6H5。
膦基(膦):-PR2,其中R是膦基取代基,例如,-H、C1-7烷基、C3-20杂环基或C5-20芳基,优选-H、C1-7烷基或C5-20芳基。膦基的实例包括但不限于-PH2、-P(CH3)2、-P(CH2CH3)2、-P(t-Bu)2和-P(Ph)2。
二氧磷基:-P(=O)2。
磷酰基(氧化膦):-P(=O)R2,其中R是氧膦基取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基或C5-20芳基。磷酰基的实例包括但不限于-P(=O)(CH3)2、-P(=O)(CH2CH3)2、-P(=O)(t-Bu)2和-P(=O)(Ph)2。
膦酸(膦酰基):-P(=O)(OH)2。
膦酸酯(膦酰基酯):-P(=O)(OR)2,其中R是膦酸酯取代基,例如,-H、C1-7烷基、C3-20杂环基或C5-20芳基,优选-H、C1-7烷基或C5-20芳基。膦酸酯基团的实例包括但不限于-P(=O)(OCH3)2、-P(=O)(OCH2CH3)2、-P(=O)(O-t-Bu)2和-P(=O)(OPh)2。
磷酸(膦酰氧基):-OP(=O)(OH)2。
磷酸酯(膦酰氧基酯):-OP(=O)(OR)2,其中R是磷酸酯取代基,例如,-H、C1-7烷基、C3-20杂环基或C5-20芳基,优选-H、C1-7烷基或C5-20芳基。磷酸酯基团的实例包括但不限于-OP(=O)(OCH3)2、-OP(=O)(OCH2CH3)2、-OP(=O)(O-t-Bu)2和-OP(=O)(OPh)2。
亚磷酸:-OP(OH)2。
亚磷酸酯:-OP(OR)2,其中R是亚磷酸酯取代基,例如,-H、C1-7烷基、C3-20杂环基或C5-20芳基,优选-H、C1-7烷基或C5-20芳基。亚磷酸酯基团的实例包括但不限于-OP(OCH3)2、-OP(OCH2CH3)2、-OP(O-t-Bu)2和-OP(OPh)2。
亚磷酰胺:-OP(OR1)-NR2 2,其中R1和R2是亚磷酰胺取代基,例如,-H、(可选取代的)C1-7烷基、C3-20杂环基或C5-20芳基,优选-H、C1-7烷基或C5-20芳基。亚磷酰胺基团的实例包括但不限于-OP(OCH2CH3)-N(CH3)2、-OP(OCH2CH3)-N(i-Pr)2和-OP(OCH2CH2CN)-N(i-Pr)2。
氨基磷酸酯:-OP(=O)(OR1)-NR2 2,其中R1和R2是氨基磷酸酯取代基,例如,-H、(可选取代的)C1-7烷基、C3-20杂环基或C5-20芳基,优选-H、C1-7烷基或C5-20芳基。氨基磷酸酯基团的实例包括但不限于-OP(=O)(OCH2CH3)-N(CH3)2、-OP(=O)(OCH2CH3)-N(i-Pr)2和-OP(=O)(OCH2CH2CN)-N(i-Pr)2。
亚烷基
C3-12亚烷基:如在本文中所使用的,术语“C3-12亚烷基”涉及通过从具有3至12个碳原子(除非另有规定)的烃化合物的相同碳原子去除两个氢原子或从两个不同的碳原子各去除一个氢原子所获得的二齿部分,其可以是脂族或脂环族,并且其可以是饱和的、部分不饱和的或完全不饱和的。因此,术语“亚烷基”包括下文讨论的以下亚类:亚烯基、亚炔基、环亚烷基等。
直链饱和C3-12亚烷基的实例包括但不限于-(CH2)n-,其中n是3至12的整数,例如,-CH2CH2CH2-(亚丙基)、-CH2CH2CH2CH2-(亚丁基)、-CH2CH2CH2CH2CH2-(亚戊基)和-CH2CH2CH2CH-2CH2CH2CH2-(亚庚基)。
支链饱和C3-12亚烷基的实例包括但不限于-CH(CH3)CH2-、-CH(CH3)CH2CH2-、-CH(CH3)CH2CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH(CH3)CH2CH2-、-CH(CH2CH3)-、-CH(CH2CH3)CH2-和-CH2CH(CH2CH3)CH2-。
直链部分不饱和的C3-12亚烷基(C3-12亚烯基和亚炔基)的实例包括但不限于-CH=CH-CH2-、-CH2-CH=CH2-、-CH=CH-CH2-CH2-、-CH=CH-CH2-C H2-CH2-、-CH=CH-CH=CH-、-CH=CH-CH=CH-CH2-、-CH=CH-CH=CH-CH2-CH2-、-CH=CH-CH2-CH=CH-、-CH=CH-CH2-CH2-CH=CH-和-CH2-C≡C-CH2-。
支链部分不饱和的C3-12亚烷基(C3-12亚烯基和亚炔基)的实例包括但不限于-C(CH3)=CH-。-C(CH3)=CH-CH2-、-CH=CH-CH(CH3)-和-C≡C-CH(CH3)-。
脂环族饱和C3-12亚烷基(C3-12环亚烷基)的实例包括但不限于亚环戊基(例如环戊-1,3-亚基)和亚环己基(例如环己-1,4-亚基)。
脂环族部分不饱和的C3-12亚烷基(C3-12环亚烷基)的实例包括但不限于亚环戊烯基(例如4-环戊烯-1,3-亚基)、亚环己烯基(例如2-环己烯-1,4-亚基;3-环己烯-1,2-亚基;2,5-环己二烯-1,4-亚基)。
包括其他形式
除非另有规定,在上文中包括这些取代基的众所周知的离子、盐、溶剂化物和保护形式。例如,提及羧酸(-COOH)还包括其阴离子(羧酸根)形式(-COO-)、盐或溶剂化物,以及常规保护形式。类似地,提及氨基包括氨基的质子化形式(-N+HR1R2)、盐或溶剂化物,例如,盐酸盐,以及氨基的常规保护形式。类似地,提及羟基还包括其阴离子形式(-O-)、盐或溶剂化物,以及常规保护形式。
盐
可以方便的或所期望的是,制备、纯化和/或处理活性化合物的相应盐,例如,药学上可接受的盐。药学上可接受的盐的实例讨论于Berge,et al.,J.Pharm.Sci.,66,1-19(1977)。
例如,如果化合物是阴离子化合物,或具有其可以是阴离子的官能团(例如,-COOH可以是-COO-),那么可以与合适的阳离子形成盐。适合的无机阳离子的实例包括但不限于碱金属离子如Na+和K+,碱土金属阳离子如Ca2+和Mg2+,以及其他阳离子如Al+3。适合的有机阳离子的实例包括但不限于铵离子(即NH4 +)和取代的铵离子(例如NH3R+、NH2R2 +、NHR3 +、NR4 +)。一些适合的取代的铵离子的实例是那些取代的铵离子,其源自:乙胺、二乙胺、二环己胺、三乙胺、丁胺、乙二胺、乙醇胺、二乙醇胺、哌嗪、苄胺、苯基苄胺、胆碱、葡甲胺和氨丁三醇(tromethamine),以及氨基酸,如赖氨酸和精氨酸。常见的季铵离子的实例是N(CH3)4 +。
如果化合物是阳离子化合物,或具有其可以是阳离子的官能团(例如-NH2可以是-NH3 +),那么可以与合适的阴离子形成盐。适合的无机阴离子的实例包括但不限于源自以下无机酸的那些:盐酸、氢溴酸、氢碘酸、硫酸、亚硫酸、硝酸、亚硝酸、磷酸和亚磷酸。
适合的有机阴离子的实例包括但不限于源自以下有机酸的那些:2-乙酰氧基苯甲酸、乙酸、抗坏血酸、天冬氨酸、苯甲酸、樟脑磺酸、肉桂酸、柠檬酸、乙二胺四乙酸、乙烷二磺酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、羟基马来酸、羟基萘甲酸、羟乙磺酸、乳酸、乳糖酸、月桂酸、马来酸、苹果酸、甲磺酸、粘酸、油酸、草酸、棕榈酸、扑酸、泛酸、苯乙酸、苯磺酸、丙酸、丙酮酸、水杨酸、硬脂酸、琥珀酸、对氨基苯磺酸、酒石酸、甲苯磺酸、三氟乙酸和戊酸。适合的高分子有机阴离子的实例包括但不限于那些高分子有机阴离子,其源自以下聚合酸:丹宁酸、羧甲基纤维素。
溶剂化物
可以方便的或所期望地制备、纯化和/或处理活性化合物的相应溶剂化物。术语“溶剂化物”在本文中以常规含义来使用,用来指溶质(例如活性化合物、活性化合物的盐)和溶剂的复合物。如果溶剂是水,溶剂化物可以方便地称作水合物,例如,一水合物、二水合物、三水合物等。
本发明包括其中横过(across)PBD部分的亚胺键添加溶剂的化合物,其示出下文,其中溶剂是水或醇(RAOH,其中RA是C1-4烷基):
这些形式可以被称为PBD的甲醇胺和甲醇胺醚形式(如在以上关于R10的部分中所描述的)。这些等式的平衡取决于发现化合物的条件以及部分本身的特性。
例如,可以通过冷冻干燥以固体形式来分离这些特定化合物。
异构体
本发明的某些化合物可以以一种或多种特定的几何形式、光学形式、对映体形式、非对映体形式、差向异构体形式、异位异构体(atropic)形式、立体异构体形式、互变异构体形式、构象形式或异头异构体(anomeric)形式,包括但不限于顺式和反式;E型和Z型;c式、t式和r式;内形式和外形式;R型、S型和内消旋型;D型和L型;d型和l型;(+)和(-)形式;酮式、烯醇式和烯醇化物形式;顺式和反式;向斜形式和背斜形式;α形式和β形式;轴向形式和平伏形式;船式、椅式、扭式、信封式和半椅式;并且它们的组合,在下文中统称为“异构体”(或“异构体形式”)。
术语“手性”是指具有镜像伴侣的非重叠(不可重叠,non-superimposability)性质的分子,而术语“非手性”是指在它们的镜像伴侣上是重叠的分子。
术语“立体异构体”是指具有相同化学构成、但是在空间上原子或基团排布不同的化合物。
“非对映异构体”是指具有两个或多个手性中心、并且其分子相互不是另一个的镜像的立体异构体。非对映异构体具有不同的物理性质,例如,熔点、沸点、光谱性质和反应性。可以在高的再溶解分析步骤下如电泳和色谱分离非对映异构体的混合物。
“对映异构体”是指化合物的两种立体异构体,其是彼此的非重叠镜像。
本文使用的立体化学限定和规定通常遵循S.P.Parker,Ed.,McGraw-HillDictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;andEliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons,Inc.,New York,1994。本发明的化合物可以包含不对称或手性中心,因此以不同的立体异构体形式存在。旨在本发明的化合物的所有立体异构体形式包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomer)以及它们的混合物(如外消旋混合物),形成本发明的一部分。许多有机化合物以光学活性形式存在,即,它们具有使平面偏振光的平面旋转的能力。在描述光学活性化合物中,前缀D和L或R和S用于表示分子关于它的手性中心的绝对构型。使用前缀d和l或(+)和(-)来指定化学物的平面偏振光旋转的符号,其中(-)或l是指化合物是左旋的。前缀为(+)或d的化合物是右旋的。对于给定的化学结构,这些立体异构体除了它们是彼此的镜像外是相同的。特定的立体异构体可以由称为对映异构体,并且经常将这种异构体的混合物称为对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体,这在不具有立体选择性或立体特异性的化学反应或过程中可以发生。术语“外消旋混合物”和“外消旋体”是指两种没有光学活性的对映异构体物质的等摩尔混合物。
要注意的是,除非如下文针对互变异构体形式所讨论的,从术语“异构体”(如在本文中所使用的)明确排除结构(或构造)异构体(即,其差异在于在原子之间的连接而不仅在于原子在空间中的位置的异构体)。例如,提及甲氧基(-OCH3)并不被解释为提及它的结构异构体(羟甲基,-CH2OH)。类似地,提及邻氯苯基并不被解释为提及它的结构异构体(间氯苯基)。然而,提及一类结构可以包括落在上述类型的范围之内的结构异构体形式(例如C1-7烷基包括正丙基和异丙基;丁基包括正丁基、异丁基、仲丁基和叔丁基;甲氧基苯基包括邻甲氧基苯基、间甲氧基苯基和对甲氧基苯基)。
上述排除并不涉及互变异构体形式,如在,例如,以下互变异构体对中:酮/烯醇(如下图所示)、亚胺/烯胺、酰胺/亚氨基醇、脒/脒、亚硝基/肟、硫酮/烯硫醇、N-亚硝基/羟基偶氮和硝基/异硝基中的例如,酮式、烯醇式和烯醇化物形式。
术语“互变异构体”或“互变异构体形式”是指不同能量的结构异构体,其通过低能量势垒是可互变的。例如,质子互变异构体(也称为质子性互变异构体)包括通过质子的迁移的互变现象,如酮-烯醇和亚胺-烯胺异构化。化合价互变异构体包括通过一些成键电子的重组(reorganization)的互变现象。
要注意的是,术语“异构体”特别包括具有一个或多个同位素取代的化合物。例如,H可以是任何同位素形式,包括1H、2H(D)和3H(T);C可以是任何同位素形式,包括12C、13C和14C;O可以是任何同位素形式,包括16O和18O;等等。
可以结合至本发明的化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,如但不限于2H(氘,D)、3H(氚)、11C、13C、14C、15N、18F、31P、32P、35S、36Cl和125I。本发明的各种同位素标记的化合物,例如放射性同位素如3H、13C、14C并入到这些化合物中。这样的同位素标记的化合物可以用于代谢研究、反应动力学研究、检测或成像技术,如正电子断层扫描成像(PET)或单光子发射计算机断层成像术(SPECT),包括药物或底物组织分布分析,或在患者的放射性治疗中。本发明的氘标记的或取代的治疗性化合物可以具有改善的DMPK(药物代谢及药物动力学)性质,涉及分布、代谢以及排泄(ADME)。用较重的同位素(如氘)取代可以提供因更高的代谢稳定性以产生的某种治疗优点,例如,体内半衰期增加或所需的剂量减少。18F标记的化合物对PET或SPECT研究是有用的。本发明的同位素标记的化合物通常能够通过以下制备:实施在如下所述的反应方案或实施例以及制备例中披露的步骤(程序),用容易获得的同位素标记的试剂代替非同位素标记的试剂。另外,用较重的同位素,尤其是氘(即,2H或D)替代,可以提供因更高的代谢稳定性以产生的某种治疗优点,例如,体内半衰期增加或所需的剂量减少或治疗指数增加。应当理解的是将上下文中的氘视作取代基。这种较重同位素(尤其是氘)的浓度可以通过同位素富集因子来限定。在本发明的化合物中,任何没有明确指明为具体同位素的原子是指该原子的任何稳定的同位素。
除非另外说明,否则提到的具体化合物包括全部这些异构体形式,包括其(全部或部分地)外消旋和其他混合物。用于这种异构体形式的制备(例如,不对称合成)和分离(例如,分步结晶和色谱法)的方法是本领域已知的,或者通过已知的方式调整本文所教导的方法或已知的方法是容易得到的。
生物活性
体外细胞增殖测定
通常,通过以下测量抗体-药物结合物(ADC)的细胞毒性或细胞抑制活性:将具有受体蛋白质,例如HER2的哺乳细胞暴露于细胞培养基中ADC的抗体;培养细胞一段约6小时至约5天的时间段;以及测量细胞生存能力。基于细胞的体外测定用于测量本发明的ADC的生存能力(增殖)、细胞毒性和细胞死亡的诱导(半胱天冬酶激活)。
可以通过细胞增殖测定测量抗体-药物结合物的体外效力。Luminescent细胞生存能力测定仪是商业可获得的(Promega Corp.,Madison,WI),基于Coleoptera luciferase的重组表达的同质测定方法(US专利号5583024;5674713和5700670)。该细胞增殖测定基于存在ATP的定量确定培养基中生存细胞的数目,该ATP是代谢活性细胞的指示(Crouch et al(1993)J.Immunol.Meth.160:81-88;US 6602677)。在96孔板中进行测定,使它可经受高通过量筛选(HTS)的检验(Cree et al(1995)AntiCancer Drugs 6:398-404)。同种测定步骤涉及直接添加单一试剂(试剂)至培养在补充血清的培养基的细胞。细胞洗涤、除去培养基和多次移液步骤是不需要的。添加试剂和混合之后,在10分钟内体系检测到384孔板中低至15细胞/孔。可以用ADC连续处理细胞,或可以处理细胞并将其与ADC分离。通常,简单处理(即,3小时)的细胞示出与连续处理的细胞的相同效力。
同质的“添加-混合-测量”模式导致胞溶作用和与存在ATP的量成比例的发光(luminescent)信号的产生。ATP的量与存在于培养基中的细胞的数目直接成比例。测定产生由荧光素酶反应产生的“生长型”发光信号,取决于使用的细胞类型和培养基,其具有通常大于5小时的半衰期。生存细胞反应在相对发光单元(RLU)上。通过重组萤火虫荧光素酶与ATP至AMP的伴随转化和光子的产生,底物Beetle Luciferin(甲虫荧光素)被氧化脱羧基。
体内效力
可以通过小鼠中肿瘤异种移植(xenograft)研究测定本发明的抗体-药物结合物(ADC)的体内效力。例如,可以过高表达HER2转基因外植体小鼠模型测定本发明的抗HER2ADC的体内效力。同种异体移植(allograft)从对疗法并不响应或响应差的Fo5mmtv转基因小鼠增殖(propagate)。用ADC按照一定的剂量水平(mg/kg)和PBD药物暴露(μg/m2);以及安慰剂缓冲剂对照物(媒介物,vehicle)处理受试者一次并在两周或更长的时间内监测以测定肿瘤翻倍的时间、细胞杀伤log和肿瘤收缩。
用途
本发明的结合物可被用于在靶向位置提供PBD结合物。
靶向位置优选地是增殖的细胞群体。抗体是用于存在于增殖细胞群体中的抗原的抗体。
在一个实施方式中,与存在于增殖细胞群体(例如,肿瘤细胞群体)中的抗原的量相比,抗原不存在或以降低水平存在于非增殖细胞群体中。
靶向位置可以是体外、体内或离体。
本发明的抗体-药物结合物(ADC)化合物包括具有用于抗癌活性效用的那些。具体地,化合物包括结合的,即,通过接头共价连接至PBD部分的抗体。
在靶位置接头可能并未被切割。本发明的抗体-药物结合物(ADC)化合物可以具有细胞毒性作用而并未发生接头的切割以释放出PBD药物部分。本发明的抗体-药物结合物(ADC)选择性地向肿瘤组织递送细胞毒性剂,从而可以实现较高的选择性,即,较少的有效剂量。
因此,一方面,本发明提供本文所描述的用于在治疗中使用的结合物化合物。
在进一步的方面,还提供本文所描述的用于在增生性疾病的治疗中使用的结合物化合物。本发明的第二方面提供结合物化合物在制备用于治疗增生性疾病的药物中的用途。
本领域普通技术人员能够容易地确定候选结合物是否治疗任何特定细胞类型的增生性病症。例如,在以下的实例中描述了这样的测定法,它们可以方便地用于评估由特定化合物所提供的活性。
术语“增生性疾病”涉及不希望的过度或异常细胞的不需要的或不受控制的细胞增生,如,新生性或增生性生长(不管是体外或体内)。
增生性病症的实例包括但不限于良性、恶化前和恶性细胞增生,包括但不限于新生物和肿瘤(例如,组织细胞瘤、胶质瘤、星形细胞瘤、骨瘤)、癌症(例如肺癌、小细胞肺癌、胃肠癌、肠癌、结肠癌、乳癌、卵巢癌、前列腺癌、睾丸癌、肝癌、肾癌、膀胱癌、胰腺癌、脑癌、肉瘤、骨肉瘤、卡波西肉瘤、黑素瘤)、白血病、牛皮癣、骨病、纤维增生性疾病(例如结缔组织的纤维增生性疾病)和动脉粥样硬化。特别感兴趣的癌症包括但不限于白血病和卵巢癌。
可以治疗任何类型的细胞,包括但不限于肺、胃肠道(包括,例如,肠、结肠)、乳(乳房)、卵巢、前列腺、肝脏(肝)、肾脏(肾)、膀胱、胰腺、脑和皮肤。
在一个实施方式中,治疗是胰腺癌的治疗。
在一个实施方式中,治疗是在细胞表面上具有ανβ6整联蛋白的肿瘤的治疗。
预期本发明的抗体-药物结合物(ADC)可被用于治疗多种疾病或紊乱,例如,由肿瘤抗原的过表达表征。示例性病症或过度增生性紊乱包括良性或恶性肿瘤;白血病、血液和淋巴系统恶性肿瘤。其他包括以下的紊乱:神经元的、神经胶质细胞的、星形细胞的、下丘脑的、腺体的、巨噬细胞的、上皮的、基质的、囊胚腔的、炎症性的、血管产生的和免疫学的,包括自身免疫性紊乱。
通常,待治疗的疾病或紊乱是过度增生性疾病,如癌症。本文中待治疗的癌症的实例包括但不限于癌、淋巴瘤、母细胞瘤、肉瘤和白血病或淋巴恶性肿瘤。这种癌症的更具体地实例包括鳞状细胞癌(例如,上皮鳞状细胞癌)、肺癌(包括小细胞肺癌、非小细胞肺癌)、肺的鳞状细胞癌和肺的腺癌、腹膜癌、肝细胞癌、胃癌或胃部癌(包括胃肠癌)、胰腺癌、成胶质细胞瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝细胞瘤、乳癌、结肠癌、直肠癌、结肠直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌或肾脏癌、前列腺癌、外阴癌、甲状腺癌、肝肿瘤、肛门癌、阴茎癌以及头颈癌。
在治疗中可以使用ADC的自身免疫疾病包括风湿性疾病(如例如,类风湿关节炎、干燥综合征、硬皮病、狼疮如SLE和狼疮性肾炎、多肌炎/皮肌炎、冷球蛋白血症、抗磷脂抗体综合征和银屑病关节炎),骨关节炎、自身免疫性胃肠和肝紊乱(如例如,炎症性肠疾病(例如,溃疡性结肠炎和克罗恩病)、自身免疫性胃炎和恶性贫血、自身免疫性肝炎、原发性胆汁性肝硬化、原发性硬化性胆管炎和乳糜泻、血管炎(如例如,ANCA相关的血管炎,包括丘-施血管炎、韦格纳肉芽肿病和多动脉炎)、自身免疫性神经紊乱(如,例如,多发性硬化、斜视眼肌阵挛综合征、重症肌无力、视神经脊髓炎、帕金森氏病、阿尔茨海默氏病和自身免疫性多发性神经病变)、肾脏疾病(如例如,肾小球肾炎、古德帕斯彻氏综合征和贝格尔氏病)、自身免疫性皮肤病紊乱(如例如,牛皮癣、荨麻疹、麻疹、寻常天疱疮、大疱性类天疱疮和皮肤红斑狼疮)、血液学紊乱(如例如,血小板减少性紫癜、血栓性血小板减少性紫癜、输血后紫癜和自身免疫性溶血性贫血)、动脉粥样硬化、葡萄膜炎、自身免疫性听觉紊乱(如例如,内耳病和听力损失)、贝切特氏病、雷诺氏综合征、器官移植和自身免疫性内分泌紊乱(如例如,糖尿病相关自身免疫病诸如胰岛素依赖性糖尿病(IDDM)、阿狄森氏病和自身免疫性甲状腺病(例如,格雷夫斯病和甲状腺炎))。更优选的这种疾病包括,例如,风湿性关节炎、溃疡性结肠炎、ANCA相关的血管炎、狼疮、多发性硬化症、干燥综合征、格雷夫斯病、IDDM、恶性贫血、甲状腺炎和肾小球肾炎。
治疗方法
本发明的结合物可以在治疗方法中使用。还提供的是一种治疗的方法,包括向需要的受试者给予治疗有效量的本发明的结合物化合物。术语“治疗有效量”是足以显示对患者有益处的量。上述益处可以是至少改善一种症状。给予的实际量以及给予的速率和时间进程将取决于待治疗的性质和严重性。治疗处方,例如剂量决定,是在全科医师和其他医生的责任范围内。
可以单独给予或与其他治疗组合给予本发明的化合物,同时给予还是顺序给予取决于待治疗的病症。治疗和疗法的实例包括但不限于化学疗法(给予活性剂,包括例如药物,如化疗);手术;和放射疗法。
不考虑作用机制,“化疗剂”是在癌症治疗中有用的化学化合物。化疗剂的类别包括但不限于烷化试剂、抗代谢物、纺锤体毒植物生物碱、细胞毒性/抗肿瘤抗生素、拓扑异构酶抑制剂、抗体、光敏剂和激酶抑制剂。化疗剂包括在“靶向疗法”和常规化疗中使用的化合物。
化疗剂的实例包括:厄洛替尼(Genentech/OSI Pharm.)、多西他赛(Sanofi-Aventis)、5-FU(氟尿嘧啶,5-氟尿嘧啶,CAS No.51-21-8)、吉西他滨(Lilly)、PD-0325901(CAS No.391210-10-9,Pfizer)、顺铂(顺-二胺,二氯铂(II),CAS No.15663-27-1)、卡铂(CAS No.41575-94-4)、紫杉醇(Bristol-Myers Squibb Oncology,Princeton,N.J.)、曲妥珠单抗(Genentech)、替莫唑胺(4-甲基-5-氧代-2,3,4,6,8-五氮杂双环[4.3.0]壬-2,7,9-三烯-9-甲酰胺,CAS No.85622-93-1,Schering Plough)、他莫昔芬((Z)-2-[4-(1,2-二苯基丁-1-烯基)苯氧基]-N,N-二甲基乙胺、)和多柔比星Akti-1/2、HPPD和雷帕霉素。
化疗剂的更多实例包括:奥沙利铂(Sanofi)、硼替佐米(Millennium Pharm.)、索坦(SU11248,Pfizer)、来曲唑(Novartis)、甲磺酸伊马替尼(Novartis)、XL-518(Mek抑制剂,Exelixis,WO 2007/044515)、ARRY-886(Mek抑制剂,AZD6244,Array BioPharma,AstraZeneca)、SF-1126(PI3K抑制剂,Semafore Pharmaceuticals)、BEZ-235(PI3K抑制剂,Novartis)、XL-147(PI3K抑制剂,Exelixis)、PTK787/ZK 222584(Novartis)、氟维司群(AstraZeneca)、亚叶酸钙(亚叶酸)、雷帕霉素(西罗莫司,Wyeth)、拉帕替尼(GSK572016,Glaxo Smith Kline)、洛那法尼(SARASARTM,SCH 66336,Schering Plough)、索拉非尼(BAY43-9006,Bayer Labs)、吉非替尼(AstraZeneca)、伊立替康(CPT-11,Pfizer)、替吡法尼(ZARNESTRATM,Johnson&Johnson)、ABRAXANETM(不含聚氧乙烯蓖麻油)、紫杉醇的白蛋白纳米设计制剂(American Pharmaceutical Partners,Schaumberg,Il)、凡德他尼(rINN,ZD6474,AstraZeneca)、苯丁酸氮芥、AG1478、AG1571(SU 5271;Sugen)、西罗莫司(Wyeth)、帕唑帕尼(GlaxoSmithKline)、莰佛(Telik)、塞替派和环磷酰胺烷基磺酸酯如白消安、英丙舒凡和哌泊舒凡;氮丙啶类例如苯佐替哌(benzodopa)、卡波醌、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙撑亚胺和甲基蜜胺(甲基蜜胺类(methylamelamines),包括六甲蜜胺、三乙撑蜜胺、三乙撑磷酰胺、三乙撑硫代磷酰胺和三羟甲基蜜胺(trimethylolomelamine);内酯(尤其是布拉它辛和布拉它辛酮);喜树碱(包括合成的类拓扑替康);苔藓抑素;callystatin;CC-1065(包括它的]阿多来新、卡折来新和比折来新合成类似物);隐藻素(特别是隐藻素1和的隐藻素8);多拉司他汀;倍癌霉素(包括合成类似物,KW-2189和CB1-TM1);eleutherobin(软珊瑚醇);水鬼蕉碱;sarcodictyin(匍枝珊瑚醇);spongistatin;氮芥如苯丁酸氮芥、萘氮芥、氯磷酰胺(chlorophosphamide)、雌莫司汀、异环磷酰胺、二氯甲基二乙胺、二氯甲基二乙胺氧化物盐酸化物、美法仑、新恩比兴、苯芥胆甾醇、泼尼氮芥、氯乙环磷酰胺、尿嘧啶氮芥;亚硝基脲如卡莫司汀、氯脲霉素、福莫司汀、洛莫司汀、尼莫司汀和ranimnustine;抗生素如烯二炔抗生素(例如卡里奇霉素、卡里奇霉素γ1I、卡里奇霉素ΩI1(Angew Chem.Intl.Ed.Engl.(1994)33:183-186);达内霉素(dynemicin)、达内霉素A;二膦酸盐,如氯膦酸盐;埃斯培拉霉素;以及新制癌菌素生色团和相关色蛋白烯二炔抗生素生色团)、阿克拉霉素,放线菌素、authramycin、重氮丝氨酸、博来霉素、放线菌素、carabicin、洋红霉素、嗜癌菌素、色霉素(chromomycinis)、更生霉素、柔红霉素、地托比星、6-重氮-5-氧代-L-正亮氨酸、吗啉代-阿霉素、氰基吗啉代-阿霉素、2-吡咯啉基-阿霉素和脱氧阿霉素、表柔比星、依索比星、伊达比星、奈莫柔比星、麻西罗霉素、丝裂霉素如丝裂霉素C、霉酚酸、诺加霉素、橄榄霉素类、培洛霉素、泊非霉素、嘌呤霉素、三铁阿霉素、罗多比星、链黑菌素、链脲菌素、结核菌素(tubercidin)、乌苯美司、净司他丁、佐柔比星;抗代谢物如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物如二甲叶酸、甲氨蝶呤、蝶罗呤、三甲曲沙;嘌呤类似物如氟达拉滨、6-巯基嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物如安西他滨、阿扎胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、二脱氧尿苷、去氧氟尿苷、依诺他滨、氟尿苷;雄激素如卡普睾酮、屈他雄酮丙酸酯、环硫雄醇、美雄烷、睾内酯;抗肾上腺如氨鲁米特(aminoglutethimide)、米托坦、曲洛司坦;叶酸补充剂如亚叶酸;醋葡醛内酯(aceglatone);醛磷酰胺糖苷;氨基乙酰丙酸;恩尿嘧啶;安吖啶;bestrabucil;比生群;依达曲沙(edatraxate);地磷酰胺(defosfamide);地美可辛(Demecolcine);地吖醌;elfornithine;依利醋铵;埃博霉素;依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明(lonidainine);美登醇(maytansinoid)如美登素(maytansine)和安丝菌素(ansamitocin);米托胍腙;米托蒽醌;mopidanmol;硝嗪(根瘤菌剂(nitraerine));喷司他丁;苯来美特;吡柔比星;洛索蒽醌;鬼臼酸(podophyllinic acid);2-乙基肼;甲基苄肼;多糖复合物(JHS Natural Products,Eugene,OR);雷佐生;根霉素;西佐喃;锗螺胺(spirogermanium);细交链孢菌酮酸;三亚胺醌;2,2’,2”-三氯三乙胺;单端孢霉烯族毒素类(尤其是T-2毒素、疣孢菌素A(verracurin A)、杆孢菌素A和蛇形菌素);乌拉坦;长春地辛;达卡巴嗪;甘露醇氮芥;二溴甘露醇;二溴卫矛醇;哌泊溴烷;gacytosine;阿糖胞苷(“Ara-C”);环磷酰胺;塞替派;6-硫鸟嘌呤;巯基嘌呤;甲氨蝶呤;铂类似物如顺铂和卡铂;长春花碱;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨诺消灵(novantrone);替尼泊苷;依达曲沙;柔红霉素;氨基蝶呤;卡培他滨(Roche);伊班膦酸盐;CPT-11;拓扑异构酶抑制剂RFS2000;二氟甲基鸟氨酸(DFMO);类视黄醇类(类维生素A)如视黄酸;以上任一种的药学上可接受的盐、酸和衍生物。
