CN116143678A - 偶联连接体,含有此连接体的细胞结合分子-药物偶联物及其制备和应用 - Google Patents
偶联连接体,含有此连接体的细胞结合分子-药物偶联物及其制备和应用 Download PDFInfo
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Abstract
本发明涉及具有一组丙酰基,取代的丙烯酰基或二取代的丙酰基的链接体以及使用这种链接基团偶联化合物,特别是用于细胞毒素分子与细胞结合分子的偶联。
Description
本申请是申请日为2016年11月14日、申请号为201680090956.2、发明名称为“偶联连接体,含有此连接体的细胞结合分子-药物偶联物及其制备和应用”的申请的分案申请。
技术领域
本发明涉及一类含有丙炔酰基,取代的丙烯酰基或二取代的丙酰基的连接体,所述的连接体用于化合物偶联,特别是细胞毒性剂与细胞结合分子的偶联。本发明还涉及制备细胞结合剂-药物(细胞毒性剂)偶联物的方法,包括首先用所述的连接体修饰药物,然后与细胞结合剂反应;或者先用所述的连接体修饰细胞结合剂,然后再与药物反应,或者将合成的连接体-药物复合物直接与细胞结合分子偶联。
技术背景
化疗药物的主要问题是其治疗窗口狭窄,原因在于它们通常不能区分正常细胞和恶性癌细胞,由此引起的副作用将药物耐受剂量限制在临床有效剂量以下。相反,免疫治疗,特别是单克隆抗体(mAb)可以与癌细胞的某些蛋白质或分子特异性结合,使正常细胞不受伤害,因而与化学疗法相比具有更少的副作用和更宽的治疗窗口。抗体-药物偶联物(ADC)是一种细胞免疫疗法,它联合了特异性结合肿瘤的单克隆抗体和高效的细胞毒性剂,一起用于癌症靶向治疗。该治疗方法非常具有前景,美国FDA已批准了治疗霍奇金淋巴瘤的药物Adcetris(brentuximab vedotin)和治疗HER-2阳性乳腺癌的药物Kadcyla(ado-trastuzumab emtansine)。在过去的二十年中,学术界和制药行业一直在增加对ADC研发的时间和金钱的投入。有超过50个ADC药物正在进行临床试验,行业的预期是在未来几年内将会有其他8-10个ADC药物可能会获得市场准入(Lambert,J.M.Ther.Deliv.2016,7,279-82;Jerjian,T.V.等Pharmacotherapy 2016,36,99-116;Donaghy,H.MAbs 2016,8,659-71;deGoeij,B.E.和Lambert,J.M.Curr Opin Immunol 2016,40,14-23;Mehrling,T.FutureOncol,2015,11,549)。
影响可临床应用的抗体-药物偶联物研制关键因素包括,在正常细胞上有限表达的肿瘤靶抗原的选择,对靶标具有高选择性的抗体,当经细胞内化和被释放后,细胞毒性分子(有效荷载)需要高效地杀死靶细胞,连接细胞毒性分子和抗体的连接体需要在体循环内保持稳定,但在目标细胞中要能释放细胞毒性剂,以及合适的将细胞毒性分子连接到抗体的偶联方法。虽然目前抗体-药物偶联物的研制已经有很多进展,但是人们对于ADC脱靶毒性背后的机制仍然知之甚少,相当数量的ADCs在临床试验阶段被终止,因为它们在临床上的治疗窗口比临床前模型显示的窄得多,其给药方案受到剂量限制性毒性(DLT)的阻碍,而DLT通常很难根据临床前数据来预测(de Goeij,B.E.和Lambert,J.M.Curr Opin Immunol2016,40,14-23)。目前ADC的研发在扩展连接体-细胞毒性剂和偶联化学的范围,已经超越单一有效的有效荷载,尤其是解决ADC上的连接体-有效负载对靶标/靶标疾病的活性(Lambert,J.M.Ther Deliv 2016,7,279-82;Zhao,R.Y.等,2011,J.Med.Chem.54,3606-23)。如今,许多药物开发者和学术机构都致力于开发新型可靠的定点ADC偶联方法,这种偶联物具有更长的循环半衰期,更高的疗效,可能更低的脱靶毒性,更好的ADC体内药代动力学(PK)特性,以及ADC生产中更好的批次间一致性(Hamblett,K.J.等,Clin.CancerRes.2004,10,7063-70;Adem,Y.T.等,Bioconjugate Chem.2014,25,656-664;Boylan,N.J.Bioconjugate Chem.2013,24,1008–1016;Strop,P.,等Chem.Biol.2013,20,161-67;Wakankar,A.mAbs,2011,3,161–172)。
近些年来也有一些定点的ADC药物制备方法(Panowsky S.,2014,mAbs 6,34)。这些方法包括:在抗体上引入非配对的半胱氨酸,如抗体工程改造的反应活性半胱氨酸,即Genentech的THIOMAB抗体(Junutula,J.R.,等Clin.Cancer Res.2010,16,4769;Junutula,J.R.,等Nat Biotechnol.2008 26,925-32;美国专利8,309,300;7,855,275;7,521,541;7,723,485;WO2008/141044);或引入谷氨酰胺标签,可通过轮枝链霉菌转谷氨酰胺酶(mTG)(Strop,P.,Bioconjugate Chem.,2014,25,855–862;Strop,P.,et al.,Chem.Biol.2013,20,161–167;美国专利8,871,908)或通过细菌来源的谷氨酰胺转胺酶(MTGase)(Dennler,P.,et al,Bioconjug.Chem.2014,25,569–578;美国专利20130189287;7,893,019)而识别;引入巯基-L-岩藻糖(Okeley,N.M.等,Bioconjugate Chem.2013,24,1650);通过诱变引入非天然氨基酸(Axup,J.Y.等,Proc.Natl.Acad.Sci.2012,109,16101–16106;Zimmerman,E.S.等,Bioconjug.Chem.2014,25,351–361;Wu,P.等,Proc.Natl.Acad.Sci.2009,106,3000-3005;Rabuka,D.等,Nat.Protoc.2012,7,1052-67;美国专利8,778,631;20100184135;WO2010/081110;WO2006/069246,2007/059312,美国专利7,332,571,7,696,312;7,638,299;WO2007/130453,美国专利7,632,492;7,829,659);引入硒代半胱氨酸(Hofer,T.等Biochemistry 2009,48,12047–12057;美国专利8,916,159);用甲酰甘氨酸生成酶(FGE)将CXPXR共有序列上的半胱氨酸转化为甲酰甘氨酸(FGly)(Drake,P.M.等,Bioconjug.Chem.2014,25,1331–1341;美国专利7,985,783;8,097,701;8,349,910;美国专利申请20140141025,20100210543);或用半乳糖或唾液酸转移酶通过糖工程引入唾液酸(Zhou,Q.等Bioconjug.Chem.,2014,25,510-520,美国专利申请20140294867)。但是上述的方法都需要抗体工程改造和重新优化细胞培养条件。在实践中可采用简单的均相偶联方法,通过重新桥接天然抗体上的被还原的链间二硫键,例如使用称为下一代马来酰亚胺(NGM)连接体的溴或二溴马来酰亚胺(Schumacher,F.F.等Org.Biomol.Chem.2014,12,7261–69;UCL Cancer Institute),或通过三碳桥使用双烷基化试剂偶联(Badescu,G.等,Bioconjug.Chem.2014,25,1124–36;WO2013/190272,WO2014/064424)。我们已经公开了几种桥联天然抗体上,链间二硫键被还原而产生的一对巯基的偶联方法,例如使用溴代马来酰亚胺和二溴马来酰亚胺连接体(WO2014/009774),2,3-二取代的琥珀酸,2-取代/2,3-二取代的富马酸或马来酸连接体(WO2015/155753,WO20160596228),乙炔二羧酸连接体(WO2015/151080,WO20160596228)或肼连接体(WO2015/151081)。在本专利申请中我们扩展了之前的范围。更重要的是,本专利申请的双硫连接体能够在每个连接体上偶联两种或更多种药物以实现更高的DAR(≥4)或与细胞结合分子上两个或更多个巯基位点偶联,或偶联两个或更多个细胞结合分子。因此,本专利申请免疫偶联物的主要优势包括:在靶向递送期间更长的偶联物半衰期;偶联两种或更多种不同功能分子/药物,使其在细胞周期的不同阶段起作用,以增加暴露于特定药物或效应物的靶细胞的数量;可能偶联两种或多种细胞结合分子,实现对增殖细胞的双重,三重或多重靶向策略;通过偶联功能分子,使药物最小量地暴露于非靶细胞,组织或器官;精确定点控制药物有效负载和药物比例,产生均一的最终产品。
发明内容
本发明申请包括一类含有取代丙烯酰基团或丙炔酰基团的,能与巯基反应的连接体,其中可选地含有磷酰胺,胺,肼,三唑,杂芳基,乙酰胺,糖苷等基团及其类似物,可以与药物和/或功能分子,和/或细胞结合剂(例如抗体)发生偶联。
本发明申请的一个方面,连接体由式(I)和(II)表示
Lv1和Lv2表示相同或不同的,可被巯基取代的离去基团。这些离去基团包括,但不限于卤化物(例如氟化物,氯化物,溴化物和碘化物),甲磺酰基(mesyl),甲苯磺酰基(tosyl),三氟甲基磺酰基(triflate),硝基苯氧基,N-琥珀酰亚胺基氧基(NHS),苯氧基;二硝基苯氧基;五氟苯氧基,四氟苯氧基,三氟苯氧基,二氟苯氧基,单氟苯氧基,五氯苯氧基,1H-咪唑-1-基,氯苯氧基,二氯苯氧基,三氯苯氧基,四氯苯氧基,N-(苯并三唑基)氧基,2-乙基-5-苯基异恶唑-3’-磺酰基,苯基恶二唑-磺酰基(-sulfone-ODA),2-乙基-5-苯基异恶唑-基,苯基恶二唑基(ODA),恶二唑基,或者与Mitsuno bu反应缩合试剂作用产生的中间体。
Y是能够与细胞毒性药物反应形成二硫化物,醚,酯,硫醚,硫酯,肽,腙,氨基甲酸酯,碳酸酯,胺(二级,三级或四级),亚胺,环杂烷基,杂芳基,烷基肟或酰胺键的官能团;优选地,Y具有以下结构:
N-羟基琥珀酰亚胺酯基;/>马来酰亚胺基;/>单取代马来酰亚胺基;/>二取代马来酰亚胺基;/>单取代的琥珀酰亚胺基;/>二取代琥珀酰亚胺基;醛基;/>乙烯基磺酰基;/>丙烯酰基;/>2-(甲苯磺酰氧基)乙酰基;
其中X1’为F,Cl,Br,I或Lv3;X2’是O,NH,N(R1)或CH2;R3和R5独立地为H,R1,芳基,杂芳基或芳香基团,其中一个或几个H原子被-R1,-卤素,-OR1,-SR1,-NR1R2,-NO2,-S(O)R1,-S(O)2R1,或-COOR1取代;Lv3是下列离去基团:硝基苯氧基,N-琥珀酰亚胺基氧基(NHS),苯氧基;二硝基苯氧基;五氟苯氧基,四氟苯氧基,二氟苯氧基,单氟苯氧基,五氯苯氧基,三氟甲基磺酰基,咪唑基,二氯苯氧基,四氯苯氧基,1-羟基苯并三唑基,甲苯磺酸基,甲磺酸基,2-乙基-5-苯基异恶唑-3’-磺酸基,自身形成,或与其它酸酐形成的酸酐,例如乙酸酐,甲酸酐,或与多肽缩合试剂作用产生的或Mitsunobu反应的中间体。
R1可以缺省,或者可以选自C1-C8(1-8个碳原子)烷基;C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或含2-8个碳原子的酯,醚或酰胺;或含有1-8个氨基酸的肽;或具有式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p是0至约1000的整数,或其上述基团的组合。
另外,R1是包含C,N,O,S,Si,和P原子的链状结构,最优含0~500个原子,共价连接于Y和L1。R1中的各个原子以所有可能的化学方式结合,比如形成烷基、亚烷基、亚烯基、亚炔基、醚、聚氧烷基、酯、胺、亚胺、聚胺、肼、腙、酰胺、脲、氨基脲、卡巴肼、烷氧胺、聚氨酯、氨基酸、多肽、酰氧胺、异羟肟酸,或这些基团的组合。
T为CH2,NH,NHNH,N(R3),N(R3)N(R3’),O,S,C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;含有1~4氨基酸单位的肽,优选自天冬氨酸,谷氨酸,精氨酸,组氨酸,赖氨酸,丝氨酸,苏氨酸,天冬酰胺,谷氨酰胺,半胱氨酸,硒代半胱氨酸,酪氨酸,苯丙氨酸,甘氨酸,脯氨酸,色氨酸,丙氨酸;或以下结构之一:
X1,X2,X3,X4,X5,X6,X1’,X2’和X3’独立地选自NHNH;N(R3);N(R3)N(R3’);O;S;C1-C6烷基;C2-C6杂烷基,烷基环烷基,杂环烷基的;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或1~8个氨基酸;其中R3和R3’独立地为H;C1-C8烷基;C2-8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或含1-8个碳原子的酯,醚或酰胺;或具有式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p是0至约1000的整数,或其上述基团的组合。
L1和L2是相同或不同的,独立地选自O,NH,S,NHNH,N(R3),N(R3)N(R3’),如式(OCH2CH2)pOR3,或(OCH2CH(CH3))pOR3,或NH(CH2C水)pR3,或NH(CH2CH(CH3)O)pR3,或N[(CH2C水)pR3][(CH2C水)p’R3’],或(OCH2CH2)pCOOR3,或CH2CH2(OCH2CH2)pCOOR3的聚乙烯氧基单元,其中p和p’是独立的选自0至约1000的整数,或它们的组合;C1-C8烷基;C2-C8杂烷基,烷基环烷基,杂环烷基的;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;其中,R3和R3’独立地为H;C1-C8烷基;C2-C8杂烷基,烷基环烷基,杂环烷基的;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或含1-8个碳原子的酯,醚或酰胺;或1~8个氨基酸;或具有式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p是0至约1000的整数,或其上述基团的组合。
L1或L2可以由一个或多个以下连接体单元构成:6-马来酰亚胺基己酰基(“MC”),马来酰亚胺丙酰基(“MP”),缬氨酸-瓜氨酸(“val-cit”或“vc”),丙氨酸-苯丙氨酸(“ala-phe”或"af”),对氨基苄氧基羰基(“PAB"),4-硫代戊酰基(“SPP”),4-(N-马来酰亚胺甲基)环己烷-1酰基(“MCC“),(4-乙酰基)氨基-苯酰基(“SIAB”),4-硫代丁酰基(SPDB),4-硫代-2-羟基磺酰基-丁酰基(2-sulfo-SPDB),或具有1~8个天然或非天然氨基酸单元的天然或非天然肽。
m1,m2,m3,m4和m5是独立的选自1到10的整数,优选1到4。
此外,L1,L2,X1,X2,X3,X1’,X2’和X3’可以独立地缺省。
另一方面,本发明包括如式(III),(IV),(V),(VI),(VII),(VIII),和(IX)的细胞结合剂-药物偶联物,其中细胞结合剂Cb和药物Drug,分别在连接体两末端反应:
其中Cb,Cb’,Cb”,Cb”’表示相同或不同的细胞结合剂或免疫治疗蛋白,优选为抗体或抗体片段。
式(III),(VII),(VIII)和(IX)的右括号(方括号)内是与细胞结合剂/分子的巯基对偶联的连接体-药物组分。巯基优选为细胞结合剂的链间二硫键被还原剂还原而产生,还原剂选自二硫苏糖醇(DTT)、二硫季戊四醇(DTE)、L-谷胱甘肽(GSH)、三(2-羧基乙基)膦(TCEP)、2-巯基乙胺(β-MEA)或/和β-巯基乙醇(β-ME,2-ME)。
Drug,Drug’,和Drug”表示相同或不同的细胞毒性剂,或治疗药物,或免疫治疗蛋白质,或用于增强细胞结合剂的结合或稳定的功能分子,或者细胞表面受体结合配体,其应用本专利申请的桥接剂,经由R1与细胞结合剂连接,R1含有C1-C8烷基;C2-C8亚烷基,亚烯基,亚炔基,芳基,醚,聚氧亚烷基,酯,胺,亚胺,多胺,肼,腙,酰胺,脲,氨基脲,卡巴肼,烷氧基胺,氨基甲酸,氨基酸,肽,酰氧基胺,异羟肟酸,二硫化物,硫醚,硫酯,氨基甲酸酯,碳酸酯,杂环,杂烷基,杂芳基,烷氧基或上述基团组合。
Drug,Drug’,和Drug”还可以是细胞毒性分子,免疫治疗化合物,化学治疗化合物,抗体或抗体片段,siRNA或DNA分子,或细胞表面结合配体。
方括号内是通过细胞结合分子上的一对硫原子与细胞结合分子偶联的试剂。
m1,m1’,m1”,m2,m2’,m2”,m3,m4,m5,m4’,m5’,m4”,m5”,m4”’,m5”’,m4””和m5””独立地是1到10的整数,优选1到4的整数。
X1,X1’,X1”,X1”’和X2””独立地选自NH;NHNH;N(R3);N(R3)N(R3’);O;S;C1-C6烷基;C2-C6杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或1~8个氨基酸;其中R3和R3’独立地为H;C1-C8烷基;C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基、杂芳基;1-8个碳原子的酯、醚或酰胺;或如式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p为从0到1000的整数;或以上的组合。此外,X1,X1’,X1”,X1”’和X2””可以独立地缺省。
R1,R1’,和R1”相同或不同,选自C1-C8烷基;C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基、杂芳基;2-8个碳原子的酯、醚或酰胺;或如式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p为从0到1000的整数;或以上的组合。
L1,L1’,L1”,L1”’,L2,L2’,L2”和L2”’的定义与式(I)和(II)中的L1和L2相同,它们也可以各不相同。
n是1~20;T与前式(I)中定义相同。
另一方面,本发明申请还包括如式(X),(XI),(XII),(XIII),(XIV),(XV)和(XVI)的经修饰的细胞结合剂,细胞结合剂Cb通过还原二硫键产生的巯基对与连接体反应,其中含有官能团Y,可以与药物反应:
更进一步的,本发明申请包含如式(XVII)和(XVIII)经修饰的药物,药物“Drug”与式(I)和(II)的连接体反应后,引入可以与巯基反应的取代丙烯酰基团或丙炔酰基团:
本发明申请进一步涉及式(III)–(IX)中细胞结合分子-药物偶联物的制备方法,其中药物“Drug”通过连接体与细胞结合剂连接。
本发明还涉及式(X)–(XVI)中修饰的细胞结合分子的制备方法,其中所述细胞结合分子与式(I)和(II)中的连接体反应。
本发明还涉及式(XVII)和(XVIII)中修饰药物的制备方法,其中药物与式(I)和(II)中的连接体反应。
附图说明
图1显示了本专利申请中含有两个或四个药物的连接体的合成,以及连接体通过一对巯基偶联抗体。
图2显示了本专利申请中含有两种或四种药物的连接体的合成,以及连接体通过一对巯基偶联抗体。
图3显示了本专利申请中含有一个药物和聚乙二醇基团连接体的合成,以及连接体通过一对巯基偶联抗体。
图4显示了本专利申请中含有一个药物的连接体的合成,以及连接体通过一对巯基偶联抗体。
图5显示了本专利申请中含有一个药物,氨基酸和聚乙二醇基团的连接体的合成,以及连接体通过一对巯基偶联抗体。
图6显示了本专利申请中含有一个药物、磷酰胺和聚乙二醇基团的连接体的合成,以及连接体通过一对巯基偶联抗体。
图7显示了本专利申请中含有一个药物和磷酰胺基团的连接体的合成,以及连接体通过一对巯基偶联抗体。
图8显示了本专利申请中含有药物和磷酰胺基团的连接体的合成,以及连接体通过一对巯基偶联抗体。
图9显示了本专利申请中含有一个药物和聚乙二醇基团的连接体的合成,以及连接体通过一对巯基偶联抗体。
图10显示了本专利申请中含有药物和连接体单元L1和L2的连接体的合成,以及连接体通过一对巯基偶联抗体。
图11显示了本专利申请中含有前列腺表面抗原(PSA)结合配体的连接体的合成。
图12显示了本专利申请中含有前列腺表面抗原(PSA)结合配体的连接体的合成,以及连接体通过一对巯基偶联抗体。
图13显示了Tubulysin类似物中间体的合成。
图14显示了可偶联的Tubulysin类似物的合成,以及通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图15显示了通过本专利申请的连接体合成抗体-MMAF类似物的偶联物。
图16显示了通过本专利申请的连接体合成抗体-MMAF类似物的偶联物。
图17显示了通过本专利申请的连接体合成抗体-MMAF类似物的偶联物。
图18显示了通过本专利申请的连接体合成抗体-MMAF类似物的偶联物。
图19显示了可偶联的Tubulysin类似物组分的合成,以及通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图20显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图21显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图22显示了通过本专利申请之连接体合成抗体-Tubulysin类似物的偶联物。
图23显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图24显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图25显示了通过本专利申请的连接体合成含有MMAF类似物和Tubulysin类似物的偶联物。
图26显示了通过本专利申请的连接体合成含有MMAF类似物和PBD二聚体类似物的偶联物。
图27显示了通过本专利申请的连接体合成含有MMAF类似物和PBD二聚体类似物的偶联物。
图28显示了通过本专利申请的连接体合成的包含两个MMAF类似物的偶联物。
图29显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图30显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图31显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图32显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图33显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图34显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物和可偶联的MMAF类似物。
图35显示通过本专利申请的连接体合成抗体-MMAF类似物的偶联物。
图36显示了通过本专利申请的连接体合成抗体-鹅膏毒素类似物的偶联物。
图37显示了通过本专利申请的连接体合成抗体-鹅膏毒素类似物的偶联物。
图38显示了通过本专利申请的连接体合成抗体-鹅膏毒素类似物的偶联物。
图39显示了通过本专利申请的连接体合成抗体-鹅膏毒素类似物的偶联物。
图40显示了通过本专利申请的连接体合成抗体-Tubulysin类似物和抗体-MMAF类似物的偶联物。
图41显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图42显示通过本专利申请的连接体合成抗体-Tubulysin类似物、抗体-PBD二聚体类似物及抗体-MMAF类似物的偶联物。
图43显示了通过本专利申请的连接体合成包含PMSA结合配体的抗体-Tubulysin类似物,包含PEG链的抗体-Tubulysin类似物的偶联物。
图44显示了含有还原剂DTT的SDS-PAGE谱。泳道1和11是生物标记物,泳道2和泳道16是偶联物232,泳道3和泳道15是偶联物339,泳道4是偶联物234,泳道5是偶联物238,泳道6是偶联物261,泳道7和泳道17是偶联物308,泳道8是偶联物239,泳道9是偶联物476,泳道10是偶联物478,泳道12是偶联物360,泳道14是偶联物238,泳道18为偶联物481,泳道19为偶联物483,泳道20为T-DM1。通过本专利申请的连接体得到的偶联物232、234、238、261、308、339、354和360的条带为75kd,表明单克隆抗体的重链和轻链被连接体交联。偶联物上两条重链之间的连接可以被DTT还原剂取代,导致150kD条带微弱。偶联物476、478、481和483的交联被SDS-PAGE内的DTT所取代(可逆结合),75kD和150kD的带也非常微弱。相比之下,无交联的T-DM1无75kD带,制备时不使用紫外光的偶联物239仅有微弱的75kD条带,表明在偶联条件下可能不存在交联。
图45显示了偶联物232、308、327、339、476、485和500与T-DM1在人胃癌N87细胞模型上抗肿瘤作用的比较,一次静脉注射,偶联物232、308、327、339、476和485的剂量为5mg/kg,偶联物339和500为4mg/kg。测试的7个偶联物显示出比T-DM1更好的抗肿瘤活性。化合物476、483、339和500组的6/6动物在第14天至第52天完全没有肿瘤。与之对照,剂量为5mg/kg的T-DM1不能消除肿瘤,仅能抑制肿瘤生长31天。偶联物232、308和327在剂量为5mg/kg时不能完全去除肿瘤。
发明概要
定义