还包括在“化疗剂”的限定中的是:(i)作用为调节或抑制肿瘤上的激素作用的抗激素试剂如抗雌激素和选择性雌激素受体调节剂(SERM),例如包括它莫西芬(包括柠檬酸它莫西芬)、雷洛昔芬、屈洛昔芬、4-羟基它莫西芬、曲沃昔芬、那洛昔芬(keoxifene)、LY117018、奥那司酮和(柠檬酸托瑞米芬);(ii)抑制酶芳香酶的芳香酶抑制剂,其调节产生于肾上腺的雌激素如例如4(5)-咪唑、氨鲁米特、(乙酸甲地孕酮)、(依西美坦;Pfizer)、福美司坦(formestanie)、法倔唑、(伏氯唑)、(来曲唑;Novartis)和(阿那曲唑;AstraZeneca);(iii)抗雄激素如氟他米特、尼鲁米特、比卡鲁胺、亮丙瑞林和戈舍瑞林;以及曲沙他滨(1,3-二氧戊环核苷胞嘧啶类似物);(iv)蛋白质激酶抑制剂如MEK抑制剂(WO 2007/044515);(v)脂质激酶抑制剂;(vi)反义寡核苷酸,特别是抑制异常细胞增殖中受影响的信号通路的基因例如PKC-α、Raf和H-Ras表达的那些,如奥利默森(oblimersen)(Genta Inc.);(vii)核糖酶如VEGF表达抑制剂(例如,)和HER2表达抑制剂;(viii)疫苗如基因疗法疫苗,例如和rIL-2;拓扑异构酶1抑制剂如rmRH;(ix)抗血管产生剂如贝伐珠单抗(Genentech)和以上任一种的药学上可接受的盐、酸和衍生物。
还包括在“化疗剂”限定中的是治疗性抗体如阿仑单抗(Campath)、贝伐珠单抗(Genentech);西妥昔单抗(Imclone);帕尼单抗(Amgen)、利妥昔单抗(Genentech/Biogen Idec)、帕妥珠单抗(OMNITARGTM,2C4,Genentech)、曲妥珠单抗(Genentech)、托西莫单抗(Bexxar,Corixia)和抗体药物结合物、吉妥珠单抗(gemtuzumab ozogamicin)(Wyeth)。
具有与本发明的结合物组合作为化疗剂的治疗潜力的人源化单克隆抗体包括:阿仑单抗、阿泊珠单抗、阿塞珠单抗、atlizumab、巴品珠单抗(bapineuzumab)、贝伐珠单抗、莫比伐珠单抗(bivatuzumab mertansine)、莫坎妥珠单抗(cantuzumab mertansine)、西利珠单抗、赛妥珠单抗(certolizumab pegol)、cidfusituzumab、cidtuzumab、达利珠单抗、依库丽单抗、依法利珠单抗、依帕珠单抗、厄利珠单抗、非维珠单抗、芳妥珠单抗(Fontolizumab)、吉妥珠单抗、英妥珠单抗(Inotuzumab Ozogamicin)、伊匹单抗、拉贝珠单抗、林妥珠单抗、马妥珠单抗、美泊利单抗、莫维珠单抗、motovizumab、那他珠单抗、尼妥珠单抗、nolovizumab、numavizumab、奥瑞珠单抗(ocrelizumab)、奥马珠单抗、帕利珠单抗、帕考珠单抗、pecfusituzumab、pectuzumab、帕妥珠单抗、培克珠单抗、ralivizumab、雷珠单抗、reslivizumab、瑞利珠单抗、resyvizumab、rovelizumab、鲁利单抗、西罗珠单抗、西利珠单抗(Siplizumab)、索土珠单抗、他珠单抗(tacatuzumab tetraxetan)、他度珠单抗、他利珠单抗、特非珠单抗、塔西单抗、托利珠单抗(toralizumab)、曲妥单抗、tucotuzumabcelmoleukin、tucusituzumab、umavizumab、乌珠单抗和维西珠单抗(visilizumab)。
按照本发明的和按照本发明使用的药物组合物,除活性成分(即,结合物化合物)以外,还可以包含药用赋形剂、载体、缓冲剂、稳定剂或本领域技术人员熟知的其他物质。这样的物质应是无毒的,并且不应干扰活性成分的效力。载体或其他物质的确切性质将取决于给予途径,该给予途径可以是口服或通过注射(例如皮肤、皮下或静脉内)。
用于口服给予的药物组合物可以是片剂、胶囊剂、散剂或液体形式。片剂可以包含固体载体或佐剂。液体药物组合物通常包含液体载体如水、石油(petroleum)、动物或植物油、矿物油或合成油。可以包括生理盐水溶液、右旋糖或其他糖溶液或二醇类如乙二醇、丙二醇或聚乙二醇。胶囊剂可以包含固体载体如明胶。
对于静脉内、皮肤或皮下注射,或在痛苦部位处的注射,活性组分将具有胃肠道外可接受的水溶液的形式,其是无热原的并具有适合的pH、等渗性和稳定性。本领域技术人员能够使用例如,等渗载体如氯化钠注射液、林格氏注射液、乳酸林格氏注射液来很好地制备适合的溶液。根据需要,可以包括防腐剂、稳定剂、缓冲剂、抗氧化剂和/或其他添加剂。
制剂
尽管可以单独使用(例如,给予)结合物化合物时,往往优选的是使其作为组合物或制剂存在。
在一个实施方式中,组合物是包含本文所描述的结合物化合物和药学上可接受的载体、稀释剂或赋形剂的药物组合物(例如,制剂、配制品、药品)。
在一个实施方式中,组合物是包含至少一种本文所描述的结合物化合物与一种或多种本领域技术人员熟知的药学上可接受的成分的药物组合物,该成分包括但不限于药学上可接受的载体、稀释剂、赋形剂、佐剂、填料、缓冲液、防腐剂、抗氧化剂、润滑剂、稳定剂、增溶剂、表面活性剂(例如,润湿剂)、掩蔽剂、着色剂、调味剂和甜味剂。
在一个实施方式中,组合物进一步包含其他活性剂,例如,其他治疗剂或预防剂。
可以在标准药品文本中找到合适的载体、稀释剂、赋形剂等。参见,例如,Handbook of Pharmaceutical Additives,2nd Edition(eds.M.Ash and I.Ash),2001(SynapseInformation Resources,Inc.,Endicott,New York,USA),Remington's Pharmaceutical Sciences,20th edition,pub.Lippincott,Williams&Wilkins,2000;和Handbook of Pharmaceutical Excipients,2nd edition,1994。
本发明的另一方面涉及制备药物组合物的方法,包括将本文限定的至少一种[11C]-放射性同位素标记的结合物或结合类化合物与一种或多种本领域技术人员熟知的其他药学上可接受的成分混合在一起,例如,载体、稀释剂、赋形剂等。如果配制为离散单元(例如,片剂等),那么每个单元包含预定量(剂量)的活性化合物。
本文所用的术语“药学上可接受的”涉及化合物、成分、材料、组合物、剂型等,其在合理的医学判断范围内、适用于与所讨论的受试者(例如,人类)的组织接触而没有过度的毒性、刺激、过敏反应或其他问题或并发症,并与合理的利益/风险比相称。每种载体、稀释剂、赋形剂等在与制剂的其他成分相容的意义上也必须是“可接受的”。
可通过药学领域熟知的任何方法来制备制剂。这样的方法包括使活性化合物与构成一种或多种辅助成分的载体结合的步骤。一般而言,制剂通过使活性化合物与载体(例如,液体载体、精细固体载体等)均匀和紧密地结合,然后如必要的话使产品成形来制备。
可以将制剂制备为快速或慢速释放;立即、延迟、即时或缓慢释放;或它们的组合。
适于胃肠外给予(例如,通过注射)的制剂包括水性或非水性的、等渗的、无热原的、无菌液体(例如溶液,悬浮液),其中活性成分被溶解、悬浮或以其他方式提供(例如,在脂质体或其他微粒中)。这种液体可以另外包含其他药学上可接受的成分如抗氧化剂、缓冲剂、防腐剂、稳定剂、抑菌剂、助悬剂、增稠剂以及使制剂与预期受体的血液(或其他相关体液)等渗的溶质。赋形剂的实例包括,例如,水、醇、多元醇、甘油、植物油等。用于此类制剂的合适等渗载体的实例包括氯化钠注射液、林格氏液(Ringer's Solution)或乳酸林格氏注射液。通常,液体中活性成分的浓度是约1ng/ml至约10μg/mL,例如约10ng/mL至约1μg/mL。该制剂可存在于单位剂量或多剂量密封容器,例如安瓿和小药烧瓶中,并且可在冷冻干燥(冻干)条件下储藏,仅需在临用前加入无菌液体载体例如注射用水。可以由无菌粉末、颗粒和片剂当场制备注射溶液和悬浮液。
剂量
本领域技术人员应当理解的是,结合物化合物和包含该结合物化合物的组合物的适当剂量可因患者而异。确定最佳剂量一般将牵涉使治疗益处的水平与任何风险或有害副作用平衡。选择的剂量水平将取决于多个因素,包括但不限于特定化合物的活性、给予途径、给予时间、化合物的排泄时间、治疗的持续时间、其他药物、化合物和/或组合使用的物质、病况的严重性和物种、性别、年龄、体重、病况、总体健康状况和患者的病史。化合物的量和给予途径最终将由医师、兽医或临床医师慎重决定,但是一般而言,将选择剂量以在作用部位达到实现所期望的作用而不会造成实质性损害或有害副作用的局部浓度。
在整个治疗过程中,可以单剂量、连续或间歇地(例如,以适当时间间隔分剂量)实现给予。确定最有效的给予手段和剂量的方法是本领域技术人员熟知的,并且将随用于疗法的制剂、疗法目的、所治疗的(多种)靶细胞和所治疗的受试者的不同而改变。可以用治疗医师、兽医或临床医师选择的剂量水平和模式进行单次或多次给予。
一般而言,活性化合物的合适剂量是在约100μg至约25mg(更通常地约1μg至约10mg)/千克受试者体重/天的范围内。在该化合物是盐、酯、酰胺、前药等的情况下,基于母体化合物计算给予量,所以所用的实际重量成比例增加。
在一个实施方式中,根据以下剂量方案将活性化合物给予至人类患者:约100mg,每天3次。
在一个实施方式中,根据以下剂量方案将活性化合物给予至人类患者:约150mg,每天2次。
在一个实施方式中,根据以下剂量方案将活性化合物给予至人类患者:约200mg,每天2次。
然而,在一个实施方式中,根据以下剂量方案将结合物化合物给予至人类患者:约50或约75mg,每天3或4次。
在一个实施方式中,根据以下剂量方案将结合物化合物给予至人类患者:约100或约125mg,每天2次。
以上描述的剂量可以适用于结合物(包含PBD部分和至抗体的接头)或适用于提供的PBD化合物的有效量,例如,接头切割后释放的化合物的量。
对于预防或治疗疾病,本发明的ADC的适当剂量将取决于待治疗的以上限定的疾病类型、疾病的严重度和情况(无论给予分子是用于预防还是治疗目的)、先前治疗、患者的临床病史和对抗体的反应,以及主治医生的判断。一次或通过一系列治疗将分子合适地给予至患者。取决于疾病的类型和严重程度,无论,例如通过一次或多次单独给予或通过连续输注,约1μg/kg至15mg/kg(例如,0.1-20mg/kg)的分子是用于给予至患者的初始候选剂量。通常的每日剂量可以在约1μg/kg至100mg/kg或更多的范围内,这取决于上述的因素。给予至患者的ADC的示例性剂量在约0.1至约10mg/kg患者重量的范围内。对于几天或更长的重复给予,取决于病症,治疗持续到实现疾病症状的期望抑制。示例性剂量方案包括给予约4mg/kg初始载药量的情况,随后每周、每两周或每三周添加另外剂量的ADC。其他剂量方案可以是有用的。该疗法的进展易于通过常规技术和测定法监测。
治疗
在治疗病症的情况下本文所使用的术语“治疗”通常涉及无论人类或动物(例如,兽医应用)的治疗和疗法,其中,其中实现了一些期望的疗效,例如,对病症发展的抑制,并且包括发展速度降低、发展速度减半、病症恢复、病症改善和病症康复。还包括作为预防性措施(即,预防、防止)的治疗。
本文所使用的术语“治疗有效量”涉及活性化合物或包含活性化合物的物质、组合物或剂型的量,当根据期望的治疗方案给予时,其对于产生一些期望的疗效是有效的、与合理的利益/风险比相当。
类似地,本文所使用的术语“预防有效量”涉及活性化合物或包含活性化合物的物质、组合物或剂型的量,当根据期望的治疗方案给予时,其对于产生一些期望的预防效果是有效的、与合理的利益/风险比相当。
抗体药物结合物的制备
可以通过本领域技术人员已知的多种途径,使用有机化学反应、条件和试剂制备抗体药物结合物,包括:(1)抗体的亲核基团与二价接头试剂反应,以经由共价键形成抗体-接头中间产物Ab-L,然后与活化的药物部分试剂反应;和(2)药物部分试剂与接头试剂反应,以经由共价键形成药物-接头试剂D-L,然后与抗体的亲核基团反应。结合方法(1)和(2)可以适用于各种抗体和接头以制备本发明的抗体-药物结合物。
抗体上的亲核基团包括但不限于侧链硫醇基团,例如,半胱氨酸。硫醇基团是亲核的并且能够与接头部分上的亲电基团(如本发明的那些)反应形成共价键。某些抗体具有可还原的链内二硫化物,即,半胱氨酸桥。通过用还原剂如DTT(克莱兰氏试剂(Cleland's),二硫代苏糖醇)或TCEP(三(2-羧乙基)磷化氢盐酸化物;Getz et al(1999)Anal.Biochem.Vol273:73-80;Soltec Ventures,Beverly,MA)处理可以使抗体与接头试剂的结合变得易反应。因此,每理论上个半胱氨酸二硫桥将形成两个反应性硫醇亲核体。通过产生胺至硫醇的转化的赖氨酸与2-亚氨基噻吩(特劳特氏(Traut’s)试剂)的反应,可以将其他亲核基团引入至抗体中。
受试者/患者
受试者/患者可以是动物、哺乳动物、胎盘哺乳动物、有袋动物(例如,袋鼠、袋熊)、单孔目动物(例如,鸭嘴兽)、啮齿动物(例如,豚鼠、仓鼠、大鼠、小鼠)、鼠科动物(例如,小鼠)、兔类动物(例如,家兔)、鸟类(例如,鸟)、犬科动物(例如,家犬)、猫科动物(例如,家猫)、马科动物(例如,马)、猪科动物(例如,家猪)、绵羊类(例如,绵羊)、牛科动物(例如,奶牛)、灵长类动物、猿类(例如,猴子或类人猿)、猴(例如,狨猴、狒狒)、类人猿(例如,大猩猩、黑猩猩、猩猩、长臂猿)或人类。
此外,受试者/患者可是其发育的任何形式,例如胎儿。在一个优选实施方式中,受试者/患者是人类。
在一个实施方式中,患者是每个患者具有在细胞表面上包含ανβ6整联蛋白的肿瘤的群体。
合成
式IVE的二聚体中间产物的一个可能合成路径如下所示:
中间产物IV可以用于制备中间产物VII
中间产物IV可以用于制备中间产物IX:
可替代地,中间产物IV可以与中间产物X偶联以制备中间产物IX:
中间产物IV可以用于制备中间产物XVI
中间产物IV可以用于制备中间产物XIX
式XIV的二聚体中间产物的一个可能合成路径如下所示:
中间产物XXI可以用于制备中间产物XXVII:
在上述图解方案中,RN、RN’和RN”各自独立地表示氮保护基团。RC和RC’分别表示OH或OProtO,其中ProtO是羟基保护基团。在本领域内,保护基团是众所周知的。RN、RN’和RN”可以是例如BOC。ProtO可以是THP。可能的是,取决于所采用的化学过程,在以上所示的合成方法的不同阶段除去N10-C11亚胺键的保护。
一般而言,可以首先将两个PBD单体与亚苯基或亚吡啶基二聚体桥连接以产生中间产物IV或XXI来制备化合物和结合物。随后可以使用中间产物IV的二聚体桥中的芳环上的卤素基团形成系链(包括接头基团G或L)以将PBD二聚体连接至细胞结合剂。
更详细地,在每个PBD单体的C8位置上具有-XH和–X'H基团的两个PBD单体(分别是中间产物I和II)可以与中间产物III或中间产物XX上的-T-Hal和-T’-Hal基团反应。这种合成方法允许PBD单体不同,而因此所获得的PBD二聚体是不对称的。同样,PBD单体可以是相同的。
PBD二聚体中间产物IV可以用于通过在许多方式中使桥中的芳基卤素基团反应以提供本发明的化合物和结合物。
首先,中间产物IV可以用于Sonogishira交叉偶联反应以提供二聚体桥的芳基基团上的乙炔基基团。Sonogishira交叉偶联反应在本领域内是众所周知的,用于在钯催化剂如PD(Ph3)4,铜催化剂如CuI,和碱如二乙胺的存在下将端炔与芳基卤化物偶联。
当乙炔用作末端乙炔时,乙炔分子的一侧通常用例如TMS保护以防止PBD二聚体的交联。一旦Sonogishira反应完成,TMS基团就可以被切割以提供炔中间产物V。
中间产物V可以与叠氮化合物反应以在叠氮-炔惠斯更(Huisgen)环加成中形成三唑衍生物。这种反应可以由铜催化剂催化。为了形成本发明的化合物和结合物,叠氮化物键连至亚乙基基团和可不同数目的PEG基团。叠氮可以用胺基团封端以进一步反应。中间产物V与氨基-叠氮化合物的反应将会提供中间产物VI。
然后中间产物VI的游离胺基基团可以与用于连接至细胞结合单元的接头基团的羧酸基团反应以形成将PBD二聚体连接至接头基团G或L的酰胺基团,以提供化合物VII。
中间产物VII的接头/反应性基团,G,可以结合至细胞结合剂以提供本发明的结合物。
作为可替代的Sonogishira反应,中间产物IV可以在钯和铜催化剂和碱的存在下偶联至乙酰胺,如炔丙胺。这种反应提供了连接至其中乙炔基团被保护并且游离端胺可用于进一步反应的PBD二聚体桥的系链的部分。例如,中间产物IV与炔丙胺的反应提供了中间产物VIII。
中间产物VIII的端胺可以与例如连接至接头/反应性基团G(用于连接至细胞结合剂)的羧酸基团反应以提供中间产物IX。
作为中间产物IX的可替代的合成,中间产物XI的羧酸基团可以与炔丙胺反应以形成中间产物XII。中间产物IV与中间产物XII在Sonogoshira反应中的反应产生中间产物XIII。
封端可变PEG链的受保护的胺基基团可以被脱保护并与中间产物XIV的羧酸基团反应以将接头/反应性基团G偶联至PBD二聚体上并生成中间产物XIV。
中间产物IV也可以用于交叉偶联胺化反应,如布赫瓦尔德-哈特维希(Buchwald-Hartwig)胺化反应中。碳-氮键经由钯催化的胺与芳基卤化物的交叉偶联(cross-coupling)形成。适用于这种交叉偶联反应的许多钯催化剂是已知的,如Pd(Ph3)4或RuPhos/RuPhosPd。
具有哌嗪官能化的中间产物IV与保护的丙-1-胺的反应提供了中间产物XV(Reaction of intermediate IV with a piperizine functionlised with a protectedpropan-1-amine provides intermediate XV)。中间产物XV的受保护的胺可以进一步与例如连接至用于连接至细胞结合剂的接头/反应性基团,G,反应以提供中间产物XVI。
中间产物IV与部分受保护的哌嗪的交叉偶联胺化反应,如布赫瓦尔德-哈特维希胺化反应,随后是(例如,用三氟乙酸)脱保护以提供中间产物XVII。
中间产物XVII的脱保护的哌嗪胺基团可以与中间产物XVIII中的羧酸基团反应以提供中间产物XIX。
可以使用中间产物XXI以形成肟中间产物XXIV。例如,部分受保护的聚PEG-二胺,中间产物XXII,可以与中间产物XIV的羧酸基团反应。脱保护作用产生中间产物XIII。
中间产物XXI和XXIII的反应会产生肟中间产物XXIV。可以使用制备HPLC拆分顺式和反式肟。
也可以使用中间产物XXI以形成丙烯酰胺中间产物XXVII。例如,醛中间产物XXI可以与丙二酸在克莱温格(Knoevenagel)缩合中反应生成丙烯酸中间产物XXV。这可以与部分保护的PEG-二胺反应以产生中间产物XXVI。脱保护作用和与中间产物XIV的偶联产生丙烯酰胺中间产物XXVII。
在以下的参考文献中进行了广泛讨论包含两个亚胺部分的PBD化合物的合成,其讨论通过引用结合于此:
a)WO 00/12508(第14至30页);
b)WO 2005/023814(第3至10页);和
c)WO 2005/085259(第31至39页)。
实施例
通用实验方法
在ADP 220旋光仪(Bellingham Stanley Ltd.)上测量旋光性并以g/100mL为单位来给出浓度(c)。使用数字熔点仪(Electrothermal)来测量熔点。用Perkin-ElmerSpectrum 1000FT IR分光计来记录IR谱。在300K下,利用Bruker Avance NMR分光计,分别在400和100MHz处获得1H和13C NMR谱。相对于TMS(δ=0.0ppm)报告化学位移,并将信号指示为s(单峰)、d(双峰)、t(三重峰)、dt(双三重峰)、dd(双峰的双峰)、ddd(双峰的双双峰)或m(多重峰),其中以赫兹(Hz)为单位来给出偶合常数。利用连接于具有Waters 2996PDA的Waters 2695HPLC上的Waters Micromass ZQ仪器来收集质谱(MS)数据。使用的WatersMicromass ZQ参数是:毛细管(kV),3.38;锥电压(V),35;提取器(V),3.0;源温度(℃),100;去溶剂化温度(℃),200;锥流速(L/h),50;去溶剂化流速(L/h),250。使用金属涂覆的硼硅玻璃尖端来将样品引入仪器,以正W模式在Waters Micromass QTOF Global上记录高分辨率质谱(HRMS)数据。在硅胶铝板(Merck 60,F254)上进行薄层色谱(TLC),并利用硅胶(Merck60,230-400目ASTM)来进行快速色谱。所有化学品和溶剂购自Sigma-Aldrich并如供应的使用而没有进一步的纯化。
通用LC/MS条件:使用水(A)(甲酸0.1%)和乙腈(B)(甲酸0.1%)的流动相运行HPLC(Waters Alliance 2695)。梯度:初始组成5%B,1.0分钟,然后,在3分钟内,从5%B到95%B。将上述组成保持在95%B下0.5分钟,然后在0.3分钟内回到5%B。总梯度运行时间等于5分钟。流速3.0mL/min,经由零死容积T形管(其通入质谱仪)来分开400μL。波长检测范围:220至400nm。功能类型:二极管阵列(535次扫描)。柱子: OnyxMonolithic C18 50×4.60mm。
实施例5至11的分析LC/MS条件如下:使用Shimadzu LCMS-2020进行阳离子模式电喷雾质谱。所用流动相是溶剂A(含0.1%甲酸的H2O)和溶剂B(含0.1%甲酸的CH3CN)。梯度:初始组成5%B保持0.25min,然后2min内从5%B升高至100%B。组成在100%B下保持长达0.5min,而随后在0.05min内恢复至5%B并就此保持0.05min。梯度运行的总持续时间等于3.0min。流速为0.8mL/min。在214nm和254nm下检测。柱:50℃下,Waters Acquity BEH Shield RP18 1.7μm 2.1×50mm。
实施例5至11的制备HPLC条件如下:在Shimadzu 机器上使用以下尺寸的 Gemini NX 5μC18柱(50℃)执行反相超快速高效液相色谱法(UFLC):150×4.6mm用于分析,而150×21.2mm用于制备工作。所使用的洗脱液是溶剂A(含0.1%甲酸的H2O)和溶剂B(含0.1%甲酸的CH3CN)。用以下梯度条件实施所有UFLC实验:从0至30min组成B从0%增加至100%并保持于100%B持续另外2min。从32.0min至32.1min,B的组成从100%降低到0%,并保持于0%B直至35.0min。梯度运行的总持续时间为35min。所使用的流速为1mL/min用于分析,而20mL/min用于制备HPLC。在254nm和280nm处进行检测。
实施例1
(a)(11S,11aS,11'S,11a'S)-二-叔丁基8,8'-(((5-卤素-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H吡咯并[2,1-c][1,4]苯并二氮杂-10(5H)-羧酸酯)(2a,2b,2c)
(i)(11S,11aS,11'S,11a'S)-二-叔丁基8,8'-(((5-碘代-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H吡咯并[2,1-c][1,4]苯并二氮杂-10(5H)-羧酸酯)(2a)。
将1,3-二(溴甲基)-5-碘苯(2.00g,5.20mmol)加入Boc/THP-保护的PBD帽单元1(4.75g,10.3mmol)、TBAI(190mg,0.52mmol)和K2CO3(1.42g,10.3mmol)在无水DMF(60mL)中的搅拌溶液中。将反应混合物加热至60℃并在氩气氛下搅拌持续3h,此时通过LC/MS的分析表明在4.15min保留时间处绝大部分产物形成(ES+)m/z 1171([M+Na]+.,~10%相对强度)。容许反应混合物冷却至室温并且通过在真空下蒸发除去DMF。获得的残余物在水(50mL)和EtOAc(50mL)之间分配并且用EtOAc(3×20mL)萃取水相。合并的有机层用水(2×20mL)、盐水(50mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱:50:50v/v EtOAc/己烷至80:20v/v EtOAc/己烷)提供为白色泡沫的二醚2a(5.42g,91%收率)。
(ii)(11S,11aS,11'S,11a'S)-二-叔丁基8,8'-(((5-溴-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-10(5H)-羧酸酯)(2b)
将1-溴-3,5-二(溴甲基)苯(1.54g,4.53mmol)加入Boc/THP-保护的PBD帽单元1(4.20g,9.06mmol)、TBAI(167mg,0.45mmol)和K2CO3(1.25g,9.06mmol)在无水DMF(52mL)中的搅拌溶液中。将反应混合物加热至60℃并在氩气氛下搅拌持续5h,此时通过LC/MS的分析表明在4.10min保留时间处绝大部分产物形成(ES+)m/z 1101([M+H]+.,~70%相对强度)。容许反应混合物冷却至室温并且通过在真空下蒸发除去DMF。获得的残余物在水(60mL)和EtOAc(60mL)之间分配而水相用EtOAc(3×25mL)萃取。合并的有机层用水(30mL)、盐水(50mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱:50:50v/v EtOAc/己烷至100%EtOAc)提供为白色泡沫的二醚2b(3.37g,68%收率)。
(iii)(11S,11aS,11'S,11a'S)-二-叔丁基8,8'-(((5-氯-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-10(5H)-羧酸酯)(2c)
将1,3-二(溴甲基)-5-氯苯(1.42g,4.80mmol)加入Boc/THP-保护的PBD帽单元1(4.42g,9.60mmol)、TBAI(177mg,0.48mmol)和K2CO3(1.33g,9.60mmol)在无水DMF中(55mL)的搅拌溶液中。将反应混合物加热至60℃并在氩气氛下搅拌持续1.5h,此时通过LC/MS的分析表明在4.08min保留时间处绝大部分产物形成(ES+)m/z 1057([M+H]+.,~30%相对强度)。容许反应混合物冷却至室温并且通过在真空下蒸发除去DMF。获得的残余物在水(60mL)和EtOAc(60mL)之间分配并且用EtOAc(3×20mL)萃取水相。合并的有机层用水(20mL)、盐水(40mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱:50:50v/v EtOAc/己烷至80:20v/v EtOAc/己烷)提供为白色泡沫的二醚2c(5.10g,99%收率)。
(b)(11S,11aS,11'S,11a'S)-二-叔丁基8,8'-(((5-乙炔基-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-10(5H)-羧酸酯)(4)
(i)(11S,11aS,11'S,11a'S)-二-叔丁基8,8'-(((5-((三甲基甲硅烷基)乙炔基)-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂10(5H)-羧酸酯)(3)
在烘箱干燥的可密封容器中将催化量的Pd(PPh3)4(15.0mg,13.1μmol)加入二醚2a(750mg,0.65mmol)、TMS-乙炔(278μL,191mg,1.96mmol)、CuI(5.0mg,26.1μmol)、二乙胺(1.35mL,956mg,13.1mmol)和烘箱干燥的分子筛丸粒在无水DMF中(5.6mL)的混合物中。混合物经过脱气并用氩气吹扫3次,随后在100℃微波中加热30min此时通过LC/MS的分析表明在4.37min保留时间处原料完全消耗且绝大部分产物形成(ES+)m/z 1142([M+Na]+.,~40%相对强度)。在3.97min保留时间处观察到峰(ES+)m/z 1069([M+Na]+.,~60%相对强度),这对应于这对应于在LC/MS条件下的TMS-断裂。容许反应混合物冷却至室温并随后通过烧结物过滤以除去分子筛(用DMF洗涤)。滤液进行真空蒸发并且获得的残余物经过快速色谱法(梯度洗脱:50:50v/v EtOAc/己烷至80:20v/v EtOAc/己烷)以提供为黄色泡沫的TMS-乙炔3(691mg,95%收率)。
(ii)(11S,11aS,11'S,11a'S)-二-叔丁基8,8'-(((5-乙炔基-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-10(5H)-羧酸酯)(4)
将固体K2CO3(383mg,2.77mmol)加入TMS-保护的化合物3(1.55g,1.39mmol)在MeOH(20mL)中的搅拌溶液中。在3h之后,室温搅拌下通过LC/MS判断认为反应进行完全[所需的产品峰在4.00min保留时间处(ES+)m/z 1047([M+H]+.,~30%相对强度)]。通过在真空下蒸发除去MeOH并且将获得的残余物在水(60mL)和EtOAc(60mL)之间分配。将这些层分离并且用EtOAc(3×20mL)萃取水相。合并的有机层用水(30mL)、盐水(30mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱:50:50v/v EtOAc/己烷至80:20v/v EtOAc/己烷)提供为橙色泡沫的炔4(1.13g,78%收率)。
(c)(11S,11aS,11'S,11a'S)-二-叔丁基8,8'-(((5-(1-(2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)乙基)-1H-1,2,3-三唑-4-基)-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂10(5H)-羧酸酯)(5)