“烷基”是指在烷烃上除去一个或两个氢原子而产生的脂肪烃基团或单价基团。它可以是直链或是支链的,在链中具有1-8个碳原子(C1-C8)。“支链”是指直链烷基上连接有一个或多个低碳数的烷基,如甲基、乙基或丙基。示例性的烷基包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、3-戊基、辛基、壬基、癸基、环戊基、环己基、2,2-二甲基丁基、2,3-二甲基丁基、2,2-二甲基戊基、2,3-二甲基戊基、3,3-二甲基戊基、2,3,4-三甲基戊基、3-甲基-己基、2,2-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、3,5-二甲基己基、2,4-二甲基戊基、2-甲基庚基、3-甲基庚基、正庚基、异庚基、正辛基和异辛基。C1-C8烷基可以是未被取代的或被一个或多个基团取代,包括但不限于-C1-C8烷基、-O-(C1-C8烷基)、-芳基、-C(O)R’、-OC(O)R’、-C(O)OR’、-C(O)NH2,-C(O)NHR’、-C(O)N(R’)2、-NHC(O)R’、-SR’、-S(O)2R’、-S(O)R’、-OH、-卤素、-N3、-NH2、-NH(R’)、-N(R’)2和-CN;其中每个R’独立地选自于-C1-C8烷基和芳基。
“杂烷基”指其中1至4个碳原子独立地被选自O、S和N的杂原子所取代的C2-C8烷基。
“碳环”指含有3到8个碳原子的饱和或不饱和单环,或含有7到13个碳原子的饱和或不饱和双环。单环碳环有3到6个环原子,典型的有5或6个环原子。双环碳环有7到12个环原子,构成[4,5]、[5,5]、[5,6]或[6,6]的双环系统,或有9个或10个环原子,构成[5、6]或[6,6]的双环系统。具有代表性的C3-C8的碳环包括但不限于:-环丙基、-环丁基、-环戊基、-环戊二烯基、-环己基、-环己烯基、-1,3-环己二烯基、-1,4-环己二烯基、-环庚基、-1,3-环庚二烯基、-1,3,5-环庚三烯基、-环辛基和-环辛二烯基。
C3-C8碳环可以是未被取代的或被一个或多个基团取代,包括但不限于-C1-C8烷基、-O-(C1-C8烷基)、-芳基、-C(O)R’、-OC(O)R’、-C(O)OR’、-C(O)NH2、-C(O)NHR’、-C(O)N(R’)2、-NHC(O)R’、-SR’、-S(O)R’、-S(O)2R’、-OH、-卤素、-N3、-NH2、-NH(R’)、-N(R’)2及-CN;其中每个R’独立地选自-C1-C8烷基和芳基。
“烯基”指含有碳-碳双键的直链或支链脂肪烃基团,链内含有2-8个碳原子。示例性的烯基包括乙烯基、丙烯基、正丁烯基、异丁烯基、3-甲基丁-2-烯基、正戊烯基、己烯基、庚烯基、辛烯基。
“炔基”指含有碳-碳三键的直链或支链脂肪烃基团,链内含有2-8个碳原子。示例性的炔基包括乙炔基、丙炔基、正丁炔基、2-丁炔基、3-甲基丁炔基、5-戊炔基、正戊炔基、己炔基、庚炔基和辛炔基。
“亚烷基”是指含1-18个碳原子的饱和的支炼或直链或环状烃基,并带有两个通过从母体烷烃的相同或两个不同碳原子上除去两个氢原子而产生的一价自由基。典型的亚烷基包括但不限于:亚甲基(-CH2-)、1,2-乙基(-CH2CH2-)、1,3-丙基(-CH2CH2CH2-)、1,4-丁基(-CH2CH2CH2CH2-)等。
“亚烯基”指含2-18个碳原子的不饱和的支炼或直链或环状烃基,并带有两个通过从母体烯烃的相同或两个不同碳原子上除去两个氢原子而产生的一价自由基。典型的亚烯基包括但不限于:1,2-亚乙基(-CH=CH-)。
“亚炔基”指含2-18个碳原子的不饱和的支炼或直链或环状烃基,并带有两个通过从母体炔的相同或两个不同碳原子上除去两个氢原子而产生的一价自由基。典型的亚炔基包括但不限于:乙炔、炔丙基和4-戊炔基。
“芳基”或“芳香基”指由一个或多个环组成的芳香或杂芳香基团,包含三至十四个碳原子,优选六至十个碳原子。术语“杂芳香基团”是指芳香基团上的一个或几个碳,最优是一个、两个、三个或四个碳原子,被氧(O)、氮(N)、硅(Si)、硒(Se)、磷(P)或(S)所取代,优选被氧、硫和氮所取代而产生的基团。术语“芳基”或“芳香基”也指其中一个或几个氢原子独立地被-R’、卤素、-OR’,-SR’、-NR’R’、-N=NR’、-N=R’、-NR’R’、-NO2、-S(O)R’、-S(O)2R’、-S(O)2OR’、-OS(O)2OR’、-PR’R’、-P(O)R’R’、-P(OR’)(OR’)、-P(O)(OR’)(OR’)或-OP(O)(OR’)(OR’)所取代而产生的芳香基团。其中R’和R’独立地为氢、烷基、烯基、炔基、杂烷基、芳基、芳烷基、羰基或其药用盐。
“杂环”指其中一到四个环碳原子独立地被O、N、S、Se、B、Si或P等杂原子所取代而产生的的环结构。优选的杂原子是O、N和S。在《化学与物理手册》第78版的225-226页(TheHandbook of Chemistry and Physics,78th Edition,CRC Press,Inc.,1997 -1998,p.225to 226)上也有杂环化合物的相关描述,在此引作参考。优选的非芳基杂环包括环氧基、氮丙啶基、硫杂丙基、吡咯烷基、吡唑烷基、咪唑烷基、环氧乙烷基、四氢呋喃基、二氧戊环基、四氢吡喃基、二恶烷基、二氧戊环基、呱啶基、呱嗪基、吗啉基、吡喃基、咪唑啉基、吡咯啉基、吡唑啉基、噻唑烷基、四氢噻喃基、二噻烷基、硫代吗啉基、二氢吡喃基、四氢吡喃基、二氢吡喃基、四氢吡啶基、二氢吡啶基、四氢嘧啶基、二氢噻喃基、氮杂环庚烷基,以及上述基团与苯基缩合得到的稠环体系。
术语“杂芳基”或“芳基杂环”是指含3到14,优选5至10个原子的芳香性杂环、包含单环、双环或多环。示例包括吡咯基、吡啶基、吡唑基、噻吩基、嘧啶基、吡嗪基、四唑基、吲哚基、喹啉基、嘌呤基、咪唑基、噻吩基、噻唑基、苯并噻唑基、呋喃基、苯并呋喃基、1,2,4-噻二唑基、异噻唑基、三唑基、四唑基、异喹啉基、苯并噻吩基、异苯并呋喃基、吡唑基、咔唑基、苯并咪唑基、异恶唑基、吡啶基-N-氧化物,以及上述基团与苯基缩合得到的稠环体系。
“烷基”、“环烷基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“杂环”等,也包含各自对应的“亚烷基”、“亚环烷基”、“亚烯基”、“亚炔基”、“亚芳基”、“亚杂芳基”、“亚杂环”等,为论述方便,本专利申请对它们未做完全区分。
“芳烷基”指一类非环烷基,其中一个与碳原子(通常为末端或sp3碳原子)键合的氢原子被芳基取代。典型的芳烷基包括芐基、2-苯基乙-1-基、2-苯基乙烯-1-基、萘基甲基、2-萘基乙-1-基、2-萘基乙-1-基、萘并芐基、2-萘基苯基-1-基等。
“杂芳烷基”指一类非环烷基,其中一个与碳原子(通常为末端或sp3碳原子)键合的氢原子被杂芳基取代。杂芳烷基的实例有2-苯并咪唑基甲基、2-呋喃基乙基。
“羟基保护基”的实例包括甲氧基甲基醚、2-甲氧基乙氧基甲基醚、四氢吡喃基醚、芐基醚、对甲氧基芐基醚、三甲基甲硅醚、三乙基硅醚、三异丙基硅醚、叔丁基二甲基硅醚、三苯基甲基硅醚、乙酸酯、取代乙酸酯、特戊酸酯、苯甲酸酯、甲磺酸酯和对甲苯磺酸酯。
“离去基团”指可以被另一个官能团取代的官能团。这些离去基团是本领域公知的、实例包括卤化物(如氯化物、溴化物和碘化物)、甲磺酰基、对甲苯磺酰基和三氟甲磺酰基。优选的离去基团选自硝基苯氧基;N-羟基琥珀酰亚胺基(NHS);苯氧基;二硝基苯氧基;五氟苯氧基;四氟苯氧基;二氟苯氧基;一氟苯氧基;五氯苯氧基;三氟甲磺酰基;咪唑基;氯酚基;四氯苯氧基;1-羟基苯并三唑基;甲苯磺酰基;甲磺酰基;2-乙基-5-苯基异恶唑-3’-磺酰基,酸酐或与其它酸酐作用形成的酸酐,例如乙酸酐、甲酸酐;或与多肽缩合试剂、Mitsunobu反应试剂作用生成的中间体。
以下缩写为本发明所采用,其定义为:Boc,叔丁氧基羰基;BroP,溴代十四烷基鏻六氟磷酸盐;CDI,1,1’-羰基二咪唑;DCC,二环己基碳二亚胺;DCE,二氯乙烷;二氯甲烷,二氯甲烷;DEAD,偶氮二甲酸二乙酯;DIAD,偶氮二甲酸二异丙基酯;DIBAL-H,二异丁基氢化铝;DIPEA或DEA,二异丙基乙胺;DEPC,二乙基氰基磷酸酯;DMA,N,N-二甲基乙酰胺;DMAP,4-(N,N-二甲基氨基)吡啶;DMF,N,N-二甲基甲酰胺;DMSO,二甲基亚砜;DTPA,二亚乙基三胺五乙酸;DTT,二硫苏糖醇;EDC,1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐;ESI-MS,电喷雾质谱;乙酸乙酯,乙酸乙酯;Fmoc,N-(9-芴基甲氧基羰基);HATU,O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐;HOBt,1-羟基苯并三唑;HPLC,高效液相色谱;NHS,N-羟基琥珀酰亚胺;MeCN,乙腈;MeOH,甲醇;MMP,4-甲基吗啉;PAB,对氨基苯甲酸;PBS,磷酸盐缓冲液(pH 7.0-7.5);Ph,苯基;Phe,L-苯丙氨酸;PyBrop,溴-三-吡咯烷-鏻六氟磷酸盐;PEG,聚乙二醇;SEC,尺寸排阻色谱;TCEP,三(2-羧乙基)膦;TFA,三氟乙酸;四氢呋喃,四氢呋喃;Val,缬氨酸;TLC,薄层色谱;UV是紫外线。
“氨基酸”可以是天然或非天然的,优选α-氨基酸。天然氨基酸可以由遗传密码所编码,它们是丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酸、谷氨酰胺、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、蛋氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、酪氨酸、色氨酸和缬氨酸。非天然氨基酸是蛋白质氨基酸的衍生物,包括羟脯氨酸、羊毛硫氨酸、2-氨基异丁酸、脱氢丙氨酸、γ-氨基丁酸(神经递质)、鸟氨酸、瓜氨酸、β-丙氨酸(3-氨基丙酸)、γ-羧基谷氨酸、硒代半胱氨酸(存在于许多非真核以及大多数真核细胞中、但不是由DNA直接进行编码)、吡咯赖氨酸(仅在一些古细菌和一种细菌中发现)、N-甲酰基甲硫氨酸(通常是细菌、线粒体和叶绿体中蛋白质中最初的氨基酸)、5-羟色氨酸、L-二羟基苯丙氨酸、三碘甲腺原氨酸、L-3,4-二羟基苯丙氨酸(DOPA)和O-磷酸丝氨酸。术语“氨基酸”还包括氨基酸同系物和模拟物。同系物是具有与天然氨基酸相同结构通式H2N(R)CHCO2H的化合物,其中R在天然氨基酸里。同系物的实例包括高丝氨酸、正亮氨酸、甲硫氨酸-亚砜和甲硫氨酸甲基锍。更优的是氨基酸模拟物,它是具有与α-氨基酸的化学结构不同、但是作用方式类似的化合物。天然氨基酸多为“L”立体化学构型,“非天然氨基酸”也用于代表“D”构型的氨基酸。在本专利申请中使用1至8个氨基酸时、其序列优选为蛋白水解酶可识别的序列。许多水解酶识别序列是本领域已知的,可以参见:Matayoshi等.Science 247:954(1990);Dunn等.Meth.Enzymol.241:254(1994);Seidah等.Meth.Enzymol.244:175(1994);Thornberry,Meth.Enzymol.244:615(1994);Weber等.Meth.Enzymol.244:595(1994);Smith等.Meth.Enzymol.244:412(1994);及Bouvier等.Meth.Enzymol.248:614(1995);此处引作参考。特别是选自以下序列:Val-Cit、Ala-Val、Ala-Ala、Val-Val、Val-Ala-Val、Lys-Lys、Ala-Asn-Val、Val-Leu-Lys、Cit-Cit、Val-Lys、Ala-Ala-Asn、Asp-Lys、Asp-Glu、Glu-Lys、Lys、Cit、Ser及Glu。
“糖苷”是糖通过糖苷键在其异头碳上与另一基团键合得到的分子。糖苷可以通过O-(产生O-糖苷)、N-(产生糖基胺)、S-(产生硫代糖苷)或C-(产生C-糖苷)糖苷键连接,其实验式为Cm(水)n(其中m可以不同于n、m、n<36),本发明中的糖苷包括葡萄糖(右旋糖)、果糖(左旋糖)、阿洛糖、阿卓糖、甘露糖、古洛糖、艾杜糖、半乳糖、塔罗糖、半乳糖胺、氨基葡萄糖、唾液酸、N-乙酰氨基葡萄糖、磺基奎诺糖(6-脱氧-6-磺基-D-吡喃葡萄糖)、核糖、阿拉伯糖、木糖、来苏糖、山梨糖醇、甘露醇、蔗糖、乳糖、麦芽糖、海藻糖、麦芽糖糊精、棉子糖、葡萄糖醛酸(葡糖苷酸)和水苏糖。它可以是D或L的构型、5原子环状呋喃糖的形式、6原子环状吡喃糖的形式,或是非环形式、α-异构体(异头碳的-OH在Haworth投影碳原子平面之下)、或β-异构体(异头碳的-OH在Haworth投影碳原子平面之上)。本发明中亦称为单糖、二糖、多元醇或含3-6个糖单元的低聚糖。
“药学上”或“药学上可接受的”是指当分子实体和组合物酌情施用于动物或人时,不会产生不利、过敏或其他不良反应。
“药学上可接受的溶剂化物”或“溶剂化物”是指一种或多种溶剂分子与本发明公开的化合物的结合物。形成药学上可接受的溶剂合物,溶剂的实例包括但不限于水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。
“药学上可接受的赋形剂”包括任何载体、稀释剂、佐剂或其它,例如防腐剂或抗氧化剂、填充剂、崩解剂、润湿剂、乳化剂、悬浮剂、溶剂、分散介质、包衣剂、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。这些介质和药剂用于药物活性物质在本领域内是熟知的。任何传统介质或药剂,除非与活性成分不兼容,也可以考虑将其用于治疗组合物中。补充活性成分也可以加入组合物中,成为合适的治疗组合。
如本文所用,“药用盐”是指所公开化合物的衍生物,通过制备母体化合物的酸盐或碱盐来获得。药学上可接受的盐包括由无毒无机酸或有机酸与母体化合物形成的常规无毒盐或季铵盐。例如,所述常规无毒盐包括衍生自无机酸(例如盐酸、氢溴酸盐、硫酸、氨基磺酸、磷酸、硝酸等)的盐;以及由有机酸(例如乙酸、丙酸、琥珀酸、酒石酸、柠檬酸、甲磺酸、苯磺酸、葡萄糖醛酸、谷氨酸、苯甲酸、水杨酸、甲苯磺酸、草酸、富马酸、马来酸及乳酸等制备的盐。另外的加成盐包括铵盐,如三甲胺、葡甲胺、丙三醇等的盐、金属盐、如钠、钾、钙、锌或镁盐。
本发明的药用盐可由含有碱性或酸性部分的母体化合物,通过常规化学方法合成。通常而言,这些盐可以通过在水或有机溶剂中或两者的混合物中,向母体化合物里,加入等当量的适当碱或酸来制备。一般来说,乙醚、乙酸乙酯、乙醇、异丙醇或乙腈是非水介质的首选。适用盐的列表见于1985年由麦克出版公司出版的《雷明顿药物科学》(Remington’sPharmaceutical Sciences),其公开内容纳入本文作参考。
“施用”或“给药”是指以任何方式向受试者转移、递送、引入或运输药物或其他药剂。这些方式包括口服用药、局部接触、静脉内、腹膜内、肌肉内、病灶内、鼻内、皮下或鞘内给药。本发明还考虑使用装置或器械来施用药剂。这种装置可以使用主动或被动型传输,而且可以是缓释或快速释放递送装置。
本文公开的新型偶联物使用了连接体,一些连接体及其合成的实施例显示在图1至34中。
连接体
图1-20显示了连接体的合成路线以及本发明申请中的细胞结合分子-药物偶联物的制备方法。连接体包含两个元素:a)取代基,一个或两个以上取代的丙烯酰基团或丙炔酰基团,可以与一对巯基反应形成共价硫醚键,和b)一个能够与一种药物发生反应的基团,例如,但不限于二硫化物,马来酰亚胺,卤代乙酰基,醛,酮,叠氮化物,胺,烷氧基胺,酰肼,乙烯磺酰基,酰基卤(酰卤),丙烯酰基和/或酸酐基团。连接体上的取代的丙烯酰基团或丙炔酰与胺,醇或巯基反应生成酰胺,酯或硫酯键。这些桥接连接体的合成及在抗体偶联物上的应用示例于图1-20中。
优选地,桥接连接体是下列式(I)和(II)的化合物:
Lv1和Lv2表示相同或不同的,可被巯基取代的离去基团。这些离去基团包括,但不限于卤化物(例如氟化物,氯化物,溴化物和碘化物),甲磺酰基(mesyl),甲苯磺酰基(tosyl),三氟甲基磺酰基(triflate),硝基苯氧基,N-琥珀酰亚胺基氧基(NHS),苯氧基;二硝基苯氧基;五氟苯氧基,四氟苯氧基,三氟苯氧基,二氟苯氧基,单氟苯氧基,五氯苯氧基,1H-咪唑-1-基,氯苯氧基,二氯苯氧基,三氯苯氧基,四氯苯氧基,N-(苯并三唑基)氧基,2-乙基-5-苯基异恶唑-3’-磺酰基,苯基恶二唑-磺酰基(-sulfone-ODA),2-乙基-5-苯基异恶唑-基,苯基恶二唑基(ODA),恶二唑基,或者与Mitsunobu反应缩合试剂作用产生的中间体。
Y是能够与细胞毒性药物反应形成二硫化物,醚,酯,硫醚,硫酯,肽,腙,氨基甲酸酯,碳酸酯,胺(二级,三级或四级),亚胺,环杂烷基,杂芳基,烷基肟或酰胺键的官能团;优选地,Y具有以下结构:
其中X1’为F,Cl,Br,I或Lv3;X2’是O,NH,N(R1)或CH2;R3和R5独立地为H,R1,芳基,杂芳基或芳香基团,其中一个或几个H原子被-R1,-卤素,-OR1,-SR1,-NR1R2,-NO2,-S(O)R1,-S(O)2R1,或-COOR1取代;Lv3是下列离去基团:硝基苯氧基,N-琥珀酰亚胺基氧基(NHS),苯氧基;二硝基苯氧基;五氟苯氧基,四氟苯氧基,二氟苯氧基,单氟苯氧基,五氯苯氧基,三氟甲基磺酰基,咪唑基,二氯苯氧基,四氯苯氧基,1-羟基苯并三唑基,甲苯磺酸基,甲磺酸基,2-乙基-5-苯基异恶唑-3’-磺酸基,自身形成,或与其它酸酐形成的酸酐,例如乙酸酐,甲酸酐,或与多肽缩合试剂作用产生的或Mitsunobu反应的中间体。
R1可以缺省,或者可以选自C1-C8(1-8个碳原子)烷基;C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或含2-8个碳原子的酯,醚或酰胺;或含有1-8个氨基酸的肽;或具有式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p是0至约1000的整数,或其上述基团的组合。
另外,R1是包含C,N,O,S,Si,和P原子的链状结构,最优含0~500个原子,共价连接于Y和L1。R1中的各个原子以所有可能的化学方式结合,比如形成烷基、亚烷基、亚烯基、亚炔基、醚、聚氧烷基、酯、胺、亚胺、聚胺、肼、腙、酰胺、脲、氨基脲、卡巴肼、烷氧胺、聚氨酯、氨基酸、多肽、酰氧胺、异羟肟酸,或这些基团的组合。
T为CH2,NH,NHNH,N(R3),N(R3)N(R3’),O,S,C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;含有1~4氨基酸单位的肽,优选自天冬氨酸,谷氨酸,精氨酸,组氨酸,赖氨酸,丝氨酸,苏氨酸,天冬酰胺,谷氨酰胺,半胱氨酸,硒代半胱氨酸,酪氨酸,苯丙氨酸,甘氨酸,脯氨酸,色氨酸,丙氨酸;或以下结构之一:
X1,X2,X3,X4,X5,X6,X1’,X2’和X3’独立地选自NHNH;N(R3);N(R3)N(R3’);O;S;C1-C6烷基;C2-C6杂烷基,烷基环烷基,杂环烷基的;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或1~8个氨基酸;其中R3和R3’独立地为H;C1-C8烷基;C2-8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或含1-8个碳原子的酯,醚或酰胺;或具有式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p是0至约1000的整数,或其上述基团的组合。
m1,m2,m3,m4和m5是独立的选自1到10的整数,优选1到4。
L1或L2可以含有自我毁灭或非自我毁灭的组分、肽单元、腙键、二硫化物、酯、肟、酰胺或硫醚键。自我毁灭单元包括但不限于,与对氨基芐基氨甲酰基(PAB)的电子结构相似的芳香化合物,例如2-氨基咪唑-5-甲醇的衍生物、杂环PAB同系物、β-葡糖苷酸、以及邻或对氨基芐基缩醛。
优选的自我毁灭型连接体单元具有以下结构之一:
其中,*标记的是额外的间隔体或可释放的连接体、或细胞毒性剂、和/或结合分子(CBA)的连接点;X1、Y1、Z2和Z3独立地为NH、O或S;Z1为H、NHR1、OR1、SR1、COX1R1,其中X1和R1如前文所定义;v为0或1;U1为H、OH、C1-C6烷基、(OCH2CH2)n、F、Cl、Br、I、OR5、SR5、NR5R5’、N=NR5、N=R5、NO2、SOR5R5’、SO2R5、SO3R5、OSO3R5、PR5R5’、POR5R5’、PO2R5R5’、OPO(OR5)(OR5’)或OCH2PO(OR5(OR5’),其中R5和R5’独立地选自H、C1-C8烷基;C2-C8烯基、炔基、杂烷基或氨基酸;C3-C8芳基、杂环、碳环、环烷基、杂环烷基、杂芳烷基、烷基羰基或糖苷;或药学上的阳离子盐。
非自我毁灭的组分具有以下结构之一:
其中,*标记的是额外的间隔体或可释放的连接体、或细胞毒性剂、和/或结合分子的连接点;X1、Y1、U1、R5、R5’如前文所定义;r为0-100;m和n独立地为0-6;
更优选地,L1或L2可以由下列一个或多个连接体单元组成:
6-马来酰亚胺己酰基(MC),马来酰亚胺丙酰基(MP),/>缬氨酸-瓜氨酸(val-cit),/>丙氨酸-苯丙氨酸(ala-phe),/>赖氨酸-苯丙氨酸(lys-phe),/>对氨基苄氧酰基(PAB),
4-硫代戊酰基(SPP),/>4-硫代丁酰基(SPDB),4-(N-马来酰亚胺甲基)环己烷-1-酰基(MCC),马来酰亚胺乙基(ME),/>4-硫代-2-羟基磺酰基-丁酰基(2-Sulfo-SPDB),/>芳基巯基(PySS),/>(4-乙酰基)氨基苯甲酰基(SIAB),/>氧苄硫基,/>氨基苄硫基,/>二氧苄硫基,/>二氨基苄硫基,氨氧基苄硫基,/>烷氧基氨基(AOA),/>亚乙基氧基(EO),/>4-甲基-4-硫代-戊酰基(MPDP),/>三唑,二硫,/>烷基磺酰基,/>烷基磺酰胺基,/>砜二磺胺基,/>膦二酰胺,/>烷基膦酰胺,/>膦酸,N-甲基烷基膦酰胺,/>N,N’-二甲基磷二酰胺,/>烷基膦二酰胺,/>肼,/>乙脒;/>肟,/>二乙酰肼,/>氨基乙基胺,/>氨基乙基-氨基乙基胺,和L-或D-,含有1-20个氨基酸的天然或非天然肽。
更为优选的是,L1或L2是可释放的连接体单元。术语“可释放的”是指连接体上包含至少一个可在生理条件下被破坏的键,例如pH、酸、碱、氧化作用、代谢、生化或酶不稳定的键。应当理解,导致键断裂不一定是生物或代谢过程、而可能是一个标准化学反应、例如水解或取代反应,这种生理条件的例子有:pH值比细胞浆内pH低的内涵体,恶性细胞内存在的毫摩尔浓度的大量谷胱甘肽,它能够与细胞内硫醇发生二硫键交换反应。
可释放连接体(L,L1或L2)的实例,包括但不限于:-(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t-,-(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t-,-(Aa)r-(CR5R6)m(CR7R8)n(OCH2CH2)t-,-(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t-,-(CR5R6)m-(CR7=CR8)(CR9R10)n(Aa)t(OCH2CH2)r-,-(CR5R6)m(NR11CO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r-,-(CR5R6)m(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-,-(CR5R6)m(CO)(Aa)t-(CR9R10)n(OCH2CH2)r-,-(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-,-(CR5R6)m-(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-,-(CR5R6)m(CO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-(CR5R6)m-苯基-CO(Aa)t(CR7R8)n-,-(CR5R6)m-呋喃-CO(Aa)t(CR7R8)n-,-(CR5R6)m-恶唑-CO(Aa)t(CR7R8)n-,-(CR5R6)m-噻唑基-CO(Aa)t(CCR7R8)n-,-(CR5R6)t-噻吩-CO(CR7R8)n-,-(CR5R6)t-咪唑-CO-(CR7R8)n-,-(CR5R6)t-吗啉-CO(Aa)t-(CR7R8)n-,-(CR5R6)t哌嗪-CO(Aa)t-(CR7R8)n-,-(CR5R6)t-N-甲基哌嗪-CO(Aa)t-(CR7R8)n-,-(CR5R)m-(Aa)t苯基-,-(CR5R6)m-(Aa)t呋喃-,-(CR5R6)m-恶唑(Aa)t-,-(CR5R6)m-噻唑基(Aa)t-,-(CR5R6)m-噻吩-(Aa)t-,-(CR5R6)m-咪唑(Aa)t-,-(CR5R6)m-吗啉-(Aa)t-,-(CR5R6)m-哌嗪-(Aa)t-,-(CR5R6)m-N-甲基哌嗪-(Aa)t-,-K(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t-,-K(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t-,-K(Aa)r-(CR5R6)m(CR7R8)n(OCH2CH2)t-,-K(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t-,-K(CR5R6)m-(CR7=CR8)(CR9R10)n(Aa)t(OCH2CH2)r-,-K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m(CO)(Aa)t-(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m-(OCO)(Aa)t(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-,-K-(CR5R6)m(CO)(Aa)t(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m-苯基-CO(Aa)t(CR7R8)n-,-K-(CR5R6)m-呋喃-CO(Aa)t-(CR7R8)n-,-K(CR5R6)m-恶唑-CO(Aa)t(CR7R8)n-,-K(CR5R6)m-噻唑基-CO(Aa)t-(CR7R8)n-,-K(CR5R6)t-噻吩-CO(CR7R8)n-,-K(CR5R6)t咪唑-CO-(CR7R8)n-,-K(CR5R6)t吗啉-CO(Aa)t(CR7R8)n-,-K(CR5R6)t哌嗪-CO(Aa)t-(CR7R8)n-,-K(CR5R6)t-N-甲基哌嗪CO(Aa)t(CR7R8)n-,-K(CR5R)m(Aa)t苯基,-K-(CR5R6)m-(Aa)t呋喃-,-K(CR5R6)m-恶唑(Aa)t-,-K(CR5R6)m-噻唑基(Aa)t-,-K(CR5R6)m-噻吩-(Aa)t-,-K(CR5R6)m-咪唑(Aa)t-,-K(CR5R6)m-吗啉(Aa)t-,-K(CR5R6)m-哌嗪-(Aa)tG,-K(CR5R6)mN-甲基哌嗪(Aa)t-;其中m,Aa,m,n,R3,R4,和R5已如上所定义;t和r独立地为0-100;R6,R7和R8独立地选自H,卤素,C1-C8烷基、芳基、烯基、炔基、醚、酯、胺或酰胺,这些基团均可以被以下成分所取代:一个或多个卤素、CN、NR1R2、CF3、OR1、芳基、杂环、S(O)R1、SO2R1、-CO2H、-SO3H、-OR1、-CO2R1、-CONR1、-PO2R1R2、-PO3H或P(O)R1R2R3;K是NR1、-SS-、-C(=O)-、-C(=O)NH-、-C(=O)O-、-C=NH-O-、-C=N-NH-、-C(=O)NH-NH-、O、S、Se、B、C3-C8的杂环或杂芳环,或含有1-20个氨基酸的肽。
另外,L1,L2,X1,X2,X3,X1’,X2’和X3’可以独立地缺省。
在式(I)或(II)中,取代的丙烯酰基团或丙炔酰基团能够与巯基反应,优选与细胞结合剂上的一对巯基反应;该优选的巯基是通过还原细胞结合剂链间二硫键所得,还原剂如二硫苏糖醇(DTT),二硫赤藓糖醇(DTE),L-谷胱甘肽(GSH),三(2-羧乙基)膦(TCEP),2-巯基乙胺(β-MEA),和/或β巯基乙醇(β-ME,2-ME)。
能够连接药物或细胞毒性剂的官能团Y的实例,包括能够产生二硫化物,硫醚,硫酯,肽,腙,酯,氨基甲酸酯,碳酸酯,烷氧肟或酰胺键连接的基团。这些官能团包括但不限于巯基,二硫化物,氨基,羧基,醛,酮,马来酰亚胺基,卤代乙酰基,肼,烷氧基氨基和/或羟基。
能够与药物/细胞毒性剂的末端胺反应的官能团Y的实例,包括但不限于N-羟基琥珀酰亚胺酯,对硝基苯酯,二硝基苯酯,五氟苯酯,酰氯或羧酸酐;能与末端巯基反应的官能团,包括但不限于,吡啶基二硫化物,硝基吡啶基二硫化物,马来酰亚胺,卤代乙酸酯,甲基砜苯基恶二唑(ODA),酰氯和羧酸酐;能与末端酮或醛反应的官能团,包括但不限于,胺,烷氧基胺,肼,酰氧基胺或酰肼;能与末端叠氮反应的官能团,包括但不限于炔烃。
在优选的实施例中,R1,L1,或L2独立地为含1-6个碳原子的直链烷基,或如式(OCH2CH2)p的聚乙烯氧基单元,p=1~100,或含有1~4个氨基酸的肽(L或D构型),或以上组合。
在优选的实施例中,Lv1和Lv2相同或独立地为OH,F,Cl,Br,I,硝基苯氧基,N-羟基琥珀酰亚胺(NHS)基,苯氧基,二硝基苯氧基,五氟苯氧基,四氟苯氧基,二氟苯氧基,单氟苯氧基,五氯苯氧基,三氟甲磺酰基,咪唑,二氯苯氧基,四氯苯氧基,1-羟基苯并三唑,甲苯磺酰基,甲磺酰基,2-乙基-5-苯基异恶唑-3’-磺酰基,或多肽缩合反应中间体或Mitsunobu反应中间体;缩合剂的例子包括:1-乙基-(3-二甲基氨基丙基)碳二亚胺(EDC)、二环己基碳二亚胺(DCC)、N,N’-二异丙基碳二亚胺(DIC)、N-环己基-N’-(2-吗啉代-乙基)碳二亚胺甲基对甲苯磺酸盐(CMC或CME-CDI)、1,1’-羰基二咪唑(CDI)、氧-(苯并三唑-1-)基)-N,N,N’,N’-四甲基脲四氟硼酸盐(TBTU)、N,N,N’,N’-四甲基-氧-(1H-苯并三唑-1-基)-六氟磷酸铵(HBTU)、(苯并三唑-1-基氧基)三(二甲基氨基)-六氟磷酸盐(BOP)、(苯并三唑-1-基氧基)三吡咯烷基六氟磷酸盐(PyBOP)、氰基膦酸二乙酯(DEPC)、氯-N,N,N’,N’-四甲基甲脒六氟磷酸盐、1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶3-氧六氟磷酸盐(HATU)、1-[(二甲氨基)(吗啉代)亚甲基]-1H-[1,2,3]三唑并[4,5-b]吡啶-1-鎓3-氧六氟磷酸盐(HDMA)、2-氯-1,3-二甲基-咪唑六氟磷酸盐(CIP)、六氟磷酸氯代吡咯烷酮鎓(PyCloP)、氟-N,N,N’,N’-双(四亚甲基)甲脒六氟磷酸盐(BTFFH)、N,N,N’,N’-四甲基-S-(1-氧代-2-吡啶基)硫脲六氟磷酸盐、氧-(2-氧代-1(2H)吡啶基)-N,N,N’,N’-四甲基脲四氟硼酸盐(TPTU)、S-(1-氧代-2-吡啶基)N,N,N’,N’-四甲基硫脲四氟硼酸盐、氧-[(乙氧基羰基)-氰基甲基氨基]-N,N,N’,N’-六氟磷酸四甲基脲(HOTU)、(1-氰基-2-乙氧基-2-氧代乙基氨基氧基)二甲氨基-吗啉代-六氟磷酸盐(COMU)、氧-(苯并三唑-1-基)-N,N,N’,N’-双(四亚甲基)六氟磷酸盐(HBPyU)、N-芐基-N’-环己基-碳二亚胺(有或没有聚合物结合)、二吡咯烷基(N-琥珀酰亚胺基氧基)碳鎓六氟磷酸盐(HSPyU)、氯二吡咯烷基六氟磷酸盐(PyClU)、2-氯-1,3-二甲基咪唑四氟硼酸盐(CIB)、(苯并三唑-1-基氧基)二呱啶碳六氟磷酸盐(HBPipU)、氧-(6-氯苯并三唑-1-基)-N,N,N’,N’-四甲基脲四氟硼酸盐(TCTU)、溴代(二甲基氨基)-六氟磷酸盐(BroP)、丙基膦酸酐(PPACA、 )、2-吗啉代乙基异氰化物(MEI)、N,N,N’,N’-四甲基-氧-(N-琥珀酰亚胺基)六氟磷酸盐(HSTU)、2-溴-1-乙基-吡啶鎓四氟硼酸盐(BEP)、氧-[(乙氧基羰基)氰基-亚甲基氨基]-N,N,N’,N’-四甲基脲四氟硼酸盐(TOTU)、4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉氯化物(MMTM、DMTMM)、N,N,N’,N’-四甲基-氧-(N-琥珀酰亚胺基)脲四氟硼酸(TSTU)、氧-(3,4-二氢-4-氧代-1,2,3-苯并三嗪-3-基)-N,N,N’,N’-四甲基脲四氟硼酸盐(TDBTU)、1,1’-(偶氮二羰基)-二呱啶(ADD)、二-(4-氯芐基)偶氮二羧酸酯(DCAD)、偶氮二羧酸二叔丁酯(DBAD)、偶氮二羧酸二异丙酯(DIAD)、偶氮二羧酸二乙酯(DEAD)。另外,Lv1和Lv2可以是酸酐,由酸本身形成或与其它C1-C8酸酐形成。
在优选的实施例中,式(I)或(II)具有以下结构:
连接体合成的详细实例如图1~33所示。通常丙炔酰基、取代的丙烯酰基或二取代的丙酰基上的取代基,可以与其它连接体单元反应,该组分含有能够与药物反应的官能团。
细胞结合剂-药物偶联物
本发明的偶联物可由式(III),(IV),(V),(VI),(VII),(VIII)或(IX)表示:
其中:
n是1~20;T与之前式(I)中描述的相同。
Cb,Cb’,Cb”,Cb”’表示相同或不同的细胞结合剂或免疫治疗蛋白,优选为抗体或抗体片段。
式(III),(VII),(VIII)和(IX)的右括号(方括号)内是与细胞结合剂/分子的巯基对偶联的连接体-药物组分。巯基优选为细胞结合剂的链间二硫键被还原剂还原而产生,还原剂选自二硫苏糖醇(DTT)、二硫季戊四醇(DTE)、L-谷胱甘肽(GSH)、三(2-羧基乙基)膦(TCEP)、2-巯基乙胺(β-MEA)或/和β-巯基乙醇(β-ME,2-ME)。
Drug,Drug’,和Drug”表示相同或不同的细胞毒性剂,或治疗药物,或免疫治疗蛋白质,或用于增强细胞结合剂的结合或稳定的功能分子,或者细胞表面受体结合配体,其应用本专利申请的桥接剂,经由R1与细胞结合剂连接,R1含有C1-C8烷基;C2-C8亚烷基,亚烯基,亚炔基,芳基,醚,聚氧亚烷基,酯,胺,亚胺,多胺,肼,腙,酰胺,脲,氨基脲,卡巴肼,烷氧基胺,氨基甲酸,氨基酸,肽,酰氧基胺,异羟肟酸,二硫化物,硫醚,硫酯,氨基甲酸酯,碳酸酯,杂环,杂烷基,杂芳基,烷氧基或上述基团组合。
Drug,Drug’,和Drug”还可以是细胞毒性分子,免疫治疗化合物,化学治疗化合物,抗体或抗体片段,siRNA或DNA分子,或细胞表面结合配体。
方括号内是通过细胞结合分子上的一对硫原子与细胞结合分子偶联的试剂。
m1,m1’,m1”,m2,m2’,m2”,m3,m4,m5,m4’,m5’,m4”,m5”,m4”’,m5”’,m4””和m5””独立地是1到10的整数,优选1到4的整数。
X1,X1’,X1”,X1”’和X2””独立地选自NH;NHNH;N(R3);N(R3)N(R3’);O;S;C1-C6烷基;C2-C6杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或1~8个氨基酸;其中R3和R3’独立地为H;C1-C8烷基;C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基、杂芳基;1-8个碳原子的酯、醚或酰胺;或如式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p为从0到1000的整数;或以上的组合。此外,X1,X1’,X1”,X1”’和X2””可以独立地缺省。
R1,R1’,和R1”相同或不同,选自C1-C8烷基;C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基、杂芳基;2-8个碳原子的酯、醚或酰胺;或如式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p为从0到1000的整数;或以上的组合。
L1,L1’,L1”,L1”’,L2,L2’,L2”和L2”’的定义与式(I)和(II)中的L1和L2相同,它们也可以各不相同。
L1,L1’,L1”,L1”’,L2,L2’,L2”和L2”’可以由一个或者多个连接体单元组成。示例的连接体单元包括6-马来酰亚胺基己酰基(“MC”),马来酰亚胺丙酰基(“MP”),缬氨酸-瓜氨酸(“val-cit”或“vc”),丙氨酸-苯丙氨酸(“ala-phe”或“af”),对氨基苄氧基酰基(“PAB”),4-硫代戊酰基(“SPP”),4-(N-马来酰亚胺甲基)环己烷-1酰基(“MCC”),(4-乙酰基)氨基-苯酰基(“SIAB”),4-硫代丁酰基(“SPDB”),4-硫代-2-羟基磺酰基-丁酰基(“2-磺基-SPDB”),作为一个或多个重复乙烯氧基-CH2C水-单元(“EO”或“PEO”)。其它的连接体单元是本领域公知的,部分示例如下:
包含连接体单元的结构例子:
(ME,含马来酰亚胺基),/>(含缬氨酸瓜氨酸),/>(MCC,含有4-(N-马来酰亚胺基甲基)环己烷-1-酰基),含((4-乙酰基)氨基苯甲酰基)/>(4-硫代-2-羟基磺酰基丁酰基,2-sulfo-SPDB),/>4-硫代戊酰基(SPP),4-硫代丁酰基(SPDB),/>4-(N-马来酰亚胺甲基)环己烷-1-酰基(MCC),/>马来酰亚胺乙基(ME),/>4-硫代-2-羟基磺酰基-丁酰基(2-Sulfo-SPDB),/>芳基巯基(PySS),(4-乙酰基)氨基苯甲酰基(SIAB),/>氧苄硫基,氨基苄硫基,/>二氧苄硫基,二氨基苄硫基,/>氨氧基苄硫基,烷氧基氨基(AOA),/>亚乙基氧基(EO),/>4-甲基-4-硫代-戊酰基(MPDP),/>三唑,/>二硫,/>烷基磺酰基,/>烷基磺酰胺基,/>砜二磺胺基,/>膦二酰胺基,烷基膦酰胺基,/>膦酸基,/>N-甲基烷基膦酰胺基,/>N,N’-二甲基磷二酰胺基,/>烷基膦二酰胺基,肼基,/>乙脒基;/>肟基,/>二乙酰肼基,/>氨基乙基胺基,/>氨基乙基-氨基乙基胺基。
见下文更详细的描述,Drug,Drug’和Drug”可以是任何小分子药物,包括但不限于,tubulysin,卡奇霉素、澳瑞他汀,美登素,CC-1065同系物,吗啉代,阿霉素,紫杉烷类,隐藻菌素,鹅膏毒肽(鹅膏毒环肽),埃博霉素,布林,格尔德霉素,多卡霉素,道诺霉素,甲氨蝶呤,长春地辛,长春新碱和苯并二氮卓系列二聚体(例如,吡咯苯并二氮卓(PBD)或托马霉素,吲哚苯并二氮卓,咪唑苯并二氮卓或噁唑苯并二氮卓二聚体)。
通常,式(III),(IV),(V)(VI),(VII),(VIII)和(IX)中的偶联物由式(I)和(II)中的化合物制备,其中“Drug”和“Cb”与式(I)和(II)中的化合物分别或同时反应。当两个以上的巯基和取代的丙烯酰基团或丙炔酰基团加成反应,形成式(III),(IV),(V)或(VI)中的偶联物时,需要使用波长范围为190-390nm的紫外光以辅助反应,优选使用340-380nm,更优选365nm。光化学反应在石英或Pyrex烧瓶或在控温的含有UV灯的浸入式井反应器中进行,优选在连续流的石英管中或Pyrex管中进行,其UV辐射最大且同时可以有效冷却,降低了细胞结合分子因热产生的不稳定。在式(VII)(VIII)或(IX)中偶联物的形成过程中,当两个以上的巯基与式(I)和(II)中两个或更多个取代的丙烯酰基团或丙炔酰基团反应时,可不使用UV光。
合成偶联物时,首先使药物或细胞毒性分子在化学溶剂或水性介质中与式(I)或(II)的连接体反应,生成式(XVII)或(XVIII)。(XVII)或(XVIII)可以被分离,也可以立即或同时或依次地在25-38℃,pH 5~9水性介质中,与细胞结合分子上还原二硫键产生的一对游离巯基反应,反应介质中可添加或不添加0~30%可溶于水(混溶)的有机溶剂,例如DMA,DMF,乙醇,甲醇,丙酮,乙腈,四氢呋喃,异丙醇,二恶烷,丙二醇或乙二醇,生成(III),(IV),(V)或(VI),此时优选需要使用365nm的UV光辅助,或形成(VII),(VIII)或(IX),此时可不使用UV光。
或者,式(III),(IV),(V)(VI),(VII),(VIII)和(IX)中的偶联物也可以首先使式(I)或(II)中的连接体在0-38℃、pH5~9水介质中与细胞结合剂上的一对巯基反应,可加或不加0~30%可溶于水(混溶)的有机溶剂,在365nm的UV光照下,形成如式(X),(XI),(XII)或(XIII)的修饰的细胞结合分子,或可选的,无UV光照下,形成如式(XIV),(XV)或(XVI)的修饰的细胞结合分子。成对的巯基优选为使用还原剂将细胞结合剂的链间二硫键还原所产生,所述还原剂可以选自二硫苏糖醇(DTT),二硫赤藓糖醇(DTE),L-谷胱甘肽(GSH),三(2-羧乙基)膦(TCEP),2-巯基乙胺(β-MEA),或/和β巯基乙醇(β-ME,2-ME),反应在pH4~9水中进行,可加入或不加入0~30%的可溶于水(混溶)的有机溶剂。
式(X),(XI),(XII),(XIII),(XIV),(XV)or(XVI)中的反应性基团Y,可以是二硫化物,马来酰亚胺基,卤代乙酰基,叠氮化物,1-炔,酮,醛,烷氧基氨基,三氟甲磺酸酯,羰基咪唑,甲苯磺酸酯,甲磺酸酯,2-乙基-5-苯基异恶唑-3’-磺酸酯,或硝基苯酚,N-羟基琥珀酰亚胺(NHS),苯酚;二硝基苯酚,五氟苯酚,四氟苯酚,二氟苯酚,单氟苯酚,五氯苯酚,二氯苯酚,四氯苯酚和1-羟基苯并三唑的羧酸酯,酸酐或酰肼基团,或其它酸的衍生物,可以与药物/细胞毒性剂Drug,Drug’或Drug”同时或依次反应,反应在15-38℃,pH 4~9.5水性介质中进行,可加入或不加入另外的0~30%可溶于水(混溶)的有机溶剂,纯化后得到(III),(IV),(V)(VI),(VII),(VIII)和(IX)。
细胞毒性分子的反应基团可以与被修饰的细胞结合剂以不同的方式反应。例如,通过二硫键连接的细胞结合剂-药物偶联物的合成,是通过修饰的细胞结合剂中的二硫键和含有游离巯基的药物之间的二硫键交换来实现的;通过硫醚键结合的细胞结合子-药物偶联物的合成,是通过经马来酰亚胺基或卤乙酰基或乙基砜修饰的细胞结合剂和含游离巯基的药物反应来实现;合成分子内含酸不稳定的腙的偶联物,可由一个连接体中的酰肼基团和羰基反应来实现,其具体方法为本领域内公知(参考P.Hamann et al.,Hinman,L.M.,et al,Cancer Res.1993,53,3336-334;B.Laguzza et al.,J.Med.Chem.,1959,32;548-555;P.Trail et al.,Cancer Res.,1997,57;100-105);合成含三唑基团的偶联物可以通过一个连接体上的1-炔与含叠氮基团的药物以点击化学反应(偶极环加成)来实现(Lutz,J-F.et al,Adv.Drug Del.Rev.2008,60,958–970;Sletten,E.M.et alAcc.Chem.Research 2011,44,666–676);合成含肟偶联物可以通过含有酮或醛的修饰的细胞结合剂和含有氧胺基的药物的反应来实现。
包含巯基的药物可以和(X),(XI),(XII),(XIII),(XIV),(XV)或(XVI)中连接体上的马来酰亚胺、卤乙酰基或乙磺酰基,在pH 5.0-9.0的缓冲液中反应,生成硫醚键连接的共轭偶联物。含巯基的药物可以与(X),(XI),(XII),(XIII),(XIV),(XV)或(XVI)中连接体上的吡啶二硫片段进行二硫键交换,生成二硫键连接的共轭偶联物。含有羟基或巯基的药物可与(X),(XI),(XII),(XIII),(XIV),(XV)或(XVI)中连接体上的卤素,尤其是α卤代羧酸上的卤素,在弱碱条件下,如pH值8.0-9.5,反应得到醚或硫醚键连接的共轭偶联物。含羟基的药物,也可以在EDC或DCC的缩合剂的作用下,和式(I)或(II)中连接体上的羧基缩合成酯。经药物修饰的连接体再与细胞结合分子进行偶联。含有氨基的药物可以和(X),(XI),(XII),(XIII),(XIV),(XV)或(XVI)中连接体上的NHS、咪唑、硝基苯酚、N-羟基丁二酰亚胺、苯酚、二硝基苯酚、五氟苯酚、2,3,5,6-四氟苯酚、二氟苯酚、单氟苯酚、五氯苯酚、三氟甲烷磺酸、二氯苯酚、四氯苯酚、1-羟基苯并三唑、甲苯磺酸、甲磺酸、2-乙基-5-苯基异恶唑-3’-磺酸的羧酸酯反应,得到酰胺键连接的共轭偶联物。
偶联物可以通过标准的生化方法纯化,如用Sephadex G25或Sephacryl S300进行凝胶过滤、吸附层析、离子交换或透析。在某些情形,如小分子细胞结合剂(如叶酸、黑素细胞刺激素、EGF等)与小分子药物结合后,可以通过HPLC、中压柱层析或离子交换色谱等色谱法纯化。
优选的实施例中,(III),(IV),(V),(VI),(VII),(VIII)或(IX)为下列结构:
修饰的细胞结合剂/分子
与本发明中的连接体反应而得到的修饰的细胞结合剂由式(X),(XI),(XII),(XIII),(XIV),(XV)或(XVI)表示:
其中R1,R1’,R1”,R2,X1,X1’,X1”,L1,L1’,L1”,L2,L2’,L2”,Cb,m1,m1’,m1”,m2,m2’,m2”,m3,m4,m5,m4’,m5’,m4”,和m5”的定义与式(III)–(IX)中相同。
其中Y,Y’,和Y”的定义与式(I)和(II)中的Y相同。
在优选的实施例中,Y,Y’和Y”独立地是二硫化物,马来酰亚胺基,卤代乙酰基,烷氧基胺,叠氮基,酮,醛,肼,炔烃,N-羟基琥珀酰亚胺酯,或苯酚,二硝基苯酚,五氟苯酚,四氟苯酚,二氟苯酚,单氟苯酚,五氯苯酚,咪唑,氯酚,四氯苯酚,1-羟基苯并三唑形成的羧基酯;甲苯磺酸酯;甲磺酸酯;三氟甲磺酸酯;2-乙基-5-苯基异恶唑-3’-磺酸酯。Y,Y’和Y”可以独立地与细胞毒性剂反应,形成二硫化物,硫醚,腙,酰胺,烷氧基,氨基甲酸酯,酯,醚键或杂芳环。修饰的细胞结合剂可以通过细胞结合剂与式(I)或(II)的连接体的反应来制备。
为了实现结构式(I)或(II)中连接体上取代丙烯酰或丙炔酰与细胞结合剂,尤其是抗体中游离的一对巯基的高效连接,需要在反应体系中或反应完成后,加入少量有机共溶剂以使得式(III)~(IX)中的结构在水中良好溶解。在修饰细胞结合剂时,首先把结构式(I)或(II)中的交联剂(连接体)溶解在可以与水混溶的极性有机溶剂中,例如:各种醇如甲醇、乙醇和丙醇,丙酮,乙腈,四氢呋喃(THF),1,4-二氧六环,二甲基甲酰胺(DMF),二甲基乙酰胺(DMA)或二甲基亚砜(DMSO);溶液浓度略高,如1-500mM。同时将细胞结合剂,如抗体以1~35mg/mL的浓度溶解在pH 4~9.5,最好6~8.5的缓冲液中,与1~20当量的TCEP或者DTT反应20分钟到48小时。还原后,用SEC色谱柱纯化除去DTT,TCEP可以用SEC色谱柱纯化或者不纯化直接进入下一步。此外,用TCEP还原的抗体或其他细胞结合剂可以在结构式(I)或(II)的连接体存在的情形下进行,此时与细胞结合剂的共轭偶联就和TCEP还原同步进行。如前文所述,式(X),(XI),(XII)或(XIII)的修饰的细胞结合分子的合成需要340-380nm的UV光辅助。但是式(XIV),(XV)或(XVI)的修饰的细胞结合分子的合成可选不用UV光的辅助。
修饰细胞结合剂的反应一般在pH 4至9,优选6.0至7.5的缓冲液里进行,可以是该pH范围内的任何没有亲核性的缓冲盐体系。典型的缓冲液包括磷酸盐、三乙醇胺盐酸盐,HEPES,和MOPS缓冲液,可以包含其它成分,如环糊精,蔗糖和盐,如氯化钠和氯化钾。将结构式(I)或(II)中的连接体溶液加入到被还原的细胞结合剂溶液中,并在4至45℃,最好是15℃-室温孵育,并通过测量溶液在254nm吸光度的下降,或者在280nm吸光度的上升,或者其他合适的波长上吸光度的变化,来监测反应的进程。在反应完成后,可以按照常规方法纯化修饰的细胞结合剂,例如使用凝胶过滤层析或吸附色谱法。
通过测量反应产生的硝基吡啶硫酮、二硝基吡啶二硫酮、吡啶硫酮、甲酰胺吡啶二硫酮和二甲酰胺吡啶二硫酮基团的紫外吸光,可以确定细胞结合剂被修饰的程度。如果偶联物没有发色团,可以用LC-MS或者更优选的UPLC-QTOF质谱,或毛细管电泳质谱(CE-MS)来分析确定。本发明中的连接体上可以含有不同种类的官能团,与各种药物反应,尤其是具有合适的取代官能团的细胞毒性药物。例如,修饰后含氨基或羟基取代基的细胞结合剂能与含N-羟基琥珀酰亚胺(NHS)酯的药物反应,修饰后含巯基的细胞结合剂能与含马来酰亚胺基或卤素乙酰基的药物反应。此外,修改后含羰基(醛或酮基)的细胞结合剂能与含酰肼或烷氧基胺的药物反应。本领域的专业技术人员可以很容易地根据其官能团的反应活性来决定使用怎样的连接体。
修饰的细胞毒性药物
通过与本发明申请的交联连接体反应而得到的修饰的细胞毒性药物,由式(XVII)和(XVIII)表示,“Drug”已与式(I)和(II)中的连接体反应,其中仍然包含取代的丙烯酰基或丙炔酰基,能够与细胞结合剂中的一对巯基反应:
通过药物分子与结构式(I)或(II)中的连接体反应,得到具有结构(XVII)和(XVIII)的修饰的药物,其中含有取代的丙烯酰基或丙炔酰基。但是对于含有巯基的药物,或者通过含硫醚、硫酯或二硫键连接细胞结合分子的药物,药物Drug最好首先通过硫醚、硫酯或二硫键与R1连接,然后将合成的R1-Drug与取代的丙烯酰基或丙炔酰基组装,形成连接体修饰的药物(XVII)和(XVIII)。
例如,含巯基的药物可在中性pH的缓冲液中与R1上的马来酰亚胺反应,形成以硫醚键结合的R1-Drug,然后与连接有取代的丙烯酰基或丙炔酰基的组分缩合,形成如式(XVII)和(XVIII)中包含硫醚键的修饰药物。含羟基的药物,在弱碱条件下,可与含有卤素、对甲苯磺酸或甲磺酸酯的R1反应,得到以醚键结合R1-Drug,然后与连接有取代的丙烯酰基或丙炔酰基的组分缩合,形成如式(XVII)和(XVIII)中包含硫醚键的修饰药物。含有羟基的药物还可与结构(I)中带有羧基的连接体,在脱水剂如EDC或DCC作用下,缩合得到如结构式(XVII)和(XVIII)中含酯键的修饰药物。含巯基的药物可与R1上的马来酰亚胺、乙烯砜基或卤代乙酰基反应,生成以硫醚键结合的R1-Drug,然后与连接有取代的丙烯酰基或丙炔酰基的组分缩合,形成如式(XVII)和(XVIII)中包含硫醚键的修饰药物。类似地,含氨基的药物也可以与连接体(I)或(II)上的羧基进行缩合,得到如式(XVII)和(XVIII)中含酰胺键的修饰药物。修饰的药物可以用标准的方法纯化,如硅胶或氧化铝柱层析、重结晶、制备薄层色谱、离子交换色谱或高效液相色谱。
在优选的实施例中,式(XVII)或(XVIII)中的化合物具有以下结构:
其中Lv1和Lv2与式(I)中定义相同;L1,L2,L3,L4,L5,L6,L7和L8相同或不同,并且与式(I)中的L1的定义相同;Drug1,Drug2,Drug3,Drug4,Drug5,Drug6,Drug7和Drug8相同或不同,并且与式(II)中的Drug1的定义相同。
细胞结合剂
本发明中的细胞结合剂,包括偶联物内和被修饰的细胞结合剂,可以是目前已知的或即将公开的,能够与具有治疗意义或者被生物学修饰的细胞片段结合,复合或反应的任何种类分子。
细胞结合剂包括,但不仅限于大分子量蛋白质,例如完整抗体(多克隆抗体,单克隆抗体,二聚体,多聚体,多特异性抗体,例如双特异性抗体);单链抗体;抗体片段如Fab,Fab’,F(ab’)2,Fv(Parham,J.Immunol.1983,131,2895-2902);由Fab表达库产生的片段,抗独特型(抗-Id)抗体;CDR;双价抗体;三价抗体;四价抗体;微抗体;小分子免疫蛋白(SIP)和免疫特异性结合癌细胞抗原的上述任何抗体的表位结合片段;病毒抗原;微生物抗原或由免疫系统产生的蛋白质,能够识别、结合特定抗原或具有期望的生物学活性(Miller et alJ.of Immunology 2003,170,4854-4861);干扰素(如I,II,III型);多肽;淋巴因子如IL-2,IL-3,IL-4,IL-5,IL-6,IL-10,GM-CSF,干扰素-γ(IFN-γ);激素例如胰岛素,TRH(促甲状腺激素释放激素),MSH(促黑色素细胞激素),类固醇激素如雄激素和雌激素;生长因子和集落刺激因子,如表皮生长因子(EGF),粒细胞巨噬细胞集落刺激因子(GM-CSF),转化生长因子(TGF)如TGFα,TGFβ,胰岛素和胰岛素样生长因子(IGF-I,IGF-II),G-CSF,M-CSF和GM-CSF(Burgess,Immunology Today 1984,5,155-158);牛痘生长因子(VGF);成纤维细胞生长因子(FGF);小分子量的蛋白质;多肽;肽和肽激素,如铃蟾肽,胃泌素,胃泌素释放肽;血小板衍生的生长因子;白细胞介素和细胞因子,例如,白细胞介素-2(IL-2),白细胞介素-6(IL-6),白血病抑制因子,粒细胞巨噬细胞集落刺激因子(GM-CSF);维生素,如叶酸;脱辅基蛋白和糖蛋白,如转铁蛋白(O’Keefe et al,J.Biol.Chem.1985 260 932-937);糖结合蛋白或脂蛋白,如凝集素;细胞营养传递分子;小分子抑制剂,如前列腺特异性膜抗原(PSMA)抑制剂和小分子酪氨酸激酶抑制剂(TKI),非肽或任何其它细胞结合分子或物质,如生物活性聚合物(Dhar,et al,Proc.Natl.Acad.Sci.2008,105,17356-61),生物活性树枝状大分子(Lee,et al,Nat.Biotechnol.2005,23,1517-26;Almutairi,et al;Proc.Natl.Acad.Sci.2009,106,685-90),纳米粒子(Liong,et al,ACS Nano,2008,19,1309-12;Medarova,et al,Nat.Med.2007,13,372-7;Javier,et al,BioconjugateChem.2008,19,1309-12),脂质体(Medinai,et al,Curr.Phar.Des.2004,10,2981-9)和病毒外壳(Flenniken,et al,Viruses Nanotechnol.2009,327,71-93)。