室温下将固体CuSO4.5H2O(13.0mg,52.0μmol)和(+)-L-抗坏血酸钠(41.0mg,0.21mmol)加入至11-叠氮基-3,6,9-三氧杂十一烷-1-胺(227mg,207μL,1.04mmol)和炔4(1.09g,1.04mmol)在t-BuOH(6mL)和H2O(6mL)中的搅拌溶液中。随着反应进行观察到由黄变绿的颜色变化。在搅拌16h之后,通过LC/MS的分析表明生成了绝大部分的所需产物的量,对应于在3.12min保留时间处的峰(ES+)m/z 1265([M+H]+.,~100%相对强度)。[注意:在反应进程失速的某些情况下,然而,一旦加入另外的CuSO4.5H2O(0.05当量)和(+)-L-抗坏血酸钠(0.2当量)就能驱使反应完全]。反应混合物在水(50mL)和EtOAc(50mL)之间分配(无需振荡分液漏斗)。用EtOAc(3×15mL)萃取水相并且合并的有机层用水(30mL)、盐水(50mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供为绿色泡沫的粗产物5(1.32g,100%粗收率)。粗产物无需进一步纯化直接用于下一步骤。
(d)(11S,11aS,11'S,11a'S)-二-叔丁基8,8'-(((5-(1-(18-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-13-氧代-3,6,9-三氧杂12-氮杂十八烷基)-1H-1,2,3-三唑-4-基)-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂10(5H)-羧酸酯)(6)
室温下将固体6-马来酰亚胺己酸N-羟基琥珀酰亚胺酯(327mg,1.06mmol)加入伯胺5(1.28g,1.01mmol)在无水DCM(30mL)中的搅拌溶液中。通过LC/MS监测进程并在3天后搅拌反应不再进行,观察到3.65min保留时间处的绝大部分的所需产品的量(ES+)m/z 1458([M+H]+.,~100%相对强度)伴随有3.15min保留时间处的未反应原料。用硅胶处理反应混合物并真空蒸发除去溶剂。获得的残余物经过快速色谱法(梯度洗脱:100%DCM至97:3v/vDCM/MeOH)以获得为泡沫的马来酰亚胺6(658mg,45%收率)。
(e)N-(2-(2-(2-(2-(4-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂8-基)氧基)甲基)苯基)-1H-1,2,3-三唑-1-基)乙氧基)乙氧基)乙氧基)乙基)-6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰胺(7)。
在0℃(冰/丙酮)下将95:5v/v TFA/H2O(5mL)的溶液加入Boc/THP-保护的化合物6(428mg,0.29mmol)的样品中。在0℃下搅拌1h之后通过LC/MS判断认为反应进行完全,所需的产品峰在2.72min保留时间处(ES+)m/z 1054([M+H]+.,~70%相对强度)。反应混合物保持冰冷并逐滴加入至NaHCO3的冷冻饱和水溶液(100mL)中。混合物用DCM(3×30mL)萃取并且合并的有机层用H2O(20mL)、盐水(40mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱:100%CHCl3至96:4v/v CHCl3/MeOH)提供为橙色泡沫的7(163mg,53%收率)。
实施例2
(a)(11S,11aS,11'S,11a'S)-二-叔丁基8,8'-(((5-(3-氨基丙-1-炔-1-基)-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-10(5H)-羧酸酯)(8)
在烘箱干燥的可密封容器中将催化量的Pd(PPh3)4(5.0mg,4.2μmol)加入二醚2a(242mg,0.21mmol)、炔丙胺(41μL,35mg,0.63mmol)、CuI(1.6mg,8.4μmol)、二乙胺(0.42mL,309mg,4.22mmol)和烘箱干燥的分子筛丸粒在无水DMF中(1.8mL)的混合物中。混合物经过脱气并用氩气吹扫3次,随后在100℃微波中加热3min,此时通过LC/MS的分析表明原料完全消耗并且绝大部分产物在3.18min保留时间处形成(ES+)m/z 1076([M+H]+.,~60%相对强度)。容许反应混合物冷却至室温并随后通过烧结物过滤以除去分子筛(用DMF洗涤)。滤液进行真空蒸发以提供不稳定的粗产物8,无需纯化或分析直接用于下一步骤中。
(b)(11S,11aS,11'S,11a'S)-二-叔丁基8,8'-(((5-(1-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-3,19-二氧代-7,10,13,16-四氧杂-4,20-二氮杂二十三-22-炔-23-基)-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂10(5H)-羧酸酯)(9)
室温下将-酸(88mg,0.21mmol)加入EDCI(41mg,0.21mmol)和粗伯胺8在无水DCM(4mL)的搅拌溶液中。在氩气氛下搅拌反应混合物3h,此时通过LC/MS的分析表明在3.58min保留时间处的所需产品的绝大部分量(ES+)m/z 1475([M+H]+.,~10%相对强度),1498([M+Na]+.,~5%相对强度)伴随在3.85min保留时间处的副产物。用DCM(30mL)稀释反应混合物并用H2O(3×10mL)、盐水(20mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱:100%DCM至96:4v/v DCM/MeOH)提供作为泡沫的马来酰亚胺9(67mg,在2个步骤内收率22%)。
(c)N-(3-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-8-基)氧基)甲基)苯基)丙-2-炔-1-基)-1-(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰胺基)-3,6,9,12-四氧杂十五烷-15-酰胺(10)
在0℃(冰/丙酮)下将95:5v/v TFA/H2O(1mL)的溶液加入Boc/THP-保护的化合物9(67mg,45.5μmol)的样品中。在0℃下搅拌1.5h之后,通过LC/MS判断认为反应进行完全,所需的产品峰在2.67min保留时间处(ES+)m/z 1070([M+H]+.,~5%相对强度)。反应混合物保持冰冷并逐滴加入至NaHCO3冷冻饱和水溶液(50mL)中。混合物用DCM(3×15mL)萃取并且合并的有机层用盐水(40mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱:100%CHCl3至96:4v/v CHCl3/MeOH)提供为橙色泡沫的10(12mg,24%收率)。
实施例3
(a)(11S,11aS,11'S,11a'S)-二-叔丁基8,8'-(((5-(4-(3-((叔丁氧基羰基)氨基)丙基)哌嗪-1-基)-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂10(5H)-羧酸酯)(11)
将二醚2c(250mg,0.24mmol)、NaOtBu(57mg,0.59mmol)、RuPhos(11mg,23.7μmol)和RuPhosPd(19mg,23.7μmol)的样品加入至烘箱干燥的可密封管内(其容许在干燥器中冷却)。混合物经过脱气并用氩气吹扫3次之后加入无水THF(5mL)并随后容许在惰性气氛下搅拌~10min直至释放出红色。加入3-(哌嗪-1-基)丙-1-胺(58mg,0.26mmol)在无水THF(1mL)中的溶液并且混合物再次脱气并用氩气吹扫3次。反应混合物在80℃预热油浴中加热2.5h,此时通过LC/MS的分析表明是3-组分混合物:期望的产物在3.35min保留时间处(ES+)m/z1264([M+H]+.,~60%相对强度),主副产物在3.95min保留时间处(2c的脱氯类似物)并且肩峰在4.13min处(痕量原料)。在容许冷却至室温之后反应混合物在水(20mL)和EtOAc(20mL)之间分配。水相用EtOAc(3×15mL)萃取并且合并的有机层用水(30mL)、盐水(50mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱:100%DCM至95:5v/v DCM/MeOH)提供为泡沫的哌嗪11(152mg,25%收率)。
(b)(11aS,11a'S)-8,8'-(((5-(4-(3-氨基丙基)哌嗪-1-基)-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-2,3-二氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂5(11aH)-酮)(12)
在0℃(冰/丙酮)下将95:5v/v TFA/H2O(2mL)的溶液加入Boc/THP-保护的化合物11(142mg,0.11mmol)的样品中。在0℃下搅拌1h之后,通过LC/MS判断认为反应进行完全,所需的产品峰在2.23min保留时间处(ES+)m/z 778([M+H2O]+.,~5%相对强度)。反应混合物保持冰冷并逐滴加入NaHCO3的冷冻饱和水溶液(50mL)中。混合物用DCM(3×20mL)萃取并且合并的有机层用盐水(15mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供为蜡状固体的粗产物12(22.6mg)。请注意,在NaHCO3中和步骤期间所需产品为蜡状固体从溶液中沉淀出来,其仅仅部分可溶于DCM中。通过将DCM不溶性固体溶解于DMF中接着真空蒸发以获得更多的产品。用乙醚捣碎由此获得的油状残余物以提供固体,其在真空下干燥以提供另外的粗产物12(54.4mg,总量=77mg,85%收率),其无需进一步纯化或分析而直接用于下一步骤。
(c)N-(3-(4-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-8-基)氧基)甲基)苯基)哌嗪-1-基)丙基)-1-(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰胺基)-3,6,9,12-四氧杂十五烷-15-酰胺(13)。
室温下将-酸(42mg,0.10mmol)加入EDCI(20mg,0.10mmol)和粗伯胺12(77mg,0.10mmol)在无水DCM(4mL)中的搅拌溶液中。在氩气氛下搅拌反应混合物3h,此时通过LC/MS的分析表明原料完全消耗,绝大部分的所需产品量在2.42min保留时间处(ES+)m/z1176([M+H2O]+.,~5%相对强度)而过量的-酸在2.05min保留时间处(二极管阵列上信号微弱,但在ES+/ES-上可检测到)。反应混合物用DCM(30mL)稀释并用H2O(15mL)、盐水(20mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱:100%CHCl3至93:7v/v CHCl3/MeOH)提供为泡沫的马来酰亚胺13(46mg,55%)。注意,使用快速色谱法并不能除去痕量的过量-酸。
实施例4
(a)(11S,11aS,11'S,11a'S)-二-叔丁基8,8'-(((5-(4-(叔丁氧基羰基)哌嗪-1-基)-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂10(5H)-羧酸酯)(14)
将2-二环己基膦基-2’,6’-二异丙氧基联苯(18mg,38μmol,0.2当量)、氯(2-二环己基膦基-2′,6′-二异丙氧基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]钯(II)(18mg,22μmol,0.12当量)、碳酸铯(0.36g,1.1mmol,5.0当量)和碘衍生物(2a)(0.307g,0.27mmol,1.0当量)置于排空并用氩气(×3)吹扫的微波小瓶中。加入无水THF(5mL)接着加入哌嗪-1-羧酸叔丁酯(70mg,0.37mmol,1.1当量)并将所得到的混合物在85℃下加热4h,随后室温下过夜。反应混合物用饱和碳酸氢钠稀释并用乙酸乙酯(3×100mL)萃取。合并的乙酸乙酯萃取物用盐水(100mL)洗涤,干燥(MgSO4)并减压蒸发。通过快速柱色谱[CHCl3/MeOH 0%至1.5%按照0.5%的增量]纯化产物14(0.111g,51%)。
分析数据:RT 4.12min;MS(ES+)m/z(相对强度)1207([M+1]+.,30)。
(b)(11aS,11a'S)-8,8'-(((5-(哌嗪-1-基)-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-2,3-二氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-5(11aH)-酮)(15)
将95%三氟乙酸的冷(冰浴)溶液(4mL)加入到已经在冰浴中冷却的化合物(14)(0.2g,0.165mmol,1当量)中。溶液在0℃下搅拌30min时通过LCMS证明反应完全。反应混合物逐滴加入到冰和饱和碳酸氢钠溶液的混合物中而中和三氟乙酸。混合物用DCM(4×75mL)萃取,并且合并的萃取液用水(100mL)、饱和盐水(100mL)洗涤,干燥(MgSO4)并减压蒸发以提供为黄色固体的产物15,其无需进一步纯化直接使用(0.116g,100%)。
分析数据:RT 2.33min;MS(ES+)m/z(相对强度)703([M+1]+.,100)。
(c)N-(15-(4-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂8-基)氧基)甲基)苯基)哌嗪-1-基)-15-氧代-3,6,9,12-四氧杂十五烷基)-3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰胺(17)
在氩气氛下将N-(3-二甲基氨基丙基)-N′-乙基碳二酰亚胺盐酸盐(35mg,0.18mmol,1.1当量)加入化合物(15)(116mg,0.165mmol,1.0当量)和1-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-3-氧代-7,10,13,16-四氧杂-4-氮杂十九-19-酸(16)(69mg,0.165mmol,1.0当量)在无水DCM(5mL)中的溶液中。所得的溶液室温下搅拌2h。反应混合物用DCM(50mL)稀释,用水(100mL)、碳酸氢钠饱和溶液(100mL)、水(100mL)、盐水(100mL)洗涤,干燥(MgSO4)并减压蒸发。通过快速柱色谱纯化[CHCl3/MeOH 0%至5%,按照1%的增量]提供为黄色玻璃样的产物17(0.058g,32%)。
分析数据:[α]18 D=[+628°](c=0.25,CHCl3);RT 2.65min;MS(ES+)m/z(相对强度)1101([M+1]+.,40)。
实施例5
(a)(42-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-37-氧代-3,6,9,12,15,18,21,24,27,30,33-十一氧杂-36-氮杂四十烷基)氧基氨基甲酸叔丁酯(19)
室温下将6-马来酰亚胺己酸(64mg,0.30mmol)加入EDCI(64mg,0.33mmol)和伯胺18(200mg,0.30mmol)在无水DCM(6mL)中的搅拌溶液中。在氩气氛下搅拌反应混合物16h,此时通过LC/MS的分析表明绝大部分的所需产品量在1.38min保留时间处{(ES+)m/z 854([M+H]+.,~30%相对强度),877([M+Na]+.,~100%相对强度)},伴随有未反应的18在1.07min保留时间处,注意,原料和产物都具有弱UV吸收(214和254nm)并在ES+TIC上最佳检测。将另外的6-马来酰亚胺己酸(32mg,0.15mmol)和EDCI(32mg,0.17mmol)加入至搅拌的混合物中直至原料完全消耗(通过LC/MS判断)。反应混合物用DCM(100mL)稀释而用H2O(3×30mL)、盐水(40mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱按照1%增量:100%DCM至96:4v/v DCM/MeOH)提供作为油的酰胺19(214mg,83%收率)。
(b)N-(35-(氨基氧基)-3,6,9,12,15,18,21,24,27,30,33-十一氧杂三十五烷基)-6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰胺(20)
在0℃(冰/丙酮)下将95:5v/v TFA/H2O(2mL)的溶液加入Boc/THP-保护的化合物19(214mg,0.25mmol)的样品中。在0℃下搅拌1h之后通过LC/MS判断认为反应进行完全,所需的产品峰在1.06min保留时间处{(ES+)m/z 754([M+H]+.,~100%相对强度)},注意,原料和产物都具有弱UV吸收(214和254nm)并在ES+TIC上最佳检测。反应混合物保持冰冷并逐滴加入至NaHCO3的冷冻饱和水溶液(100mL)中。混合物用DCM(3×30mL)萃取并且合并的有机层用盐水(50mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供为油的羟胺20(161mg,85%收率),其无需进一步纯化而直接用于下一步骤。
(c)(11S,11aS,11'S,11a'S)-二-叔丁基8,8'-(((5-甲酰基-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-10(5H)-羧酸酯)(21)
将3,5-二(溴甲基)苯甲醛(260mg,0.90mmol)[Enrique D1′ez-Barra et alJ.Org.Chem.2001,66,5664–5670]加入Boc/THP-保护的PBD帽单元7(826mg,1.79mmol)、TBAI(33mg,89.7μmol)和K2CO3(247mg,1.79mmol)在无水DMF中(12mL)的搅拌溶液中。反应混合物加热至60℃并在氩气氛下搅拌持续2.5h,此时通过LC/MS的分析表明绝大部分产物形成在1.92min保留时间处{(ES+)m/z 1051([M+H]+.,~65%相对强度)1073([M+Na]+.,~25%相对强度)}。容许反应混合物冷却至室温并且通过在真空下蒸发除去DMF。获得的残余物在水(50mL)和EtOAc(50mL)之间分配并且水相用EtOAc(3×15mL)萃取。合并的有机层用水(2×20mL)、盐水(30mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱,按照10%的增量:50:50v/v EtOAc/己烷至80:20v/v EtOAc/己烷)提供为白色泡沫的二醚21(717mg,76%收率)。注意,21作为由THP保护基团产生的非对映体的混合物而分离出来。
(d)(11S,11aS,11'S,11a'S)-二-叔丁基8,8'-(((5-((顺/反)-45-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-40-氧代-3,6,9,12,15,18,21,24,27,30,33,36-十二氧杂-2,39-二氮杂四十五-1-烯-1-基)-1,3-亚苯基)二(亚甲基))二(氧基))二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂10(5H)-羧酸酯)(22)
在0℃(冰/丙酮)下将PTSA(4.1mg,21.4μmol)加入醛21(224mg,0.21mmol)和羟基胺20(161mg,0.21mmol)在无水DCM(3mL)中的搅拌溶液中。反应混合物容许在0℃氩气氛下搅拌并搅拌3h,通过LC/MS的分析表明羟基胺20(保留时间1.06min)完全消耗,所需产物的存在{保留时间1.85min(ES+)m/z 1787([M+H]+.,~25%相对强度)1810([M+Na]+.,~90%相对强度)}和未反应的醛21(保留时间1.91min)。为了避免不利THP断裂(在更早的测试反应中观察到),反应在此时停止尽管醛并未完全消耗:混合物用DCM(50mL)稀释并用NaHCO3(3×15mL)、盐水(30mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱按照1%的增量:100%DCM至96:4v/v DCM/MeOH)提供为白色泡沫的顺/反肟22(215mg,56%收率)。在快速色谱法期间回收未反应的醛21(83mg)。注意,22作为由THP保护基团产生的非对映体混合物而分离出来。
(e)N-((顺/反)-1-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-8-基)氧基)甲基)苯基)-3,6,9,12,15,18,21,24,27,30,33,36-十二氧杂-2-氮杂三十八-1-烯-38-基)-6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰胺(23)
在0℃(冰/丙酮)下将95:5v/v TFA/H2O(1mL)的溶液加入Boc/THP-保护的化合物22(204mg,0.11mmol)的样品中。在0℃下搅拌30min之后,通过LC/MS判断认为反应进行完全,所需的产品峰在1.42min保留时间处{(ES+)m/z 1383([M+H]+.,<5%相对强度)}。反应混合物保持冰冷并逐滴加入至NaHCO3的冷冻饱和水溶液(50mL)中。混合物用DCM(3×15mL)萃取并且合并的有机层用盐水(30mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱按照1%的增量:100%CHCl3至96:4v/v CHCl3/MeOH)提供为黄色薄膜的脱保护的顺/反肟23(85mg,54%收率)。反相超高效液相色谱分析(参见条件的通用信息部分)表明主要的两峰出现于16.15min(顺式异构体,次要组分)和16.42min(反式异构体,主要组分)。
(f)N-((反)-1-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-8-基)氧基)甲基)苯基)-3,6,9,12,15,18,21,24,27,30,33,36-十二氧杂-2-氮杂三十八-1-烯-38-基)-6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰胺(24)
化合物23通过制备HPLC进行纯化(参见条件的通用信息部分)。将在16.42min的保留时间下洗脱的峰分离出来并冻干以提供反式肟24(9.9mg):1H NMR(400MHz,CDCl3)δ8.12(s,1H),7.66(d,2H,J=4.4Hz),7.62–7.59(m,2H),7.53–7.51(m,3H),6.82(s,2H),6.68(s,2H),6.16(br s,2H),5.25–5.14(m,8H),4.33(t,2H,J=4.8Hz),4.28(br s,4H),3.96(s,6H),3.90–3.84(m,2H),3.82–3.78(m,2H),3.67–3.49(m,43H),3.46–3.42(m,2H),3.15–3.08(m,2H),2.98–2.90(m,2H),2.16(t,2H,J=7.6Hz),1.70–1.54(m,4H),1.36–1.24(m,2H)。
(g)N-((顺)-1-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-8-基)氧基)甲基)苯基)-3,6,9,12,15,18,21,24,27,30,33,36-十二氧杂-2-氮杂三十八-1-烯-38-基)-6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰胺(25)
化合物23通过制备HPLC进行纯化(参见条件的通用信息部分)。将在保留时间16.15min下的洗脱峰分离出来并冻干以提供顺式肟25(5.2mg):1H NMR(400MHz,CDCl3)δ7.93–7.91(m,2H),7.66(d,2H,J=4.4Hz),7.57–7.55(m,1H),7.52(s,2H),7.32(s,1H),6.82(s,2H),6.68(s,2H),6.18(br s,2H),5.26–5.14(m,8H),4.35(t,2H,J=5.1Hz),4.28(br s,4H),3.96(s,6H),3.90–3.84(m,2H),3.81(t,2H,J=5.1Hz),3.68–3.48(m,43H),3.46–3.42(m,2H),3.15–3.07(m,2H),2.97–2.90(m,2H),2.16(t,2H,J=7.6Hz),1.70–1.54(m,4H),1.36–1.24(m,2H)。
实施例6
(a)二-叔丁基8,8'-(((5-(1-氨基-15-氧代-3,6,9,12-四氧杂-16-氮杂十九-18-炔-19-基)-1,3-亚苯基)二(亚甲基))二(氧基))(11S,11aS,11'S,11a'S)-二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂10(5H)-羧酸酯)(29)
(i)(15-氧代-3,6,9,12-四氧杂-16-氮杂十九-18-炔-1-基)氨基甲酸叔丁酯(27)
室温下将EDCI(263mg,1.37mmol)加入t-boc-N-酰胺基--酸(26)(500mg,1.37mmol,Stratech Scientific Limited)和炔丙胺(88μL,76mg,1.37mmol)在无水DCM(10mL)中的搅拌溶液中。在氩气氛下搅拌反应混合物16h,此时通过LC/MS的分析表明绝大部分的所需产品量在1.26min保留时间处(ES+)m/z 403([M+H]+.,~50%相对强度),425([M+Na]+.,~100%相对强度),注意,原料和产物都具有弱UV吸收(214和254nm)并在ES+TIC上最佳检测。反应混合物用DCM(100mL)稀释并用H2O(30mL)、盐水(40mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱按照1%的增量:100%DCM至98:2v/v DCM/MeOH)提供作为油的酰胺27(392mg,71%收率)。
(ii)二-叔丁基8,8'-(((5-(2,2-二甲基-4,20-二氧代-3,8,11,14,17-五氧杂-5,21-二氮杂二十四-23-炔-24-基)-1,3-亚苯基)二(亚甲基))二(氧基))(11S,11aS,11'S,11a'S)-二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂10(5H)-羧酸酯)(28)
在烘箱干燥的可密封容器中将催化量的Pd(PPh3)4(23.0mg,19.5μmol)加入碘芳基化合物2a(1.02g,0.89mmol),Boc-乙炔27(393mg,0.98mmol)、CuI(7.4mg,39.1μmol)、二乙胺(2.02mL,1.43g,19.5mmol)和烘箱干燥的分子筛丸粒在无水DMF(9mL)中的混合物中。混合物经过脱气并用氩气吹扫3次,随后在100℃微波中加热26min,此时通过LC/MS的分析表明绝大部分产物形成在1.89min保留时间处(ES+)m/z 1446([M+Na]+.,~100%相对强度,1424([M+H]+.,~15%相对强度)。容许反应混合物冷却至室温并随后通过烧结物过滤以除去分子筛(用DMF洗涤)。滤液进行真空蒸发以获得的残余物溶解于DCM(100mL)中并用H2O(20mL)、盐水(30mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱按照1%的增量:100%DCM至97:3v/v DCM/MeOH)提供为黄色泡沫的炔28(882mg,70%收率)。
(iii)二-叔丁基8,8'-(((5-(1-氨基-15-氧代-3,6,9,12-四氧杂-16-氮杂十九-18-炔-19-基)-1,3-亚苯基)二(亚甲基))二(氧基))(11S,11aS,11'S,11a'S)-二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂10(5H)-羧酸酯)(29)
室温下将TBDMSOTf(1.42mL,1.64g,6.2mmol)加入三-Boc保护的化合物28(882mg,0.62mmol)和2,6-二甲基吡啶(0.96mL,883mg,8.25mmol)在无水DCM(15mL)中的搅拌溶液中。容许在氩气氛下搅拌反应混合物16h,在此时段期间通过LC/MS的分析表明TBS氨基甲酸酯形成在2.09min保留时间处(ES+)m/z 1504([M+Na]+.,~100%相对强度)。反应混合物用DCM(60mL)稀释并用饱和NH4Cl(2×20mL)、H2O(20mL)、盐水(30mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗TBS氨基甲酸酯。产物重新溶解于THF(15mL)中并在室温下用TBAF(744μL的1.0M的THF溶液,0.744mmol)的溶液处理。容许室温下搅拌反应混合物1h,此时通过LC/MS的分析表明绝大部分产物形成在1.45min保留时间处(ES+)m/z1324([M+H]+.,~60%相对强度),连同对应于1N 10Boc/1THP断裂的产物在1.29min保留时间处(ES+)m/z 1121([M+H]+.,~10%相对强度),1138([M+H2O]+.,~20%相对强度)和对应于2N10Boc/2THP断裂的产物在1.12min保留时间处(ES+)m/z 919([M+H]+.,~2.5%相对强度),937([M+H2O]+.,~3%相对强度),955([M+2H2O]+.,~5%相对强度)一起。通过真空下蒸发除去THF并且将获得的残余物重新溶解于DCM(60mL)并用饱和NH4Cl(2×20mL)、H2O(20mL)、盐水(30mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供为粉红泡沫的关键胺29。
(b)(R)-2-(吡啶-2-基二硫基)丙基(19-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂8-基)氧基)甲基)苯基)-15-氧代-3,6,9,12-四氧杂-16-氮杂十九-18-炔-1-基)氨基甲酸酯(33)
(i)(R)-2-(吡啶-2-基二硫基)丙基氯甲酸酯(31)
将三光气(9.36mg,31.5μmol)加入(R)-2-(吡啶-2-基二硫基)丙-1-醇(30)(18mg,0.09mmol)和吡啶(6.7μL,6.6mg,0.08mmol)在无水DCM(1mL)中的搅拌溶液中。容许在氩气氛下搅拌反应混合物30min在此时间之后通过真空下蒸发除去溶剂以提供为白色泡沫的粗氯甲酸酯31。注意:产物无需纯化或分析直接用于下一步骤。
(ii)二-叔丁基8,8'-(((5-((R)-5,21-二氧代-2-(吡啶-2-基二硫基)-4,9,12,15,18-五氧杂-6,22-二氮杂二十五-24-炔-25-基)-1,3-亚苯基)二(亚甲基))二(氧基))(11S,11aS,11'S,11a'S)-二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂10(5H)-羧酸酯)(32)
室温下将31(~23mg,~0.09mmol)在无水DCM(1mL)中的溶液逐滴加入胺29(~116mg,~0.09mmol)和吡啶(7.8μL,7.7mg,0.1mmol)在无水DCM(1mL)的搅拌溶液中。容许在氩气氛下搅拌反应混合物3h,此时通过LC/MS的分析( column)表明绝大部分产物形成在2.02min保留时间处(ES+)m/z 1550([M+H]+.,~20%相对强度),伴随还存在的未反应的原料29在1.51min保留时间处。通过在真空下蒸发除去溶剂以提供粗氨基甲酸酯32,其无需进一步纯化或分析而直接用于下一步骤。
(iii)(R)-2-(吡啶-2-基二硫基)丙基(19-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂8-基)氧基)甲基)苯基)-15-氧代-3,6,9,12-四氧杂-16-氮杂十九-18-炔-1-基)氨基甲酸酯(33)
在0℃(冰/丙酮)下将95:5v/v TFA/H2O(1mL)的溶液加入Boc/THP-保护的化合物32(~136mg,88μmol)的粗样品中。在0℃下搅拌1h之后通过LC/MS判断认为反应进行完全(柱),所需的产品峰在1.42min保留时间处(ES+)m/z 1146([M+H]+.,~90%相对强度)。反应混合物保持冰冷并逐滴加入NaHCO3的冷冻饱和水溶液(50mL)中。混合物用DCM(3×15mL)萃取并且合并的有机层用盐水(20mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱:100%CHCl3至95:5v/v CHCl3/MeOH)提供为膜的33(10mg,7%收率):LC/MS(15-min运行),保留时间5.79min(ES+)m/z 1146([M+H]+ .,~8%相对强度);1H NMR(400MHz,CDCl3)δ8.44(d,1H,J=4.8Hz),7.75–7.58(m,2H),7.66(d,2H,J=4.4Hz),7.52(s,2H),7.45–7.40(m,3H),7.08–7.05(m,1H),6.95–6.85(m,1H),6.79(s,2H),5.43–5.41(m,1H),5.23–5.09(m,8H),4.30–4.23(m,6H),4.19–4.10(m,4H),3.97–3.94(m,2H),3.96(s,6H),3.91–3.85(m,2H),3.75(t,2H,J=5.8Hz),3.66–3.58(m,8H),3.52(t,2H,J=5.1Hz),3.34–3.30(m,2H),3.23–3.08(m,3H),2.96–2.90(m,2H),2.52(t,2H,J=5.7Hz),1.31(d,3H,J=7.0Hz)。
实施例7
(a)(±)-4-(吡啶-2-基二硫基)戊酸(35)
室温下将AldrithiolTM-2(176mg,0.86mmol)加入(±)-4-巯基戊酸34(107mg,0.80mmol,Aurora Fine Chemicals LLC)在EtOH(2mL)中的搅拌溶液中。容许在氩气氛下搅拌反应混合物16h,此时通过LC/MS的分析表明绝大部分产物形成在1.32min保留时间处(ES+)m/z 244([M+H]+.,~95%相对强度)。通过在真空下蒸发除去溶剂并且所获得的残余物通过快速色谱法(梯度洗脱:90:10v/v己烷/EtOAc至80:20v/v己烷/EtOAc)纯化以提供为白色固体的35(92mg,47%收率)。
(b)(±)-二-叔丁基-8,8'-(((5-(5,21-二氧代-24-(吡啶-2-基二硫基)-8,11,14,17-四氧杂-4,20-二氮杂二十五-1-炔-1-基)-1,3-亚苯基)二(亚甲基))二(氧基))(11S,11aS,11'S,11a'S)-二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-10(5H)-羧酸酯)(36)
室温下将EDCI(22mg,0.12mmol)加入(±)-4-(吡啶-2-基二硫基)戊酸(35)(26mg,0.10mmol)和胺29(~139mg,0.1mmol)在无水DCM(2mL)的搅拌溶液中。在氩气氛下搅拌反应混合物20h,此时通过LC/MS的分析表明绝大部分的所需产品量(分裂峰)在1.88min保留时间处(ES+)m/z 1548([M+H]+.,~40%相对强度)伴随有对应于1N10Boc/1THP断裂的产物,在1.67min保留时间处(ES+)m/z 1346([M+H]+.,~20%相对强度),1138([M+H2O]+.,~20%相对强度)和对应于2N10Boc/2THP断裂的产物在1.43min保留时间处(ES+M+未观察到)。反应混合物用DCM(30mL)稀释并用H2O(15mL)、盐水(20mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供为泡沫的粗产物36。
(c)(±)-N-(3-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂8-基)氧基)甲基)苯基)丙-2-炔-1-基)-1-(4-(吡啶-2-基二硫基)戊酰胺基)-3,6,9,12-四氧杂十五烷-15-酰胺(37)
在0℃(冰/丙酮)下将95:5v/v TFA/H2O(1mL)的溶液加入Boc/THP-保护的化合物36(~163mg,0.10mmol)的粗样品中。在0℃下搅拌1h之后通过LC/MS判断认为反应进行完全,所需的产品峰在1.44min保留时间处(ES+)m/z 1144([M+H]+.,~3%相对强度)。反应混合物保持冰冷并逐滴加入NaHCO3的冷冻饱和水溶液(60mL)中。混合物用DCM(3×30mL)萃取并且合并的有机层用盐水(30mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱:100%CHCl3至96:4v/v CHCl3/MeOH)提供为橙色泡沫的37(69mg,57%收率):LC/MS(15-min运行),保留时间5.72min(ES+)m/z 1144([M+H]+ .,~3%相对强度);1H NMR(400MHz,CDCl3)δ8.42(d,1H,J=4.3Hz),7.72–7.59(m,2H),7.66(d,2H,J=4.3Hz),7.52(s,2H),7.45–7.40(m,3H),7.09–7.04(m,1H),6.98–6.94(m,1H),6.80(s,2H),6.40–6.35(m,1H),5.23–5.09(m,8H),4.30–4.23(m,6H),4.19–4.10(m,4H),3.96(s,6H),3.91–3.85(m,2H),3.75(t,2H,J=5.7Hz),3.66–3.58(m,8H),3.51(t,2H,J=5.0Hz),3.42–3.39(m,2H),3.23–3.08(m,2H),2.96–2.90(m,3H),2.52(t,2H,J=5.6Hz),2.34(t,2H,J=7.4Hz),1.94(q,2H,J=7.4Hz),1.30(d,3H,J=6.7Hz)。
实施例8
(a)3-(((丙-2-炔-1-基氧基)羰基)氨基)丙酸(39)
室温下将氯甲酸丙炔酯(315μL,383mg,3.23mmol)在甲苯(2mL)中的溶液逐滴加入β-丙氨酸(38)(250mg,2.81mmol)和NaHCO3(678mg,8.1mmol)在H2O(7mL)中的搅拌混合物中。容许强力搅拌反应混合物16h,在此时间之后使之分配。水层用H2O(20mL)稀释,用Et2O(4×10mL)洗涤,冷却至0~5℃(冰/丙酮)并用浓HCl酸化至pH 2。酸性溶液用EtOAc(3×20mL)萃取并且合并的有机层用H2O(10mL)、盐水(20mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供为油的粗产物39,其无需进一步纯化而直接用于下一步骤。
(b)二-叔丁基8,8'-(((5-(5,9,25-三氧代-4,13,16,19,22-五氧杂-6,10,26-三氮杂二十九-1,28-二炔-29-基)-1,3-亚苯基)二(亚甲基))二(氧基))(11S,11aS,11'S,11a'S)-二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂10(5H)-羧酸酯)(40)
室温下将EDCI(24mg,0.13mmol)加入3-(((丙-2-炔-1-基氧基)羰基)氨基)丙酸(39)(18mg,0.10mmol)和胺29(~139mg,0.10mmol)在无水DCM(3mL)中的搅拌溶液中。在氩气氛下搅拌反应混合物1.5h,此时通过LC/MS的分析表明绝大部分的所需产品量在1.84min保留时间处(ES+)m/z 1477([M+H]+.,~20%相对强度),1499([M+Na]+.,~22%相对强度)连同有对应于1N10Boc/1THP断裂的产物在1.60min保留时间处(ES+)m/z 1274([M+H]+.,~10%相对强度)和未反应的5在1.47min保留时间处(ES+)m/z 1324([M+H]+.,~5%相对强度)。反应混合物用DCM(20mL)稀释并用H2O(2×10mL)、盐水(20mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供作为泡沫的粗产物40。
(c)(23-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-8-基)氧基)甲基)苯基)-3,19-二氧代-7,10,13,16-四氧杂-4,20-二氮杂二十三-22-炔-1-基)氨基甲酸丙-2-炔-1-基酯(41)
在0℃(冰/丙酮)下将95:5v/v TFA/H2O(2mL)的溶液加入Boc/THP-保护的化合物40(~155mg,0.10mmol)的粗样品中。在0℃下搅拌1.5h之后,通过LC/MS判断认为反应进行完全,所需的产品峰在1.41min保留时间处(ES+)m/z 1073([M+H]+.,~30%相对强度)。反应混合物保持冰冷并逐滴加入NaHCO3的冷冻饱和水溶液(60mL)中。混合物用DCM(3×20mL)萃取并且合并的有机层用盐水(25mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱:100%CHCl3至95:5v/v CHCl3/MeOH)提供为黄色泡沫的41(51mg,45%收率):LC/MS(15-min运行),保留时间5.71min(ES+)m/z 1073([M+H]+ .,~30%相对强度);1H NMR(400MHz,CDCl3)δ7.67(d,2H,J=4.5Hz),7.52(s,2H),7.46–7.43(m,3H),7.07–7.02(m,1H),6.80(s,2H),6.64–6.57(m,1H),5.78–5.72(m,1H),5.21–5.09(m,8H),4.64(d,2H,J=2.2Hz),4.29–4.25(m,6H),3.96(s,6H),3.90–3.85(m,2H),3.76(t,2H,J=5.9Hz),3.65–3.35(m,18H),3.16–3.07(m,2H),2.93(d,2H,J=16Hz),2.52(t,2H,J=5.9Hz),2.48–2.45(m,1H),2.40(t,2H,J=5.9Hz)。
实施例9
(a)二-叔丁基8,8'-(((5-(1-(4-((S)-2-((S)-2-(6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰胺基)-3-甲基丁酰胺基)-5-脲基戊酰胺基)苯基)-3,19-二氧代-2,7,10,13,16-五氧杂-4,20-二氮杂二十三-22-炔-23-基)-1,3-亚苯基)二(亚甲基))二(氧基))(11S,11aS,11'S,11a'S)-二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-10(5H)-羧酸酯)(43)
室温下将DIPEA(44μL,32mg,0.25mmol)加入关键胺29(~155mg,0.11mmol)和碳酸硝基苯酯42(84mg,0.11mmol)在无水DMF(3mL)中的搅拌溶液中。容许在氩气氛下搅拌反应混合物3天,在此时间段之后通过LC/MS的分析表明观察到所需产物在1.80min保留时间处(ES+)m/z 1922([M+H]+.,~40%相对强度),1944([M+Na]+.,~20%相对强度)连同有对应于1N10Boc/1THP断裂的产物在1.61min保留时间处(ES+)m/z1720([M+H]+.,~20%相对强度)。通过真空下蒸发除去DMF并且获得的产物43无需进一步纯化或分析而直接用于下一步骤。
(b)4-((S)-2-((S)-2-(6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰胺基)-3-甲基丁酰胺基)-5-脲基戊酰胺基)苄基(19-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂8-基)氧基)甲基)苯基)-15-氧代-3,6,9,12-四氧杂-16-氮杂十九-18-炔-1-基)氨基甲酸酯(44)
在0℃(冰/丙酮)下将95:5v/v TFA/H2O(3mL)的溶液加入Boc/THP-保护的化合物43(~173mg,0.11mmol)的粗样品中。在0℃下搅拌1.5h之后,通过LC/MS判断认为反应进行完全,所需的产品峰在1.42min保留时间处(ES+)m/z 1518([M+H]+.,~40%相对强度)。反应混合物保持冰冷并逐滴加入NaHCO3的冷冻饱和水溶液(100mL)中。混合物用DCM(3×30mL)萃取并且合并的有机层用盐水(20mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱:100%CHCl3至80:20v/v CHCl3/MeOH)提供为黄色泡沫的粗产物(72mg,42%粗收率)。物质进一步通过制备HPLC纯化以提供为薄膜的纯44(4.5mg,3%收率):LC/MS(15-min运行),保留时间5.44min(ES+)m/z 1518([M+H]+.,~30%相对强度)。
实施例10
(a)1-(3-氨基丙酰胺基)-N-(3-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂8-基)氧基)甲基)苯基)丙-2-炔-1-基)-3,6,9,12-四氧杂十五烷-15-酰胺(47)
(i)二-叔丁基8,8'-(((5-(1-(9H-芴-9-基)-3,7,23-三氧代-2,11,14,17,20-五氧杂-4,8,24-三氮杂二十七-26-炔-27-基)-1,3-亚苯基)二(亚甲基))二(氧基))(11S,11aS,11'S,11a'S)-二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂10(5H)-羧酸酯)(45)
室温下将EDCI(49mg,0.25mmol)加入Fmoc-β-丙氨酸(66mg,0.21mmol)和胺29(~279mg,0.21mmol)在无水DCM(5mL)的搅拌溶液中。在氩气氛下搅拌反应混合物3h,此时通过LC/MS的分析表明绝大部分的所需产品量在1.76min保留时间处(ES+)m/z 1617([M+H]+.,~10%相对强度),1639([M+Na]+.,~80%相对强度)连同有对应于1N10Boc/1THP断裂的产物在1.56min保留时间处(ES+)m/z 1415([M+H]+.,~10%相对强度)。反应混合物用DCM(30mL)稀释并用H2O(20mL)、盐水(20mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供为泡沫的粗产物45。
(ii)(23-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-8-基)氧基)甲基)苯基)-3,19-二氧代-7,10,13,16-四氧杂-4,20-二氮杂二十三-22-炔-1-基)氨基甲酸(9H-芴-9-基)甲基酯(46)
在0℃(冰/丙酮)下将95:5v/v TFA/H2O(4mL)的溶液加入Boc/THP-保护的化合物45(~341mg,0.21mmol)的粗样品中。在0℃下搅拌1h之后通过LC/MS判断认为反应进行完全,所需的产品峰在1.44min保留时间处(ES+)m/z 1212([M+H]+.,~30%相对强度)。反应混合物保持冰冷并逐滴加入NaHCO3的冷冻饱和水溶液(80mL)中。混合物用DCM(3×20mL)萃取并且合并的有机层用NaHCO3(2×20mL)、盐水(20mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱:100%CHCl3至95:5v/v CHCl3/MeOH)提供为黄色泡沫的纯产物46(179mg,70%收率)。
(iii)1-(3-氨基丙酰胺基)-N-(3-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂8-基)氧基)甲基)苯基)丙-2-炔-1-基)-3,6,9,12-四氧杂十五烷-15-酰胺(47)
室温下将二甲胺(735μL 2.0M THF溶液,1.47mmol)加入Fmoc保护的化合物46(89mg,73.5μmol)在THF(3mL)中的搅拌溶液中。在室温下搅拌3h之后,,通过LC/MS的分析表明反应完全而所需产物在1.14min保留时间处(ES+)m/z 990([M+H]+.,~8%相对强度),1008([M+H2O]+.,~10%相对强度),1026([M+2H2O]+.,~15%相对强度)连同有Fmoc断裂的副产物在1.88min保留时间处。真空蒸发混合物并且粗47无需进一步纯化或分析直接用于下一步骤。
(b)N-(3-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂8-基)氧基)甲基)苯基)丙-2-炔-1-基)-1-(3-(2-溴乙酰胺基)丙酰胺基)-3,6,9,12-四氧杂十五烷-15-酰胺(48)
将溴乙酸酐(23mg,88.2μmol)加入粗胺47(~73mg,73.5μmol)在DCM(3mL)中的搅拌溶液中。容许在氩气氛下室温搅拌反应混合物3h,此时通过LC/MS的分析表明反应完全并且观察到产物在1.34min保留时间处(ES+)m/z 1112([M+H]+.,~30%相对强度)。通过在真空下蒸发除去溶剂以提供粗产物。通过快速色谱法的纯化(梯度洗脱:100%CHCl3至93:7v/v CHCl3/MeOH)提供为黄色泡沫的产物(38mg,46%粗收率)。物质通过制备HPLC进一步纯化以提供为薄膜的纯48(5mg,6%收率):LC/MS(15-min运行),保留时间4.96min(ES+)m/z1112([M+H]+.,~10%相对强度);1H NMR(400MHz,CDCl3)δ7.67(d,2H,J=4.4Hz),7.52(s,2H),7.46–7.43(m,4H),7.10–7.07(m,1H),6.80(s,2H),5.21–5.09(m,8H),4.29–4.25(m,6H),3.96(s,6H),3.90–3.85(m,2H),3.82(s,2H),3.77(t,2H,J=5.9Hz),3.65–3.40(m,18H),3.16–3.07(m,2H),2.94(d,2H,J=16Hz),2.53(t,2H,J=5.9Hz),2.43(t,2H,J=5.9Hz)。
实施例11–10的替代合成
(a)8,8'-(((5-(1-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-3,19-二氧代-7,10,13,16-四氧杂-4,20-二氮杂二十三-22-炔-23-基)-1,3-亚苯基)二(亚甲基))二(氧基))(11S,11aS,11'S,11a'S)-二(7-甲氧基-2-亚甲基-5-氧代-11-((四氢-2H-吡喃-2-基)氧基)-2,3,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-10(5H)-羧酸二-叔丁酯(9)
室温下将EDCI(61mg,0.32mmol)加入N-马来酰基-β-丙氨酸(53mg,0.32mmol)和胺29(~418mg,0.32mmol)在无水DCM(6mL)中的搅拌溶液中。在氩气氛下搅拌反应混合物3h,此时通过LC/MS的分析表明绝大部分的所需产品量在1.80min保留时间处(ES+)m/z 1474([M+H]+.,~15%相对强度),1497([M+Na]+.,~100%相对强度),连同有对应于1N10Boc/1THP断裂的产物在1.56min保留时间处1272([M+H]+.,~80%相对强度),1295([M+Na]+.,~45%相对强度)和对应于2N10Boc/2THP断裂的产物在1.31min保留时间处(ES+M+未观察到)。反应混合物用DCM(30mL)稀释并用H2O(15mL)、盐水(20mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供为泡沫的粗产物9。
(b)N-(3-(3,5-二((((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-8-基)氧基)甲基)苯基)丙-2-炔-1-基)-1-(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰胺基)-3,6,9,12-四氧杂十五烷-15-酰胺(10)
在0℃(冰/丙酮)下将95:5v/v TFA/H2O(5mL)的溶液加入Boc/THP-保护的化合物9(~466mg,0.32mmol)的粗样品中。在0℃下搅拌1h之后通过LC/MS判断认为反应进行完全,所需的产品峰在1.32min保留时间处(ES+)m/z 1070([M+H]+.,~100%相对强度)。反应混合物保持冰冷并逐滴加入NaHCO3的冷冻饱和水溶液(120mL)中。混合物用DCM(3×40mL)萃取并且合并的有机层用盐水(50mL)洗涤,干燥(MgSO4),过滤并真空蒸发以提供粗产物。通过快速色谱法的纯化(梯度洗脱:100%CHCl3至96:4v/v CHCl3/MeOH)提供为橙色泡沫的10(202mg,60%收率):[α]21 D=+351°(c=0.47,CHCl3);LC/MS(15-min运行),保留时间4.88min(ES+)m/z 1070([M+H]+.,~100%相对强度);1H NMR(400MHz,CDCl3)δ7.66(d,2H,J=4.4Hz),7.52(s,2H),7.45–7.40(m,3H),6.98–6.94(m,1H),6.80(s,2H),6.66(s,2H),6.55–6.50(m,1H),5.22–5.07(m,8H),4.30–4.22(m,6H),3.96(s,6H),3.91–3.85(m,2H),3.82(t,2H,J=7.2Hz),3.76(t,2H,J=5.8Hz),3.65–3.43(m,16H),3.16–3.08(m,2H),2.94(d,2H,J=15.7Hz),2.54–2.44(m,4H)。
ThioMabs的氧化/还原用于结合
将在CHO细胞中表达的半胱氨酸工程化的全长单克隆抗体(Junutula,et al.,2008b Nature Biotech.,26(8):925-932;Dornan et al(2009)Blood 114(13):2721-2729;US 7521541;US 7723485;WO2009/052249,Shen et al(2012)Nature Biotech.,30(2):184-191;Junutula et al(2008)Jour of Immun.Methods 332:41-52)用约20-40倍过量的TCEP(三(2-羧乙基)膦盐酸盐)或DTT(二硫苏糖醇)在含2mM EDTA的50mM Tris pH 7.5中、在37℃下还原3小时或室温下过夜(Getz et al(1999)Anal.Biochem.Vol 273:73-80;Soltec Ventures,Beverly,MA)。还原的ThioMab经过稀释并且在10mM乙酸钠pH 5中加载HiTrap S柱上,并用含有0.3M氯化钠的PBS洗脱。可替代地,抗体通过加入1/20体积的10%乙酸进行酸化,用10mM琥珀酸盐pH 5稀释,加载到柱子上并随后用10柱体积的琥珀酸盐缓冲液洗涤。柱子用50mM Tris pH 7.5,2mM EDTA洗脱。
用15倍摩尔过量的DHAA(脱氢抗坏血酸)或200mM硫酸铜(CuSO4)水溶液处理洗脱的还原的ThioMab。在约3h或更长的时间内完成链间二硫键的氧化。环境空气氧化也是有效的。将再氧化的抗体透析至20mM琥珀酸钠pH 5、150mM NaCl、2mM EDTA中并在-20℃下冷冻储存。
Thio-Mabs与化合物结合以制备抗体-药物结合物
将去封闭的、再氧化的、硫代抗体(ThioMab)与6-8倍摩尔过量的化合物7、10、13、17、24、25、33、37、44、48(来自DMSO原液,浓度20mM)在50mM Tris pH 8中反应,直至通过反应混合物的LC-MS分析确定反应完全(16-24h)。
在用20mM琥珀酸钠pH 5稀释之后将粗抗体-药物结合物(ADC)随后施加于阳离子交换柱。柱子用至少10倍柱体积的20mM琥珀酸钠、pH 5洗涤,并用PBS洗脱抗体。使用凝胶过滤柱采用240mM蔗糖将抗体药物结合物配制于20mM His/乙酸pH 5中。通过UV谱来测定蛋白浓度、用于聚集分析的分析SEC(尺寸排阻色谱)和用赖氨酸C肽链内切酶处理之前和之后的LC-MS表征抗体-药物结合物。
采用Shodex KW802.5柱子在0.2M磷酸钾pH 6.2中、用0.25mM氯化钾和15%IPA以0.75mL/min的流速进行尺寸排阻色谱。通过在280nm处洗脱峰面积吸光度的积分测定结合物的聚集状态。
使用安捷伦Agilent QTOF 6520ESI仪进行LC-MS分析。作为实例,用1:500w/w蛋白内切酶Lys C(Promega)在Tris,pH 7.5中、在37℃下处理使用这种化学方法产生的抗体-药物结合物30min。将所获得的断裂片段加载到加热到80℃的1000A,8μm PLRP-S柱上,并且在5min内用30%B至40%B的梯度来洗脱。流动相A是含有0.05%TFA的H2O而流动相B是含0.04%TFA的乙腈。流速为0.5mL/min。在进行电喷雾电离和质谱分析之前,通过UV吸光度280nm检测监测蛋白洗脱。通常实现未结合Fc片段、剩余未结合Fab和成药的Fab的色谱拆分。使用Mass HunterTM软件(Agilent Technologies)解卷积得到的m/z谱以计算抗体片段的质量。
与7的ADC Thio-结合物
与10的ADC Thio-结合物
与13的ADC Thio-结合物
与17的ADC Thio-结合物
与24的ADC Thio-结合物
与25的ADC Thio-结合物
与33的ADC Thio-结合物
与37的ADC Thio-结合物
与44的ADC Thio-结合物
与48的ADC Thio-结合物
以下的体外和体内分析测试也描述于文献Phillips et al(2008)Cancer Res.68(22):9280-9290中。
体外细胞增殖分析测试
通过采用以下方案(CellTiter Glo Luminescent Cell Viability Assay,Promega Corp.Technical Bulletin TB288;Mendoza et al(2002)Cancer Res.62:5485-5488)的细胞增殖分析测试法测定ADC的效力。所有的细胞系获自美国典型培养物保藏中心(American Type Culture Collection):
1.将100μL的含有约104个细胞的细胞培养物(例如,KPL-4,人乳癌细胞系,Kurebayashi et al(1999)Brit.Jour.Cancer 79(5-6):707-717)或SKBR-3)在培养基中的等分式样沉积于96-孔、不透明壁孔板的各孔中。
2.制备含有培养基而无细胞的对照物孔。
3.将ADC加入实验孔中并培养3-5天。
4.将孔板平衡至室温持续约30min。
5.加入等于每个孔中存在的细胞培养物体积的CellTiter-Glo试剂体积。
6.在定轨摇床上混合内容物2分钟以诱导细胞裂解。