一般而言,如果适当的单克隆抗体是可用的,则优选单克隆抗体作为细胞表面结合剂。抗体可以是鼠源,人源,人源化,嵌合或源于其他物种。
用于本发明中的抗体的生产包括体内或体外方法或其组合。生产多克隆抗受体肽抗体的方法在本领域是公知的,例如美国专利4,493,795中所述。通常是通过将骨髓瘤细胞,与已经用所需抗原免疫的小鼠的脾细胞融合,来制备单克隆抗体(G.;Milstein,C.Nature 1975,256:495-497)。详细的过程在“Antibodies--A Laboratory Manual,Harlow and Lane,eds.,Cold Spring Harbor Laboratory Press,New York(1988)”中有描述,此处引作参考。具体地,可以用目标抗原,如完整的靶细胞,从靶细胞分离的抗原,完整的病毒,灭活的全病毒和病毒蛋白质,免疫小鼠,大鼠,仓鼠或任何其它哺乳动物。通常使用聚乙二醇(PEG)6000将脾细胞与骨髓瘤细胞融合。通过对HAT(次黄嘌呤-氨基蝶呤-胸腺嘧啶)的敏感性来筛选融合细胞。通过它们免疫反应特异性受体的能力或抑制靶细胞上的受体活性的能力,可以确定实施本发明的单克隆抗体的杂交瘤。
用于本发明中的单克隆抗体的生产在单克隆杂交瘤培养物里进行,其中包含营养培养基和能分泌具有合适抗原特异性的抗体分子的杂交瘤。培养物在合适的条件下保持充足的一段时间,以使杂交瘤将抗体分子分泌到培养基。然后收集含有抗体的培养基。使用通过公知的技术进一步分离抗体分子,如蛋白质A亲和层析,阴离子、阳离子、疏水或体积排阻色谱法(特别是通过蛋白质A亲和层析和体积排阻色谱法),离心,差异溶解度或任何其他纯化蛋白质的标准技术。
培养物里的培养基在本领域中是公知的,并且可商业获得,也包括合成培养基。一个合成的培养基的例子是Dulbecco最少必需培养基(DMEM;Dulbecco et al.,Virol.1959,8,396)补充有4.5g/ml葡萄糖,0-20mM谷氨酰胺,0-20%胎牛血清,几个ppm的Cu,Mn,Fe或Zn等重金属或/和重金属盐,以及消泡剂如聚氧乙烯-聚氧丙烯嵌段共聚物。
另外,生产抗体的细胞系也可以通过融合以外的技术来获得,例如将成瘤DNA转化至B淋巴细胞,或成瘤病毒转染,如爱泼斯坦-巴尔病毒(EBV,也称为人类疱疹病毒4(HHV-4))或卡波西肉瘤相关疱疹病毒(KSHV),见于美国专利4,341,761;4,399,121;4,427,783;4,444,887;4,451,570;4,466,917;4,472,500;4,491,632;4,493,890。单克隆抗体也可以通过含末端羧基的抗受体肽或肽制备,这些都为如本领域所公知,可参考文献Niman etal.,Proc.Natl.Acad.Sci.USA,1983,80:4949-4953;Geysen et al.,Proc.Natl.Acad.Sci.USA,1985,82:178-182;Lei et al.Biochemistry 1995,34(20):6675-6688。通常,抗受体肽或肽同系物作为产生抗受体肽单克隆抗体免疫原,可以单独使用或与免疫原性载体连接。
用作本发明中结合分子的单克隆抗体也可以通过其他本领域已知的技术获得。特别有用的是制造完整人源抗体的方法。一种方法是噬菌体显示技术,它使用亲和富集的方式,可用于选择能与抗原特异性结合的人源抗体。噬菌体展示技术在文献中也有详细描述,噬菌体展示库的构建和筛选在本领域也是众所周知的,可参考文献Dente et al,Gene.1994,148(1):7-13;Little et al,Biotechnol Adv.1994,12(3):539-55;Clacksonet al.,Nature 1991,352:264-628;Huse et al.,Science 1989,246:1275-1281。
通过与非人如小鼠细胞融合的杂交瘤产生的单克隆抗体,可以被人源化以避免产生人类抗小鼠抗体。常见的抗体人源化方法是互补决定区移植技术,这些方法也已被详细地描述,如美国专利5,859,205和6,797,492;Liu et al,Immunol Rev.2008,222:9-27;Almagro et al,Front Biosci.2008,13:1619-33;Lazar et al,MolImmunol.2007,44(8):1986-98;Li et al,Proc.Natl.Acad.Sci.U S A.2006,103(10):3557-62,此处引为参考。完整人抗体也可以通过用免疫原免疫携带大部分的人类球蛋白重轻链的转基因小鼠、兔子、猴子或其他哺乳动物来制备。这些老鼠的例子有:Xenomouse(Abgenix/Amgen),HuMAb-Mouse(Medarex/BMS)和VelociMouse(Regeneron),参考美国专利6596541,6207418,6150584,6111166,6075181,5922545,5661016,5545806,5436149和5569825。用于人类治疗时,小鼠的可变区域和人的恒定区域也可以被融合,成为“嵌合抗体”,它在人类身上的免疫原性显著低于小鼠单抗(Kipriyanovet al,MolBiotechnol.2004,26:39-60;Houdebine,CurrOpinBiotechnol.2002,13:625-9)。另外,在抗体可变区域的定点诱变能导致抗体具有较高的亲和性和特异性(Brannigan et al,Nat Rev Mol Cell Biol.2002,3:964-70;Adams et al,J Immunol Methods.1999,231:249-60),抗体恒定区域的改变可以提高其介导结合和细胞毒性的效应功能。
恶性细胞抗原的免疫特异性抗体也可以从商业途径获得或通过任何已知方法生产,例如化学合成或重组表达技术。对恶性细胞抗原具有免疫特异性的抗体的核苷酸序列编码可以商业获得,例如从GenBank数据库或类似数据库,文献出版物获得,或通过常规克隆和测序得到。
除了抗体之外,与目标细胞上的表位或相应受体相互作用(结合、阻断、靶向或其他类型作用)的一种肽或蛋白质也可以作为结合分子。这些肽或蛋白质可能是任何随机的肽或蛋白质,它们对表位或相应的受体有亲和力,不一定非得是免疫球蛋白家族成员。这些肽可以通过类似噬菌体显示抗体的技术分离出来(Szardenings,J Recept SignalTransduct Res.2003;23(4):307-49)。从随机肽库中获得的肽可以与抗体和抗体片段类似地被使用。肽或蛋白质结合分子可以偶联或连接至大分子或其他物质,包括但不限于白蛋白、聚合物、脂质体、纳米粒子、树形分子,只要这样的连接能保留肽或蛋白质的抗原结合特异性。
在用于治疗癌症、自身免疫性疾病和/或传染性疾病的偶联物上,和药物分子通过本专利申请的连接体连接的抗体的例子包括,但不限于3F8(抗GD2),阿巴单抗(抗CA-125),阿昔单抗(抗CD41(整联蛋白α-IIb),阿达木单抗(抗TNF-α),Adecatumumab(抗EpCAM,CD326),阿非莫单抗(抗TNF-α),Afutuzumab(抗CD20),Alacizumab单抗(抗VEGFR2),ALD518(抗IL-6),Alemtuzumab(Campath,MabCampath,抗CD52),Altumomab(抗CEA),Anatumomab(抗TAG-72),Anrukinzumab(IMA-638,抗-IL-13),Apolizumab(抗-HLA-DR),阿奇单抗(抗-CEA),阿塞珠单抗(抗-L-选择蛋白CD62L),Atlizumab(tocilizumab,Actemra,RoActemra,抗-IL-6受体),Atorolimumab(抗-Rhesus因子),Bapineuzumab(抗-β淀粉样蛋白),Basiliximab(Simulect,抗CD25(IL-2受体的α链)),Bavituximab(抗磷脂酰丝氨酸),Bectumomab(LymphoScan,抗-CD22),贝利单抗(Benlysta,LymphoStat-B,抗BAFF),Benralizumab(抗CD125),Bertilimumab(抗CCL11(eotaxin-1)),Besilesomab(Scintimun,抗CEA相关抗原),贝伐单抗(Avastin,抗VEGF-A),Biciromab(FibriScint,抗纤维蛋白IIβ链),Bivatuzumab(抗-CD44v6),Blinatumomab(BiTE,抗CD19),Brentuximab(cAC10,抗-CD30 TNRSF8),Briakinumab(抗IL-12,IL-23),Canakinumab(Ilaris,抗IL-1),Cantuzumab(C242,抗CanAg),Capromab,Catumaxomab(Removab,抗EpCAM,抗CD3),CC49(抗TAG-72),Cedelizumab(抗CD4),Certolizumab单抗(Cimzia抗TNF-α),西妥昔单抗(爱必妥,IMC-C225,抗EGFR),Citatuzumab bogatox(抗EpCAM),Cixutumumab(抗IGF-1),Clenoliximab(抗CD4),Clivatuzu-mab(抗MUC1),Conatumumab(抗TRAIL-R2),CR6261(抗流感A血凝素),Dacetuzumab(抗CD40),Daclizumab(Zenapax,抗CD25(IL-2受体α链)),Daratumumab(抗CD38(环ADP核糖水解酶),Denosumab(Prolia,抗RANKL),Detumomab(抗B淋巴瘤细胞),Dorlimomab,Dorlixizumab,Ecromeximab(抗GD3神经节苷脂),Eculizumab(Soliris,抗-C5),Edobacomab(抗内毒素),Edrecolomab(Panorex,MAb17-1A,抗-EpCAM),Efalizumab(Raptiva,抗LFA-1(CD11a)),Efungumab(Mycograb,抗Hsp90),Elotuzumab(抗SLAMF7),Elsilimomab(抗IL-6),Enlimomab单抗(抗ICAM-1(CD54)),Epitumomab(抗episialin),依他珠单抗(抗-CD22),Erlizumab(抗-ITGB2(CD18)),Ertumaxomab(Rexomun,抗HER2/neu,CD3),依他拉单抗(Abegrin,抗整联蛋白αvβ3),Exbivirumab(抗乙肝表面抗原),Fanolesomab(NeutroSpec,抗CD15),Faralimomab(抗干扰素受体),Farletuzumab(抗叶酸受体1),Felvizumab(抗呼吸道合胞病毒),Fezakinumab(抗-IL-22),Figitumumab(抗-IGF-1受体),Fontolizumab(抗-IFN-γ),Foravirumab(抗狂犬病病毒糖蛋白),Fresolimumab(抗TGF-β),Galiximab(抗CD80),Gantenerumab(抗β淀粉样蛋白),Gavilimomab(抗CD147(basigin)),Gemtuzumab(抗CD33),Girentuximab(抗碳酸酐酶9),Glembatumumab(CR011,抗GPNMB),Golimumab(Simponi,抗-TNF-α),Gomiliximab(抗-CD23(IgE受体)),Ibalizumab(抗-CD4),Ibritumomab(抗CD20),Igovomab(Indimacis-125,抗CA-125),Imciromab(Myoscint,抗心肌肌凝蛋白),Infliximab(Remicade,抗TNF-α),Intetumumab(抗CD51),Inolimomab(抗CD25(IL-2受体α链),伊珠单抗(抗-CD22),Ipilimumab(抗CD152),Iratumumab(抗CD30(TNFRSF8)),Keliximab(抗-CD4),Labetuzumab(CEA-Cide,抗CEA),Lebrikizumab(抗IL-13),Lemalesomab(抗NCA-90(粒细胞抗原)),Lerdelimumab(抗TGFβ2),Lexatumumab(抗TRAIL-R2),Libivirumab(抗乙肝表面抗原),Lintuzumab(抗CD33),鲁米木单抗(抗CD40),鲁米单抗(抗CD23(IgE受体),Mapatumumab(抗TRAIL-R1),马西莫单抗(抗T-细胞受体),马妥珠单抗(抗EGFR),Mepolizumab(Bosatria,抗IL-5),Metelimumab(抗TGFβ1),Milatuzumab(抗CD74),Minretumomab(抗TAG-72),Mitumomab(BEC-2,抗GD3神经节苷脂),Morolimumab(抗恒河猴因子),Motavizumab(Numax,抗呼吸道合胞病毒),Muromonab-CD3(Orthoclone OKT3,抗CD3),Nacolomab(抗C242),Naptumomab(抗5T4),那他珠单抗(Tysabri,抗整联蛋白α4),奈巴单抗(抗内毒素),Necitumumab(抗EGFR),Nerelimomab(抗-TNF-α),Nimotuzumab(Theracim,Theraloc,抗-EGFR),Nofetumomab,Ocrelizumab(抗CD20),澳利木单抗(Afolimomab,抗LFA-1(CD11a)),Ofatumumab(Arzerra,抗CD20),Olaratumab(抗PDGF-Rα),Omalizumab(Xolair,抗IgE Fc区)Oportuzumab(抗EpCAM),Oregovomab(OvaRex,抗CA-125),Otelixizumab(抗CD3),Pagibaximab(抗脂磷壁酸),Palivizumab(Synagis,Abbosynagis,抗呼吸道合胞病毒),帕尼单抗(Vectibix,ABX-EGF,抗EGFR),Panobacumab(抗铜绿假单胞菌(Pseudomonas aeruginosa)),帕考珠单抗(抗IL-4),Pemtumomab(Theragyn,抗MUC1),Pertuzumab(Omnitarg,2C4,抗HER2/neu),Pexelizumab(抗C5),Pintumomab(抗腺癌抗原),Priliximab(抗-D4),Pritumumab(抗波形蛋白),PRO140(抗-CCR5),Racotumomab(1E10,抗-N-羟乙酰神经氨酸(NeuGc,NGNA)-神经节苷脂GM3)),Rafivirumab(抗狂犬病病毒糖蛋白),Ramucirumab(抗VEGFR2),Ranibizumab(Lucentis,抗VEGF-A),Raxibacumab(抗炭疽毒素,保护性抗原),Regavirumab(抗巨细胞病毒糖蛋白B),Reslizumab(抗-IL-5),Rilotumumab(抗-HGF),Rituximab(MabThera,Rituxanmab,抗-CD20),Robatumumab(抗-IGF-1受体),Rontalizumab(抗IFN-α),Rovelizumab(LeukAr-rest,抗CD11,CD18),Ruplizumab(Antova,抗CD154(CD40L)),Satumomab(抗TAG-72),Sevirumab(抗巨细胞病毒),Sibrotuzumab(抗FAP),西法木单抗(抗IFN-α),Siltuximab(抗IL-6),Siplizumab(抗CD2),Smart MI95(抗CD33),Solanezumab(抗β淀粉状蛋白),Sonepcizumab(抗鞘氨醇-1-磷酸),Sontuzumab(抗-episialin),Stamulumab(抗-myostatin),Sulesomab(LeukoScan,抗NCA-90(粒细胞抗原)),Tacatuzumab(抗α甲胎蛋白),Tadocizumab(抗整联蛋白αIIbβ3),Talizumab(抗IgE),Tanezumab(anti-NGF),Taplitumomab(抗CD19),Tefibazumab(Aurexis,(抗凝聚因子A)),Telimomab,Tenatumomab(抗腱生蛋白C),Teneliximab(抗CD40),Teplizumab(抗CD3),TGN1412(抗CD28),Ticilimumab(Tremelimumab,抗-CTLA-4),Tigatuzumab(抗TRAIL-R2),TNX-650(抗IL-13),Tocilizumab(Atlizumab,Actemra,RoActemra,IL-6受体),Toralizumab(抗CD154(CD40L)),Tositumomab(抗CD20),曲妥珠单抗(赫赛汀,抗HER2/neu),Tremelimumab(抗CTLA-4),Tucotuzumab celmoleukin(抗EpCAM),Tuvirumab(抗乙型肝炎病毒),Urtoxazumab(抗大肠杆菌),Ustekinumab(Stelara,抗-IL-12,IL-23),Vapaliximab(抗-AOC3(VAP-1)),维多珠单抗(抗整联蛋白α4β7),维妥珠单抗(抗CD20),Vepalimomab(抗AOC3(VAP-1)),Visilizumab(Nuvion,抗CD3),Vitaxin(抗血管整合素avb3),Volociximab(抗整联蛋白α5β1),Votumumab(HumaSPECT,抗肿瘤抗原CTAA16.88),Zalutumumab(HuMax-EGFR,Zanolimumab(HuMax-CD4,抗-CD4),Ziralimumab(抗-CD147(basigin)),Zolimomab(抗-CD5),依那西普Alefacept/> Abatacept/>Rilonacept(Arcalyst),14F7(抗IRP-2(铁调节蛋白2)),14G2a(抗GD2神经节苷脂,源于Nat.Cancer Inst.,治疗黑素瘤和实体瘤),J591(抗-PSMA,源于WeillCornell医学院,治疗前列腺癌),225.28S(抗HMW-MAA(高分子量黑素瘤相关抗原),SorinRadiofarmaci SRL(源于意大利米兰,治疗黑色素瘤),COL-1(抗CEACAM3,CGM1,源于NatCancer Inst.治疗结肠直肠癌和胃癌),CYT-356(/>治疗前列腺癌),HNK20(OraVax Inc.治疗呼吸道合胞病毒感染),ImmuRAIT(源于Immunomedics,治疗NHL),Lym-1(抗HLA-DR10,Peregrine Pharm),MAK-195F(抗TNF(肿瘤坏死因子,TNFA,TNF-α,TNFSF2,源于Abbott/Knoll,治疗脓毒症中毒性休克),MEDI-500(T10B9,抗CD3,TRαβ(T细胞受体α/β),源于MedImmune Inc,用于移植物抗宿主疾病病),RING SCAN(抗TAG 72(肿瘤相关糖蛋白72),源于Neoprobe Corp.,用于乳腺癌,结肠癌和直肠癌),Avicidin(抗EPCAM(上皮细胞粘附分子)),抗-TACSTD1(肿瘤相关钙信号转导1),抗GA733-2(胃肠肿瘤相关蛋白2),抗EGP-2(上皮糖蛋白2),抗KSA,KS1/4抗原,M4S,肿瘤抗原17-1A,CD326(源于NeoRx公司,治疗结肠癌,卵巢癌,前列腺癌和NHL),LymphoCide(源于Immunomedics),Smart ID10(源于ProteinDesign Labs),Oncolym(源于Techniclone Inc),Allomune(源于BioTransplant),抗VEGF(源于Genentech);CEAcide(源于Immunomedics),IMC-1C11(源于ImClone Systems)和Cetuximab(源于ImClone)。
其他可作为细胞结合分子/配体的抗体,包括但不限于,以下抗原的抗体:氨肽酶N(CD13),膜联蛋白A1,B7-H3(CD276,各种癌症),CA125(卵巢癌),CA15-3(各种癌症),CA19-9(各种癌症),L6(各种癌症),路易斯Y(各种癌症),路易斯X(各种癌症),甲胎蛋白(各种癌症),CA242(结直肠癌),胎盘碱性磷酸酶(各种癌症),前列腺特异抗原(前列腺癌),前列腺酸磷酸酶(前列腺癌),表皮生长因子(各种癌症),CD2(霍奇金症,NHL淋巴瘤,多发性骨髓瘤),CD3ε(T细胞淋巴瘤,肺癌,乳腺癌,胃癌,卵巢癌,自身免疫性疾病,恶性腹水),CD19(B细胞恶性肿瘤),CD20(非霍奇金淋巴瘤),CD22(白血病,淋巴瘤,多发性骨髓瘤,SLE),CD30(霍奇金淋巴瘤),CD33(白血病,自身免疫性疾病),CD38(多发性骨髓瘤),CD40(淋巴瘤,多发性骨髓瘤,白血病(CLL)),CD51(转移性黑色素瘤,肉瘤),CD52(白血病),CD56(小细胞肺癌,卵巢癌,梅克细胞癌,以及液体肿瘤,多发性骨髓瘤),CD66e(各种癌症),CD70(转移性肾细胞癌和非霍奇金淋巴瘤),CD74(多发性骨髓瘤),CD80(淋巴瘤),CD98(各种癌症),粘液素(各种癌症),CD221(实体肿瘤)、CD227(乳腺癌、卵巢癌)、CD262(非小细胞肺癌及其他癌症)、CD309(卵巢癌)、CD326(实体肿瘤)、CEACAM3(结肠直肠癌、胃癌)、CEACAM5(癌胚抗原,CEA,CD66e)(乳腺,结直肠癌和肺癌),DLL4,EGFR(表皮生长因子受体,各种癌症),CTLA4(黑色素瘤),CXCR4(CD184,血液肿瘤,实体肿瘤),Endoglin(CD105,实体瘤),EPCAM(上皮细胞粘附分子,膀胱癌,头颈癌,结肠癌,NHL前列腺癌,卵巢癌),ERBB2(表皮生长因子受体2,肺癌,乳腺癌,前列腺癌),FCGR1(自身免疫性疾病),FOLR(叶酸受体,卵巢癌),GD2神经节苷(各种癌症),G-28(细胞表面抗原糖脂质,黑色素瘤),GD3独特型(各自癌症),热休克蛋白(各种癌症),HER1(肺癌,胃癌),HER2(乳腺癌,肺癌和卵巢癌),HLA-DR10(NHL),HLA-DRB(NHL,B细胞白血病),人绒毛膜促性腺激素(各种癌症),IGF1R(类胰岛素生长因子1受体,实体瘤,血癌),IL-2受体(白介素2受体,T细胞白血病和淋巴瘤),IL-6R(白介素6受体,多发性骨髓瘤,风湿性关节炎,Castleman病,白细胞介素6依赖肿瘤),整合蛋白(αvβ3、α5β1、α6β4、αllβ3、α5β5、αvβ5,各种癌症),MAGE-1(各种癌症),MAGE-2(各种癌症),MAGE-3(各种癌症),MAGE 4(各种癌症),抗转铁蛋白受体(各种癌症),p97(黑色素瘤),MS4A1(跨膜4结构域亚家族A成员1,非霍奇金B细胞淋巴瘤,白血病),MUC1或MUC1-KLH(乳腺癌、卵巢癌、子宫颈癌、支气管癌和α胃肠道癌),MUC16(CA125)(卵巢癌),CEA(结直肠癌),gp100(黑色素瘤),MART1(黑色素瘤),MPG(黑素瘤),MS4A1(跨膜4结构域亚家族A成员1,小细胞肺癌,NHL),Nucleolin,Neu癌基因产物(各自癌症),P21(各种癌),抗(N-羟乙酰神经氨酸)抗体结合部位(乳腺癌,黑色素瘤),类PLAP睾丸碱性磷酸酶(卵巢癌、睾丸癌),PSMA(前列腺瘤),PSA(前列腺癌),ROBO4,TAG 72(肿瘤相关糖蛋白72,AML,胃癌、结肠直肠癌、卵巢癌),T细胞跨膜蛋白(各种癌症),Tie(CD202b),TNFRSF10B(肿瘤坏死因子受体超家族成员10B,各种癌症),TNFRSF13B(肿瘤坏死因子受体超家族成员13B,多发性骨髓瘤,NHL,其他癌症,RA和SLE),TPBG(滋养细胞糖蛋白,肾细胞癌),TRAIL-R1(TNF相关坏死诱导配体受体1,淋巴瘤,NHL,结直肠癌,肺癌),VCAM-1(CD106,黑色素瘤),VEGF,VEGF-a,VEGF-2(CD309)(各种癌症)。其它肿瘤相关,可被抗体识别的抗原已被总结和评述(Gerber,et al,mAbs 2009,1:3,247-253;Novellino et al,Cancer ImmunolImmunother.2005,54(3),187-207;Franke,et al,Cancer BiotherRadiopharm.2000,15,459-76)。