7.在室温下培养孔板10分钟以稳定发光信号。
8.记录发光并以作为RLU=相对发光单位的曲线图报告。
将某些细胞按照1000-2000/孔或2000-3000/孔、50μL/孔接种于96-孔板中。经过一或两天之后,按照50μL的体积加入ADC至9000、3000、1000、333、111、37、12.4、4.1或1.4ng/mL的最终浓度,而“无ADC”对照物孔只接受培养基。条件是一式两份或一式三份。在3-5天后,加入100μL/孔的Cell TiterGlo II(基于荧光素酶的分析检测;通过ATP水平测量增殖)并用光度计测定细胞计数。数据绘制为每一组重复的发光的平均值,具有标准偏差误差线。方案是CellTiter Glo发光细胞活力分析检测(CellTiter Glo Luminescent CellViability Assay)(Promega)的改版:
1.将1000个细胞/孔接种于50μL/孔的FBS/谷氨酰胺培养基中。使细胞吸附过夜。
2.将ADC按照1:3连续稀释于培养基中,开始于工作浓度18μg/mL(这获得9μg/mL的最终浓度)。将0.50μL稀释的ADC加入到已经在孔中的50μL的细胞和培养基中。
3.孵育72-96h(标准是72h,但要注意细胞为85%~95%汇合时停止分析测试的0ug/mL浓度)。
4.加入100μL/孔的Promega Cell Titer Glo试剂,振摇3分钟,并在光度计上读数。
结果
针对SK-BR-3、KPL-4和MCF-7(Levenson et al(1997)Cancer Res.57(15):3071-3078)细胞测试抗体-药物结合物,曲妥珠单抗7(110)、曲妥珠单抗10(120)和曲妥珠单抗17(130)以测定5天研究中的体外细胞活力。110针对SK-BR-3的IC50值(ng/mL)为22.90。120针对SK-BR-3的IC50值为11.14。130针对SK-BR-3的IC50值为16.8。SK-BR-3细胞是表达HER2+的、曲妥珠单抗敏感性的。110、120和130针对MCF-7是有效惰性的,MCF-7是不表达HER2的人类乳癌细胞系。因此,结合物110,120和130证实具有使被靶向细胞杀伤效力。
在高表达HER2转基因外植体小鼠中的肿瘤生长抑制作用体内效力
适于转基因实验的动物可以获自标准商业源如Taconic(Germantown,N.Y.)。许多品系是合适的,但FVB雌性小鼠是优选的,因为它们对于肿瘤形成具有更高的易感性。FVB雄性被用于交配并且输精管结扎的CD.1种鼠(stud)用于刺激假孕。输精管结扎小鼠可以获自任何商业供应商。用FVB小鼠或用129/BL6×FVB p53杂合子小鼠育成新群体建立者(founders)。在p53等位基因上具有杂合性的小鼠被用于潜在地增加肿瘤形成。然而,这已被证明是不必要的。因此,一些F1肿瘤是混合株系的肿瘤。新群体建立者肿瘤只是FVB。所获得的六个新群体建立者具有一些发展中的肿瘤而无凋落物(litter)。
用单或多剂量、通过IV注射ADC治疗具有肿瘤的动物(同种异体移植物传播(propagate)自Fo5mmtv转基因小鼠)。在注射后不同时间点评估肿瘤体积。
肿瘤容易出现于表达neu(HER2的大鼠同源物)的突变活化形式的转基因小鼠中,但在人类乳癌中过表达的HER2并未突变并且在过表达未突变的HER2的转基因小鼠中肿瘤形成较不强健(Webster et al(1994)Semin.Cancer Biol.5:69-76)。
为了改善具有未突变的HER2的肿瘤形成,使用其中上游ATG被缺失以防止翻译始于该上游ATG密码子处(这将降低翻译始于HER2的下游真正起始密码子的频率(例如,参Child et al(1999)J.Biol.Chem.274:24335-24341))的HER2cDNA质粒产生转基因小鼠。另外,嵌合内含子加入5'端,这应该如增强早期报道的表达水平(Neuberger and Williams(1988)Nucleic Acids Res.16:6713;Buchman and Berg(1988)Mol.Cell.Biol.8:4395;Brinster et al(1988)Proc.Natl.Acad.Sci.USA 85:836)。嵌合内含子衍生自Promega载体,Pci-neo哺乳动物表达载体(bp 890-1022)。cDNA 3'-端由人类生长激素外显子4和5以及聚腺苷酸化序列侧接。此外,使用FVB小鼠是因为该品系对于肿瘤发展是更易感的。将来自MMTV-LTR的启动子用于确保乳腺中的组织特异性的HER2表达。动物饲喂AlN 76A饮食而增加对肿瘤形成的易感性(Rao et al(1997)Breast Cancer Res.and Treatment 45:149-158)。
Fo5小鼠乳房肿瘤模型
Fo5模型是这样的转基因小鼠模型,其中,在小鼠乳房肿瘤病毒启动子(MMTV-HER2)的转录调节下,人类HER2基因过度表达于乳腺上皮细胞中。过表达引起过表达人类HER2受体的乳房肿瘤的自发发展。通过肿瘤片段的系列移植将新群体建立者动物中的一个(新群体建立者#5[Fo5])的乳房肿瘤传播于FVB小鼠的后续世代中。在用于体内效力研究之前,将MMTV-HER2Fo5转基因乳房肿瘤以测量的约2×2mm的片段经外科手术移植到nu/nu小鼠(来自Charles River Laboratories)的No.2/3乳房脂肪垫中。当肿瘤达到所需体积时,将带有肿瘤的小鼠随机分组并通过IV注射ADC提供单剂量。
结果
图1示出在第0天用以下各项单次iv给药之后、在接种到CRL nu/nu小鼠中的乳癌模型MMTV-HER2Fo5乳房同种异体移植物肿瘤中、体内平均肿瘤体积随时间变化的作图:(1)媒介物20mM组氨酸乙酸酯,pH 5.5,240mM蔗糖,(2)按照6mg/kg的xCD22-7(115),(3)按照1mg/kg的曲妥珠单抗-7(110),(4)按照3mg/kg的曲妥珠单抗-7(110),和(5)按照6mg/kg的曲妥珠单抗-7(110)。图中的线用以下符号指示:
图2示出在第0天用以下各项单次IV给药之后、在接种到CRL nu/nu小鼠中的乳癌模型MMTV-HER2Fo5乳房同种异体移植物肿瘤中、体内平均肿瘤体积随时间变化的作图:(1)媒介物20mM组氨酸乙酸酯,pH 5.5,240mM蔗糖,(2)按照3mg/kg的xCD22-10(125),(3)按照0.3mg/kg的曲妥珠单抗-10(120),(4)按照1mg/kg的曲妥珠单抗-10(120),和(5)按照3mg/kg的曲妥珠单抗-10(120)。图中的线用以下符号指示:
图3示出在第0天用以下各项单次iv给药之后、在接种到CRL nu/nu小鼠中的乳癌模型MMTV-HER2Fo5乳房同种异体移植物肿瘤中、体内平均肿瘤体积随时间变化的作图:(1)媒介物20mM组氨酸乙酸酯,pH 5.5,240mM蔗糖,(2)按照3mg/kg的xCD22-17(135),(3)按照0.3mg/kg的曲妥珠单抗-17(130),(4)按照1mg/kg的曲妥珠单抗-17(130),和(5)按照3mg/kg的曲妥珠单抗-17(130)。图中的线用以下符号指示:
缩写
Ac 乙酰基
Acm 乙酰氨基甲基
Alloc 烯丙氧基羰基
Boc 二碳酸二叔丁基酯
t-Bu 叔丁基
Bzl 苄基,其中,Bzl-OMe是甲氧基苄基以及Bzl-Me是甲基苄基
Cbz或Z 苄氧基-羰基,其中Z-Cl和Z-Br分别是氯苄氧基羰基和溴苄氧基羰基
DMF N,N-二甲基甲酰胺
Dnp 二硝基苯基
DTT 二硫苏糖醇
Fmoc 9H-芴-基甲氧基羰基
imp N-10亚胺保护基团:3-(2-甲氧基乙氧基)丙酸酯-Val-Ala-PAB
MC-OSu 马来酰亚胺己酰基-O-N-琥珀酰亚胺
Moc 甲氧基羰基
MP 马来酰亚胺丙酰胺
Mtr 4-甲氧基-2,3,6-三甲基苯磺酰基
PAB 对氨基苄氧基羰基
PEG 乙烯氧基
PNZ 对硝基苄基氨基甲酸酯
Psec 2-(苯基磺酰基)乙氧基羰基
TBDMS 叔丁基二甲基甲硅烷基
TBDPS 叔丁基二苯基甲硅烷基
Teoc 2-(三甲基甲硅烷基)乙氧基羰基
Tos 甲苯磺酰基
Troc 2,2,2-三氯乙氧基羰基氯化物
Trt 三苯甲基
Xan 呫吨基
参考文献
以下参考文献以其全部内容结合于本文中作为参考:
EP 0522868
EP 0875569
EP 1295944
EP 1347046
EP 1394274
EP 1394274
EP 1439393
JP 05003790
JP 2004113151
JP 58180487
US 2001/055751
US 2002/034749
US 2002/042366
US 2002/150573
US 2002/193567
US 2003/0228319
US 2003/060612
US 2003/064397
US 2003/065143
US 2003/091580
US 2003/096961
US 2003/105292
US 2003/109676
US 2003/118592
US 2003/119121
US 2003/119122
US 2003/119125
US 2003/119126
US 2003/119128
US 2003/119129
US 2003/119130
US 2003/119131
US 2003/124140
US 2003/124579
US 2003/129192
US 2003/134790-A1
US 2003/143557
US 2003/157089
US 2003/165504
US 2003/185830
US 2003/186372
US 2003/186373
US 2003/194704
US 2003/206918
US 2003/219806
US 2003/224411
US 2003/224454
US 2003/232056
US 2003/232350
US 20030096743
US 20030130189
US 2003096743
US 2003130189
US 2004/0001827
US 2004/005320
US 2004/005538
US 2004/005563
US 2004/005598
US 2004/0101899
US 2004/018553
US 2004/022727
US 2004/044179
US 2004/044180
US 2004/101874
US 2004/197325
US 2004/249130
US 20040018194
US 20040052793
US 20040052793
US 20040121940
US 2005/271615
US 2006/116422
US 4816567
US 5362852
US 5440021
US 5583024
US 5621002
US 5644033
US 5674713
US 5700670
US 5773223
US 5792616
US 5854399
US 5869445
US 5976551
US 6011146
US 6153408
US 6214345
US 6218519
US 6268488
US 6518404
US 6534482
US 6555339
US 6602677
US 6677435
US 6759509
US 6835807
US 7223837
US 7375078
US 7521541
US 7723485
WO 00/012508
WO 00/12507
WO 00/12508
WO 01/16318
WO 01/45746
WO 02/088172
WO 03/026577
WO 03/043583
WO 04/032828
WO 2000/12130
WO 2000/14228
WO 2000/20579
WO 2000/22129
WO 2000/32752
WO 2000/36107
WO 2000/40614
WO 2000/44899
WO 2000/55351
WO 2000/75655
WO 200053216
WO 2001/00244
WO 2001/38490
WO 2001/40269
WO 2001/40309
WO 2001/41787
WO 2001/46232
WO 2001/46261
WO 2001/48204
WO 2001/53463
WO 2001/57188
WO 2001/62794
WO 2001/66689
WO 2001/72830
WO 2001/72962
WO 2001/75177
WO 2001/77172
WO 2001/88133
WO 2001/90304
WO 2001/94641
WO 2001/98351
WO 2002/02587
WO 2002/02624
WO 2002/06317
WO 2002/06339
WO 2002/101075
WO 2002/10187
WO 2002/102235
WO 2002/10382
WO 2002/12341
WO 2002/13847
WO 2002/14503
WO 2002/16413
WO 2002/16429
WO 2002/22153
WO 2002/22636
WO 2002/22660
WO 2002/22808
WO 2002/24909
WO 2002/26822
WO 2002/30268
WO 2002/38766
WO 2002/54940
WO 2002/59377
WO 2002/60317
WO 2002/61087;
WO 2002/64798
WO 2002/71928
WO 2002/72596
WO 2002/78524
WO 2002/81646
WO 2002/83866
WO 2002/86443
WO 2002/88170
WO 2002/89747
WO 2002/92836
WO 2002/94852
WO 2002/98358
WO 2002/99074
WO 2002/99122
WO 2003/000842
WO 2003/002717
WO 2003/003906
WO 2003/003984
WO 2003/004989
WO 2003/008537
WO 2003/009814
WO 2003/014294
WO 2003/016475
WO 2003/016494
WO 2003/018621
WO 2003/022995
WO 2003/023013
WO 2003/024392
WO 2003/025138
WO 2003/025148
WO 2003/025228
WO 2003/026493
WO 2003/029262
WO 2003/029277
WO 2003/029421
WO 2003/034984
WO 2003/035846
WO 2003/042661
WO 2003/045422
WO 2003/048202
WO 2003/054152
WO 2003/055439
WO 2003/055443
WO 2003/062401
WO 2003/062401
WO 2003/072035
WO 2003/072036
WO 2003/077836
WO 2003/081210
WO 2003/083041
WO 2003/083047
WO 2003/083074
WO 2003/087306
WO 2003/087768
WO 2003/088808
WO 2003/089624
WO 2003/089904
WO 2003/093444
WO 2003/097803
WO 2003/101283
WO 2003/101400
WO 2003/104270
WO 2003/104275
WO 2003/105758
WO 2003004529
WO 2003042661
WO 2003104399
WO 2004/000997
WO 2004/001004
WO 2004/009622
WO 2004/011611
WO 2004/015426
WO 2004/016225
WO 2004/020595
WO 2004/022709
WO 2004/022778
WO 2004/027049
WO 2004/031238
WO 2004/032828
WO 2004/032842
WO 2004/040000
WO 2004/043361
WO 2004/043963
WO 2004/044178
WO 2004/045516
WO 2004/045520
WO 2004/045553
WO 2004/046342
WO 2004/047749
WO 2004/048938
WO 2004/053079
WO 2004/063355
WO 2004/063362
WO 2004/063709
WO 2004/065577
WO 2004/074320
WO 2004000221
WO 2004020583
WO 2004042346
WO 2004065576
WO 2005/023814
WO 2005/082023
WO 2005/085251
WO 2006/111759
WO 2007/044515
WO 2007/085930
WO 2009/052249
WO 2010/091150
WO 91/02536
WO 92/07574
WO 92/17497
WO 94/10312
WO 94/28931
WO 9630514
WO 97/07198
WO 97/44452
WO 98/13059
WO 98/37193
WO 98/40403
WO 98/51805
WO 98/51824
WO 99/28468
WO 99/46284
WO 99/58658
Am.J.Hum.Genet.49(3):555-565(1991)
Amiel J.,et al Hum.Mol.Genet.5,355-357,1996
Amir et al(2003)Angew.Chem.Int.Ed.42:4494-4499
Amsberry,et al(1990)J.Org.Chem.55:5867
Angew Chem.Intl.Ed.Engl.(1994)33:183-186
Annu.Rev.Neurosci.21:309-345(1998)
Arai H.,et al J.Biol.Chem.268,3463-3470,1993
Arai H.,et al Jpn.Circ.J.56,1303-1307,1992
Arima,et al.,J.Antibiotics,25,437-444(1972)
Attie T.,et al,Hum.Mol.Genet.4,2407-2409,1995
Auricchio A.,et al Hum.Mol.Genet.5:351-354,1996
Barel M.,et al Mol.Immunol.35,1025-1031,1998
Barella et al(1995)Biochem.J.309:773-779
Barnett T.,et al Genomics 3,59-66,1988
Beck et al(1992)J.Mol.Biol.228:433-441
Beck et al(1996)J.Mol.Biol.255:1-13
Berge,et al.,J.Pharm.Sci.,66,1-19(1977)
Biochem.Biophys.Res.Commun.(2000)275(3):783-788
Biochem.Biophys.Res.Commun.255(2),283-288(1999)
Blood(2002)100(9):3068-3076
Blood 99(8):2662-2669(2002)
Blumberg H.,et al Cell 104,9-19,2001
Bose,et al.,Tetrahedron,48,751-758(1992)
Bourgeois C.,et al J.Clin.Endocrinol.Metab.82,3116-3123,1997
Brinster et al(1988)Proc.Natl.Acad.Sci.USA 85:836
Buchman and Berg(1988)Mol.Cell.Biol.8:4395
Cancer Res.61(15),5857-5860(2001)
Carl et al(1981)J.Med.Chem.24:479-480
Carlsson et al(1978)Biochem.J.173:723-737
Carter,P.(2006)Nature Reviews Immunology 6:343-357
Cell 109(3):397-407(2002)
CellTiter Glo Luminescent Cell Viability Assay,Promega Corp.Technical
Bulletin TB288
Chakravarty et al(1983)J.Med.Chem.26:638-644
Chan,J.and Watt,V.M.,Oncogene 6(6),1057-1061(1991)
Child et al(1999)J.Biol.Chem.274:24335-24341
Cho H.-S.,et al Nature 421,756-760,2003
Ciccodicola,A.,et al EMBO J.8(7):1987-1991(1989)
Clackson et al(1991)Nature,352:624-628
Clark H.F.,et al Genome Res.13,2265-2270,2003
Corey E,Quinn JE,Buhler KR,et al.LuCap35:a new model of prostatecancer progression to androgen independence.The Prostate 2003;55:239-46
Coussens L.,et al Science(1985)230(4730):1132-1139
Cree et al(1995)AntiCancer Drugs 6:398-404
Crouch et al(1993)J.Immunol.Meth.160:81-88
Davis et al(2001)Proc.Natl.Acad.Sci USA 98(17):9772-9777
de Groot et al(2001)J.Org.Chem.66:8815-8830
de Groot et al(2003)Angew.Chem.Int.Ed.42:4490-4494
Dennis et al.(2002)"Albumin Binding As A General Strategy ForImproving
The Pharmacokinetics Of Proteins"J Biol Chem.277:35035-35043
Dobner et al(1992)Eur.J.Immunol.22:2795-2799
Dornan et al(2009)Blood 114(13):2721-2729
Doronina et al(2006)Bioconj.Chem.17:114-124
Dubowchik et al.Bioconjugate Chemistry,2002,13,855-869
Dubowchik,et al.(1997)Tetrahedron Letters,38:5257-60
Dumoutier L.,et al J.Immunol.167,3545-3549,2001
E. and K.Lübke,The Peptides,volume 1,pp 76-136(1965)Academic
Press
Ehsani A.,et al(1993)Genomics 15,426-429
Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",JohnWiley&Sons,Inc.,New York,1994
Elshourbagy N.A.,et al J.Biol.Chem.268,3873-3879,1993
Erickson et al(2006)Cancer Res.66(8):1-8
Feild,J.A.,et al(1999)Biochem.Biophys.Res.Commun.258(3):578-582
Fields,G.and Noble,R.(1990)"Solid phase peptide synthesis utilizing9-fluoroenylmethoxycarbonyl amino acids",Int.J.Peptide Protein Res.35:161-214
Fuchs S.,et al Mol.Med.7,115-124,2001
Fujisaku et al(1989)J.Biol.Chem.264(4):2118-2125)
Gary S.C.,et al Gene 256,139-147,2000
Gaugitsch,H.W.,et al(1992)J.Biol.Chem.267(16):11267-11273)
Geiser et al"Automation of solid-phase peptide synthesis"inMacromolecular
Sequencing and Synthesis,Alan R.Liss,Inc.,1988,pp.199-218
Genome Res.13(10):2265-2270(2003)
Genomics 62(2):281-284(1999)
Geoghegan&Stroh,(1992)Bioconjugate Chem.3:138-146
Getz et al(1999)Anal.Biochem.Vol 273:73-80
Glynne-Jones et al(2001)Int J Cancer.Oct 15;94(2):178-84
Gregson et al.,Chem.Commun.1999,797-798
Gregson et al.,J.Med.Chem.2001,44,1161-1174
Gu Z.,et al Oncogene 19,1288-1296,2000
Ha et al(1992)J.Immunol.148(5):1526-1531
Haendler B.,et al J.Cardiovasc.Pharmacol.20,s1-S4,1992
Hamann P.(2005)Expert Opin.Ther.Patents 15(9):1087-1103
Hamblett et al(2004)Clin.Cancer Res.10:7063-7070
Handbook of Pharmaceutical Additives,2nd Edition(eds.M.Ash andI.Ash),2001(Synapse Information Resources,Inc.,Endicott,New York,USA)
Handbook of Pharmaceutical Excipients,2nd edition,1994
Hara,et al.,J.Antibiotics,41,702-704(1988)
Hashimoto et al(1994)Immunogenetics 40(4):287-295
Hay et al.(1999)Bioorg.Med.Chem.Lett.9:2237
Herdwijn,P.et al.,Canadian Journal of Chemistry.1982,60,2903-7
Hermanson,G.T.(1996)Bioconjugate Techniques;Academic Press:New York,p234-242
Hochlowski,et al.,J.Antibiotics,40,145-148(1987)
Hofstra R.M.W.,et al Eur.J.Hum.Genet.5,180-185,1997
Hofstra R.M.W.,et al Nat.Genet.12,445-447,1996
Horie et al(2000)Genomics 67:146-152
Hubert,R.S.,et al(1999)Proc.Natl.Acad.Sci.U.S.A.96(25):14523-14528)
Hurley and Needham-VanDevanter,Acc.Chem.Res.,19,230-237(1986)
Immunogenetics 54(2):87-95(2002)
Int.Rev.Cytol.196:177-244(2000)
Itoh,et al.,J.Antibiotics,41,1281-1284(1988)
J.Biol.Chem.270(37):21984-21990(1995)
J.Biol.Chem.276(29):27371-27375(2001)
J.Biol.Chem.277(22):19665-19672(2002)
J.Biol.Chem.278(33):30813-30820(2003)
Janeway,C.,Travers,P.,Walport,M.,Shlomchik(2001)Immuno Biology,5thEd.,Garland Publishing,New York
Jeffrey et al(2005)J.Med.Chem.48:1344-1358
Jonsson et al(1989)Immunogenetics 29(6):411-413
Junutula,et al.,2008b Nature Biotech.,26(8):925-932
Kang,G-D.,et al.,Chem.Commun.,2003,1680-1689
Kasahara et al(1989)Immunogenetics 30(1):66-68
King et al(2002)Tetrahedron Letters 43:1987-1990
Kingsbury et al(1984)J.Med.Chem.27:1447
Kohler et al(1975)Nature 256:495
Kohn,in Antibiotics III.Springer-Verlag,New York,pp.3-11(1975).
Konishi,et al.,J.Antibiotics,37,200-206(1984)
Kovtun et al(2006)Cancer Res.66(6):3214-3121
Kuhns J.J.,et al J.Biol.Chem.274,36422-36427,1999
Kuminoto,et al.,J.Antibiotics,33,665-667(1980)
Kurebayashi et al(1999)Brit.Jour.Cancer 79(5-6):707-717
Lab.Invest.82(11):1573-1582(2002)
Lambert J.(2005)Current Opin.in Pharmacol.5:543-549
Langley and Thurston,J.Org.Chem.,52,91-97(1987)
Larhammar et al(1985)J.Biol.Chem.260(26):14111-14119
Law et al(2006)Cancer Res.66(4):2328-2337
Le et al(1997)FEBS Lett.418(1-2):195-199
Leber,et al.,J.Am.Chem.Soc.,110,2992-2993(1988)
Leimgruber,et al.,J.Am.Chem.Soc.,87,5791-5793(1965)
Leimgruber,et al.,J.Am.Chem.Soc.,87,5793-5795(1965)
Levenson et al(1997)Cancer Res.57(15):3071-3078
Liang et al(2000)Cancer Res.60:4907-12
Manfré,F.et al.,J.Org.Chem.1992,57,2060-2065
Marks et al(1991)J.Mol.Biol.,222:581-597
McDonagh(2006)Protein Eng.Design&Sel.,19(7):299-307
Mendoza et al(2002)Cancer Res.62:5485-5488
Miller et al(2003)Jour.of Immunology 170:4854-4861
Miura et al(1996)Genomics 38(3):299-304
Miura et al(1998)Blood 92:2815-2822
Moore M.,et al Proc.Natl.Acad.Sci.U.S.A.84,9194-9198,1987
Morrison et al(1984)Proc.Natl.Acad.Sci.USA,81:6851-6855
Muller et al(1992)Eur.J.Immunol.22(6):1621-1625
Mungall A.J.,et al Nature 425,805-811,2003
Nagase T.,et al(2000)DNA Res.7(2):143-150)
Nakamuta M.,et al Biochem.Biophys.Res.Commun.177,34-39,1991
Nakayama et al(2000)Biochem.Biophys.Res.Commun.277(1):124-127
Naruse et al(2002)Tissue Antigens 59:512-519
Nature 395(6699):288-291(1998)
Neuberger and Williams(1988)Nucleic Acids Res.16:6713
Novabiochem Catalog 2006/2007
Ogawa Y.,et al Biochem.Biophys.Res.Commun.178,248-255,1991
Okamoto Y.,et al Biol.Chem.272,21589-21596,1997
Oncogene 10(5):897-905(1995)
Oncogene 14(11):1377-1382(1997))
Parrish-Novak J.,et al J.Biol.Chem.277,47517-47523,2002
Payne,G.(2003)Cancer Cell 3:207-212
Phillips et al(2008)Cancer Res.68(22):9280-9290
Pingault V.,et al(2002)Hum.Genet.111,198-206
Pletnev S.,et al(2003)Biochemistry 42:12617-12624
Preud'homme et al(1992)Clin.Exp.Immunol.90(1):141-146
Proc.Natl.Acad.Sci.U.S.A.(2003)100(7):4126-4131
Proc.Natl.Acad.Sci.U.S.A.93(1):136-140(1996)
Proc.Natl.Acad.Sci.U.S.A.98(17):9772-9777(2001)
Proc.Natl.Acad.Sci.U.S.A.99(26):16899-16903(2002)
Proc.Natl.Acad.Sci.U.S.A.96(20):11531-11536(1999)
Protective Groups in Organic Synthesis,Greene and Wuts,3rd Edition,1999,John Wiley&Sons Inc.
Puffenberger E.G.,et al Cell 79,1257-1266,1994
Rao et al(1997)Breast Cancer Res.and Treatment 45:149-158
Reiter R.E.,et al Proc.Natl.Acad.Sci.U.S.A.95,1735-1740,1998
Remington's Pharmaceutical Sciences,20th edition,pub.Lippincott,Williams&Wilkins,2000
Rodrigues et al(1995)Chemistry Biology 2:223
Ross et al(2002)Cancer Res.62:2546-2553
S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)
McGraw-Hill Book Company,New York
Sakaguchi et al(1988)EMBO J.7(11):3457-3464
Sakamoto A.,Yanagisawa M.,et al Biochem.Biophys.Res.Commun.178,656-663,1991
Sanderson et al(2005)Clin.Cancer Res.11:843-852
Semba K.,et al Proc.Natl.Acad.Sci.U.S.A.82,6497-6501,1985
Servenius et al(1987)J.Biol.Chem.262:8759-8766
Shamis et al(2004)J.Am.Chem.Soc.126:1726-1731
Sheikh F.,et al(2004)J.Immunol.172,2006-2010
Shimizu,et al,J.Antibiotics,29,2492-2503(1982)
Sinha S.K.,et al(1993)J.Immunol.150,5311-5320
Storm et al(1972)J.Amer.Chem.Soc.94:5815
Strausberg et al(2002)Proc.Natl.Acad.Sci USA 99:16899-16903
Sun et al(2002)Bioorganic&Medicinal Chemistry Letters 12:2213-2215
Sun et al(2003)Bioorganic&Medicinal Chemistry 11:1761-1768
Svensson P.J.,et al Hum.Genet.103,145-148,1998
Swiercz J.M.,et al J.Cell Biol.165,869-880,2004
Syrigos and Epenetos(1999)Anticancer Research 19:605-614
Takeuchi,et al.,J.Antibiotics,29,93-96(1976)
Tawaragi Y.,et al Biochem.Biophys.Res.Commun.150,89-96,1988
ten Dijke,P.,et al Science 264(5155):101-104(1994)
Thompson,J.S.,et al Science 293(5537),2108-2111(2001)WO 2004/058309
Thurston,et al.,Chem.Brit.,26,767-772(1990)
Thurston,et al.,Chem.Rev.1994,433-465(1994)
Toki et al(2002)J.Org.Chem.67:1866-1872
Tonnelle et al(1985)EMBO J.4(11):2839-2847
Touchman et al(2000)Genome Res.10:165-173
Trail et al(2003)Cancer Immunol.Immunother.52:328-337
Tsunakawa,et al.,J.Antibiotics,41,1366-1373(1988)
Tsutsumi M.,et al Gene 228,43-49,1999
Uchida et al(1999)Biochem.Biophys.Res.Commun.266:593-602
Verheij J.B.,et al Am.J.Med.Genet.108,223-225,2002
Von Hoegen et al(1990)J.Immunol.144(12):4870-4877
Webster et al(1994)Semin.Cancer Biol.5:69-76
Weis J.J.,et al J.Exp.Med.167,1047-1066,1988
Weis J.J.,et al Proc.Natl.Acad.Sci.U.S.A.83,5639-5643,1986
Wilson et al(1991)J.Exp.Med.173:137-146
Wu et al(2005)Nature Biotech.23(9):1137-1145
Xie et al(2006)Expert.Opin.Biol.Ther.6(3):281-291
Xu,M.J.,et al(2001)Biochem.Biophys.Res.Commun.280(3):768-775 WO 2004/016225
Xu,X.Z.,et al Proc.Natl.Acad.Sci.U.S.A.98(19):10692-10697(2001)
Yamaguchi,N.,et al Biol.Chem.269(2),805-808(1994)
Yamamoto T.,et al Nature 319,230-234,1986
Yu et al(1992)J.Immunol.148(2)633-637
Claims (46)
1.一种式(A)的结合物:
其中:
R2是其中R36a和R36b是H;
R6和R9是H;
R7是OR7A,其中,R7A是可选取代的C1-4烷基;
Y选自式A1、A2、A3、A4和A5:
L是连接至细胞结合剂的接头;
CBA是所述细胞结合剂,所述细胞结合剂是结合至一个或多个选自(1)-(38)的肿瘤相关的抗原或细胞表面受体的抗体:
(1)BMPR1B;
(2)E16;
(3)STEAP1;
(4)0772P;
(5)MPF;
(6)Napi3b;
(7)Sema 5b;
(8)PSCA hlg;
(9)ETBR;
(10)MSG783;
(11)STEAP2;
(12)TrpM4;
(13)CRIPTO;
(14)CD21;
(15)CD79b;
(16)FcRH2;
(17)HER2;
(18)NCA;
(19)MDP;
(20)IL20Rα;
(21)短缩素;
(22)EphB2R;
(23)ASLG659;
(24)PSCA;
(25)GEDA;
(26)BAFF-R;
(27)CD22;
(28)CD79a;
(29)CXCR5;
(30)HLA-DOB;
(31)P2X5;
(32)CD72;
(33)LY64;
(34)FcRH1;
(35)IRTA2;
(36)TENB2;
(37)CD33;和
(38)LGR5/GPR49;
n是选自0至48的范围内的整数;
RA4是C1-6亚烷基基团;
其中
(a)R10是H,并且R11是OH、ORA,其中RA是C1-4烷基;或
(b)R10和R11形成它们键连的氮和碳原子之间的氮-碳双键;或
(c)R10是H和R11是OSOzM,其中z为2或3并且M是单价药用阳离子;
其中R16、R17、R19、R20、R21和R22如分别对R6、R7、R9、R10、R11和R2所限定的;
其中Z是CH或N;
其中T和T’’独立地选自单键或C1-9亚烷基,其链可以被一个或多个杂原子例如O、S、N(H)、NMe中断,条件是X和X’之间的原子的最短链中的原子数是3至12个原子;
X和X’是O;并且
或者
(a)L是下式:
-LA-(CH2)m- (L1);或
(b)L是下式:
其中m为0至6;
X1和X2是氨基酸基团,选自天然氨基酸,其是修饰的或未修饰的;
LA选自:
其中Ar代表C5-6亚芳基基团。
2.根据权利要求1所述的结合物,其中R7A是Me。
3.根据权利要求1所述的结合物,其中T选自单键、C1,和C2亚烷基基团。
4.根据权利要求3所述的结合物,其中T是C1亚烷基基团。
5.根据权利要求1至4中任一项所述的结合物,其中R10是H,和R11是OH。
6.根据权利要求1至4中任一项所述的结合物,其中R10和R11形成它们键连的氮和碳原子之间的氮-碳双键。
7.根据权利要求1至4中任一项所述的结合物,其中R16、R17、R19、R20、R21、R22、X’和T’分别与R6、R7、R9、R10、R11、R2、X和T相同。
8.根据权利要求1至4中任一项所述的结合物,其中,L是式(L1)并且LA选自LA1-1和LA3-2。
9.根据权利要求1至4中任一项所述的结合物,其中,L是式(L1)并且m为2、3或5。
10.根据权利要求1至4中任一项所述的结合物,其中,L是式(L4)并且基团-X1-X2-选自:
-Phe-Lys-、
-Val-Ala-、
-Val-Lys-、
-Ala-Lys-、
-Val-Cit-。
11.根据权利要求1至4中任一项所述的结合物,其中,L是式(L4)并且m为5。
12.根据权利要求1至4中任一项所述的结合物,其中n是0至16之间的整数。
13.根据权利要求1至4中任一项所述的结合物,其中n是0至8之间的整数。
14.根据权利要求1至4中任一项所述的结合物,其中n为3或4。
15.根据权利要求1所述的结合物,其中所述抗体选自:
MUC16、Napi2b、HER2、CD22、CD33和LGR5。
16.根据权利要求1所述的结合物,其中所述抗体是半胱氨酸工程化的抗体。
17.根据权利要求1或权利要求16所述的结合物,其中所述抗体是结合至ErbB受体的抗体。
18.根据权利要求17所述的结合物,其中所述抗体是曲妥珠单抗。
19.根据权利要求1或权利要求16所述的结合物,其中Ab是抗HER2、抗Steap1或抗CD22抗体。
20.根据权利要求1所述的结合物,其中药物(D)对抗体(Ab)的载药量(p)是1至8的整数。
21.根据权利要求20所述的结合物,其中所述载药量为1、2、3或4。
22.根据权利要求21所述的结合物,包含所述抗体-药物结合物化合物的混合物,其中在抗体-药物结合物化合物的混合物中,平均载药量/抗体为2至5。
23.根据权利要求1至22中任一项所述的结合物在制备用于在疗法中使用的药物中的应用。
24.一种药物组合物,所述药物组合物包含权利要求1至22中任一项所述的结合物和赋形剂。
25.根据权利要求24所述的药物组合物,其中,所述赋形剂是药用稀释剂或载体。
26.根据权利要求1至22中任一项所述的结合物或根据权利要求24-25中任一项所述的药物组合物在制备用于在受试者内的增生性疾病的治疗中使用的药物中的应用。
27.根据权利要求26所述的应用,其中所述疾病是癌症。
28.根据权利要求1至22中任一项的结合物或者根据权利要求24或25的药物组合物在制备用于在医学治疗中使用的药物的用途。
29.根据权利要求26或权利要求27所述的药物组合物在制备用于医学治疗的药物中的用途。
30.根据权利要求29所述的用途,其中所述医学治疗的方法是用于治疗癌症。
31.根据权利要求30所述的用途,其中结合所述结合物将化疗剂给予患者。
32.根据权利要求1至22中任一项的化合物在生产用于治疗增生性疾病的药物的方法中的用途。
33.有效量的根据权利要求1至22中任一项的化合物或者根据权利要求26或权利要求27所述的药物组合物在制备用于治疗患有增生性疾病的哺乳动物的药物中的应用。
34.一种式(B)的化合物:
其中:
R2、R6、R7、R9、R10、R11、R22、R16、R17、R19、R20、R21、Z、T、T’、X和X’是如在权利要求1至7中任一项所限定的;
YL选自式B1、B2、B3、B4、和B5的组中:
G是用于连接至细胞结合剂的反应性基团
其中n和RA4是如在权利要求1至14中所限定的,并且
其中
(a)G是下式:
GA-(CH2)m- (G1);或
(b)G是下式:
其中m为0至6;
X1和X2是氨基酸基团,选自天然氨基酸,其是修饰的或未修饰的;和
GA选自:
其中Ar代表C5-6亚芳基。
35.根据权利要求34所述的化合物,其中,G是式(G1)并且GA选自GA1-1和GA3-3。
36.根据权利要求34或权利要求35所述的化合物,其中,G是式(G1)并且m为2、3或5。
37.根据权利要求34所述的化合物,其中,G是式(G4)并且m为5。
38.一种式(C)的化合物:
其中:
R2、R6、R7、R9、R22、R16、R17、R19、Z、T、T’、X和X’是如在权利要求1至7中任一项所限定的;
YC选自式C1、C2、C3、C4和C5的组中:
其中n和RA4是如在权利要求1至14中任一项所限定的;
其中
(a)R30是H,和R31是OH、ORA,其中RA是C1-4烷基;或
(b)R30和R31形成它们键连的氮和碳原子之间的氮-碳双键;或
(c)R30是H和R31是OSOzM,其中z为2或3并且M是单价药用阳离子;或
(d)R30是氮保护基团并且R31是OProtO,其中ProtO是羟基保护基团;和
R40和R41是如分别对R30和R31所限定的。
39.根据权利要求38所述的化合物,其中R30是H,和R31是OH。
40.根据权利要求38所述的化合物,其中R30和R41形成它们键连的氮和碳原子之间的氮-碳双键。
41.根据权利要求38所述的化合物,其中R30是氮保护基团并且R31是OProtO,其中ProtO是羟基保护基团。
42.根据权利要求41所述的化合物,其中所述氮保护基团是Boc。
43.根据权利要求41或权利要求42所述的化合物,其中所述羟基保护基团是THP。
44.一种以下式(D)的化合物:
其中:
R2、R6、R7、R9、R22、R16、R17、R19、Z、T、T’、X和X’是如在权利要求1至7中任一项中所限定的;
R30、R31、R40和R41是如在权利要求38至43中任一项中所限定;
YD选自式D2、D3、D4和D6的组中:
其中RA4是如在权利要求1至14中任一项中所限定的。
45.一种式(E)的化合物:
其中:
R2、R6、R7、R9、R22、R16、R17、R19、Z、T、T’、X和X’是如在权利要求1至7中任一项中所限定的;
R30、R31、R40和R41是如在权利要求38至43中任一项中所限定的;
YE选自式E1、E2和E5的组中:
其中
RE1选自H和TMS;和
RE2选自Br、Cl和I。
46.一种合成根据权利要求1至33中任一项所述的化合物的方法,包括将根据权利要求34至37中任一项所述的化合物与细胞结合剂结合的步骤。
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Families Citing this family (73)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0819095D0 (en) | 2008-10-17 | 2008-11-26 | Spirogen Ltd | Pyrrolobenzodiazepines |
NZ602933A (en) | 2010-04-15 | 2014-09-26 | Seattle Genetics Inc | Pyrrolobenzodiazepines used to treat proliferative diseases |
MX2012011900A (es) | 2010-04-15 | 2013-03-21 | Seattle Genetics Inc | Conjugados de pirrolobenzodiazepina diana. |
CN103987718A (zh) | 2011-09-20 | 2014-08-13 | 斯皮罗根有限公司 | 作为非对称二聚体pbd化合物用于内含在靶向结合物中的吡咯并苯并二氮杂卓 |
US9526798B2 (en) | 2011-10-14 | 2016-12-27 | Seattle Genetics, Inc. | Pyrrolobenzodiazepines and targeted conjugates |
CN103998450B (zh) | 2011-10-14 | 2017-03-08 | 麦迪穆有限责任公司 | 吡咯并苯并二氮杂卓 |
KR101961976B1 (ko) | 2011-10-14 | 2019-03-25 | 시애틀 지네틱스, 인크. | 피롤로벤조디아제핀 및 표적 접합체 |
US9388187B2 (en) | 2011-10-14 | 2016-07-12 | Medimmune Limited | Pyrrolobenzodiazepines |
EP2879708A4 (en) | 2012-08-02 | 2016-03-16 | Genentech Inc | ANTIBODY AND ANTI-ETBR IMMUNOCONJUGATES |
WO2014057120A1 (en) | 2012-10-12 | 2014-04-17 | Adc Therapeutics Sàrl | Pyrrolobenzodiazepine-antibody conjugates |
MX364326B (es) | 2012-10-12 | 2019-04-23 | Medimmune Ltd | Conjugados del anticuerpo pirrolobenzodiazepina - anti-psma. |
US10736903B2 (en) | 2012-10-12 | 2020-08-11 | Medimmune Limited | Pyrrolobenzodiazepine-anti-PSMA antibody conjugates |
MX364329B (es) | 2012-10-12 | 2019-04-23 | Medimmune Ltd | Conjugados del anticuerpo pirrolobenzodiazepina. |
JP6367204B2 (ja) | 2012-10-12 | 2018-08-01 | メドイミューン・リミテッドMedImmune Limited | 結合用のピロロベンゾジアゼピン誘導体の合成および中間体 |
NZ745069A (en) | 2012-10-12 | 2019-05-31 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
JP5993093B2 (ja) | 2012-10-12 | 2016-09-14 | メドイミューン・リミテッドMedImmune Limited | ピロロベンゾジアゼピン類およびその複合体 |
SI2906296T1 (en) | 2012-10-12 | 2018-06-29 | Adc Therapeutics Sa | Pyrrolobenzodiazepine-antibody conjugates |
PT2906251T (pt) | 2012-10-12 | 2017-12-04 | Medimmune Ltd | Conjugados de pirrolobenzodiazepina-anticorpo anti-cd22 |
US9567340B2 (en) | 2012-12-21 | 2017-02-14 | Medimmune Limited | Unsymmetrical pyrrolobenzodiazepines-dimers for use in the treatment of proliferative and autoimmune diseases |
EA031585B1 (ru) | 2012-12-21 | 2019-01-31 | Медимьюн Лимитед | Пирролобензодиазепины и их конъюгаты |
CA2904044C (en) | 2013-03-13 | 2020-03-31 | Medimmune Limited | Pyrrolobenzodiazepines and conjugates thereof |
SG11201507214SA (en) | 2013-03-13 | 2015-10-29 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
GB201317981D0 (en) | 2013-10-11 | 2013-11-27 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
EP3054985B1 (en) | 2013-10-11 | 2018-12-26 | Medimmune Limited | Pyrrolobenzodiazepine-antibody conjugates |
US10010624B2 (en) | 2013-10-11 | 2018-07-03 | Medimmune Limited | Pyrrolobenzodiazepine-antibody conjugates |
GB201317982D0 (en) | 2013-10-11 | 2013-11-27 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
US9956299B2 (en) | 2013-10-11 | 2018-05-01 | Medimmune Limited | Pyrrolobenzodiazepine—antibody conjugates |
WO2015089344A1 (en) * | 2013-12-13 | 2015-06-18 | Genentech, Inc. | Anti-cd33 antibodies and immunoconjugates |
WO2015095124A1 (en) | 2013-12-16 | 2015-06-25 | Genentech Inc. | Peptidomimetic compounds and antibody-drug conjugates thereof |
EP3160513B1 (en) | 2014-06-30 | 2020-02-12 | Glykos Finland Oy | Saccharide derivative of a toxic payload and antibody conjugates thereof |
WO2016037644A1 (en) | 2014-09-10 | 2016-03-17 | Medimmune Limited | Pyrrolobenzodiazepines and conjugates thereof |
TW201625690A (zh) | 2014-09-12 | 2016-07-16 | 建南德克公司 | 抗-cll-1抗體及免疫結合物 |
GB201416112D0 (en) * | 2014-09-12 | 2014-10-29 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
RU2727663C2 (ru) | 2014-09-17 | 2020-07-22 | Дженентек, Инк. | Иммуноконъюгаты, содержащие антитела против her2 и пирролбензодиазепины |
CA2968447A1 (en) | 2014-11-25 | 2016-06-02 | Adc Therapeutics Sa | Pyrrolobenzodiazepine-antibody conjugates and their use to treat neoplasms |
CN107428780B (zh) | 2015-01-14 | 2020-09-04 | 百时美施贵宝公司 | 苯并二氮杂*二聚体、其缀合物及制备和使用方法 |
JP6676058B2 (ja) | 2015-01-14 | 2020-04-08 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | ヘテロアリーレン架橋したベンゾジアゼピン二量体、そのコンジュゲート、ならびに製造および使用方法 |
CN107636016B (zh) * | 2015-03-09 | 2022-02-11 | 海德堡医药有限责任公司 | 鹅膏毒素-抗体轭合物 |
GB201506411D0 (en) | 2015-04-15 | 2015-05-27 | Bergenbio As | Humanized anti-axl antibodies |
GB201506402D0 (en) | 2015-04-15 | 2015-05-27 | Berkel Patricius H C Van And Howard Philip W | Site-specific antibody-drug conjugates |
JP6996983B2 (ja) | 2015-06-16 | 2022-02-21 | ジェネンテック, インコーポレイテッド | 抗cll-1抗体及び使用方法 |
BR112017027258A2 (pt) | 2015-06-23 | 2018-08-28 | Bristol-Myers Squibb Company | dímeros de benzodiazepina macrocíclicos, conjugados dos mesmos, preparação e usos |
MA43354A (fr) * | 2015-10-16 | 2018-08-22 | Genentech Inc | Conjugués médicamenteux à pont disulfure encombré |
TWI778491B (zh) | 2015-11-30 | 2022-09-21 | 美商輝瑞股份有限公司 | 位點專一性her2抗體藥物共軛體 |
GB201601431D0 (en) | 2016-01-26 | 2016-03-09 | Medimmune Ltd | Pyrrolobenzodiazepines |
GB201602356D0 (en) | 2016-02-10 | 2016-03-23 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
GB201602359D0 (en) | 2016-02-10 | 2016-03-23 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
GB201607478D0 (en) | 2016-04-29 | 2016-06-15 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
GB201617466D0 (en) | 2016-10-14 | 2016-11-30 | Medimmune Ltd | Pyrrolobenzodiazepine conjugates |
EP3548515A1 (en) | 2016-12-01 | 2019-10-09 | Regeneron Pharmaceuticals, Inc. | Radiolabeled anti-pd-l1 antibodies for immuno-pet imaging |
DK3544636T3 (da) | 2017-02-08 | 2021-05-10 | Adc Therapeutics Sa | Pyrrolobenzodiazepin-antistof-konjugater |
GB201702031D0 (en) | 2017-02-08 | 2017-03-22 | Medlmmune Ltd | Pyrrolobenzodiazepine-antibody conjugates |
RS63502B1 (sr) | 2017-04-18 | 2022-09-30 | Medimmune Ltd | Konjugati pirolobenzodiazepina |
CA3057748A1 (en) | 2017-04-20 | 2018-10-25 | Adc Therapeutics Sa | Combination therapy with an anti-axl antibody-drug conjugate |
UA127900C2 (uk) | 2017-06-14 | 2024-02-07 | Ейдісі Терапьютікс Са | Схема дозування для введення adc до cd19 |
WO2019034764A1 (en) | 2017-08-18 | 2019-02-21 | Medimmune Limited | CONJUGATES OF PYRROLOBENZODIAZEPINE |
CN109180681B (zh) * | 2017-08-18 | 2021-08-20 | 四川百利药业有限责任公司 | 一种dna毒性二聚体化合物 |
SG11202001430SA (en) | 2017-09-29 | 2020-04-29 | Daiichi Sankyo Co Ltd | Antibody-pyrrolobenzodiazepine derivative conjugate |
CN111727075B (zh) | 2017-11-27 | 2024-04-05 | 普渡制药公司 | 靶向人组织因子的人源化抗体 |
GB201803342D0 (en) | 2018-03-01 | 2018-04-18 | Medimmune Ltd | Methods |
GB201806022D0 (en) * | 2018-04-12 | 2018-05-30 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
CN113227119A (zh) | 2018-12-10 | 2021-08-06 | 基因泰克公司 | 用于与含Fc的蛋白质进行位点特异性缀合的光交联肽 |
EP3898693A4 (en) | 2018-12-21 | 2022-09-21 | Avidity Biosciences, Inc. | ANTI-TRANSFERRIN RECEPTOR ANTIBODIES AND USES THEREOF |
US20220096641A1 (en) * | 2019-01-03 | 2022-03-31 | Legochem Biosciences, Inc. | Pyrrolobenzodiazepine dimer compound with improved safety and use thereof |
KR20200084802A (ko) * | 2019-01-03 | 2020-07-13 | 주식회사 레고켐 바이오사이언스 | 안전성이 향상된 피롤로벤조디아제핀 이량체 화합물 및 이의 용도 |
KR20210124308A (ko) | 2019-01-30 | 2021-10-14 | 트루바인딩 아이엔씨. | 항-gal3 항체 및 이의 용도 |
EP4045511A1 (en) * | 2019-10-16 | 2022-08-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Visual detection of pbd induced dna crosslinks |
WO2021080608A1 (en) | 2019-10-25 | 2021-04-29 | Medimmune, Llc | Branched moiety for use in conjugates |
IL310900A (en) | 2020-03-19 | 2024-04-01 | Avidity Biosciences Inc | Preparations and methods for the treatment of facial, back and arm muscle atrophy |
WO2021195469A1 (en) | 2020-03-27 | 2021-09-30 | Avidity Biosciences, Inc. | Compositions and methods of treating muscle dystrophy |
GB202102396D0 (en) | 2021-02-19 | 2021-04-07 | Adc Therapeutics Sa | Molecular adjuvant |
WO2023288252A1 (en) | 2021-07-13 | 2023-01-19 | Truebinding, Inc. | Methods of preventing protein aggregation |
KR20240055874A (ko) | 2021-09-16 | 2024-04-29 | 어비디티 바이오사이언시스 인크. | 안면견갑상완 근이영양증을 치료하는 조성물 및 방법 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011133039A2 (en) * | 2010-04-21 | 2011-10-27 | Syntarga B.V. | Novel conjugates of cc-1065 analogs and bifunctional linkers |
WO2012014147A1 (en) * | 2010-07-26 | 2012-02-02 | Sanofi | Anticancer derivatives, preparation thereof and therapeutic use thereof |
WO2012112687A1 (en) * | 2011-02-15 | 2012-08-23 | Immunogen, Inc. | Methods of preparation of conjugates |
CN102753559A (zh) * | 2009-08-25 | 2012-10-24 | 赛诺菲 | 作为抗癌剂的吡咯并[1,4]苯并二氮杂*二聚物的共轭物 |
CN102933236A (zh) * | 2010-04-15 | 2013-02-13 | 斯皮罗根发展有限公司 | 吡咯并苯二氮卓类及其结合物 |
Family Cites Families (346)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS58180487A (ja) | 1982-04-16 | 1983-10-21 | Kyowa Hakko Kogyo Co Ltd | 抗生物質dc−81およびその製造法 |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US5583024A (en) | 1985-12-02 | 1996-12-10 | The Regents Of The University Of California | Recombinant expression of Coleoptera luciferase |
AU6355090A (en) | 1989-08-23 | 1991-04-03 | Scripps Clinic And Research Foundation | Compositions and methods for detection and treatment of epstein-barr virus infection and immune disorders |
JPH053790A (ja) | 1990-04-19 | 1993-01-14 | Fujisawa Pharmaceut Co Ltd | デヒドロペプチダーゼ−i |
US5256643A (en) | 1990-05-29 | 1993-10-26 | The Government Of The United States | Human cripto protein |
AU9016591A (en) | 1990-10-25 | 1992-05-26 | Tanox Biosystems, Inc. | Glycoproteins associated with membrane-bound immunoglobulins as antibody targets on B cells |
US5440021A (en) | 1991-03-29 | 1995-08-08 | Chuntharapai; Anan | Antibodies to human IL-8 type B receptor |
US5543503A (en) | 1991-03-29 | 1996-08-06 | Genentech Inc. | Antibodies to human IL-8 type A receptor |
DE69231223T3 (de) | 1991-03-29 | 2008-01-17 | Genentech, Inc., South San Francisco | Menschliche pf4a rezeptoren und ihre verwendung |
ATE255131T1 (de) | 1991-06-14 | 2003-12-15 | Genentech Inc | Humanisierter heregulin antikörper |
JP3050424B2 (ja) | 1991-07-12 | 2000-06-12 | 塩野義製薬株式会社 | ヒトエンドセリンリセプター |
US5264557A (en) | 1991-08-23 | 1993-11-23 | The United States Of America As Represented By The Department Of Health And Human Services | Polypeptide of a human cripto-related gene, CR-3 |
US5362852A (en) | 1991-09-27 | 1994-11-08 | Pfizer Inc. | Modified peptide derivatives conjugated at 2-hydroxyethylamine moieties |
US6011146A (en) | 1991-11-15 | 2000-01-04 | Institut Pasteur | Altered major histocompatibility complex (MHC) determinant and methods of using the determinant |
US6153408A (en) | 1991-11-15 | 2000-11-28 | Institut Pasteur And Institut National De La Sante Et De La Recherche Medicale | Altered major histocompatibility complex (MHC) determinant and methods of using the determinant |
IL107366A (en) | 1992-10-23 | 2003-03-12 | Chugai Pharmaceutical Co Ltd | Genes coding for megakaryocyte potentiator |
US5644033A (en) | 1992-12-22 | 1997-07-01 | Health Research, Inc. | Monoclonal antibodies that define a unique antigen of human B cell antigen receptor complex and methods of using same for diagnosis and treatment |
US5801005A (en) | 1993-03-17 | 1998-09-01 | University Of Washington | Immune reactivity to HER-2/neu protein for diagnosis of malignancies in which the HER-2/neu oncogene is associated |
US5869445A (en) | 1993-03-17 | 1999-02-09 | University Of Washington | Methods for eliciting or enhancing reactivity to HER-2/neu protein |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
US5773223A (en) | 1993-09-02 | 1998-06-30 | Chiron Corporation | Endothelin B1, (ETB1) receptor polypeptide and its encoding nucleic acid methods, and uses thereof |
EP0647450A1 (en) | 1993-09-09 | 1995-04-12 | BEHRINGWERKE Aktiengesellschaft | Improved prodrugs for enzyme mediated activation |
US5750370A (en) | 1995-06-06 | 1998-05-12 | Human Genome Sciences, Inc. | Nucleic acid encoding human endothlein-bombesin receptor and method of producing the receptor |