细胞结合剂,优选为抗体,可以是任何能够抗肿瘤细胞,病毒感染细胞,微生物感染细胞,寄生虫感染细胞,自身免疫细胞,活化的细胞,骨髓细胞,激活T细胞,B细胞,或黑色素细胞的分子。更具体地,细胞结合剂可以是任何能够抗下列抗原或受体之一的药物/分子:CD3,CD4,CD5,CD6,CD7,CD8,CD9,CD10,CD11a,CD11b,CD11c,CD12w,CD14,CD15,CD16,CDw17,CD18,CD19,CD20,CD21,CD22,CD23,CD24,CD25,CD26,CD27,CD28,CD29,CD30,CD31,CD32,CD33,CD34,CD35,CD36,CD37,CD38,CD39,CD40,CD41,CD42,CD43,CD44,CD45,CD46,CD47,CD48,CD49b,CD49c,CD51,CD52,CD53,CD54,CD55,CD56,CD58,CD59,CD61,CD62E,CD62L,CD62P,CD63,CD66,CD68,CD69,CD70,CD72,CD74,CD79,CD79a,CD79b,CD80,CD81,CD82,CD83,CD86,CD87,CD88,CD89,CD90,CD91,CD95,CD96,CD98,CD100,CD103,CD105,CD106,CD109,CD117,CD120,CD125,CD126,CD127,CD133,CD134,CD135,CD138,CD141,CD142,CD143,CD144,CD147,CD151,CD147,CD152,CD154,CD156,CD158,CD163,CD166,.CD168,CD174,CD180,CD184,CDw186,CD194,CD195,CD200,CD200a,CD200b,CD209,CD221,CD227,CD235a,CD240,CD262,CD271,CD274,CD276(B7-H3),CD303,CD304,CD309,CD326,4-1BB,5AC,5T4(Trophoblast糖蛋白,TPBG,WNT-活化抑制因子1或WAIF1),腺癌抗原,AGS-5,AGS-22M6,激活素受体激酶1,AFP,AKAP-4,ALK,α整合素,αvβ6,氨基肽酶N,淀粉样蛋白β,雄激素受体,促血管新生蛋白因子2,促血管新生蛋白因子3,膜联蛋白A1,炭疽毒素保护性抗原,抗转移蛋白受体,AOC3(VAP-1),B7-H3,炭疽杆菌,BAFF(B细胞激活因子),B淋巴瘤细胞,bcr-abl,蛙皮素,BORIS,C5,C242抗原,CA125(糖抗原125,MUC16),CA-IX(或CAIX,碳酸酐酶9),CALLA,CanAg,犬红斑狼疮IL31,碳酸酐酶IX,心肌肌凝蛋白,CCL11(C-C片段趋化因子11),CCR4(C-C趋化因子受体4,CD194),CCR5,CD3E(ε),CEA(癌胚抗原),CEACAM3,CEACAM5(癌胚抗原),CFD(因子D),Ch4D5,胆囊收缩素2(CCK2R),CLDN18(Claudin-18),丛生因子A,CRIPTO,FCSF1R(集落刺激因子1受体,CD115),CSF2(集落刺激因子2,粒细胞-巨噬细胞集落刺激因子(GM-CSF)),CTLA4(细胞毒性T淋巴细胞相关蛋白4),CTAA16.88肿瘤抗原,CXCR4(CD184),C-X-C趋化因子受体4,环状ADP核糖核酸酶,细胞周期蛋白B1,CYP1B1,巨细胞病毒,巨细胞病毒糖蛋白B,Dabigatran,DLL4(类Δ配体4),DPP4(双肽-肽酶4),DR5(死亡受体5),大肠杆菌shiga毒素类型-1,大肠杆菌shiga毒素类型-2,ED-B,EGFL7(类EGF结构域蛋白7),EGFR,EGFRII,EGFRvIII,内皮因子(CD105),内皮素B受体,内毒素,EpCAM(上皮细胞粘附分子),EphA2,Episialin,ERBB2(表皮生长因子受体2),ERBB3,ERG(TMPRSS2 ETS融合基因),大肠杆菌,ETV6-AML,FAP(成纤维细胞活化蛋白α),FCGR1,甲胎蛋白,纤维蛋白IIβ链,纤连蛋白额外结构域-B,FOLR(叶酸受体),叶酸受体α,叶酸水解酶,Fos相关抗原1,呼吸道合胞病毒的F蛋白,卷曲的受体,岩藻糖GM1,GD2神经节苷脂,G-28(细胞表面抗原糖脂),GD3独特型,GloboH,Glypican 3,N-羟乙酰神经氨酸,GM3,GMCSF受体α链,生长分化因子8,GP100,GPNMB(跨膜糖蛋白NMB),GUCY2C(鸟苷酸环化酶2C),鸟苷酸环化酶C(GC-C),肠鸟苷酸环化酶,鸟苷酸环化酶C受体,热稳定肠毒素受体(hSTAR),热休克蛋白,血凝素,乙肝表面抗原,乙型肝炎病毒,HER1(人类表皮生长因子受体1),HER2,HER2/neu,HER3(ERBB-3),IgG4,HGF/SF(肝细胞生长因子/分散因子),HHGFR,HIV-1,组蛋白复合物,HLA-DR(人类白细胞抗原),HLA-DR10,HLA-DRB,HMWMAA,人类绒毛膜促性腺激素,HNGF,人类分散因子受体激酶,HPV E6/E7,Hsp90,hTERT,ICAM-1(细胞间粘附分子1),独特型,IGF1R(IGF–1,类胰岛素生长因子1受体),IGHE,IFN-γ,流感血凝素,IgE,IgE Fc区,IGHE,IL–1,IL-2R(白介素2受体),IL–4,IL-5,IL–6,IL-6R(白介素6受体),IL-9,IL–10,IL–12,IL-13,IL-17,IL-17A,IL-20,IL-22,IL-23,IL31RA,ILGF2(类胰岛素生长因子2),整合蛋白(α4、αIIbβ3、αvβ3、α4β7、α5β1、α6β4、α7β7、αllβ3、α5β5、αvβ5),干扰素γ诱导蛋白质,ITGA2,ITGB2,KIR2D,LCK,Le,Legumain,Lewis-Y抗原,LFA-1(淋巴细胞功能相关抗原1,CD11a),LHRH,LINGO-1,脂磷壁酸,LIV1A,LMP2,LTA,MAD-CT-1,MAD-CT-2,MAGE-1,MAGE-2,MAGE-3,MAGE A1,MAGE A3,MAGE4,MART1,MCP-1,MIF(巨噬细胞迁移抑制因子,或糖基抑制因子(GIF)),MS4A1(跨膜4结构域亚家族A成员1),MSLN(间皮素),MUC1(粘蛋白1,细胞表面相关(MUC1)或多态性上皮粘蛋白(PEM)),MUC1-KLH,MUC16(CA125),MCP1(单核细胞趋化蛋白1),MelanA/MART1,ML-IAP,MPG,MS4A1,MYCN,髓磷脂相关糖蛋白,Myostatin,NA17,NARP-1,NCA-90(粒细胞抗原),Nectin-4(ASG-22ME),NGF,神经细胞凋亡调控蛋白酶1,NOGO-A,Notch受体,核仁素,Neu致癌基因产物,NY-BR-1,NY-ESO-1,OX-40,OxLDL(氧化低密度脂蛋白),OY-TES1,P21,p53非突变体,P97,PAP,抗(N-羟乙酰神经氨酸)抗体结合部位,PAX3,PAX5,PCSK9,PDCD1(PD-1、程序性细胞死亡蛋白1,CD279),PDGF-Rα(α血小板源生长因子受体),PDGFR-β,PDL-1,PLAC1,类PLAP睾丸碱性磷酸酶,血小板衍生生长因子受体β,磷酸钠联合转运体,PMEL 17,聚唾液酸,蛋白酶3(PR1),前列腺癌,PS(磷脂酰丝氨酸),前列腺癌细胞,铜绿假单胞菌,PSMA,PSA,PSCA,狂犬病病毒糖蛋白,RHD(Rh多肽1(RhPI),CD240),Rhesus因子,RANKL,RhoC,Ras突变,RGS5,ROBO4,呼吸道合胞病毒,RON,肉瘤易位断点,SART3,Sclerostin,SLAMF7(SLAM成员7),Selectin P,SDC1(多配体蛋白聚糖1),系统性红斑狼疮(a),生长调节素C,SIP(1-磷酸鞘氨醇),生长激素抑制素,精子蛋白17,SSX2,STEAP1(6-跨膜上皮前列腺抗原1),STEAP2,STn,TAG-72(肿瘤相关糖蛋白),存活素,T细胞受体,T细胞跨膜蛋白,TEM1(肿瘤血管内皮标记1),TENB2,Tenascin C(TN-C),TGF-α,TGF-β(转化生长因子β),TGF-β1,TGF-β2(转化生长因子2),Tie(CD202b),Tie2,TIM-1(CDX-014),Tn,TNF,TNF-α,TNFRSF8,TNFRSF10B(肿瘤坏死因子受体超家族成员10B),TNFRSF13B(肿瘤坏死因子受体超家族成员13B),TPBG(滋养细胞糖蛋白),TRAIL-R1(TNF相关坏死诱导配体受体1),TRAILR2(死亡受体5(DR5)),肿瘤相关的钙信号传感器2,肿瘤特异糖基化的MUC1,TWEAK受体,TYRP1(糖蛋白75),TRP-2,酪氨酸酶,VCAM-1(CD106),VEGF,VEGF-A,VEGF-2(CD309),VEGFR-1,VEGFR2,vimentin,WT1,XAGE 1,表达任何胰岛素生长因子受体的细胞,或任何表皮生长因子受体。
在另一个具体的实施例中,通过本专利申请的连接体连接的细胞结合剂-药物偶联物,可用于癌症靶向治疗。目标癌症包括但不限于,肾上腺皮质癌、肛门癌、膀胱癌、大脑肿瘤(脑干神经胶质瘤、小脑星形细胞瘤、脑星形细胞瘤、室管膜瘤、成神经管细胞瘤、幕上原始神经外胚层和松果体肿瘤、视觉通路和下丘脑胶质瘤)、乳腺癌、类癌肿瘤、胃肠道癌症、未知小细胞癌、宫颈癌、结肠癌、子宫内膜癌、食道癌、肝外胆管癌、尤因家族肿瘤(PNET)、颅内生殖细胞肿瘤、眼癌、眼内黑色素瘤、胆囊癌、胃癌(胃癌)、性腺外生殖细胞瘤、孕周滋养细胞瘤、头颈癌、下咽癌、胰岛细胞癌、肾癌(肾细胞癌)、喉癌、白血病(急性淋巴细胞,急性髓系,慢性淋巴细胞,慢性粒细胞,毛细胞)、嘴唇和口腔癌症、肝癌、肺癌(非小细胞,小细胞)、淋巴瘤(艾滋病相关,中枢神经系统,皮肤T细胞,霍奇金病,非霍奇金病)、恶性间皮瘤、黑色素瘤、梅克尔细胞癌、转移性鳞状颈癌与隐匿性原发性癌、多发性骨髓瘤和其他浆细胞肿瘤、蕈样肉芽肿、骨髓增生异常综合征、骨髓增生异常、鼻咽癌、神经母细胞瘤、口腔癌、口咽癌、骨肉瘤、卵巢癌(上皮、生殖细胞瘤、低恶性肿瘤)、胰腺癌(外分泌,胰岛细胞癌)、副鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、嗜铬细胞瘤、垂体肿瘤、浆细胞肿瘤、前列腺癌横纹肌肉瘤、直肠癌、肾细胞癌(肾癌)、肾盂和输尿管(移行细胞)、唾腺癌、赛塞里综合症、皮肤癌(皮肤T细胞淋巴瘤,卡波西氏肉瘤,黑色素瘤)、小肠肿瘤、软组织肉瘤、胃癌、睾丸癌、胸腺瘤(恶性)、甲状腺癌、尿道癌症、子宫癌、不寻常的少年癌症、阴道肿瘤、外阴肿瘤和维尔姆斯瘤。
在另一个具体的实施例中,通过本专利申请的连接体连接的细胞结合剂-药物偶联物,可用作治疗或预防自身免疫疾病的成分和方法。自身免疫性疾病包括但不限于,Achlorhydra自身免疫性活动性慢性肝炎,急性播散性脑脊髓炎,急性出血性脑白质炎,艾迪生病,无精症,斑秃,肌萎缩侧索硬化症,强直性脊柱炎,抗GBM/TBM肾炎,抗磷脂综合征,抗异常酶综合征,关节炎,特应性过敏,特应性皮炎,自身免疫性再生障碍性贫血,自身免疫性心肌病,自身免疫性溶血性贫血,自身免疫性肝炎,自身免疫性内耳疾病,自身免疫性淋巴组织增生综合征,自身免疫性周围神经病,自身免疫性胰腺炎,自身免疫性多内分泌综合征I,II和III型,自身免疫性黄体酮皮炎,自身免疫性血小板减少性紫癜,自身免疫性葡萄膜炎,Balo病/Balo同心硬化症,Bechets综合征,Berger氏病,Bickerstaff脑炎,Blau综合征,大疱性类天疱疮,Castleman病,Chagas病,慢性疲劳免疫功能障碍综合征,慢性炎性脱髓鞘性多发性神经病,慢性复发性多灶性骨髓炎,慢性莱姆病,慢性阻塞性肺病,Churg-Strauss综合征,瘢痕性类天疱疮,乳糜泄,Cogan综合征,冷凝集素病,补体成分2缺乏症,颅骨动脉炎,CREST综合征,Crohns病(特发性炎症性肠病),库欣综合征,皮肤白细胞增多性血管炎,德戈氏病,Dercum氏病,疱疹样皮炎,皮肌炎,1型糖尿病,弥漫性皮肤系统性硬化症,Dressler综合征,盘状红斑狼疮,湿疹,子宫内膜异位症,附着点炎相关的关节炎,Eosinophilic筋膜炎,大疱性表皮松解症,结节性红斑,特发性混合性冷球蛋白血症,伊文氏综合征,纤维发育不良性骨化症,纤维肌痛,纤维化性肌炎,纤维性肺泡炎,胃炎,胃肠类天疱疮,巨细胞动脉炎,肾小球肾炎,古德帕斯丘尔综合征,格雷夫斯病,格林-巴利综合征,桥本氏脑炎,桥本氏甲状腺炎,溶血性贫血,过敏性紫癜,妊娠性肝炎,化脓性汗腺炎,休斯综合征(抗磷脂综合征),低丙球蛋白血症,特发性炎性脱髓鞘疾病,特发性肺纤维化,特发性血小板减少性紫癜(自身免疫性血小板减少性紫癜),IgA肾病(伯杰氏病),包涵体肌炎,炎性脱髓鞘性多神经炎,间质性膀胱炎,过敏性肠综合征,少年特发性关节炎,青少年类风湿性关节炎,川崎氏病,朗伯-伊顿重症肌无力综合征,白细胞碎屑性血管炎,扁平苔癣,硬化性硬化症,线状IgA疾病(LAD),Lou Gehrig病(也称肌萎缩侧索硬化症),狼疮性肝炎,红斑狼疮,Majeed综合征,美尼尔氏病,显微镜下多动脉炎,米勒-费希尔综合征,混合性结缔组织病,硬斑病,穆罕默德-哈贝曼病,麦考利综合征,多发性骨髓瘤,多发性硬化症,重症肌无力,肌炎,嗜睡症,视神经脊髓炎(Devic病),神经性肌强直,眼睑瘢痕性类天疱疮,Opsoclonus myoclonus综合征,Ord甲状腺炎,回文风湿病,PANDAS(与链球菌相关的小儿自身免疫性神经精神病),Paraneoplastic小脑变性,阵发性睡眠性血红蛋白尿症,ParryRomberg综合征,Parsonnage-Turner综合征,睫状体平部炎,天疱疮,寻常型天疱疮,贫血,周围脑脊髓炎,POEMS综合征,结节性多动脉炎,风湿性多肌痛,多发性肌炎,原发性胆汁性肝硬化,原发性硬化性胆管炎,进行性炎症性神经病变,牛皮癣,牛皮癣性关节炎,坏疽性皮肤炎,纯红细胞再生障碍,Rasmussen脑炎,雷诺现象,复发性多软骨炎,赖特综合征,不宁腿综合症,后神经纤维化,类风湿性关节炎,类风湿热,结节病,精神分裂症,施密特综合征,Schnitzler综合征,施尼茨勒综合征,巩膜炎,硬皮病,干燥综合征,脊椎关节病,粘稠血症,Still病,僵人综合征,亚急性细菌性心内膜炎,苏萨克综合征,Sweet综合征,小舞蹈病,交感神经性贫血,Takayasu动脉炎,颞动脉炎(巨细胞动脉炎),Tolosa-Hunt综合征,横贯性脊髓炎,溃疡性结肠炎(特发性炎性肠病),未分化结缔组织病,未分化脊柱关节病,血管炎,白癜风,韦格纳肉芽肿病,威尔逊氏综合征,威斯科特-澳尔德里奇综合征。
在另一个具体的实施例中,在用于治疗或预防自身免疫性疾病的偶联物上,和药物分子通过本发明的连接体连接的结合分子,包括但不限于,抗弹性蛋白抗体,Abys抗上皮细胞抗体,抗地下室膜IV型胶原蛋白抗体,抗核抗体,抗ds DNA,抗ss DNA,抗心磷脂抗体IgM,IgG,抗乳糜泻抗体,抗磷脂抗体IgK,IgG,抗SM抗体,抗线粒体抗体,甲状腺抗体,微粒体抗体,T细胞抗体,甲状腺球蛋白抗体,抗SCL-70,抗Jo,抗U.sub.1RNP,抗La/SSB,抗SSA,抗SSB,抗壁细胞抗体,抗组蛋白,抗RNP,C-ANCA,P-ANCA,抗着丝粒,抗纤维蛋白原,抗GBM抗体,抗神经节苷脂抗体,抗Desmogein 3抗体,抗p62抗体,抗sp100抗体,抗线粒体(M2)抗体,类风湿因子抗体,抗MCV抗体,抗拓扑异构酶抗体,抗中性粒细胞胞质(cANCA)抗体。
在某些优选的实施例中,本专利申请中偶联物上的结合分子,可以与自身免疫性疾病相关的激活淋巴细胞上表达的受体或受体复合物相结合。受体或受体复合物包含,免疫球蛋白基因超家族成员(例如CD2,CD3,CD4,CD8,CD19,CD20,CD22,CD28,CD30,CD33,CD37,CD38,CD56,CD70,CD79,CD79b,CD90,CD125,CD147,CD152/CTLA-4,PD-1或ICOS),TNF受体超家族成员(例如CD27,CD40,CD95/Fas,CD134/OX40,CD137/4-1BB,INF-R1,TNFR-2,RANK,TACI,BCMA,骨保护素,Apo2/TRAIL-R1,TRAIL-R2,TRAIL-R3,TRAIL-R4和APO-3),整合蛋白,细胞因子受体,趋化因子受体,主要组织相容性蛋白,凝集素(C型,S型或I型)或补体控制蛋白。
在另一个具体实施例中,可用的对病毒或微生物抗原具有免疫特异性的细胞结合配体是人源化或人单克隆抗体。“病毒抗原”包括但不限于,任何能够引发免疫应答的病毒肽,多肽蛋白(例如HIV gp120,HIV nef,RSV F糖蛋白,流感病毒神经氨酸苷酶,流感病毒血凝素,HTLV Tax,疱疹单纯疱疹病毒糖蛋白(例如gB,gC,gD和gE)和乙型肝炎表面抗原)。“微生物抗原”包括但不限于,任何能够引发免疫应答的微生物肽,多肽,蛋白质,糖,多糖或脂质分子(例如细菌,真菌,致病原生动物或酵母多肽,包括如LPS和荚膜多糖)。可用于治疗病毒或微生物感染的抗体的实例,包括但不限于:帕利珠单抗,它是用于治疗RSV感染的,人源化抗呼吸道合胞病毒单克隆抗体;PRO542,是一种CD4融合抗体,用于治疗HIV感染;澳斯他韦,是一种用于治疗乙型肝炎病毒的人抗体;PROTVIR,是一种人源化IgG1抗体,用于治疗巨细胞病毒,和抗LPS抗体。
通过本专利申请的连接体制得的细胞结合分子-药物偶联物可用于治疗感染性疾病。这些感染性疾病包括但不限于,不动杆菌属感染,放线菌病,非洲昏睡病(非洲锥虫病),艾滋病(获得性免疫缺陷综合症),阿米巴病,无形体病,炭疽,溶血性耶尔森菌感染,阿根廷出血热,蛔虫病,曲霉病,星状病毒感染,巴贝斯虫病,蜡状芽孢杆菌感染,细菌性肺炎,细菌性阴道炎,类杆菌感染,小袋虫病,蛔虫感染,BK病毒感染,黑色发结节病,人芽囊原虫感染,芽生菌病,玻利维亚出血热,疏螺旋体感染,肉毒中毒(和婴儿肉毒中毒),巴西出血热,布鲁氏杆菌病,伯克霍尔德氏菌感染,布鲁里溃疡,杯状病毒感染(诺如病毒和沙波病毒),弯曲杆菌病,念珠菌病(念珠菌病,鹅口疮),猫抓病,蜂窝组织炎,Chagas病(美洲锥虫病),子囊,水痘,衣原体,肺炎衣原体感染,霍乱,色素母细胞瘤,华支睾吸虫,艰难梭状芽孢杆菌感染,球孢子菌病,科罗拉多蜱热病,普通感冒(急性病毒性鼻咽炎,急性鼻炎),克雅氏病,克里米亚-刚果出血热,隐球菌病,隐孢子虫病,皮肤幼虫迁徙,环孢子虫病,肠杆菌感染,肠道病毒感染,流行性斑疹伤寒,传染性红斑(第五种疾病),急疹,姜片虫病,肝片吸虫病,致命性家族性失眠,丝虫病,产气荚膜梭菌食物中毒,自由活体阿米巴感染,梭杆菌感染,气性坏疽(梭菌性肌坏死),地丝菌病,格斯特曼-斯特拉斯勒-谢克尔病综合征,贾第鞭毛虫病,马鼻疽,淋病,肉芽肿性腹泻(第五性病),A群链球菌感染,B群链球菌感染,流感嗜血杆菌感染,手足口病(HFMD),汉坦病毒肺综合征,幽门螺杆菌感染,溶血性尿毒综合征,肾综合征出血热,甲型肝炎,乙型肝炎,丙型肝炎,丁型肝炎,戊型肝炎,单纯性疱疹,组织胞浆菌病,钩虫感染,人类博卡病毒感染,人类ewingii埃里希体病,人类粒细胞无形体病,人类偏肺病毒感染,人类单核细胞埃里希体病,人乳头瘤病毒感染,人副流感病毒感染,膜壳绦虫病,艾巴氏病毒传染性单核细胞增多症(单),流行性感冒,等孢子虫病,川崎病,角膜炎,金格杆菌感染,库鲁病,拉沙热,军团病,军团病(庞蒂亚克热),利什曼病,莱姆病,淋巴丝虫病(象皮病),淋巴细胞性脉络丛脑膜炎,疟疾,马尔堡出血热,麻疹,类鼻疽病(惠氏病),脑膜炎,脑膜炎球菌病,后殖吸虫病,微孢子虫病,传染性软疣,腮腺炎,小鼠斑疹伤寒(地方性斑疹伤寒),支原体肺炎,足菌肿,蝇蛆病,新生儿结膜炎(新生儿眼病),变异型克雅氏病(vCJD,nvCJD),诺卡氏菌病,盘尾丝虫病(河盲症),副球孢子菌病(南美芽生菌病),肺吸虫病,巴斯德氏菌病,头虱,体虱,阴虱,盆腔炎,百日咳,鼠疫,肺炎球菌感染,肺孢子虫肺炎,肺炎,脊髓灰质炎,普氏菌感染,原发性阿米巴脑膜脑炎,进行性多灶性白质脑病,鹦鹉热,Q热,狂犬病,鼠咬热,呼吸道合胞病毒感染,鼻孢子虫病,鼻病毒感染,立克次体感染,立克次体痘,裂谷热,落基山斑疹热,轮状病毒感染,风疹,沙门氏菌病,SARS(严重急性呼吸综合征),疥疮,血吸虫病,败血症,志贺氏菌病(Bacillary痢疾),带状疱疹(带状疱疹),天花(天花),孢子丝菌,葡萄球菌食物中毒,感染金黄色葡萄球菌,粪类圆线虫病,梅毒,绦虫病,破伤风,须癣(Barber痒),头皮癣,体癣,股癣,手癣,掌黑癣,足癣,甲癣(灰指甲),花斑癣,弓蛔虫病(眼幼虫移行症),弓蛔虫病(内脏幼虫移行症),弓形体病,旋毛虫病,滴虫病,鞭虫病(鞭虫感染),肺结核,兔热病,解脲脲原体感染,委内瑞拉马脑炎,委内瑞拉出血热,病毒性肺炎,西尼罗河热,白毛结节病(白癣),假结核耶尔森氏菌,耶尔森氏鼠疫杆菌肠道病,黄热病,接合菌病。
本发明的细胞结合剂,更优选为抗体,抗的病原菌株包括但不限于,鲍氏不动杆菌,以色列放线菌,放线菌和丙酸杆菌,布氏锥虫,HIV(人免疫缺陷病毒病毒),溶组织内阿米巴,无形体属,炭疽芽孢杆菌,溶血弧菌,胡宁病毒,蛔虫属,曲霉属,星状病毒科,巴贝虫属,蜡状芽孢杆菌,多种细菌,拟杆菌属,大肠杆菌,蛔虫属,BK病毒,结节菌,人芽囊原虫,皮炎芽生菌,马丘波病毒,疏螺旋体属,肉毒梭菌,清风藤属,布鲁氏菌属,通常为洋葱伯克霍尔德菌和其他伯克霍尔德氏菌种,溃疡分枝杆菌,杯状病毒科,弯曲杆菌属,通常为白色假丝酵母和其他假丝酵母属,汉赛巴尔通体,A群链球菌和葡萄球菌,克氏锥虫,杜克雷嗜血杆菌,VZV,沙眼衣原体,科罗拉多蜱热病毒,鼻病毒,冠状病毒,CJD朊病毒,克里米亚-刚果出血热病毒,新型隐球菌,隐孢子虫属,巴西钩虫,多种寄生虫,环孢子虫,带状绦虫,巨细胞病毒,登革热病毒(DEN-1,DEN-2,DEN-3和DEN-4)-黄病毒,脆弱双歧杆菌,白喉棒状杆菌,裂头绦虫,麦地那龙线虫,埃博拉病毒,棘球绦虫属,埃立克体肠球菌属,肠道病毒属,普氏立克次体,细小病毒B19,人疱疹病毒6和人疱疹病毒7,布氏姜片虫,肝片吸虫和巨大片吸虫,FFI朊病毒,丝虫目超家族,产气荚膜梭菌,梭杆菌属,其他梭状芽孢杆菌,白地霉,GSS朊病毒,肠道贾第虫,伯克霍尔德氏菌,刺孢小芽孢杆菌和革兰氏假丝酵母,淋球菌,肉芽肿克雷伯氏菌,化脓性链球菌,无乳链球菌,流感嗜血杆菌,肠道病毒,主要是柯萨奇A病毒和肠道病毒71,无名病毒,幽门螺旋杆菌,大肠杆菌O157:H7,布尼亚病毒科,甲型肝炎病毒,乙型肝炎病毒,丙型肝炎病毒,丁型肝炎病毒,戊型肝炎病毒,单纯疱疹病毒1,单纯疱疹病毒2,荚膜组织胞浆菌,十二指肠腺瘤和壶腹癌流感嗜血杆菌,人博卡病毒,埃里希体,嗜吞噬细胞无嗜血杆菌,人偏肺病毒,查菲埃里希体,人乳头瘤病毒,人副流感病毒,微小膜壳绦虫和缩小膜壳绦虫,艾巴氏病毒,正粘病毒科家族,贝氏等孢球虫,金格杆菌,肺炎克雷伯菌,克雷伯氏菌,嗜肺军团菌,嗜肺军团菌,嗜肺军团菌,利什曼原虫属,麻风分枝杆菌和结核分枝杆菌,钩端螺旋体属,单核细胞增多性李斯特氏菌,伯氏疏螺旋体和其他疏螺旋体属物种,班氏旋毛虫和马来丝虫,淋巴细胞脉络丛脑膜炎病毒(LCMV)疟原虫属,马尔堡病毒,麻疹病毒,类鼻疽伯克霍尔德氏菌,脑膜炎奈瑟氏球菌,横川后殖吸虫,小孢子虫目门,传染性软疣病毒(MCV),腮腺炎病毒,伤寒立克次氏体,肺炎支原体,多种细菌和真菌寄生双翅蝇幼虫,沙眼衣原体和淋病奈瑟菌,vCJD朊病毒,诺卡氏菌和其他诺卡氏菌属,盘尾丝虫属,盘鲍拟亚科,副龙属西马尼和其他副属,巴斯德氏菌属,头虱,人体虱,百日咳博德特氏菌鼠疫耶尔森氏菌,肺炎链球菌,肺炎球菌,脊髓灰质炎病毒,普雷沃氏菌属,奈氏格氏杆菌,JC病毒,鹦鹉热衣原体,伯氏考克斯体,狂犬病病毒,单链球菌和螺旋菌,呼吸道合胞病毒,鼻孢子菌,鼻病毒,立克次体属,由小株立克次体,裂谷热病毒,立克次体立克次体,轮状病毒,风疹,沙门氏菌属,SARS冠状病毒,人疥螨,血吸虫属,体细胞属,志贺菌属,水痘带状疱疹病毒,天花少校或天花小,申克孢子丝菌,金黄色葡萄球菌属,金黄色葡萄球菌,链球菌化脓,圆线虫,梅毒螺旋体,绦虫属,破伤风,癣属癣音铀,癣属,絮状表皮癣菌,红色毛癣菌,须毛癣菌,红色毛癣菌,威尼克外瓶黴,毛癣菌属属,细胞死亡属,弓箭毒或弓箭毒,刚地弓形虫、旋毛虫,阴道毛滴虫,三丘里三种,结核分枝杆菌,弗朗西拉图拉菌,尿素和马脑炎病毒,委内瑞拉马脑炎病毒,霍乱弧菌,瓜纳里托病毒,西尼罗河病毒,beigelii丝孢,假结核耶尔森氏菌,小肠结肠炎耶尔森氏菌,黄热病病毒,毛霉菌目阶(毛霉菌病)和虫霉目阶(虫霉属真菌病),毛霉菌目绿脓杆菌,弯曲杆菌(弧菌),气单胞菌,艾氏菌,耶尔森氏菌,志贺痢疾杆菌,志贺氏杆菌,志贺氏菌,沙门氏菌,伤寒沙门氏菌,雅司螺旋体,奋森氏螺旋体,伯氏疏螺旋体,细螺旋体,卡氏肺孢子虫,流产布鲁氏菌,布鲁杆菌,布鲁氏菌,支原体属,普氏立克次体,恙虫病立克次氏体,衣原体属,致病性真菌(烟曲霉,白色念珠菌,荚膜组织胞浆菌),原生动物(溶组织内阿米巴,Tenas毛滴虫,Hominis毛滴虫,冈比亚锥虫,罗得西亚锥虫,罗氏利什曼原虫,热带利什曼原虫,巴西利什曼原虫,肺孢子虫肺炎,间日疟原虫,恶性疟原虫,疟原虫疟疾)或Helminiths(日本血吸虫,曼氏血吸虫,埃及血吸虫和钩虫)。
其他用作本专利申请细胞结合剂,治疗病毒性疾病的抗体,包括但不限于,对下列致病性病毒抗原的抗体:痘病毒;疱疹病毒;腺病毒;小黄病毒;肠病毒;小核糖核酸病毒;细小病毒;呼肠病毒;逆转录病毒;流感病毒;副流感病毒;腮腺炎;麻疹;呼吸道合胞病毒;风疹;虫媒病毒;弹状病毒;沙门氏菌;非a/非b型肝炎病毒;鼻病毒;冠状病毒;罗托病毒;致癌病毒,如HBV(肝细胞癌),人乳头状瘤病毒(宫颈癌,肛门癌),卡波济氏肉瘤相关的疱疹病毒(卡波济氏肉瘤肉瘤)、人类疱疹病毒第四型(鼻咽癌、伯基特淋巴瘤、原发性中枢神经系统淋巴瘤)、瘤病毒(默克尔细胞癌)、SV40(猿猴病毒40)、HCV(肝细胞癌),HTLV-1(成人T细胞白血病/淋巴瘤);免疫紊乱导致病毒,如人类免疫缺陷病毒(艾滋病);中枢神经系统病毒,如JCV(进行性多灶性脑白质病),丙型肝炎病毒(亚急性硬化性全脑炎),LCV(淋巴细胞性脉络丛脑膜炎),亚博病毒脑炎,正粘病毒(脑炎性脑炎),RV(狂犬病),长鼻病毒,疱疹病毒脑膜炎,拉姆齐亨特综合征II型,脊髓灰质炎病毒(脊髓灰质炎病毒,后脊髓灰质炎综合征),HTLV-1(热带麻痹性麻痹));巨细胞病毒(巨细胞病毒视网膜炎,HSV(疱疹性角膜炎);心血管病毒,如CBV(心包炎,心肌炎);呼吸系统/急性病毒性鼻内炎/病毒性肺炎,如爱泼斯坦-巴尔病毒(EBV感染/传染性单核病),巨细胞病毒,非典冠状病毒(严重急性呼吸综合征)或正黏液病毒,流感病毒a/b/c(流感/禽流感),副粘病毒,人类副流感病毒,RSV(人类呼吸道合胞病毒),hMPV;消化系统病毒(腮腺炎病毒,巨细胞病毒(巨细胞病毒食管炎),腺病毒(腺病毒感染),轮状病毒,诺瓦克病毒,星状病毒,冠状病毒,乙型肝炎病毒,CBV,甲型肝炎病毒,丙型肝炎病毒,丁型肝炎病毒,戊型肝炎病毒,HGV);泌尿生殖病毒,如BK病毒,MuV(腮腺炎)。