JPH08336393A (ja) | 1995-04-13 | 1996-12-24 | Mitsubishi Chem Corp | 光学活性なγ−置換−β−ヒドロキシ酪酸エステルの製造法 |
US5707829A (en) | 1995-08-11 | 1998-01-13 | Genetics Institute, Inc. | DNA sequences and secreted proteins encoded thereby |
US20020193567A1 (en) | 1995-08-11 | 2002-12-19 | Genetics Institute, Inc. | Secreted proteins and polynucleotides encoding them |
JP3646191B2 (ja) | 1996-03-19 | 2005-05-11 | 大塚製薬株式会社 | ヒト遺伝子 |
US6218519B1 (en) | 1996-04-12 | 2001-04-17 | Pro-Neuron, Inc. | Compounds and methods for the selective treatment of cancer and bacterial infections |
WO1997044452A1 (en) | 1996-05-17 | 1997-11-27 | Schering Corporation | Human b-cell antigens, related reagents |
US6590088B1 (en) | 1996-07-19 | 2003-07-08 | Human Genome Sciences, Inc. | CD33-like protein |
CA2264227A1 (en) | 1996-09-27 | 1998-04-02 | Raymond A. Firestone | Hydrolyzable prodrugs for delivery of anticancer drugs to metastatic cells |
US6759509B1 (en) | 1996-11-05 | 2004-07-06 | Bristol-Myers Squibb Company | Branched peptide linkers |
US5945511A (en) | 1997-02-20 | 1999-08-31 | Zymogenetics, Inc. | Class II cytokine receptor |
US20030185830A1 (en) | 1997-02-25 | 2003-10-02 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of prostate cancer |
US7033827B2 (en) | 1997-02-25 | 2006-04-25 | Corixa Corporation | Prostate-specific polynucleotide compositions |
EP1514876B1 (en) | 1997-03-10 | 2013-05-08 | The Regents of The University of California | Antibody against prostate stem cell antigen (PSCA) |
US6541212B2 (en) | 1997-03-10 | 2003-04-01 | The Regents Of The University Of California | Methods for detecting prostate stem cell antigen protein |
US6261791B1 (en) | 1997-03-10 | 2001-07-17 | The Regents Of The University Of California | Method for diagnosing cancer using specific PSCA antibodies |
US6555339B1 (en) | 1997-04-14 | 2003-04-29 | Arena Pharmaceuticals, Inc. | Non-endogenous, constitutively activated human protein-coupled receptors |
US6319688B1 (en) | 1997-04-28 | 2001-11-20 | Smithkline Beecham Corporation | Polynucleotide encoding human sodium dependent phosphate transporter (IPT-1) |
WO1998051805A1 (en) | 1997-05-15 | 1998-11-19 | Abbott Laboratories | Reagents and methods useful for detecting diseases of the prostate |
WO1998051824A1 (en) | 1997-05-15 | 1998-11-19 | Abbott Laboratories | Reagents and methods useful for detecting disease of the urinary tract |
US6602677B1 (en) | 1997-09-19 | 2003-08-05 | Promega Corporation | Thermostable luciferases and methods of production |
US20030060612A1 (en) | 1997-10-28 | 2003-03-27 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US20020034749A1 (en) | 1997-11-18 | 2002-03-21 | Billing-Medel Patricia A. | Reagents and methods useful for detecting diseases of the breast |
US6110695A (en) | 1997-12-02 | 2000-08-29 | The Regents Of The University Of California | Modulating the interaction of the chemokine, B Lymphocyte Hemoattractant, and its Receptor, BLR1 |
WO2004031238A2 (en) | 2002-10-03 | 2004-04-15 | Mcgill Univeristy | Antibodies and cyclic peptides which bind cea (carcinoembryonic antigen) and their use as cancer therapeutics |
WO1999046284A2 (en) | 1998-03-13 | 1999-09-16 | The Burnham Institute | Molecules that home to various selected organs or tissues |
ATE518956T1 (de) | 1998-05-13 | 2011-08-15 | Epimmune Inc | Expressionsvektoren zur stimulierung einer immunantwort und verfahren zu deren verwendung |
US20030064397A1 (en) | 1998-05-22 | 2003-04-03 | Incyte Genomics, Inc. | Transmembrane protein differentially expressed in prostate and lung tumors |
US20020187472A1 (en) | 2001-03-09 | 2002-12-12 | Preeti Lal | Steap-related protein |
AU3733399A (en) | 1998-05-22 | 1999-12-13 | Daiichi Pharmaceutical Co., Ltd. | Drug composites |
GB9818731D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Compounds |
GB9818732D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collection of compounds |
WO2000012130A1 (en) | 1998-08-27 | 2000-03-09 | Smithkline Beecham Corporation | Rp105 agonists and antagonists |
GB9818730D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collections of compounds |
AU757510C (en) | 1998-08-27 | 2003-09-11 | Medimmune Limited | Pyrrolobenzodiazepines |
JP4689781B2 (ja) | 1998-09-03 | 2011-05-25 | 独立行政法人科学技術振興機構 | アミノ酸輸送蛋白及びその遺伝子 |
AU5963699A (en) | 1998-10-02 | 2000-04-26 | Mcmaster University | Spliced form of (erb)b-2/neu oncogene |
US6858710B2 (en) | 1998-12-17 | 2005-02-22 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US6962980B2 (en) | 1999-09-24 | 2005-11-08 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US20030091580A1 (en) | 2001-06-18 | 2003-05-15 | Mitcham Jennifer L. | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US20020119158A1 (en) | 1998-12-17 | 2002-08-29 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US6468546B1 (en) | 1998-12-17 | 2002-10-22 | Corixa Corporation | Compositions and methods for therapy and diagnosis of ovarian cancer |
US20030190669A1 (en) | 1998-12-30 | 2003-10-09 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
JP2002536966A (ja) | 1998-12-30 | 2002-11-05 | ベス・イスラエル・ディーコニス・メディカル・センター・インコーポレーテッド | カルシウムチャネルファミリーの特徴付け |
KR100766653B1 (ko) | 1999-01-29 | 2007-10-15 | 코릭사 코포레이션 | HER-2/neu 융합단백질 |
GB9905124D0 (en) | 1999-03-05 | 1999-04-28 | Smithkline Beecham Biolog | Novel compounds |
AU3395900A (en) | 1999-03-12 | 2000-10-04 | Human Genome Sciences, Inc. | Human lung cancer associated gene sequences and polypeptides |
US7312303B2 (en) | 1999-05-11 | 2007-12-25 | Genentech, Inc. | Anti-PRO4980 antibodies |
US6268488B1 (en) | 1999-05-25 | 2001-07-31 | Barbas, Iii Carlos F. | Prodrug activation using catalytic antibodies |
AU4952600A (en) | 1999-06-03 | 2000-12-28 | Takeda Chemical Industries Ltd. | Screening method with the use of cd100 |
EP2283867B1 (en) | 1999-06-25 | 2014-05-21 | ImmunoGen, Inc. | Methods of treatment using anti-ERBB antibody-maytansinoid conjugates |
US6949245B1 (en) | 1999-06-25 | 2005-09-27 | Genentech, Inc. | Humanized anti-ErbB2 antibodies and treatment with anti-ErbB2 antibodies |
US20030119113A1 (en) | 1999-07-20 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US7297770B2 (en) | 1999-08-10 | 2007-11-20 | Genentech, Inc. | PRO6496 polypeptides |
US7294696B2 (en) | 1999-08-17 | 2007-11-13 | Genentech Inc. | PRO7168 polypeptides |
US6909006B1 (en) | 1999-08-27 | 2005-06-21 | Spirogen Limited | Cyclopropylindole derivatives |
AU7573000A (en) | 1999-09-01 | 2001-03-26 | Genentech Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US20030232056A1 (en) | 1999-09-10 | 2003-12-18 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US20030129192A1 (en) | 1999-09-10 | 2003-07-10 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US20030206918A1 (en) | 1999-09-10 | 2003-11-06 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
ES2309012T3 (es) | 1999-10-29 | 2008-12-16 | Genentech, Inc. | Composiciones del anticuerpo anti-psca y a sus procedimientos contra celulas cancerigenas que expresen psca. |
ES2586850T3 (es) | 1999-11-29 | 2016-10-19 | The Trustees Of Columbia University In The City Of New York | Aislamiento de cinco genes novedosos que codifican nuevos melanomas de tipo receptor de Fc implicados en la patogénesis del linfoma/melanoma |
CA2392510A1 (en) | 1999-11-30 | 2001-06-07 | Corixa Corporation | Compositions and methods for therapy and diagnosis of breast cancer |
JP2003530083A (ja) | 1999-12-10 | 2003-10-14 | エピミューン インコーポレイテッド | ペプチドおよび核酸組成物を使用する、HER2/neuに対する細胞性免疫応答の誘導 |
US6610286B2 (en) | 1999-12-23 | 2003-08-26 | Zymogenetics, Inc. | Method for treating inflammation using soluble receptors to interleukin-20 |
NZ502058A (en) | 1999-12-23 | 2003-11-28 | Ovita Ltd | Isolated mutated nucleic acid molecule for regulation of ovulation rate |
EP1743648B1 (en) | 1999-12-23 | 2010-03-03 | ZymoGenetics, Inc. | Method for treating inflammation |
DE60045139D1 (de) | 1999-12-23 | 2010-12-02 | Zymogenetics Inc | Löslicher Interleukin-20-Rezeptor |
CA2921260A1 (en) | 1999-12-24 | 2001-06-28 | Genentech, Inc. | Methods and compositions for prolonging elimination half-times of bioactive compounds |
US20040001827A1 (en) | 2002-06-28 | 2004-01-01 | Dennis Mark S. | Serum albumin binding peptides for tumor targeting |
US7297333B2 (en) | 2000-01-20 | 2007-11-20 | Genentech, Inc. | Anti-PRO10268 antibodies |
US20030224379A1 (en) | 2000-01-21 | 2003-12-04 | Tang Y. Tom | Novel nucleic acids and polypeptides |
US20020039573A1 (en) | 2000-01-21 | 2002-04-04 | Cheever Martin A. | Compounds and methods for prevention and treatment of HER-2/neu associated malignancies |
AU2001243142A1 (en) | 2000-02-03 | 2001-08-14 | Hyseq, Inc. | Novel nucleic acids and polypeptides |
US20030219806A1 (en) | 2000-02-22 | 2003-11-27 | Millennium Pharmaceuticals, Inc. | Novel 18607, 15603, 69318, 12303, 48000, 52920, 5433, 38554, 57301, 58324, 55063, 52991, 59914, 59921 and 33751 molecules and uses therefor |
US20020142377A1 (en) | 2000-02-22 | 2002-10-03 | Glucksmann Maria Alexandra | 18607, a novel human calcium channel |
US20040052793A1 (en) | 2001-02-22 | 2004-03-18 | Carter Paul J. | Caspase activivated prodrugs therapy |
US20040005561A1 (en) | 2000-03-01 | 2004-01-08 | Corixa Corporation | Compositions and methods for the detection, diagnosis and therapy of hematological malignancies |
US20040002068A1 (en) | 2000-03-01 | 2004-01-01 | Corixa Corporation | Compositions and methods for the detection, diagnosis and therapy of hematological malignancies |
CA2402293A1 (en) | 2000-03-07 | 2001-09-13 | Hyseq, Inc. | Novel nucleic acids and polypeptides |
JP2004521602A (ja) | 2000-03-24 | 2004-07-22 | ファハリ サッチオグリュ | 前立腺特異的または精巣特異的な新規の核酸分子、ポリペプチド、ならびに診断法および治療法 |
AU2001250412A1 (en) | 2000-03-31 | 2001-10-08 | Ipf Pharmaceuticals Gmbh | Diagnostic and medicament for analysing the cell surface proteome of tumour and inflammatory cells and for treating tumorous and inflammatory diseases, preferably using specific chemokine receptor analysis and the chemokine receptor-ligand interaction |
WO2001075177A2 (en) | 2000-04-03 | 2001-10-11 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Tumor markers in ovarian cancer |
IL152136A0 (en) | 2000-04-07 | 2003-05-29 | Arena Pharm Inc | Non-endogenous, constitutively activated known g protein-coupled receptors |
EP1276389A2 (en) | 2000-04-14 | 2003-01-22 | Novozymes Biotech, Inc. | Enzymatic treatment of potato products |
US20030119115A1 (en) | 2000-05-17 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
WO2001088133A2 (en) | 2000-05-18 | 2001-11-22 | Lexicon Genetics Incorporated | Human semaphorin homologs and polynucleotides encoding the same |
AU2001274888A1 (en) | 2000-05-19 | 2001-12-03 | Human Genome Sciences, Inc. | Nucleic acids, proteins, and antibodies |
AU2001275437A1 (en) | 2000-06-09 | 2001-12-17 | Idec Pharmaceuticals Corporation | Gene targets and ligands that bind thereto for treatment and diagnosis of ovarian carcinomas |
AU2001268471A1 (en) | 2000-06-16 | 2002-01-02 | Incyte Genomics, Inc. | G-protein coupled receptors |
EP1294885A2 (en) | 2000-06-30 | 2003-03-26 | Amgen, Inc. | B7-like molecules and uses thereof |
WO2002002587A1 (en) | 2000-06-30 | 2002-01-10 | Human Genome Sciences, Inc. | B7-like polynucleotides, polypeptides, and antibodies |
EP1383892A2 (en) | 2000-06-30 | 2004-01-28 | Incyte Genomics, Inc. | Human extracellular matrix and cell adhesion polypeptides |
AU2002214531A1 (en) | 2000-07-03 | 2002-01-30 | Curagen Corporation | Proteins and nucleic acids encoding same |
US20040044179A1 (en) | 2000-07-25 | 2004-03-04 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
WO2002010187A1 (en) | 2000-07-27 | 2002-02-07 | Mayo Foundation For Medical Education And Research | B7-h3 and b7-h4, novel immunoregulatory molecules |
DE60134178D1 (de) | 2000-07-28 | 2008-07-03 | Ulrich Wissenbach | Trp8 krebsmarker |
US7229623B1 (en) | 2000-08-03 | 2007-06-12 | Corixa Corporation | Her-2/neu fusion proteins |
US6759045B2 (en) | 2000-08-08 | 2004-07-06 | Immunomedics, Inc. | Immunotherapy for chronic myelocytic leukemia |
WO2002013847A2 (en) | 2000-08-14 | 2002-02-21 | Corixa Corporation | Methods for diagnosis and therapy of hematological and virus-associated malignancies |
BR0113235A (pt) | 2000-08-14 | 2004-06-08 | Corixa Corp | Composições e métodos para a terapia e a diagnose de malignidades associadas com her-2/neu |
JP2004520806A (ja) | 2000-08-24 | 2004-07-15 | ジェネンテック・インコーポレーテッド | 腫瘍の診断と治療のための組成物と方法 |
GB0020953D0 (en) | 2000-08-24 | 2000-10-11 | Smithkline Beecham Biolog | Vaccine |
WO2002022660A2 (en) | 2000-09-11 | 2002-03-21 | Hyseq, Inc. | Novel nucleic acids and polypeptides |
US7855269B2 (en) | 2000-09-15 | 2010-12-21 | Zymogenetics, Inc. | Method for treating inflammation |
US20060073551A1 (en) | 2000-09-15 | 2006-04-06 | Genentech, Inc. | Pro4487 polypeptides |
US6613567B1 (en) | 2000-09-15 | 2003-09-02 | Isis Pharmaceuticals, Inc. | Antisense inhibition of Her-2 expression |
UA83458C2 (uk) | 2000-09-18 | 2008-07-25 | Байоджен Айдек Ма Інк. | Виділений поліпептид baff-r (рецептор фактора активації в-клітин сімейства tnf) |
CA2422814A1 (en) | 2000-09-18 | 2002-03-21 | Biogen, Inc. | Cripto mutant and uses thereof |
JP5010089B2 (ja) | 2000-09-19 | 2012-08-29 | スピロジェン リミテッド | Cc−1065およびデュオカルマイシンのアキラルアナログの組成物およびその使用方法 |
EP1474528A4 (en) | 2000-10-13 | 2006-06-14 | Protein Design Labs Inc | METHODS FOR DIAGNOSING PROSTATE CANCER, COMPOSITIONS AND METHODS FOR SCREENING PROSTATE CANCER MODULATORS |
ES2329012T3 (es) | 2000-11-07 | 2009-11-20 | Zymogenetics, Inc. | Receptor del factor de necrosis tumoral humano. |
US20020150573A1 (en) | 2000-11-10 | 2002-10-17 | The Rockefeller University | Anti-Igalpha-Igbeta antibody for lymphoma therapy |
US20040018194A1 (en) | 2000-11-28 | 2004-01-29 | Francisco Joseph A. | Recombinant anti-CD30 antibodies and uses thereof |
WO2002061087A2 (en) | 2000-12-19 | 2002-08-08 | Lifespan Biosciences, Inc. | Antigenic peptides, such as for g protein-coupled receptors (gpcrs), antibodies thereto, and systems for identifying such antigenic peptides |
AU2002243495A1 (en) | 2001-01-12 | 2002-07-24 | University Of Medicine And Dentistry Of New Jersey | Bone morphogenetic protein-2 in the treatment and diagnosis of cancer |
US20030119125A1 (en) | 2001-01-16 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US20030119126A1 (en) | 2001-01-16 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US7754208B2 (en) | 2001-01-17 | 2010-07-13 | Trubion Pharmaceuticals, Inc. | Binding domain-immunoglobulin fusion proteins |
CA2440703A1 (en) | 2001-01-24 | 2002-08-01 | Protein Design Labs, Inc. | Methods of diagnosis of breast cancer, compositions and methods of screening for modulators of breast cancer |
AU2002251841A1 (en) | 2001-01-30 | 2002-08-12 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of pancreatic cancer |
WO2002064798A1 (en) | 2001-02-12 | 2002-08-22 | Bionomics Limited | Dna sequences differentially expressed in tumour cell lines |
WO2002071928A2 (en) | 2001-03-14 | 2002-09-19 | Millennium Pharmaceuticals, Inc. | Nucleic acid molecules and proteins for the identification, assessment, prevention, and therapy of ovarian cancer |
EP1243276A1 (en) | 2001-03-23 | 2002-09-25 | Franciscus Marinus Hendrikus De Groot | Elongated and multiple spacers containing activatible prodrugs |
AU2002311787A1 (en) | 2001-03-28 | 2002-10-15 | Zycos Inc. | Translational profiling |
WO2003008537A2 (en) | 2001-04-06 | 2003-01-30 | Mannkind Corporation | Epitope sequences |
US6820011B2 (en) | 2001-04-11 | 2004-11-16 | The Regents Of The University Of Colorado | Three-dimensional structure of complement receptor type 2 and uses thereof |
WO2002083866A2 (en) | 2001-04-17 | 2002-10-24 | The Board Of Trustees Of The University Of Arkansas | Repeat sequences of the ca125 gene and their use for diagnostic and therapeutic interventions |
JP2005527180A (ja) | 2001-04-18 | 2005-09-15 | プロテイン デザイン ラブス, インコーポレイテッド | 肺がんの診断方法、肺がんの修飾因子の組成及びスクリーニングの方法 |
KR100592357B1 (ko) | 2001-04-26 | 2006-06-22 | 바이오겐 아이덱 엠에이 인코포레이티드 | 크립토 차단 항체 및 그 용도 |
WO2003083041A2 (en) | 2002-03-22 | 2003-10-09 | Biogen, Inc. | Cripto-specific antibodies |
US6884869B2 (en) | 2001-04-30 | 2005-04-26 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
EP1515982A4 (en) | 2001-05-09 | 2005-10-26 | Corixa Corp | METHODS AND COMPOSITIONS FOR THE THERAPY AND DIAGNOSIS OF PROSTATE CANCER |
US20030078399A1 (en) | 2001-05-11 | 2003-04-24 | Sloan-Kettering Institute For Cancer Research | Nucleic acid sequence encoding ovarian antigen, CA125, and uses thereof |
KR100976743B1 (ko) | 2001-05-24 | 2010-08-19 | 지모제넥틱스, 인코포레이티드 | Taci-면역글로불린 융합 단백질 |
US7157558B2 (en) | 2001-06-01 | 2007-01-02 | Genentech, Inc. | Polypeptide encoded by a polynucleotide overexpresses in tumors |
WO2003000842A2 (en) | 2001-06-04 | 2003-01-03 | Curagen Corporation | Novel proteins and nucleic acids encoding same |
AU2002314901A1 (en) | 2001-06-04 | 2002-12-16 | Eos Biotechnology, Inc. | Methods of diagnosis and treatment of androgen-dependent prostate cancer, prostate cancer undergoing androgen-withdrawal, and androgen-independent prostate cancer |
WO2002099060A2 (en) | 2001-06-05 | 2002-12-12 | Exelixis, Inc. | Dgks as modifiers of the p53 pathway and methods of use |
JP2005501528A (ja) | 2001-06-05 | 2005-01-20 | エクセリクシス・インコーポレイテッド | p53経路のモディファイヤーとしてのGFATsおよび使用方法 |
US7235358B2 (en) | 2001-06-08 | 2007-06-26 | Expression Diagnostics, Inc. | Methods and compositions for diagnosing and monitoring transplant rejection |
US7125663B2 (en) | 2001-06-13 | 2006-10-24 | Millenium Pharmaceuticals, Inc. | Genes, compositions, kits and methods for identification, assessment, prevention, and therapy of cervical cancer |
US7189507B2 (en) | 2001-06-18 | 2007-03-13 | Pdl Biopharma, Inc. | Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer |
CA2451465A1 (en) | 2001-06-18 | 2002-12-27 | Eos Biotechnology Inc. | Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer |
AU2002322280A1 (en) | 2001-06-21 | 2003-01-21 | Millennium Pharmaceuticals, Inc. | Compositions, kits, and methods for identification, assessment, prevention, and therapy of breast cancer |
US20030108958A1 (en) | 2001-06-28 | 2003-06-12 | Rene De Waal Malefyt | Biological activity of AK155 |
AU2002314433A1 (en) | 2001-07-02 | 2003-01-21 | Licentia Ltd. | Ephrin-tie receptor materials and methods |
US20040076955A1 (en) | 2001-07-03 | 2004-04-22 | Eos Biotechnology, Inc. | Methods of diagnosis of bladder cancer, compositions and methods of screening for modulators of bladder cancer |
WO2003003984A2 (en) | 2001-07-05 | 2003-01-16 | Curagen Corporation | Novel proteins and nucleic acids encoding same |
JP4262941B2 (ja) | 2001-07-06 | 2009-05-13 | ヘイロ エルエスアイ インコーポレイテッド | アドレシング方法及び装置、記憶サイト読み出し方法及び装置、プログラミング方法及び装置、並びに、セル単位での消去方法及び装置 |
WO2003055439A2 (en) | 2001-07-18 | 2003-07-10 | The Regents Of The University Of California | Her2/neu target antigen and use of same to stimulate an immune response |
AU2002337657A1 (en) | 2001-07-25 | 2003-02-17 | Millennium Pharmaceuticals, Inc. | Novel genes, compositions, kits, and methods for identification, assessment, prevention, and therapy of prostate cancer |
BR0211614A (pt) | 2001-08-03 | 2006-10-31 | Genentech Inc | polipeptìdeo tacis e br3 e empregos dos mesmos |
US20070015145A1 (en) | 2001-08-14 | 2007-01-18 | Clifford Woolf | Nucleic acid and amino acid sequences involved in pain |
US20030092013A1 (en) | 2001-08-16 | 2003-05-15 | Vitivity, Inc. | Diagnosis and treatment of vascular disease |
WO2003018621A2 (en) | 2001-08-23 | 2003-03-06 | Oxford Biomedica (Uk) Limited | Genes |
US6902930B2 (en) | 2001-08-29 | 2005-06-07 | Vanderbilt University | Human Mob-5 (IL-24) receptors and uses thereof |
US20030124579A1 (en) | 2001-09-05 | 2003-07-03 | Eos Biotechnology, Inc. | Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer |
JP2005505271A (ja) | 2001-09-06 | 2005-02-24 | アジェンシス, インコーポレイテッド | 癌の処置および検出において有用なsteap−1と名称が与えられる核酸および対応するタンパク質 |
AU2002330039A1 (en) | 2001-09-17 | 2003-04-01 | Eos Biotechnology, Inc. | Methods of diagnosis of cancer compositions and methods of screening for modulators of cancer |
US20050004017A1 (en) | 2001-09-18 | 2005-01-06 | Yuval Reiss | Methods and compositions for treating hcap associated diseases |
NZ531674A (en) | 2001-09-18 | 2009-03-31 | Genentech Inc | Compositions and methods for the diagnosis and treatment of tumor |
CA2460621A1 (en) | 2001-09-19 | 2003-03-27 | Nuvelo, Inc. | Novel nucleic acids and polypeptides |
US7091186B2 (en) | 2001-09-24 | 2006-08-15 | Seattle Genetics, Inc. | p-Amidobenzylethers in drug delivery agents |
WO2003026577A2 (en) | 2001-09-24 | 2003-04-03 | Seattle Genetics, Inc. | P-amidobenzylethers in drug delivery agents |
US20030077644A1 (en) | 2001-09-28 | 2003-04-24 | Bing Yang | Diagnosis and treatment of diseases caused by mutations in CD72 |
WO2003029277A2 (en) | 2001-10-03 | 2003-04-10 | Rigel Pharmaceuticals, Inc. | Modulators of lymphocyte activation and migration |
WO2003029421A2 (en) | 2001-10-03 | 2003-04-10 | Origene Technologies, Inc. | Regulated breast cancer genes |
US20050123925A1 (en) | 2002-11-15 | 2005-06-09 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
AU2002351505B2 (en) | 2001-10-19 | 2008-04-03 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of inflammatory bowel disorders |
US20040241703A1 (en) | 2002-08-19 | 2004-12-02 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
AU2002356858A1 (en) | 2001-10-24 | 2003-05-06 | National Jewish Medical And Research Center | Structure of tall-1 and its cognate receptor |
RU2336902C2 (ru) | 2001-10-31 | 2008-10-27 | Алькон, Инк. | Морфогенные белки кости (вмр), рецепторы вмр и связывающие вмр белки и их применение для диагностики и лечения глаукомы |
WO2003042661A2 (en) | 2001-11-13 | 2003-05-22 | Protein Design Labs, Inc. | Methods of diagnosis of cancer, compositions and methods of screening for modulators of cancer |
US20030232350A1 (en) | 2001-11-13 | 2003-12-18 | Eos Biotechnology, Inc. | Methods of diagnosis of cancer, compositions and methods of screening for modulators of cancer |
WO2003043583A2 (en) | 2001-11-20 | 2003-05-30 | Seattle Genetics, Inc. | Treatment of immunological disorders using anti-cd30 antibodies |
AU2002339691A1 (en) | 2001-11-29 | 2003-06-10 | Genset | Agonists and antagonists of prolixin for the treatment of metabolic disorders |
WO2003048202A2 (en) | 2001-12-03 | 2003-06-12 | Asahi Kasei Pharma Corporation | Nf-kappab activating genes |
EP1504099A4 (en) | 2001-12-10 | 2006-05-10 | Nuvelo Inc | NEW NUCLEIC ACIDS AND POLYPEPTIDES |
US20030134790A1 (en) | 2002-01-11 | 2003-07-17 | University Of Medicine And Dentistry Of New Jersey | Bone Morphogenetic Protein-2 And Bone Morphogenetic Protein-4 In The Treatment And Diagnosis Of Cancer |
US7452675B2 (en) | 2002-01-25 | 2008-11-18 | The Queen's Medical Center | Methods of screening for TRPM4b modulators |
KR20040094705A (ko) | 2002-02-21 | 2004-11-10 | 듀크 유니버시티 | 자가면역질환에 대한 시약 및 치료 방법 |
CA2476518A1 (en) | 2002-02-22 | 2003-09-04 | Genentech, Inc. | Compositions and methods for the treatment of immune related diseases |
WO2003074674A2 (en) | 2002-03-01 | 2003-09-12 | Exelixis, Inc. | MSRAs AS MODIFIERS OF THE p53 PATHWAY AND METHODS OF USE |
WO2003101400A2 (en) | 2002-06-04 | 2003-12-11 | Avalon Pharmaceuticals, Inc. | Cancer-linked gene as target for chemotherapy |
WO2003104399A2 (en) | 2002-06-07 | 2003-12-18 | Avalon Pharmaceuticals, Inc | Cancer-linked gene as target for chemotherapy |
EP2258712A3 (en) | 2002-03-15 | 2011-05-04 | Multicell Immunotherapeutics, Inc. | Compositions and Methods to Initiate or Enhance Antibody and Major-histocompatibility Class I or Class II-restricted T Cell Responses by Using Immunomodulatory, Non-coding RNA Motifs |
WO2004000997A2 (en) | 2002-03-19 | 2003-12-31 | Curagen Corporation | Therapeutic polypeptides, nucleic acids encoding same, and methods of use |
JP2005534286A (ja) | 2002-03-21 | 2005-11-17 | サネシス ファーマシューティカルズ, インコーポレイテッド | キナーゼインヒビターの同定 |
US7193069B2 (en) | 2002-03-22 | 2007-03-20 | Research Association For Biotechnology | Full-length cDNA |
CA2480404A1 (en) | 2002-03-25 | 2003-10-30 | Uab Research Foundation | Fc receptor homolog, reagents, and uses thereof |
WO2003083074A2 (en) | 2002-03-28 | 2003-10-09 | Idec Pharmaceuticals Corporation | Novel gene targets and ligands that bind thereto for treatment and diagnosis of colon carcinomas |
US20030194704A1 (en) | 2002-04-03 | 2003-10-16 | Penn Sharron Gaynor | Human genome-derived single exon nucleic acid probes useful for gene expression analysis two |
MXPA04009728A (es) | 2002-04-05 | 2005-06-08 | Agenysys Inc | Acido nucleico y proteina correspondiente titulada 98p4b6 en el tratamiento y deteccion del cancer. |
US20040101874A1 (en) | 2002-04-12 | 2004-05-27 | Mitokor Inc. | Targets for therapeutic intervention identified in the mitochondrial proteome |
MXPA04010092A (es) | 2002-04-16 | 2004-12-13 | Genentech Inc | Composiciones y metodos para el diagnostico y tratamiento de tumores. |
US20030224467A1 (en) | 2002-04-17 | 2003-12-04 | Osborne C. Kent | AIB1 as a prognostic marker and predictor of resistance to endocrine therapy |
AU2003228869A1 (en) | 2002-05-03 | 2003-11-17 | Incyte Corporation | Transporters and ion channels |
CA2485983A1 (en) | 2002-05-15 | 2003-11-27 | Avalon Pharmaceuticals | Cancer-linked gene as target for chemotherapy |
US20030224454A1 (en) | 2002-05-30 | 2003-12-04 | Ryseck Rolf Peter | Human solute carrier family 7, member 11 (hSLC7A11) |
AU2003240495A1 (en) | 2002-06-04 | 2003-12-19 | Incyte Corporation | Diagnostics markers for lung cancer |
WO2003104270A2 (en) | 2002-06-06 | 2003-12-18 | Ingenium Pharmaceuticals Ag | Dudulin 2 genes, expression products, non-human animal model: uses in human hematological disease |
WO2003104275A2 (en) | 2002-06-06 | 2003-12-18 | Oncotherapy Science, Inc. | Genes and polypeptides relating to human colon cancers |
WO2003105758A2 (en) | 2002-06-12 | 2003-12-24 | Avalon Pharmaceuticals, Inc. | Cancer-linked gene as target for chemotherapy |
US20040249130A1 (en) | 2002-06-18 | 2004-12-09 | Martin Stanton | Aptamer-toxin molecules and methods for using same |
AU2003247576A1 (en) | 2002-06-18 | 2003-12-31 | Archemix Corp. | Aptamer-toxin molecules and methods for using same |
WO2004000221A2 (en) | 2002-06-20 | 2003-12-31 | The Regents Of The University Of California | Compositions and methods for modulating lymphocyte activity |
US20060275287A1 (en) | 2002-06-21 | 2006-12-07 | Brad St Croix | Scroll compressor |
AU2003281515A1 (en) | 2002-07-19 | 2004-02-09 | Cellzome Ag | Protein complexes of cellular networks underlying the development of cancer and other diseases |
CA2492447A1 (en) | 2002-07-25 | 2004-02-05 | Genentech, Inc. | Taci antibodies and uses thereof |
US20050180972A1 (en) | 2002-07-31 | 2005-08-18 | Wahl Alan F. | Anti-CD20 antibody-drug conjugates for the treatment of cancer and immune disorders |
JP2004121218A (ja) | 2002-08-06 | 2004-04-22 | Jenokkusu Soyaku Kenkyusho:Kk | 気管支喘息または慢性閉塞性肺疾患の検査方法 |
WO2004015426A1 (en) | 2002-08-06 | 2004-02-19 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with human cxc chemokine receptor 5(cxcr5) |
EP1572957A4 (en) | 2002-08-27 | 2007-10-10 | Bristol Myers Squibb Pharma Co | IDENTIFICATION OF POLYNUCLEOTIDES FOR PREDICTING THE ACTIVITY OF COMPOUNDS INTERACTING WITH AND / OR MODULATING TYROSINE KINASE PROTEINS AND / OR TYROSINE KINASE PROTEIN PATHWAYS IN MAMMARY CELLS |
WO2004020595A2 (en) | 2002-08-29 | 2004-03-11 | Five Prime Therapeutics, Inc. | Novel human polypeptides encoded by polynucleotides |
AU2003256038A1 (en) | 2002-08-30 | 2004-03-19 | Ramot At Tel Aviv University Ltd. | Self-immolative dendrimers releasing many active moieties upon a single activating event |
AU2002951346A0 (en) | 2002-09-05 | 2002-09-26 | Garvan Institute Of Medical Research | Diagnosis of ovarian cancer |
EP1545610A4 (en) | 2002-09-06 | 2006-11-08 | Mannkind Corp | EPITOPE SEQUENCES |
CA2498264A1 (en) | 2002-09-09 | 2004-05-13 | Nura, Inc. | G protein coupled receptors and uses thereof |
JP2004113151A (ja) | 2002-09-27 | 2004-04-15 | Sankyo Co Ltd | 癌遺伝子及びその用途 |
JP2006501849A (ja) | 2002-10-04 | 2006-01-19 | ヴァン アンデル リサーチ インスティチュート | 腎腫瘍の分子サブ分類および新規診断マーカーの発見 |
HUE026914T2 (en) | 2002-11-07 | 2016-08-29 | Immunogen Inc | Anti-CD33 antibodies and a method of treating acute myeloid leukemia |
EP1581169A4 (en) | 2002-11-08 | 2008-09-17 | Genentech Inc | COMPOSITIONS AND METHODS FOR TREATING DISEASES RELATED TO NATURAL K CELLS |
EP1578940A4 (en) | 2002-11-13 | 2007-12-12 | Genentech Inc | METHOD AND COMPOSITIONS FOR DYSPLASED DIAGNOSIS |
WO2004043493A1 (en) | 2002-11-14 | 2004-05-27 | Syntarga B.V. | Prodrugs built as multiple self-elimination-release spacers |
GB0226593D0 (en) | 2002-11-14 | 2002-12-24 | Consultants Ltd | Compounds |
EP1578372A4 (en) | 2002-11-15 | 2007-10-17 | Univ Arkansas | CA125 GENE AND ITS USE IN DIAGNOSTIC AND THERAPEUTIC INTERVENTIONS |
AU2003298650B2 (en) | 2002-11-15 | 2010-03-11 | Musc Foundation For Research Development | Complement receptor 2 targeted complement modulators |
WO2004046342A2 (en) | 2002-11-20 | 2004-06-03 | Biogen Idec Inc. | Novel gene targets and ligands that bind thereto for treatment and diagnosis of carcinomas |
EP1624753B1 (en) | 2002-11-21 | 2012-01-25 | The University of Utah Research Foundation | Purinergic modulation of smell |
US20040253606A1 (en) | 2002-11-26 | 2004-12-16 | Protein Design Labs, Inc. | Methods of detecting soft tissue sarcoma, compositions and methods of screening for soft tissue sarcoma modulators |
AU2003302774A1 (en) | 2002-12-06 | 2004-06-30 | Diadexus, Inc. | Compositions, splice variants and methods relating to ovarian specific genes and proteins |
US20040157278A1 (en) | 2002-12-13 | 2004-08-12 | Bayer Corporation | Detection methods using TIMP 1 |
US7276372B2 (en) | 2002-12-20 | 2007-10-02 | Pdl Biopharma, Inc. | Antibodies against GPR64 and uses thereof |
US20050249671A9 (en) | 2002-12-23 | 2005-11-10 | David Parmelee | Neutrokine-alpha conjugate, neutrokine-alpha complex, and uses thereof |
CA2512536A1 (en) | 2003-01-08 | 2004-07-29 | Bristol-Myers Squibb Company | Biomarkers and methods for determining sensitivity to epidermal growth factor receptor modulators |
US20050227301A1 (en) | 2003-01-10 | 2005-10-13 | Polgen | Cell cycle progression proteins |
WO2004063355A2 (en) | 2003-01-10 | 2004-07-29 | Protein Design Labs, Inc. | Novel methods of diagnosis of metastatic cancer, compositions and methods of screening for modulators of matastatic cancer |
US20040171823A1 (en) | 2003-01-14 | 2004-09-02 | Nadler Steven G. | Polynucleotides and polypeptides associated with the NF-kappaB pathway |
WO2004065576A2 (en) | 2003-01-15 | 2004-08-05 | Millennium Pharmaceuticals, Inc. | Methods and compositions for the treatment of urological disorder using differential expressed polypeptides |
US20060228710A1 (en) | 2003-02-14 | 2006-10-12 | Morris David W | Novel therapeutic targets in cancer |
US20030224411A1 (en) | 2003-03-13 | 2003-12-04 | Stanton Lawrence W. | Genes that are up- or down-regulated during differentiation of human embryonic stem cells |
GB0321295D0 (en) | 2003-09-11 | 2003-10-15 | Spirogen Ltd | Synthesis of protected pyrrolobenzodiazepines |
GB0416511D0 (en) | 2003-10-22 | 2004-08-25 | Spirogen Ltd | Pyrrolobenzodiazepines |
AU2005216251B2 (en) | 2004-02-23 | 2011-03-10 | Genentech, Inc. | Heterocyclic self-immolative linkers and conjugates |
GB0404577D0 (en) | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
GB0404578D0 (en) | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
PL2270010T3 (pl) | 2004-03-01 | 2012-07-31 | Medimmune Ltd | Pochodne 11-hydroksy-5h-pirolo[2,1-c][1,4]benzodiazepin-5-onu jako kluczowe związki pośrednie do otrzymywania c2 podstawionych pirolobenzodiazepin |
GB0404574D0 (en) | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Amino acids |
US7528126B2 (en) | 2004-03-09 | 2009-05-05 | Spirogen Limited | Pyrrolobenzodiazepines |
FR2869231B1 (fr) | 2004-04-27 | 2008-03-14 | Sod Conseils Rech Applic | Composition therapeutique contenant au moins un derive de la pyrrolobenzodiazepine et la fludarabine |
WO2005110276A1 (en) | 2004-05-11 | 2005-11-24 | The General Hospital Corporation Dba Massachusetts General Hospital | Methods for making oxidation resistant polymeric material |
GB0410725D0 (en) | 2004-05-13 | 2004-06-16 | Spirogen Ltd | Pyrrolobenzodiazepine therapeutic agents |
BRPI0516284A (pt) | 2004-09-23 | 2008-09-02 | Genentech Inc | anticorpo construìdo com cisteìna, método de selecionar anticorpos, compostos conjugados de droga-anticorpo, composição farmacêutica, método para matar ou inibir a proliferação de células de tumor, métodos de inibir a proliferação celular e o crescimento de células de tumor, artigo manufaturado e método para produzir um composto |
US9035035B2 (en) * | 2004-11-05 | 2015-05-19 | Genovoxx Gmbh | Macromolecular nucleotide compounds and methods for using the same |
NZ563136A (en) | 2005-04-21 | 2009-11-27 | Spirogen Ltd | Pyrrolobenzodiazepines |
WO2007039752A1 (en) | 2005-10-05 | 2007-04-12 | Spirogen Limited | Alkyl 4- [4- (5-oxo-2, 3, 5, 11a-tetrahyd0-5h-pyrr0l0 [2, 1-c] [1, 4] benzodiazepine-8-yloxy) -butyrylamino]-1h-pyrrole-2-carboxylate derivatives and related compounds for the treatment of a proliferative disease |
US20070154906A1 (en) | 2005-10-05 | 2007-07-05 | Spirogen Ltd. | Methods to identify therapeutic candidates |
CN109053523B (zh) | 2005-10-07 | 2022-03-25 | 埃克塞利希斯股份有限公司 | 作为用于治疗增生性疾病的mek抑制剂的吖丁啶 |
RS52060B (en) | 2006-01-25 | 2012-04-30 | Sanofi | CYTOTOXIC AGENTS CONTAINING NEW TOMAIMYCIN DERIVATIVES |
ES2595094T3 (es) | 2006-03-10 | 2016-12-27 | Institut Pasteur De Lille | Cepas de Bordetella vivas, atenuadas, como vacuna de dosis única contra la tos ferina |
SG10201501103RA (en) | 2006-05-30 | 2015-04-29 | Genentech Inc | Antibodies And Immunoconjugates And Uses Therefor |
USRE47123E1 (en) | 2006-07-18 | 2018-11-13 | Sanofi | EPHA2 receptor antagonist antibodies |
EP1914242A1 (en) | 2006-10-19 | 2008-04-23 | Sanofi-Aventis | Novel anti-CD38 antibodies for the treatment of cancer |
WO2008050140A2 (en) | 2006-10-27 | 2008-05-02 | Spirogen Limited | Compounds for treatment of parasitic infection |
JP5290276B2 (ja) | 2007-05-08 | 2013-09-18 | ジェネンテック, インコーポレイテッド | システイン改変抗muc16抗体および抗体−薬物結合体 |
SI2019104T1 (sl) | 2007-07-19 | 2013-12-31 | Sanofi | Citotoksična sredstva, ki obsegajo nove tomaimicinske derivate, in njihova terapevtska uporaba |
WO2009052249A1 (en) | 2007-10-19 | 2009-04-23 | Genentech, Inc. | Cysteine engineered anti-tenb2 antibodies and antibody drug conjugates |
GB0722088D0 (en) | 2007-11-09 | 2007-12-19 | Spirogen Ltd | Pyrrolobenzodiazepines |
GB0722087D0 (en) | 2007-11-09 | 2007-12-19 | Spirogen Ltd | Polyamides |
KR20210005318A (ko) | 2008-04-30 | 2021-01-13 | 이뮤노젠 아이엔씨 | 가교제 및 그 용도 |
PT2291659E (pt) * | 2008-05-13 | 2016-01-22 | Univ Yale | Moléculas quiméricas pequenas para o recrutamento de anticorpos contra células cancerosas |
US8563700B2 (en) | 2008-06-16 | 2013-10-22 | Immunogen, Inc. | Synergistic effects |
GB0813432D0 (en) | 2008-07-22 | 2008-08-27 | Spirogen Ltd | Pyrrolobenzodiazepines |
GB0819097D0 (en) | 2008-10-17 | 2008-11-26 | Spirogen Ltd | Pyrrolobenzodiazepines |
GB0819095D0 (en) | 2008-10-17 | 2008-11-26 | Spirogen Ltd | Pyrrolobenzodiazepines |
NZ594177A (en) | 2009-02-05 | 2014-02-28 | Immunogen Inc | Novel benzodiazepine derivatives |
BR112012020102A2 (pt) | 2010-02-10 | 2016-11-29 | Immunogen Inc | anticorpos cd20 e usos dos mesmos. |
US9175086B2 (en) | 2010-02-10 | 2015-11-03 | Immunogen, Inc. | CD20 antibodies and uses thereof |
NZ602933A (en) | 2010-04-15 | 2014-09-26 | Seattle Genetics Inc | Pyrrolobenzodiazepines used to treat proliferative diseases |
MX2012011900A (es) | 2010-04-15 | 2013-03-21 | Seattle Genetics Inc | Conjugados de pirrolobenzodiazepina diana. |
GB201006340D0 (en) | 2010-04-15 | 2010-06-02 | Spirogen Ltd | Synthesis method and intermediates |
US9135118B2 (en) | 2011-03-07 | 2015-09-15 | Aptare, Inc. | System to catalog and search point-in-time instances of a file system |
CN103987718A (zh) | 2011-09-20 | 2014-08-13 | 斯皮罗根有限公司 | 作为非对称二聚体pbd化合物用于内含在靶向结合物中的吡咯并苯并二氮杂卓 |
WO2013053872A1 (en) | 2011-10-14 | 2013-04-18 | Spirogen Sàrl | Synthesis method and intermediates useful in the preparation of pyrrolobenzodiazepines |
CN103998450B (zh) | 2011-10-14 | 2017-03-08 | 麦迪穆有限责任公司 | 吡咯并苯并二氮杂卓 |
PT2750713E (pt) | 2011-10-14 | 2016-01-20 | Genentech Inc | Pirrolobenzodiazepinas e conjugados das mesmas |
US9388187B2 (en) | 2011-10-14 | 2016-07-12 | Medimmune Limited | Pyrrolobenzodiazepines |
KR101961976B1 (ko) | 2011-10-14 | 2019-03-25 | 시애틀 지네틱스, 인크. | 피롤로벤조디아제핀 및 표적 접합체 |
US9526798B2 (en) | 2011-10-14 | 2016-12-27 | Seattle Genetics, Inc. | Pyrrolobenzodiazepines and targeted conjugates |
JP2013194140A (ja) | 2012-03-19 | 2013-09-30 | Fuji Xerox Co Ltd | トナー用ポリエステル樹脂、静電荷像現像用トナー、静電荷像現像剤、トナーカートリッジ、プロセスカートリッジ、画像形成装置及び画像形成方法 |
EP2855482B1 (en) | 2012-04-30 | 2017-03-01 | MedImmune Limited | Pyrrolobenzodiazepines |
KR101960130B1 (ko) | 2012-04-30 | 2019-03-19 | 메디뮨 리미티드 | 피롤로벤조디아제핀 |
US9062577B2 (en) | 2012-05-14 | 2015-06-23 | Southwest Research Institute | Diesel engine operation for fast transient response and low emissions |
EP2869849A1 (en) | 2012-07-09 | 2015-05-13 | Genentech, Inc. | Immunoconjugates comprising anti-cd22 antibodies |
AU2013288930A1 (en) | 2012-07-09 | 2014-12-04 | Genentech, Inc. | Immunoconjugates comprising anti-CD79b antibodies |
EP2879708A4 (en) | 2012-08-02 | 2016-03-16 | Genentech Inc | ANTIBODY AND ANTI-ETBR IMMUNOCONJUGATES |
SI2906296T1 (en) | 2012-10-12 | 2018-06-29 | Adc Therapeutics Sa | Pyrrolobenzodiazepine-antibody conjugates |
EP2906252B1 (en) | 2012-10-12 | 2017-06-14 | ADC Therapeutics SA | Pyrrolobenzodiazepine-anti-her2 antibody conjugates |
JP6367204B2 (ja) | 2012-10-12 | 2018-08-01 | メドイミューン・リミテッドMedImmune Limited | 結合用のピロロベンゾジアゼピン誘導体の合成および中間体 |
WO2014057118A1 (en) | 2012-10-12 | 2014-04-17 | Adc Therapeutics Sarl | Pyrrolobenzodiazepine-anti-cd22 antibody conjugates |
WO2014057120A1 (en) | 2012-10-12 | 2014-04-17 | Adc Therapeutics Sàrl | Pyrrolobenzodiazepine-antibody conjugates |
PT2906251T (pt) | 2012-10-12 | 2017-12-04 | Medimmune Ltd | Conjugados de pirrolobenzodiazepina-anticorpo anti-cd22 |
JP5993093B2 (ja) | 2012-10-12 | 2016-09-14 | メドイミューン・リミテッドMedImmune Limited | ピロロベンゾジアゼピン類およびその複合体 |
MX364329B (es) | 2012-10-12 | 2019-04-23 | Medimmune Ltd | Conjugados del anticuerpo pirrolobenzodiazepina. |
US10736903B2 (en) | 2012-10-12 | 2020-08-11 | Medimmune Limited | Pyrrolobenzodiazepine-anti-PSMA antibody conjugates |
MX364326B (es) | 2012-10-12 | 2019-04-23 | Medimmune Ltd | Conjugados del anticuerpo pirrolobenzodiazepina - anti-psma. |
NZ745069A (en) | 2012-10-12 | 2019-05-31 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
EA031585B1 (ru) | 2012-12-21 | 2019-01-31 | Медимьюн Лимитед | Пирролобензодиазепины и их конъюгаты |
US9567340B2 (en) | 2012-12-21 | 2017-02-14 | Medimmune Limited | Unsymmetrical pyrrolobenzodiazepines-dimers for use in the treatment of proliferative and autoimmune diseases |
WO2014130879A2 (en) | 2013-02-22 | 2014-08-28 | Stem Centrx, Inc. | Novel antibody conjugates and uses thereof |
CA2904044C (en) | 2013-03-13 | 2020-03-31 | Medimmune Limited | Pyrrolobenzodiazepines and conjugates thereof |
SG11201507214SA (en) | 2013-03-13 | 2015-10-29 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
NZ712035A (en) | 2013-03-13 | 2019-06-28 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
US20160106861A1 (en) | 2013-04-26 | 2016-04-21 | Spirogen Sarl | Axl antibody-drug conjugate and its use for the treatment of cancer |
EP3054985B1 (en) | 2013-10-11 | 2018-12-26 | Medimmune Limited | Pyrrolobenzodiazepine-antibody conjugates |
GB201317981D0 (en) | 2013-10-11 | 2013-11-27 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
EP3054984A1 (en) | 2013-10-11 | 2016-08-17 | Medimmune Limited | Pyrrolobenzodiazepine-antibody conjugates |
GB201317982D0 (en) | 2013-10-11 | 2013-11-27 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
US9956299B2 (en) | 2013-10-11 | 2018-05-01 | Medimmune Limited | Pyrrolobenzodiazepine—antibody conjugates |
US10010624B2 (en) | 2013-10-11 | 2018-07-03 | Medimmune Limited | Pyrrolobenzodiazepine-antibody conjugates |
WO2015095124A1 (en) | 2013-12-16 | 2015-06-25 | Genentech Inc. | Peptidomimetic compounds and antibody-drug conjugates thereof |
GB201406767D0 (en) | 2014-04-15 | 2014-05-28 | Cancer Rec Tech Ltd | Humanized anti-Tn-MUC1 antibodies anf their conjugates |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102753559A (zh) * | 2009-08-25 | 2012-10-24 | 赛诺菲 | 作为抗癌剂的吡咯并[1,4]苯并二氮杂*二聚物的共轭物 |
CN102933236A (zh) * | 2010-04-15 | 2013-02-13 | 斯皮罗根发展有限公司 | 吡咯并苯二氮卓类及其结合物 |
WO2011133039A2 (en) * | 2010-04-21 | 2011-10-27 | Syntarga B.V. | Novel conjugates of cc-1065 analogs and bifunctional linkers |
WO2012014147A1 (en) * | 2010-07-26 | 2012-02-02 | Sanofi | Anticancer derivatives, preparation thereof and therapeutic use thereof |
WO2012112687A1 (en) * | 2011-02-15 | 2012-08-23 | Immunogen, Inc. | Methods of preparation of conjugates |
Non-Patent Citations (1)
Title |
---|
"2-芳基-4-苯基-2,3-二氢-1,5-苯并二氮杂卓";王洪钟;《有机化学》;20000229;第2卷(第2期);第218-223页 |
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