更进一步,本发明也包括用桥接体连接的共轭偶联物和可接受的载体,稀释剂或辅料构成的组合物,以治疗癌症、感染或自身免疫性疾病。治疗癌症、感染和自身免疫性疾病的方法可以在体外,体内或离体实施。体外用途的实例包括用它处理细胞培养物,以杀死除了不表达靶抗原的变体以外的所有细胞;或者杀死表达不需要的抗原的变体。离体使用的例子包括在进行移植(HSCT)之前对造血干细胞(HSC)进行处理,以杀死患病或恶性细胞。例如,在癌症治疗中的自体移植之前或在自身免疫性疾病的治疗中从骨髓中去除肿瘤细胞或淋巴细胞,或在移植之前为了防止移植物抗宿主疾病从同种异体骨髓或组织中除去T细胞和其他淋巴细胞。这样的临床离体治疗可以按如下步骤进行:从患者或其他个体收获骨髓,然后在含有血清的培养基中约37℃下孵育约30分钟至约48小时,在该培养基中加入本发明的偶联物,浓度范围从约1pM至0.1mM。具体的药物浓度和孵育时间应当由专业临床医师决定。孵育后,用含血清的培养基洗涤骨髓细胞,并按照已知的方法通过静脉注射给患者。若患者在骨髓采集和再输注治疗细胞之间,还接受其它治疗(例如消融化疗或全身辐射疗程)的情况下,应使用标准医疗设备将处理后的骨髓细胞在液氮中冷冻储存。
在临床体内的使用中,可将本专利申请连接体连接的偶联物作为溶液或冻干固体供应,固体可以被重新溶解在注射用无菌水中。偶联物施用方案的实例如下:偶联物每周一次性静脉注射,连续给予8至20周。在50-500ml生理盐水中给予推注剂量,可以向其中加入人血清白蛋白(例如0.5至1mL的人血清白蛋白的浓缩溶液,100mg/mL)。静脉注射剂量将是约50μg至200mg/kg(体重)每周(每次注射10μg至200mg/kg)。治疗后周,患者可以接受第二疗程治疗。有关施用途径,赋形剂,稀释剂,剂量,次数等的具体临床方案可以由专业临床医生确定。
可用体内或离体方法治疗的医学病症的实例,包括任何类型癌症的恶性肿瘤,自身免疫疾病,移植物排斥和感染(病毒,细菌或寄生虫)。
为达到期望的生物效应所需的偶联物的量将随多种因素而变化,所述因素包括偶联物的化学特性,效力和生物利用度,疾病的类型,患者种族,患者的疾病发展状态,给药途径,所有因素决定了所需剂量、给药方式和给药方案。
一般而言,可将本发明的偶联物配制成含有0.1至10%w/v偶联物的水性生理缓冲溶液中,供注射使用。典型的剂量范围是从1μg/kg至0.1g/kg(体重),每天1次。优选的剂量范围是0.01mg/kg至20mg/kg体重/每天或每周,或幼儿等效剂量。待施用的药物的优选剂量可能取决于诸如疾病或病症的进展的类型和程度,特定患者的总体健康状况,所选化合物的相对生物功效,药物的配方,给药途径(静脉内,肌肉内或其他),药物指定运送途径的药代动力学性质,以及给药速度(推注或连续输注)和给药方案(给定时间内的重复次数)。
本发明的偶联物还能够以单位剂量形式给药,其中术语“单位剂量”是指能够给予患者的单次剂量,并且可以很容易地处置和包装,保持物理和化学上稳定的剂量,它含有活性偶联物本身或如下文所述的药学上可接受的组合物。典型的每日/周/双周/月总剂量范围是从0.01至100mg/kg(体重)。作为一般指导原则,人的单位剂量其范围为每天,每周,每两周,每三周或者每月1mg到3000mg。单位剂量范围优选1至500mg,一周一次至四次,更优选为1mg至100mg,一周一次,两周一次,三周一次或每月一次。本文提供的偶联物可以通过与一种或多种药学上可接受的赋形剂混合而配制成药物组合物。这样的单位剂量组合物可以通过口服给药,如片剂,简单胶囊或软凝胶胶囊的形式的药物;或鼻内给药,如粉剂,滴鼻剂或气雾剂的药物;或皮肤给药,如使用局部用软膏,乳膏,乳液,凝胶或喷雾剂或通过透皮贴剂给药。
药物/细胞毒素分子
可以与本发明中的细胞结合分子偶联的药物是包括细胞毒性剂在内的小分子药物,它们可以被连接到,或者被修饰后连接到细胞结合剂上。这里的“小分子药物”在本文中广泛用于指有机,无机或有机金属化合物,其可具有例如100至2500,更合适地为120至1500的分子量。这些小分子药物在本领域文献中已被充分描述,如WO05058367A2和美国专利4,956,303等,此处引作参考。小分子药物包括已知的药物和即将被公开的药物。
已知的药物包括,但不限于:
1)化疗剂:a)烷基化剂,如氮芥:氯苯那普,氯普那嗪,环磷酰胺,达卡巴嗪,雌二醇氮芥,异环磷酰胺,氮芥,盐酸二甲氧胺,氧化二氮芥,盐酸氨氯地平,麦考酚酸,卫矛醇,哌泊溴烷,新氮芥,苯芥胆甾醇,松龙苯芥,噻替哌,曲磷胺对,尿嘧啶;CC-1065(包括其阿多来新,卡折来新和比折来新合成类似物);多卡霉素(包括合成类似物KW-2189和CBI-TMI);苯并二氮卓二聚体(例如吡咯并苯二氮卓(PBD)或托美霉素,吲哚并苯并二氮卓,咪唑并苯并噻二氮卓或恶唑烷并苯并二氮卓的二聚体);亚硝基脲(卡莫司汀,洛莫司汀,氯化梭菌素,福莫司汀,尼莫司汀,拉莫司汀);烷基磺酸盐(白消安,硫丹,硫丹和硫磺);三氮烯(达卡巴嗪);含铂化合物(卡铂,顺铂,澳沙利铂);吖丙啶类,如苯并二氢吡喃酮,卡洛酮,美妥替派和乌雷多巴;乙烯亚胺和甲基三聚氰胺,包括六甲蜜胺,三亚乙基三胺,三乙基磷酰胺,三亚乙基硫代磷酰胺和三羟甲基甲基胺;b)植物生物碱:如长春花生物碱(长春新碱,长春碱,长春地辛,长春瑞滨,去甲长春碱);紫杉烷(紫杉醇,多西紫杉醇)及其类似物;美登素(DM1,DM2,DM3,DM4,美登素和安沙霉素)及其类似物;cryptophycin(特别是cryptophycin 1和cryptophycin 8);埃博霉素,软珊瑚醇,迪莫利德,草苔虫内酯,海兔毒素,澳瑞他汀,tubulysin,cephalostatin,pancratistatin,sarcodictyin,海绵抑制素;c)DNA拓扑异构酶抑制剂,例如依托泊苷替尼(9-氨基喜树碱,喜树碱,克立那托,道诺霉素,依托泊苷,磷酸依托泊苷,伊立替康,米托蒽醌,诺消灵,视黄酸(视黄醇),替尼泊苷,拓扑替康,9-硝基喜树碱(RFS 2000));丝裂霉素(丝裂霉素C);d)抗代谢物,例如抗叶酸剂,DHFR抑制剂(甲氨蝶呤,曲麦克特,二甲叶酸,蝶罗呤,氨喋呤(4-氨基苯甲酸)或其他叶酸类似物);IMP脱氢酶抑制剂(麦考酚酸,噻唑呋林,利巴韦林,EICAR);核糖核苷酸还原酶抑制剂(羟基脲,去铁胺);嘧啶类似物,尿嘧啶类似物(安西他滨,阿扎胞苷,6-氮尿嘧啶,卡培他滨(希罗达),卡莫氟,阿糖胞苷,双脱氧尿苷,去氧氟尿苷,依诺他滨,5-氟尿嘧啶,氟尿苷,ratitrexed(Tomudex);胞嘧啶类似物(阿糖胞苷,胞嘧啶阿拉伯糖苷,氟达拉滨);嘌呤类似物(硫唑嘌呤,氟达拉滨,巯嘌呤,硫胺素,硫鸟嘌呤);叶酸补充剂,如弗洛林酸;e)激素疗法剂,如受体拮抗剂,抗雌激素(甲地孕酮,雷洛昔芬,他莫昔芬),LHRH兴奋剂(戈斯他林,醋酸亮丙瑞林);抗雄激素药(比卡鲁胺,氟他胺,卡鲁司酮,丙酸倍他雄酮,表雄甾醇,戈舍瑞林,亮丙瑞林,美替利定,尼鲁米特,睾内酯,曲洛司坦及其他雄激素抑制剂);维甲类化合物,维生素D3类似物(CB1093,EB1089KH1060,胆钙化醇,麦角钙化甾醇);光动力疗法剂(维替泊芬,酞菁,光敏剂Pc4,去甲氧基-竹红菌素A);细胞因子(干扰素-α,干扰素-γ,肿瘤坏死因子(TNF),含TNF的人蛋白);f)激酶抑制剂,如BIBW 2992(抗-EGFR/Erb2),伊马替尼,吉非替尼,哌加他尼,索拉非尼,达沙替尼,舒尼替尼,厄洛替尼,尼洛替尼,拉帕替尼,阿西替尼,帕唑帕尼,凡德他尼,E7080(抗VEGFR2),mubritinib,普纳替尼(AP24534),bafetinib(INNO-406),bosutinib(SKI-606),卡博替尼,维莫德吉,iniparib,鲁索利替尼,CYT387,阿西替尼,tivozanib,索拉非尼,贝伐单抗,西妥昔单抗,曲妥珠单抗,雷珠单抗,帕尼单抗,伊斯平斯;g)聚(ADP核糖)聚合酶(PARP)抑制剂,如澳拉帕里、尼拉帕里、尼帕里、他拉唑帕里、维利帕里、维利帕里、CEP 9722(Cephalon)、E7016(Eisai)、BGB-290(BeiGene)、3-氨基苯甲酰胺。h)抗生素,如烯二炔类抗生素(加利车霉素,特别是加利车霉素γ1,δ1,α1和β1(参考J.Med.Chem.1996,39(11),2103-2117;Angew Chem Intl.Ed.Engl.1994,33:183-186),达因霉素,包括达因霉素A和脱氧米霉素,埃斯培拉霉素,卡达霉素,C-1027,maduropeptin以及新制癌菌素发色团和相关色蛋白烯二炔抗生素发色团),aclacinomysins,放线菌素,安曲霉素,重氮丝氨酸,博来霉素,卡诺霉素,卡拉霉素,洋红霉素,嗜癌素,阿霉素,阿霉素,吗啉代阿霉素,2-吡咯啉阿霉素和脱氧柔红霉素,表柔比星,阿柔比星,伊达比星,马可霉素,霉素,霉酚酸,洛匹霉素,培洛霉素,培洛霉素,嘌呤霉素,三铁阿霉素,阿霉素,链脲霉素,链脲佐菌素,杀结核菌素,乌苯美司,净司他丁,佐柔比星;i)其他,如聚酮化合物(番荔素),特别是bullatacin和bullatacinone,吉西他滨,环氧酶素(如卡菲偌米布),硼替佐米,沙利度胺,来那度胺,pomalidomide,tosedostat,zybrestat,PLX4032,STA-9090,Stimuvax,allovectin-7,Xegeva,Provenge,Yervoy,异戊二烯化抑制剂(如洛伐他汀),多巴胺能神经毒素(如星形孢菌素),放线菌素(如放线菌素D,更生霉素),博莱霉素(如博来霉素A2,博莱霉素B2,培洛霉素),蒽环类抗生素(如柔红霉素),阿霉素(亚德里亚霉素),伊达比星,表柔比星,吡柔比星,佐柔比星,米托蒽醌,MDR抑制剂(如维拉帕米),Ca2+ATP酶抑制剂(如毒胡萝卜素),组蛋白去乙酰酶抑制剂(伏立诺他,罗米地辛,帕比司他,丙戊酸,Mocetinostat(MGCD0103),Belinostat,PCI-24781,恩替诺特,SB939,Resminostat,Givinostat,AR-42,CUDC-101,萝卜硫素,曲古抑菌素A);塞来昔布,格列酮类,表没食子儿茶素没食子酸酯,双硫仑,Salinosporamide A;抗肾上腺药物,如氨鲁米特,米托坦,曲洛司坦,醋葡醛内酯,醛磷酰胺,氨基乙酰丙酸,安吖啶,阿拉伯糖苷,bestrabucil,比生群,edatraxate,defofamine,美可辛,地吖醌,依氟鸟氨酸(DFMO),elfomithine,依利醋铵,乙基葡糖酸,硝酸镓,胞嘧啶,羟基脲,伊班膦酸盐,香菇多糖,氯尼达明,米托胍腙,米托蒽醌,莫哌达醇,二胺硝吖啶,喷司他丁,蛋氨氮芥,吡柔比星,鬼臼酸,2-乙肼,甲基苄肼,哌嗪二酮丙烷,根霉素,西佐,螺环锗,细格孢氮杂酸,三亚胺醌,三氯三乙胺,单端孢霉烯(特别是T-2毒素,疣孢菌素A,杆孢菌素A和anguidine),聚氨酯,siRNA,反义药物和核酸分解酶。
2)自身免疫疾病药物,包括但不限于环孢菌素,环孢菌素A,氨基己酸,硫唑嘌呤,溴隐亭,苯丁酸氮芥,氯喹,环磷酰胺,皮质类固醇(例如安西奈德,地塞米松,曲安奈德,丙酸倍氯米松,DHEA,依那西普,羟基氯喹,英夫利昔单抗,美洛昔康,甲氨蝶呤,麦考酚酸酯,泼尼松,西罗莫司,他克莫司。
3)抗感染性疾病药物,包括但不限于a)氨基糖苷类:阿米卡星,阿司米星,庆大霉素(奈替米星,西索米星,异帕米星),潮霉素B,卡那霉素(阿米卡星,阿贝卡星,氨基去氧卡那霉素,地贝卡星,妥布霉素),新霉素(framycetin,巴龙霉素,核糖霉素),奈替米星,壮观霉素,链霉素,妥布霉素,甲基姿苏霉素;b)酰胺醇类:叠氮氯霉素,氯霉素,氟苯尼考,甲砜霉素;c)安沙霉素:格尔德霉素,除莠霉素;d)碳青霉烯类:比阿培南,多利培南,厄他培南,亚胺培南/西司他丁,美罗培南,帕尼培南;e)头孢烯:碳头孢烯(洛拉卡比),头孢乙腈,氯氨苄青霉素,头孢拉定,头孢羟氨,头孢洛宁,头孢噻啶,头孢噻吩或头孢金素,头孢氨苄,头孢来星,头孢孟多,头孢匹林,羟胺唑头孢菌素,氟唑头孢菌素,孢西酮,唑啉头孢菌素,头孢拉宗,头孢卡品,头孢达肟,头孢吡,头孢克肟,头孢西丁,头孢罗齐,头孢甲氧环烯胺,头孢替唑,头孢呋辛,头孢克肟,头孢地尼,头孢托仑,头孢吡,头孢他美,头孢甲肟,头孢地嗪,头孢尼西,头孢哌酮,头孢雷特,头孢噻肟,噻乙胺唑头孢菌素,头孢唑兰,头孢氨苄,头孢咪唑,头孢匹胺,头孢匹罗,头孢泊肟,头孢罗齐,头孢喹诺,头孢磺啶,头孢他啶,头孢特仑,头孢布腾,头孢噻林,头孢唑肟,头孢吡普,头孢曲松,头孢呋辛,头孢唑南,头霉素(头孢西丁,头孢替坦,头孢氰唑),氧(碳)头孢烯(氟氧头孢,头孢);f)糖肽:博来霉素,万古霉素(澳利万星,特拉万星),替考拉宁(达巴万星),雷莫拉宁,g)甘氨酰环素:如替加环素,h)β-内酰胺酶抑制剂:青霉烷(舒巴坦,他唑巴坦),氧青霉烷(克拉维酸);i)林可酰胺:克林霉素,林可霉素;j)脂肽:达托霉素,A54145,钙依赖性抗生素(CDA);k)大环内酯类:阿奇霉素,克霉素,克拉霉素,地红霉素,红霉素,氟雷霉素,交沙霉素,酮内酯(泰利霉素,塞红霉素),麦迪霉素,米卡霉素,竹桃霉素,利福霉素(异烟肼、利福平,利福布丁,利福喷汀),罗匹霉素,罗红霉素,大观霉素,螺旋霉素,他克莫司(FK506),醋竹桃霉素,泰利霉素;l)单环胺:氨曲南,替吉莫南;m)恶唑烷酮类:利奈唑胺;n)青霉素类:阿莫西林,氨苄青霉素(匹氨西林,海洛西林,巴氨西林,氨苄青霉素,阿霉素),阿替代西林,阿洛西林,苄青霉素,苄星青霉素苄青霉素,苄星青霉素苯氧甲基青霉素,克洛西林,普鲁卡因青霉素(美替西林),美洛西林,甲氧西林,萘夫西林,苯唑西林,醋甲西林,青霉素,非奈西林,苯氧基甲基青霉素,哌拉西林,氨苄西林,磺苯西林,替莫西林,替卡西林;o)多肽:杆菌肽,粘菌素,多粘菌素B,p)喹诺酮类:阿拉曲沙星,巴洛沙星,环丙沙星,克林沙,达氟沙星,二氟沙星,依诺沙星,恩诺沙星,加雷沙星,加替沙星,吉米沙星,格帕沙星,卡诺曲伐沙星,左氧氟沙星,洛美沙星,麻保沙星,莫西沙星,那氟沙星,诺氟沙星,澳比沙星,氧氟沙星,培氟沙星,曲伐沙星,格帕沙星,西他沙星,司帕沙星,替马沙星,托沙星,曲伐沙星;q)链阳性菌素:普那霉素,奎奴普丁/达福普汀,r)磺胺类药物:磺胺类药物:磺胺类药物,磺胺嘧啶,磺胺嘧啶,磺胺嘧啶,柳氮磺胺吡啶,磺胺异恶唑,三苯氧胺,甲氧苄氨嘧啶-磺胺甲恶唑(复方新诺明);s)类固醇抗菌药物:如夫西地酸;t)四环素类:强力霉素,金霉素,氯米西环素,地美环素,雷莫昔林,美西环素,美他环素,米诺环素,土霉素,青霉素V钾哌四环素,吡咯烷甲基四环素,四环素,甘氨酰环素(如替加环素):u)其他类型的抗生素:番荔枝素,胂凡纳明,细菌萜醇抑制剂(杆菌),DANAL/AR抑制剂(环丝氨酸),dictyostatin,圆皮海绵内酯,软珊瑚醇,埃博霉素,乙胺丁醇,依托泊苷,法罗培南,夫西地酸,呋喃唑酮,异烟肼,laulimalide,甲硝唑,莫匹罗星,NAM合成抑制剂(例如磷霉素),呋喃妥因,紫杉醇,普兰西霉素,吡嗪酰胺,奎奴普丁/达福普汀,利福平(利福平),他唑巴坦替硝唑,乌菊花素。
4)抗病毒药物:a)进入/融合抑制剂:阿帕韦洛,马拉韦罗,vicriviroc,gp41(恩夫韦肽),PRO 140,CD4(艾巴利珠单抗);b)整合酶抑制剂:雷特格韦,elvitegravir,globoidnan A;c)成熟抑制剂:bevirimat,vivecon;d)神经氨酸酶抑制剂:澳司他韦,扎那米韦,帕拉米韦;e)核苷和核苷酸:阿巴卡韦,阿昔单韦,阿德福韦,阿莫西韦,阿昔单抗,溴夫定,西多福韦,克拉夫定,地塞米松,去羟肌苷(ddI),elvucitabine,恩曲他滨(FTC),恩替卡韦,泛昔洛韦,氟拉西林(5-FU),3’-氟取代的2’,3’-脱氧核苷类似物(如3,3’-氟-2′,3′-双脱氧胸苷(FLT)和3’-氟-2’,3’-双脱氧鸟苷(FLG),福米韦生,9-鸟嘌呤,碘苷,拉米夫定(3TC),1-核苷(例如β-1-胸苷和β-1-2’-脱氧胞苷),喷昔洛韦,racivir,利巴韦林,迪替丁,司他夫定(d4T),塔利巴韦林(viramidine),替比夫定,替诺福韦,三氟尿苷伐昔洛韦,缬更昔洛韦,扎西他滨(ddC),齐多夫定(AZT);f)非核苷类:金刚烷胺,阿替吡啶,卡普韦林,二芳基嘧啶(依曲韦林,rilpivirine),地拉夫定,二十二烷醇,乙米韦林,依法韦仑,膦甲酸(磷酰基甲酸),咪喹莫特,聚乙二醇干扰素,洛韦胺,洛德腺苷,甲吲噻腙,奈韦拉平,NOV-205,长效干扰素α,鬼臼毒素,利福平,金刚乙胺,瑞喹莫德(R-848),醋胺金刚烷;g)蛋白酶抑制剂:安普那韦阿扎那韦,boceprevir,darunavir,福沙那韦,印地那韦,洛匹那韦,奈非那韦,普来可那立,利托那韦,沙奎那韦,telaprevir(VX-950),替拉那韦;h)其它类型的抗病毒药物:抗氧化酶,阿比朵尔,卡拉诺莱德,ceragenin,氰维林-n,二芳基嘧啶,表没食子儿茶素没食子酸酯(EGCG),膦甲酸,格里菲辛,taribavirin(viramidine),羟基脲,KP-1461,米替福新,普来可那立,混成抑制剂,利巴韦林,seliciclib。
5)通过本发明的连接体连接的药物也包括放射性同位素。放射性同位素(放射性核素)的实例有3H,11C,14C,18F,32P,35S,64Cu,68Ga,86Y,99Tc,111In,123I,124I,125I,131I,133Xe,177Lu,211At或213Bi。放射性同位素标记的抗体可用于受体靶向成像实验,或者可用于如本发明的抗体-药物偶联物的靶向治疗(Wu等Nature Biotechnology 2005,23(9):1137-1146)。细胞结合分子,例如抗体可以通过本专利申请的连接体连接配体试剂,进行标记。配体可以用文献(Current Protocols in Immunology,Volumes 1和2,Coligen等,Ed.Wiley-Interscience,New York,N.Y.,Pubs.(1991))所述的方法与放射性金属结合、螯合或生成复合物。可以络合金属离子的螯合配体包括DOTA,DOTP,DOTMA,DTPA和TETA(Macrocyclics,Dallas,TX)等。
6)上述任何药物的药学上可接受的盐,酸或衍生物。
在另一个实施例中,结构式(II)和(IV)中的药物可以是发色分子,偶联物可用于检测,监测或研究细胞结合分子与靶细胞的相互作用。发色分子可以吸收一种光,如紫外光,荧光,红外光,近红外光或可见光;发色分子包括黄色素,红细胞,虹彩色素,白细胞,黑色素和蓝绿色素的一类或一个亚类,荧光分子(吸收光后再发光的荧光化学物质)的一类或一个亚类,视觉光转导分子的一类或一个亚类,光子分子的一类或一个亚类,冷光分子的一类或一个亚类和荧光素化合物的一类或一个亚类。
发色分子可选自但不限于,非蛋白质有机荧光团,例如氧杂蒽衍生物(荧光素,罗丹明,俄勒冈绿,伊红和德克萨斯红);花青衍生物(花青,吲哚羰花青,氧杂花青,硫代花青和部花青);方酸衍生物和环取代的方酸,包括Seta,SeTau和Square染料;萘衍生物(丹酰和氟硅酸钠衍生物);香豆素衍生物;恶二唑衍生物(吡啶基恶唑,硝基苯并恶唑和苯并恶二唑);蒽衍生物(蒽醌类,包括DRAQ5,DRAQ7和CyTRAK橙);芘衍生物(级联蓝等);恶嗪衍生物(尼罗红,尼罗蓝,甲酚紫,恶嗪170等);吖啶衍生物(黄醇黄素,吖啶橙,吖啶黄等);芳基甲胺衍生物(金胺,结晶紫,孔雀石绿)和四吡咯衍生物(卟吩,酞菁,胆红素)。
生色分子选自以下荧光化合物的任何类似物和衍生物:CF染料(Biotium),DRAQ和CyTRAK探针(BioS-tatus),BODIPY(Invitrogen),Alexa Fluor(Invitrogen),DyLightFluor(Thermo Scientific,Pierce),Atto和Tracy(Sigma Aldrich),FluoProbes(Interchim),Abberior染料(Abberior),DY和MegaStokes染料(Dyomics),Sulfo Cy染料(Cyandye),HiLyte Fluor(AnaSpec),Seta,SeTau和Square染料(BiosearchTechnologies),SureLight染料(APC,RPEPerCP,Phycobilisomes)(ColumbiaBiosciences),APC,APCXL,RPE,BPE(Phyco-Biotech)。
广泛使用的可与本发明连接体反应或偶联的荧光化合物的实例有:别藻蓝蛋白(APC),氨基胭脂蛋白,APC-Cy7偶联物,BODIPY-FL,Cascade Blue,Cy2,Cy3,Cy3.5,Cy3B,Cy5,Cy5.5,Cy7,荧光素,FluorX,羟基香豆素,丽丝胺罗丹明B,萤光黄,Me-甲氧基香豆素,NBD,Pacific Blue,Pacific Orange,PE-Cy5偶联物,PE-R-藻红蛋白(PE),Red 613,Seta-555-Azide,Seta-555-DBCO,Seta-555-NHS,Seta-580-NHS,Seta-680-NHS,Seta-APC-780,Seta-PerCP-680,Seta-R-PE-670,SeTau-380-NHS,SeTau-405-马来酰亚胺,SeTau-405-NHS,SeTau-425-NHS,SeTau-647-NHS,Texas Red,TRITC,TruRed,X-Rhodamine。
可以与本发明的连接体相连,用于研究核酸或蛋白质的荧光化合物,选自下列化合物或其衍生物:7-AAD(7-氨基放线菌素D,CG-选择性的),吖啶橙,色霉素A3,CyTRAK橙(Biostatus),DAPI,DRAQ5,DRAQ7,溴化乙锭,Hoechst33258,Hoechst33342,LDS 751,光辉霉素,碘化丙啶(PI),SYTOX蓝,SYTOX绿,SYTOX橙,噻唑橙,TO-PRO,菁染料单体,TOTO-1,TO-PRO-1,TOTO-3,TO-PRO-3,YOSeta-1,YOYO-1。可以与本发明的连接体相连,用于研究细胞的荧光化合物,选自下列化合物或其衍生物:DCFH(2’,7’-二氯二氢荧光素,氧化形式),DHR(二氢罗丹明123,氧化形式,光催化氧化),Fluo-3(AM酯,pH>6),Fluo-4(AM酯,pH7.2),Indo-1(AM酯,低/高钙(Ca 2+)),SNARF(pH 6/9)。优选的荧光化合物选自:别藻蓝蛋白(APC),AmCyan1(四聚体,Clontech),AsRed2(四聚体,Clontech),蓟绿(单体,MBL),Azurite,B-藻红蛋白(BPE),Cerulean,CyPet,DsRed单体(Clontech),DsRed2(RFP,Clontech),EBFP,EBFP2,ECFP,EGFP(弱二聚体,Clontech),Emerald(弱二聚体,Invitrogen),EYFP(弱二聚体,Clontech),GFP(S65A突变),GFP(S65C突变),GFP(S65L突变)GFP(Y66H突变),GFP(Y66W突变),GFPuv,HcRed1,J-Red,Katusha,Kusabira Orange(单聚体,MBL),mCFP,mCherry(单体,MBL),mKate(TagFP635,单体,Evrogen),mKeima-Red(单体,MBL),mKO,mOrange,mPlum,mRaspberry,mRFP1(单体,Tsien实验室),mStrawberry,mTFP1,mTurquoise2,P3(藻胆体复合物),多甲藻黄素-叶绿素-蛋白质复合物(PerCP),R-phycoerythrin(RPE),T-Sapphire,TagCFP(二聚体,Evrogen),TagGFP(二聚体,Evrogen),TagRFP(二聚体,Evrogen),TagYFP(二聚体,Evrogen),tdTomato(串联二聚体),Topaz,TurboFP602(二聚体,Evrogen),TurboFPP635(二聚体,Evrogen),TurboGFP(二聚体,Evrogen),TurboRFP(二聚体,Evrogen),TurboYFP(二聚体,Evrogen),Venus,野生型GFP型,YPet,ZsGreen1(四聚体,Clontech),ZsYellow1(四聚体,Clontech)。
通过本发明的连接体连接的抗体-发色团分子偶联物的实例如Ac01,Ac02,Ac03,Ac04,Ac05,Ac06,和Ac07所示:
在另一个实施例中,式(I)和(II)中的药物分子是聚乙烯二醇类分子,可用于哺乳动物给药时,延长细胞结合分子半衰期。聚乙烯二醇类分子包括但不限于聚(乙二醇)(PEG),聚(丙二醇)以及环氧乙烷和环氧丙烷的共聚物;特别优选的是PEG,更优选的是单官能活化的羟基PEG(例如,在单个末端活化的羟基PEGs,包括羟基PEG-单羧酸的活性酯,羟基PEG-单醛,羟基PEG-单胺,羟基PEG-单酰肼,羟基PEG-单肼基甲酸酯,羟基PEG-单碘乙酰胺,羟基PEG-单马来酰亚胺,羟基PEG-单原甲基吡啶基二硫化物,羟基PEG-单肟,羟基PEG-单苯基碳酸酯,羟基PEG-单苯基乙二醛,羟基PEG-单噻唑烷-2-硫酮,羟基PEG-单硫代酯,羟基PEG-单巯基,羟基PEG-单三嗪和羟基PEG-单乙烯基砜)。
在某些这样的实施例中,聚乙烯二醇分子量为约10Da至约200kDa,优选约88Da至约40kDa的;两个分支,每个分子具有约88Da至约40kDa的分子量;更优选两个分支,每个分支约88Da至约20kDa。在一个具体的实施例中,聚乙烯二醇类分子是聚乙二醇并且具有约10kDa的分子量;约20kDa,或约40kDa。在具体的实施方案中,PEG是PEG 10kDa(线性或分支),PEG 20kDa(线性或分支)或PEG 40kDa(线性或分支)。许多美国专利公公布了直链或支链“非抗原性”PEG聚合物及其衍生物或其偶联物的制备,例如,美国专利5428128;5621039;5622986;5643575;5728560;5730990;5738846;5811076;5824701;5840900;5880131;5900402;5902588;5919455;5951974;5965119;5965566;5969040;5981709;6011042;6042822;6113906;6127355;6132713;6177087和6180095.通过连接体连接的抗体-聚乙烯二醇偶联物的结构如Pg01,Pg02和Pg03所示:
其中mAb是抗体;R’是H或CH3;m3是1至5000的整数;R3是OH,H或R1;表示单键或双键;m1,m2,n,L1,L2,X1,X2,R1,R2,和R与式(I)和(II)中定义的相同。另外,R1和R3可以独立地为H,OH,OCH3或OC2H5;p是1-2000;Drug1与式(III)中定义相同。
在另一个实施方案中,通过本专利申请的连接体连接至细胞结合分子的优选细胞毒性剂是tubulysin类,美登木素生物碱类,紫杉烷类(taxanes),CC-1065类似物,柔红霉素或多柔比星化合物,鹅膏毒肽,苯并二氮卓类二聚体(例如吡咯并苯二氮卓(PBD)的二聚体,托美霉素,氨茴霉素,吲哚并苯并二氮杂二聚体,咪唑并苯并二氮杂二聚体,或者恶唑烷苯并二氮杂卓),加利车霉素或烯二炔抗生素,放线菌素,重氮丝氨酸,博来霉素,表柔比星,艾日布林,他莫昔芬,伊达比星,多拉司他汀,澳瑞他汀衍生物(例如MMAE,MMAF,澳瑞他汀PYE,澳瑞他汀TP,澳瑞他汀2-AQ,6-AQ,EB(AEB)和EFP(AEFP))及其类似物,多卡霉素,格尔德霉素,甲氨喋呤,噻替派,长春地辛,长春新碱,半米塔林,nazumamides,microginin,放射敏素,链霉素,SN38或喜树碱的其他类似物或代谢物,alterobactins,microsclerodermins,theonellamides,esperamicin,PNU-159682,和它们的类似物及其衍生物。
Tubulysin化合物优选用于本发明中偶联物,它是本领域公知的,并且可以根据已知方法从天然来源分离,或者根据已知方法合成制备,如Balasubramanian,R.,等J.Med.Chem.,2009,52,238–40;Wipf,P.,等Org.Lett.,2004,6,4057–60;Pando,O.,等J.Am.Chem.Soc.,2011,133,7692–5;Reddy,J.A.,等Mol.Pharmaceutics,2009,6,1518–25;Raghavan,B.,等J.Med.Chem.,2008,51,1530–33;Patterson,A.W.,等J.Org.Chem.,2008,73,4362–9;Pando,O.,等Org.Lett.,2009,11(24),5567–9;Wipf,P.,等Org.Lett.,2007,9(8),1605–7;Friestad,G.K.,Org.Lett.,2004,6,3249–52;Peltier,H.M.,等J.Am.Chem.Soc.,2006,128,16018–9;Chandrasekhar,S.,等J.Org.Chem.,2009,74,9531–4;Liu,Y.,等Mol.Pharmaceutics,2012,9,168–75;Friestad,G.K.,等Org.Lett.,2009,11,1095–8;Kubicek,K.,等,Angew Chem Int Ed Engl,2010.49:4809-12;Chai,Y.,等,ChemBiol,2010,17:296-309;Ullrich,A.,等,Angew Chem Int Ed Engl,2009,48,4422-5;Sani,M.,等Angew Chem Int Ed Engl,2007,46,3526-9;Domling,A.,等,Angew Chem IntEd Engl,2006,45,7235-9;专利申请:Zanda,M.,等,Can.Pat.Appl.CA 2710693(2011);Chai,Y.,等Eur.Pat.Appl.2174947(2010),WO 2010034724;Leamon,C.等,WO2010033733,WO 2009002993;Ellman,J.,等,PCT WO2009134279;WO 2009012958,USappl.20110263650,20110021568;Matschiner,G.,等,WO2009095447;Vlahov,I.,等,WO2009055562,WO 2008112873;Low,P.,等,WO2009026177;Richter,W.,WO2008138561;Kjems,J.,等,WO 2008125116;Davis,M.;等,WO2008076333;Diener,J.;等,U.S.Pat.Appl.20070041901,WO2006096754;Matschiner,G.,等,WO2006056464;Vaghefi,F.,等,WO2006033913;Doemling,A.,德国专利DE102004030227,WO2004005327,WO2004005326,WO2004005269;Stanton,M.,等,美国专利20040249130;Hoefle,G.,等,德国专利DE10254439,DE10241152,DE10008089;Leung,D.,等,WO2002077036;Reichenbach,H.,等,德国专利DE19638870;Wolfgang,R.,US20120129779;Chen,H.,美国专利20110027274等。专利申请PCT/IB2012/053554中描述了用于与细胞结合分子偶联的tubulysin化合物的优选结构。
通过本发明的连接体连接的抗体-tubulysin类似物的偶联物的结构示例如T01,T02,T03,T04,T05,T06 T07,T08,T09,T10和T11:
其中mAb是抗体或细胞结合分子;n,m1,m2,Drug1,X1,X2,L1,L2,L3,R1,R2,R3,R4和R5与式(I)和(II)中的定义相同;优选地,R1,R2,R3,和R4独立地为H,C1-C8直链或支链烷基,芳基,杂芳基,杂烷基,烷基环烷基,酯,醚,酰胺,胺,杂环烷基或酰氧基胺;或含有1-8个氨基酸的肽或如式(OCH2CH2)p或(OCH2CH(CH3))p的聚氧乙烯单元,其中p是1至约2000的整数。两个R,R1R2,R2R3,R1R3或R3R4可以形成3~8元环烷基,芳基,杂芳基,杂烷基或烷基环烷基;X3为H,CH3或X1’R1’,其中X1’为NH,N(CH3),NHNH,O或S,R1’为H,C1-C8直链或支链烷基,芳基,杂芳基,杂烷基,烷基环烷基,酰氧基胺;R3’是H,C1-C6直链或支链烷基;p为0-2000;Z3为H,OH,OP(O)(OM1)(OM2),OCH2OP(O)(OM1)(OM2),OSO3M1,R1,或O-糖苷(葡萄糖苷,半乳糖苷,甘露糖苷,葡萄糖醛酸苷/葡糖苷酸,异香糖苷,果糖苷等),NH-糖苷,S-糖苷或CH2-糖苷;表示单键或双键;M1和M2独立地为H,Na,K,Ca,Mg,NH4,NR1R2R3;此外,R1’可以是在本专利申请中所描述的细胞毒性剂。
加利车霉素及其相关的烯二炔抗生素优选用于本专利申请中细胞结合分子-药物偶联物,相关文献包括Nicolaou,K.C.等,Science 1992,256,1172-1178;Proc.Natl.Acad.Sci USA.1993,90,5881-8),美国专利4970198;5053394;5108912;5264586;5384412;5606040;5712374;5714586;5739116;5770701;5770710;5773001;5877296;6015562;6124310;8153768。通过连接体连接的抗体-加利车霉素类似物偶联物的结构示例如C01和C02:
其中mAb是抗体或细胞结合分子;n,m1,X1,L1,L2,和R1与式(I)和(II)中定义相同;R1’和R3’独立地为H或C1-C6直链或支链烷基;p是0-2000。此外,R1’可以是本发明中描述的细胞毒性剂。
美登木素生物碱包括美登醇及其类似物优选用于本发明,相关描述见于美国专利4256746,4361650,4307016,4294757,4294757,4371533,4424219,4331598,4450254,4364866,4313946,4315929 4362663,4322348,4371533,4424219,5208020,5416064,5208020,5416064,6333410,6441163,6716821,7276497,7301019,7303749,7368565,7411063,7851432和8163888。通过本专利申请的连接体连接的抗体-美登木素生物碱偶联物结构示例如My01,My02和My03:
其中mAb是抗体或细胞结合分子;n,m1,X1,L1,L2,和R1与式(I)和(II)中定义相同;R1’和R3’独立地为H或C1-C6直链或支链烷基;p是0-2000。此外,R1’可以是本发明中描述的细胞毒性剂。
紫杉烷,包括紫杉醇(Taxol),一种细胞毒性天然产物,和多西紫杉醇(Taxotere),一种半合成衍生物,以及它们的类似物优选用于以本专利申请的连接体连接的偶联物,其描述可见于K C.Nicolaou等,J.Am.Chem.Soc.117,2409-20,(1995);Ojima等,J.Med.Chem.39:3889-3896(1996);40:267-78(1997);45,5620-3(2002);Ojima等,Proc.Natl.Acad.Sci.,96:4256-61(1999);Kim等,Bull.Korean Chem.Soc.,20,1389-90(1999);Miller,等J.Med.Chem.,47,4802-5(2004);美国专利5475011;5728849;5811452;6340701;6372738;6391913,6436931;6589979;6596757;6706708;7008942;7186851;7217819;7276499;7598290和7667054。通过本专利申请的连接体连接的抗体-紫杉烷偶联物的结构示例如Tx01,Tx02和Tx03:
其中mAb是抗体或细胞结合分子;表示单键或双键;n,m1,X1,L1,L2,和R1与式(I)和(II)中定义的相同;R1’和R3’独立地为H或C1-C6直链或支链烷基;p为0-2000;此外,R1’可以是本专利申请中描述的细胞毒性剂。
CC-1065类似物和多卡霉素类似物也优选用于以本专利申请的连接体连接的偶联物。CC-1065类似物和多卡霉素类似物的实例及其合成记载于Warpehoski,等,J.Med.Chem.31:590-603(1988);D.Boger等,J.Org.Chem;66;6654-61,2001;美国专利4169888,4391904,4671958,4816567,4912227,4923990,4952394,4975278,4978757,4994578,5037993,5070092,5084468,5101038,5117006,5137877,5138059,5147786,5187186,5223409,5225539,5288514,5324483,5332740,5332837,5334528,5403484,5427908,5475092,5495009,5530101,5545806,5547667,5569825,5571698,5573922,5580717,5585089,5585499,5587161,5595499,5606017,5622929,5625126,5629430,5633425,5641780,5660829,5661016,5686237,5693762,5703080,5712374,5714586,5739116,5739350,5770429,5773001,5773435,5786377 5786486,5789650,5814318,5846545,5874299,5877296,5877397,5885793,5939598,5962216,5969108,5985908,6060608,6066742,6075181,6103236,6114598,6130237,6132722,6143901,6150584,6162963,6172197,6180370,6194612,6214345,6262271,6281354,6310209,6329497,6342480,6486326,6512101,6521404,6534660,6544731,6548530,6555313,6555693,6566336,6,586,618,6593081,6630579,6756397,6759509,6762179,6884869,6897034,6946455,7049316,7087600,7091186,7115573,7129261,7214663,7223837,7304032,7329507,7329760,7388026,7655660,7655661,7906545,和8012978。通过本专利申请的连接体连接的抗体-CC-1065类似物的偶联物的结构示例如CC01,CC02和CC03:
其中mAb是抗体;Z3为H,PO(OM1)(OM2),SO3M1,CH2PO(OM1)(OM2),CH3N(CH2CH2)2NC(O)-,O(CH2CH2)2NC(O)-,R1,或糖苷;X3为O,NH,NHC(O),OC(O),-C(O)O,R1或缺省;表示单键或双键;n,m1,m2,“-,”X1,X2,R1,R2与式(I)和(II)中的定义相同;R1’和R3’独立地为H或C1-C6直链或支链烷基;p是0-2000。此外,R1’可以是在本专利申请中描述的细胞毒性剂。
柔红霉素/多柔比星类似物也优选用于以本专利申请的连接体连接的偶联物。优选化合物的结构及其合成可见于Hurwitz,E.,等,Cancer Res.35,1175-81(1975).Yang,H.M.,和Reisfeld,R.A.,Proc.Natl.Acad.Sci.85,1189-93(1988);Pietersz,C.A.,E.,等,Cancer Res.48,926-311(1988);Trouet,等,79,626-29(1982);Z.Brich等,J.ControlledRelease,19,245-58(1992);Chen等,Syn.Comm.,33,2377-90,2003;King等,Bioconj.Chem.,10,279-88,1999;King等,J.Med.Chem.,45,4336-43,2002;Kratz等,J MedChem.45,5523-33,2002;Kratz等,Biol Pharm Bull.Jan.21,56-61,1998;Lau等,Bioorg.Med.Chem.3,1305-12,1995;Scott等,Bioorg.Med.Chem.Lett.6,1491-6,1996;Watanabe等,Tokai J.Experimental Clin.Med.15,327-34,1990;Zhou等,J.Am.Chem.Soc.126,15656-7,2004;WO 01/38318;美国专利5106951;5122368;5146064;5177016;5208323;5824805;6146658;6214345;7569358;7803903;8084586;8053205.通过本专利申请的连接体连接的抗体-CC-1065类似物的偶联物结构示例如Da01,Da02,Da03和Da04:
其中mAb是抗体或细胞结合分子;表示单键或双键;n,m1,X1,X2,L1,L2,和R1与式(I)和(II)中的定义相同;R1’和R3’独立地为H或C1-C6直链或支链烷基;p是0-2000。此外,R1’可以是本专利申请中描述的细胞毒性剂。
澳瑞他汀和多拉司他汀优选用于以本专利申请的连接体连接的偶联物。澳瑞他汀(如多澳瑞他汀E(AE),澳瑞他汀EB(AEB),澳瑞他汀EFP(AEFP),单甲基澳瑞他汀E(MMAE),单甲基澳瑞他汀F(MMAF),澳瑞他汀F苯二胺(AFP)和MMAE的苯丙氨酸变体)是多拉司他汀的类似物,在如下文献中有描述:Int.J.Oncol.15:367-72(1999);Molecular CancerTherapeutics,vol.3,No.8,pp.921-32(2004);美国专利11134826,20060074008,2006022925,4414205,4753894,4764368,4816444,4879278,4943628,4978744,5122368,5165923,5169774,5286637,5410024,5521284,5530097,5554725,5585089,5599902,5629197,5635483,5654399,5663149,5665860,5708146,5714586,5741892,5767236,5767237,5780588,5821337,5840699,5965537,6004934,6033876,6034065,6048720,6054297,6054561,6124431,6143721,6162930,6214345,6239104,6323315,6342219,6342221,6407213,6569834,6620911,6639055,6884869,6913748,7090843,7091186,7097840,7098305,7098308,7498298,7375078,7462352,7553816,7659241,7662387,7745394,7754681,7829531,7837980,7837995,7902338,7964566,7964567,7851437,7994135。通过桥连接体连接的抗体-澳瑞他汀偶联物结构的实例如Au01,Au02,Au03,Au04,Au05,Au06,Au07,Au08,Au09,Au10,Au11,Au12和Au13:
其中n,m1,m2,X1,X2,R1,R2,R3,R4和R5与式(I)或(II)或(III)中的定义相同;mAb是抗体或细胞结合分子;L1,L2,L3,L4,和L5定义同式(I)中L1;Z3’是H,OP(O)(OM1)(OM2),OOCCH3,OC水P(O)(OM1)(OM2),OSO3M1,R1,或O-糖苷(葡萄糖苷,半乳糖苷,甘露糖苷,葡萄糖醛酸苷,异香糖苷,果糖苷等),NH-糖苷,S-糖苷或CH2-糖苷;另外,两个R,R1R2,R2R3,R1R3或R3R4可以形成3~8元环状烷基,芳基,杂芳基,杂烷基或烷基环烷基;X3为H,CH3或X1’R1’,其中X1’为NH,N(CH3),NHNH,O或S,R1’为H或C1-C8的直链或支链烷基,芳基,杂芳基,杂烷基,烷基环烷基,酰氧基胺;R3’是H或C1-C6直链或支链烷基;p为0-2000;M1和M2独立地为H,Na,K,Ca,Mg,NH4,NR1R2R3;此外,R1’,Drug1和Drug2可以是本专利申请中描述的细胞毒性剂。
苯并二氮卓二聚体(例如吡咯并苯二氮卓(PBD),托美霉素,吲哚并苯并二氮卓,咪唑并苯并噻二氮卓或恶唑烷并苯并二氮卓的二聚体)是本发明中优选的细胞毒性分子,在本领域的文献中也有描述:美国专利8163736;8153627;8034808;7834005;7741319;7704924;7691848;7678787;7612062;7608615;7557099;7528128;7528126;7511032;7429658;7407951;7326700;7312210;7265105;7202239;7189710;7173026;7109193;7067511;7064120;7056913;7049311;7022699;7015215;6979684;6951853;6884799;6800622;6747144;6660856;6608192;6562806;6977254;6951853;6909006;6344451;5880122;4935362;4764616;4761412;4723007;4723003;4683230;4663453;4508647;4464467;4427587;4000304;美国专利申请20100203007,20100316656,20030195196。通过本发明连接体连接的的抗体-苯并二氮杂二聚体偶联物的结构示例如PB01,PB02,PB03,PB04,PB05,PB06,PB07,PB08,PB09,PB10和PB11:
其中mAb是抗体;X3是CH2,O,NH,NHC(O),NHC(O)NH,C(O),OC(O),OC(O)(NR3),R1,NHR1,NR1,C(O)R1或缺省;X4为CH2,C(O),C(O)NH,C(O)N(R1),R1,NHR1,NR1,C(O)R1 or C(O)O;M1和M2独立地为H,Na,K,Ca,Mg,NH4,NR1R2R3;表示单键或双键;n,m1,m2,X1,X2,L1,L2,R1,R2和R3与式(I)和(II)中的定义相同。R1’和R3’独立地为H或C1-C6直链或支链烷基;p是0-2000。此外,R1’可以是本专利申请中描述的细胞毒性剂。
鹅膏毒肽是至少十种最初在几种有毒蘑菇属中,最著名的是毒鹅膏和几种其他蘑菇种类,发现的有毒化合物,也优选用于以本专利申请的连接体连接的偶联物。目前,十种已知的鹅膏毒肽,α-鹅膏蕈碱,β-鹅膏蕈碱,γ-鹅膏蕈碱,ε-鹅膏蕈碱,鹅膏无毒环肽,一羟鹅膏毒肽羧酸,鹅膏毒肽酰胺,三羟鹅膏毒肽和鹅膏毒肽酰胺原为刚性双环多肽,其合成始于35个氨基酸的前蛋白,最终的八个氨基酸由脯氨酰寡肽酶切割而产生(Litten,W.1975Scientific American 232(3):90–101;H.E.Hallen,等2007Proc.Nat.Aca.Sci.USA104,19097–101;.K.Baumann,等,1993Biochemistry 32(15):4043–50;Karlson-Stiber C,Persson H.2003,Toxicon 42(4):339–49;Horgen,P.A.等1978Arch.Microbio.118(3):317-9)。鹅膏毒肽通过抑制RNA聚合酶II(Pol II)和关闭基因转录和蛋白质生物合成来杀死细胞(Brodner,O.G.和Wieland,T.1976Biochemistry,15(16):3480–4;Fiume,L.,Curr ProblClin Biochem,1977,7:23-8;Karlson-Stiber C,Persson H.2003,Toxicon 42(4):339–49;Chafin,D.R.,Guo,H.&Price,D.H.1995J.Biol.Chem.270(32):19114–19;Wieland(1983)Int.J.Pept.Protein Res.22(3):257-76.)。鹅膏毒肽可以从采集的毒鹅膏蘑菇中获得(Yocum,R.R.1978Biochemistry 17(18):3786-9;Zhang,P.等,2005,FEMSMicrobiol.Lett.252(2),223-8),或用担子菌发酵(Muraoka,S.和Shinozawa T.,2000J.BiosciBioeng.89(1):73-6,美国专利申请20100267019)或用A.fissa进行发酵,或通过培养盔孢伞束状带或黄褐盔孢伞而生成(WO/1990/009799,JP11137291)。然而,这些分离和发酵的方式的产量非常低(低于5mg/L培养物)。在过去的三十年中,也有鹅膏毒肽类和它们的类似物的化学合成方法的报道(W.E.Savige,A.Fontana,Chem.Commun.1976,600–1;Zanotti,G.,等,Int J Pept Protein Res,1981.18(2):162-8;Wieland,T.,等,Eur.J.Biochem.1981,117,161–4;P.A.Bartlett,等,Tetrahedron Lett.1982,23,619–22;Zanotti,G.,等,Biochim Biophys Acta,1986.870(3):454-62;Zanotti,G.,等,Int.J.Peptide Protein Res.1987,30,323–9;Zanotti,G.,等,Int.J.Peptide ProteinRes.1987,30,450–9;Zanotti,G.,等,Int J Pept Protein Res,1988.32(1):9-20;G.Zanotti,T.等,Int.J.Peptide Protein Res.1989,34,222–8;Zanotti,G.,等,Int JPept Protein Res,1990.35(3):263-70;Mullersman,J.E.和J.F.Preston,3rd,Int JPept Protein Res,1991.37(6):544-51;Mullersman,J.E.,等,Int J Pept Protein Res,1991.38(5):409-16;Zanotti,G.,等,Int J Pept Protein Res,1992.40(6):551-8;Schmitt,W.等,J.Am.Chem.Soc.1996,118,4380–7;Anderson,M.O.,等,J.Org.Chem.,2005,70(12):4578-84;J.P.May,等,J.Org.Chem.2005,70,8424–30;F.Brueckner,P.Cramer,Nat.Struct.Mol.Biol.2008,15,811–8;J.P.May,D.M.Perrin,Chem.Eur.J.2008,14,3404–9;J.P.May,等,Chem.Eur.J.2008,14,3410–17;Q.Wang,等,Eur.J.Org.Chem.2002,834–9;May,J.P.和D.M.Perrin,Biopolymers,2007.88(5):714-24;May,J.P.,等,Chemistry,2008.14(11):3410-7;S.De Lamo Marin,等,Eur.J.Org.Chem.2010,3985–9;Pousse,G.,等,Org Lett,2010.12(16):3582-5;Luo,H.,等,Chem Biol,2014.21(12):1610-7;Zhao,L.,等,Chembiochem,2015.16(10):1420-5),并且这些大部分是通过部分合成实现的。由于其极高的效力和独特的细胞毒性机制,鹅膏毒肽已被用作偶联物的有效载荷(Fiume,L.,Lancet,1969.2(7625):853-4;Barbanti-Brodano,G.和L.Fiume,Nat New Biol,1973.243(130):281-3;Bonetti,E.,M.等,Arch Toxicol,1976.35(1):p.69-73;Davis,M.T.,Preston,J.F.Science 1981,213,1385–1388;Preston,J.F.,等,Arch Biochem Biophys,1981.209(1):63-71;H.Faulstich,等,Biochemistry 1981,20,6498–504;Barak,L.S.,等,Proc Natl Acad Sci U S A,1981.78(5):3034-8;Faulstich,H.和L.Fiume,MethodsEnzymol,1985.112:225-37;Zhelev,Z.,A.等,Toxicon,1987.25(9):981-7;Khalacheva,K.,等,Eksp Med Morfol,1990.29(3):26-30;U.Bermbach,H.Faulstich,Biochemistry1990,29,6839–45;Mullersman,J.E.和J.F.Preston,Int.J.Peptide Protein Res.1991,37,544–51;Mullersman,J.E.和J.F.Preston,Biochem Cell Biol,1991.69(7):418-27;J.Anderl,H.Echner,H.Faulstich,Beilstein J.Org.Chem.2012,8,2072–84;Moldenhauer,G.,等,J.Natl.Cancer Inst.2012,104,622–34;A.Moshnikova,等;Biochemistry 2013,52,1171–8;Zhao,L.,等,Chembiochem,2015.16(10):1420-5;Zhou,B.,等,Biosens Bioelectron,2015.68:189-96;WO2014/043403,US20150218220,EP1661584)。我们也一直在研究鹅膏毒肽的偶联。通过本发明中的连接体连接的抗体-鹅膏毒肽偶联物结构的实例如Am01,Am02,Am03,Am0和Am05:
其中mAb是抗体;X3为CH2,O,NH,NHC(O),NHC(O)NH,C(O),OC(O),OC(O)(NR3),R1,NHR1,NR1,C(O)R1或缺省;R7,R8,R9,R10和R11独立地为H,OH,OR1,NH2,NHR1,C1-C6烷基或缺省;Y1为O,O2,S,NH或缺省;表示单键或双键;n,m1,m2,X1,X2,L1,L2,R1,R2和R3与式(I)和(II)中的定义相同。R1’和R3’独立地为H或C1-C6直链或支链烷基;p是0-2000。此外,R1’可以是本专利申请中描述的细胞毒性剂。/>
在另一个实施方案中,优选两个或更多细胞毒性剂通过本专利申请的连接体偶联至细胞结合分子。两个或更多细胞毒性剂可以选自下列分子的任意组合:tubulysin,美登木素生物碱类,紫杉烷类,CC-1065类似物,柔红霉素或多柔比星化合物,苯并二氮卓二聚体(例如吡咯并苯二氮卓(PBD),托美霉素,吲哚并苯并二氮卓,咪唑并苯并噻二氮卓或恶唑烷并苯并二氮卓的二聚体),加利车霉素或烯二炔抗生素,放线菌素,重氮丝氨酸,博来霉素,表柔比星,艾日布林,他莫昔芬,伊达比星,多拉司他汀,澳瑞他汀衍生物(例如MMAE,MMAF,澳瑞他汀PYE,澳瑞他汀TP,澳瑞他汀2-AQ,6-AQ,EB(AEB)和EFP(AEFP)),多卡霉素,格尔德霉素,甲氨喋呤,噻替派,长春地辛,长春新碱,半米塔林,nazumamide,microginin,放射敏素,alterobactins,microsclerodermins,theonellamides,esperamicins,PNU-159682,及其上述化合物的类似物和衍生物。通过连接体连接两种或更多种不同细胞毒性剂的偶联物结构的实例Z01,Z02,Z02,Z04,Z05,Z06,Z07,Z08,Z09,Z10,Z12,Z13,Z14,Z15,Z16,Z17和Z18:
其中mAb是抗体;X3和X3’独立地为CH2,O,NH,NHC(O),NHC(O)NH,C(O),OC(O),OC(O)(NR3),R1,NHR1,NR1,C(O)R1或缺省;X4和X4’独立地为H,CH2,OH,O,C(O),C(O)NH,C(O)N(R1),R1,NHR1,NR1,C(O)R1或C(O)O;M1和M2独立地为H,Na,K,Ca,Mg,NH4,NR1R2R3;n,m1,m2,“-”,X1,X2,R1,R2和R3与式(I)和(II)中的定义相同。另外,R1和/或R2可以独立地缺省。
在另一个实施例中,免疫毒素可以通过本专利申请的连接体与细胞结合分子偶联。本专利申请中的免疫毒素是大分子药物,通常是源自细菌或植物蛋白的细胞毒性蛋白,例如白喉毒素(DT),霍乱毒素(CT),天花粉蛋白(TCS),Dianthin,假单胞菌外毒素A(ETA’),红细胞毒素,白喉毒素,AB毒素,TypeIII型外毒素等。它也可能是一种剧毒的细菌成孔原毒素,需要蛋白水解加工才能被激活。这种原毒素的一个例子是proaerolysin及它被基因改造的分子topsalysin。Topsalysin是一种经过改造的重组蛋白,经过改造后可以被前列腺中的酶选择性激活,导致局部细胞死亡和组织破坏,而不会损伤邻近的组织和神经。
在另一个实施例中,细胞结合配体或细胞受体激动剂可以通过本专利申请的连接体与细胞结合分子偶联。这些偶联的细胞结合配体或细胞受体激动剂,特别是抗体-受体偶联物,不仅可以作为靶向导体/导向剂将偶联物递送至恶性细胞,还可以用于调节或共刺激期望的免疫反应或改变信号传导途径。
在免疫疗法中,细胞结合配体或受体激动剂优选与TCR(T细胞受体)T细胞,或CAR(嵌合抗原受体)T细胞或B细胞受体(BCR),自然杀伤(NK)细胞或细胞毒性细胞的抗体偶联。抗体优选为抗CD3,CD4,CD8,CD16(FcγRIII),CD27,CD40,CD40L,CD45RA,CD45RO,CD56,CD57,CD57bright,TNFβ,Fas配体,MHC I类分子(HLA-A,B,C)或NKR-P1。细胞结合配体或受体激动剂选自,但不限于:叶酸衍生物(与叶酸受体结合,卵巢癌和其他恶性肿瘤中过表达的蛋白质)(Low,P.S.等2008,Acc.Chem.Res.41,120-9);谷氨酸脲衍生物(与前列腺特异性膜抗原结合,前列腺癌细胞的表面标记物)(Hillier,S.M.等,2009,Cancer Res.69,6932-40);生长抑素(也称为生长激素抑制激素(GHIH)或生长激素释放抑制因子(SRIF))或生长激素释放抑制激素)及其类似物,如澳曲肽(Sandostatin)和兰瑞肽(Somatuline)(特别用于神经内分泌肿瘤,分泌GH垂体腺瘤,副神经节瘤,无功能性垂体腺瘤,嗜铬细胞瘤)(Ginj,M.,等,2006,Proc.Natl.Acad.Sci.U.S.A.103,16436-41);一般而言,生长抑素及其受体亚型(sst1,sst2,sst3,sst4和sst5)已在许多类型的肿瘤中被发现,如神经内分泌肿瘤,特别是在分泌GH的垂体腺瘤(Reubi J.C.,Landolt,A.M.1984J.Clin.Endocrinol Metab 59:1148–51;Reubi J.C.,Landolt A.M.1987J Clin Endocrinol Metab 65:65–73;Moyse E,等,J Clin Endocrinol Metab 61:98–103),胃肠胰腺肿瘤(Reubi J.C.,等,1987J ClinEndocrinol Metab 65:1127–34;Reubi,J.C,等,1990Cancer Res 50:5969–77),嗜铬细胞瘤(Epel-baum J,等1995J Clin Endocrinol Metab 80:1837–44;Reubi J.C.,等,1992JClin Endocrinol Metab 74:1082–9),成神经细胞瘤(Prevost G,1996Neuroendocrinology 63:188–197;Moertel,C.L,等1994Am J Clin Path 102:752–756),甲状腺髓样癌(Reubi,J.C,等1991Lab Invest 64:567–573),小细胞肺癌(Sagman U,等,1990Cancer 66:2129–2133),非神经内分泌肿瘤包括脑肿瘤如脑膜瘤,成神经管细胞瘤或神经胶质瘤(Reubi J.C.,等1986J Clin Endocrinol Metab 63:433–8;Reubi J.C.,等1987Cancer Res 47:5758–64;Fruhwald,M.C,等1999Pediatr Res 45:697–708),乳腺癌(Reubi J.C.,等1990Int J Cancer 46:416–20;Srkalovic G,等1990J Clin EndocrinolMetab 70:661–669),淋巴瘤(Reubi J.C.,等1992,Int J Cancer50:895–900),肾细胞癌(Reubi J.C.,等1992,Cancer Res 52:6074–6078),间叶组织肿瘤(Reubi J.C.,等1996Cancer Res 56:1922–31),前列腺癌(Reubi J.C.,等1995,J.Clin.Endocrinol Metab80:2806–14;等1989,Prostate 14:191–208;Halmos G,等J.Clin.Endo-crinol Metab 85:2564–71),卵巢癌(Halmos,G,等,2000J Clin Endocrinol Metab 85:3509–12;ReubiJ.C.,等1991Am J Pathol 138:1267–72),胃癌(Reubi J.C.,等1999,Int J Cancer 81:376–86;Miller,G.V,1992Br J Cancer 66:391–95),肝细胞癌(Kouroumalis E,等1998Gut42:442–7;Reubi J.C.,等1999Gut 45:66–774)和鼻咽癌(Loh K.S,等,2002Virchows Arch441:444–8);某些芳香磺酰胺类化合物,尤其是碳酸酐酶IX特异性的(缺氧和肾细胞癌标志物)(Neri,D.,等,Nat.Rev.Drug Discov.2011,10,767-7);垂体腺苷酸环化酶激活肽(PACAP)(PAC1),用于嗜铬细胞瘤和副神经节瘤;血管活性肠肽(VIP)及其受体亚型(VPAC1,VPAC2),用于肺癌,胃癌,结肠癌,直肠癌,乳腺癌,前列腺癌,胰腺导管癌,肝癌,膀胱癌和上皮肿瘤的癌症;各种肿瘤的α-黑素细胞刺激激素(α-MSH)受体;胆囊收缩素(CCK)/胃泌素受体及其受体亚型(CCK1(以前称为CCK-A)和CCK2),用于小细胞肺癌,甲状腺髓样癌,星形细胞瘤,胰岛素瘤和卵巢癌;蛙皮素(Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2)/胃泌素释放肽(GRP)及其受体亚型(BB1,GRP受体亚型(BB2),BB3和BB4),用于肾细胞癌,乳腺癌,肺癌,胃癌和前列腺癌以及神经母细胞瘤和神经母细胞瘤(Ohlsson,B.,等,1999,Scand.J.Gastroenterology 34(12):1224–9;Weber,H.C.,2009,Cur.Opin.Endocri.Diab.Obesity 16(1):66–71,Gonzalez N,等,2008,Cur.Opin.Endocri.Diab.Obesity 15(1),58-64);神经降压素受体及其受体亚型(NTR1,NTR2,NTR3),用于小细胞肺癌,成神经细胞瘤,胰腺癌,结肠癌和尤因肉瘤;物质P受体及其受体亚型(例如神经胶质肿瘤的NK1受体,Hennig I.M.,等1995Int.J.Cancer 61,786–792);神经肽Y(NPY)受体及其受体亚型(Y1-Y6),用于乳腺癌;归巢肽包括RGD(Arg-Gly-Asp),NGR(Asn-Gly-Arg),二聚和多聚环状RGD肽(如cRGDfV),可识别肿瘤表面上的受体(整联蛋白)(Laakkonen P,Vuorinen K.Integr Biol(Camb)),2010,2(7–8):326–337;Chen K,Chen X.Theranostics.2011,1:189–200;Garanger E,等,Anti-Cancer Agents MedChem.7(5):552–558;Kerr,J.S.等,Anticancer Research,19(2A),959-968;Thumshirn,G,等,Chem.Eur.J.2003,9,2717-2725),和TAASGVRSMH或LTLRWVGLMS(硫酸软骨素蛋白多糖NG2受体)和F3肽(结合细胞表面表达的核素受体的31个氨基酸的肽)(Zitzmann,S.,CancerRes.,2002,62,18,pp.5139–5143,Temminga,K.,Drug Resistance Updates,2005,8,381–402;P.Laakkonen和K.Vuorinen,Integrative Biol,2010,2(7-8),326–337;M.A.Burg,Cancer Res.,1999,59(12),2869–2874;K.Porkka,等Proc.Nat.Acad.Sci.USA 2002,99(11),7444-9);细胞穿透肽(Nakase I,等,J.Control Release.2012,159(2),181–188);肽激素,如促黄体激素释放激素(LHRH)激动剂和拮抗剂,和促性腺激素释放激素(GnRH)激动剂,通过靶向卵泡刺激素(FSH)和黄体生成素(LH)以及睾酮生成起作用,例如布舍瑞林(Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-NHEt),戈那瑞林(Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2),戈舍瑞林(Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-AzGly-NH2),组氨瑞林(Pyr-His-Trp-Ser-Tyr-D-His(N-benzyl)-Leu-Arg-Pro-NHEt),醋酸亮丙瑞林(Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt),那法瑞林(Pyr-His-Trp-Ser-Tyr-2Nal-Leu-Arg-Pro-Gly-NH2),曲普瑞林(Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2),那法瑞林,德舍瑞林,阿巴瑞克(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-isopropylLys-Pro-DAla-NH2),西曲瑞克(Ac-D-2Nal-D-4-chloro-Phe-D-3-(3-pyridyl)Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2),加瑞克(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-4-aminoPhe(L-hydroorotyl)-D-4-aminoPhe(carba-moyl)-Leu-isopropylLys-Pro-D-Ala-NH2)和加尼瑞克(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-Tyr-D-(N9,N10-diethyl)-homoArg-Leu-(N9,N10-diethyl)-homoArg-Pro-D-Ala-NH2)(Thundimadathil,J.,J.AminoAcids,2012,967347,doi:10.1155/2012/967347;Boccon-Gibod,L.;等,TherapeuticAdvances in Urology 2011,3(3):127–140;Debruyne,F.,Future Oncology,2006,2(6),677–696;Schally A.V;Nagy,A.Eur J Endocrinol 1999,141:1–14;Koppan M,等Prostate1999,38:151–158);和模式识别受体(PRR),如Toll样受体(TLR),C型凝集素和Nodlike受体(NLRs)(Fukata,M.,等,Semin.Immunol.2009,21,242–253;Maisonneuve,C.,等,Proc.Natl.Acad.Sci.U.S.A.2014,111,1–6;Botos,I.,等,Structure 2011,19,447–459;Means,T.K.,等,Life Sci.2000,68,241–258),其范围从小分子(咪喹莫特,鸟嘌呤和腺苷类似物)到大而复杂的生物大分子如脂多糖(LPS),核酸(CpG DNA,polyI:C)和脂肽(Pam3CSK4)(Kasturi,S.P.,等,2011,Nature 470,543–547;Lane,T.,2001,J.R.Soc.Med.94,316;Hotz,C.,和Bourquin,C.,2012,Oncoimmunology 1,227-228;Dudek,A.Z.,等,2007,Clin.Cancer Res.13,7119–25);降钙素受体,一种32-氨基酸神经肽,在很大程度上通过其对破骨细胞和肾脏的作用来调节钙水平(Zaidi M,等,1990Crit Rev ClinLab Sci 28,109–174;Gorn,A.H.,等1995J Clin Invest 95:2680–91);整合素受体及其受体亚型(例如αVβ1,αVβ3,αVβ5,αVβ6,α6β4,α7β1,αLβ2,αIIbβ3等),其通常在血管发生中起重要作用,在各种细胞的表面上表达,特别是破骨细胞,内皮细胞和肿瘤细胞(Ruoslahti,E.等,1994Cell 77,477-8;Albelda,S.M.等,1990Cancer Res.,50,6757-64);短肽,GRGDSPK和环状RGD五肽,如环(RGDfV)(L1)及其衍生物[cyclo(-N(Me)R-GDfV),cyclo(R-Sar-DfV),cyclo-(RG-N(Me)D-fV),cyclo(RGD-N(Me)f-V),cyclo(RGDf-N(Me)V-)(西仑吉肽)]已显示与整合素受体的高结合亲和力(Dechantsreiter,M.A.等,J.Med.Chem.1999,42,3033-40,Goodman,S.L.,等,J.Med.Chem.2002,45,1045-51)。
细胞结合分子或配体或细胞受体激动剂可以是基于Ig和非基于Ig的蛋白质支架分子。基于Ig的支架可以选自,但不限于,纳米抗体(VHH的衍生物(骆驼科动物Ig))(Muyldermans S.,2013Annu Rev Biochem.82,775–97);结构域抗体(dAb,VH或VL结构域的衍生物)(Holt,L.J,等,2003,Trends Biotechnol.21,484–90);双特异性T细胞接头(BiTE、双特异性双抗体)(Baeuerle,P.A等,2009,Curr.Opin.Mol.Ther.11,22–30);双重亲和力重定向剂(DART,双特异性双抗体)(Moore PA P等.2011,Blood 117(17),4542–51);四价串联抗体(T和Ab,、二聚双特异性双抗体)(Cochlovius,B等.2000,Cancer Res.60(16):4336–4341)。非Ig支架可以选自,但不限于,Anticalin(Lipocalins的衍生物)(Skerra A.2008,FEBS J.,275(11):2677–83;Beste G等,1999Proc.Nat.Acad.USA.96(5):1898–903;Skerra,A.2000Biochim Biophys Acta,1482(1-2):337–50;Skerra,A.2007,Curr OpinBiotechnol.18(4):295–304;Skerra,A.2008,FEBS J.275(11):2677–83);Adnectin(第10个FN3(纤连蛋白))(Koide,A等,1998J.Mol.Biol.,284(4):1141–51;Batori V,2002,Protein Eng.15(12):1015–20;Tolcher,A.W,2011,Clin.Cancer Res.17(2):363–71;Hackel,B.J,2010,Protein Eng.Des.Sel.23(4):211–19);设计的锚蛋白重复蛋白(DARPins)(锚蛋白重复(AR)蛋白的衍生物)(Boersma,Y L等,2011Curr OpinBiotechnol.22(6):849–57),例如DARPin C9、DARPin Ec4及DARPin E69_LZ3_E01(WinklerJ等,2009Mol Cancer Ther.8(9),2674–83;Patricia MK.M.等,Clin Cancer Res.2011;17(1):100–10;Boersma Y.L等,2011J.Biol.Chem.286(48),41273–85);高亲和性多聚体(域A/低密度脂蛋白(LDL)受体)(Boersma Y.L,2011J.Biol.Chem.286(48):41273–41285;Silverman J等,2005Nat.Biotechnol.,23(12):1556–61)。
通过本专利申请的连接体连接的抗体-细胞结合配体或抗体-细胞受体激动剂的偶联物示例如下:LB01(叶酸偶联物),LB02(PMSA配体偶联物),LB03(PMSA配体偶联物),LB04(生长抑素偶联物),LB05(澳曲肽,生长抑素类似物偶联物),LB06(兰瑞肽,生长抑素类似物偶联物),LB07(Vapreotide(Sanvar),生长抑素类似物偶联物),LB08(CAIX配体偶联物),LB09(CAIX配体偶联物),LB10(胃泌素释放肽受体(GRPr),MBA偶联物),LB11(促黄体激素释放激素(LH-RH)和GnRH配体偶联物),LB12(促黄体激素释放激素(LH-RH)和GnRH配体偶联物),LB13(GnRH拮抗剂,Abarelix偶联物),LB14(钴胺素,维生素B12类似物偶联物),LB15(钴胺素,维生素B12类似物)偶联物),LB16(αvβ3整联蛋白受体的环状RGD五肽偶联物),LB17(VEGF受体的异二价肽配体偶联物),LB18(神经介素B偶联物),LB19(G蛋白偶联受体的铃蟾肽偶联物),LB20(类Toll受体的TLR2偶联物),L B21(雄激素受体偶联物),LB22(αv整合素受体的西仑吉肽/环(RGDfV)偶联物,LB23(氟氢可的松偶联物),LB24(丙酸氟替卡松偶联物),LB25(丙酸倍氯米松偶联物),LB26(二丙酸倍氯米松偶联物),LB27(曲安奈德偶联物),LB28(泼尼松偶联物),LB29(泼尼松龙偶联物),LB30(甲泼尼松龙偶联物),LB32(伊立替康类似物偶联物),LB33(克唑替尼类似物偶联物),LB34(硼替佐米类似物偶联物),LB35(Carfilzomib类似物偶联物),LB36(Carfilzomib类似物偶联物),LB37(Leuprolide类似物偶联物),LB38(Triptorelin类似物偶联物),LB39(Liraglutide类似物偶联物),LB40(Semaglutide类似物偶联物)和LB41(Lixisenatide类似物偶联物),其结构示例如下:
其中mAb为抗体;X3为CH2,O,NH,NHC(O),NHC(O)NH,C(O),OC(O),OC(O)(NR3),R1,NHR1,NR1,C(O)R1或缺省;X4为H,CH2,OH,O,C(O),C(O)NH,C(O)N(R1),R1,NHR1,NR1,C(O)R1 orC(O)O;X5为H,CH3,F,或Cl;M1和M2独立地为H,Na,K,Ca,Mg,NH4,NR1R2R3;R6为5’-脱氧腺苷,Me,OH,或CN;为单间或者双键;m1,m2,n,“-,”X1,X2,R1和R2与式(I)中定义相同。此外,R1可缺省,R2可为H。
在另一个实施例中,一种,两种或多种DNA,RNA,mRNA,小干扰RNA(siRNA),微RNA(miRNA)和PIWI相互作用RNA(piRNA)是本发明中优选的分子,通过本专利申请的连接体与细胞结合分子偶联。已知小RNA(siRNA,miRNA,piRNA)和长的非编码反义RNA负责细胞内的表观遗传变化(Goodchild,J(2011),Methods in molecular biology(Clifton,N.J.),764:1–15)。本文中的DNA,RNA,mRNA,siRNA,miRNA或piRNA可以是单链或双链,核苷酸单元为3至1百万,其中一些核苷酸可以是非天然(合成)形式,例如具有硫代磷酸酯键的寡核苷酸,例如Fomivirsen,或核苷酸通过硫代磷酸酯键连接而不是天然RNA和DNA的磷酸二酯键,分子中间的糖是脱氧核糖,在两端是2’-O-甲氧基乙基修饰的核糖,例如Mipomersen,或由肽核酸(PNA),吗啉代,硫代磷酸酯,硫代氨基磷酸酯,或2’-O-甲氧基乙基(MOE),2’-O-甲基,2’-氟,锁核酸(LNA),或核糖的双环核酸(BNA)产生的寡核苷酸,或核酸被修饰以去除糖环中的2’-3’碳键(Whitehead,K.A.;等(2011),Annual Review of Chemical andBiomolecular Engineering 2:77–96;Bennett,C.F.;Swayze,E.E.(2010),Annu.Rev.Pharmacol.Toxicol.50:259–29)。优选地,寡核苷酸的长度范围为约8至超过100个核苷酸。偶联物结构的例子如下所示:
其中mAb,m1,m2,n,X1,X2,X3,X4,R1’,R2’,L1,L2,L3,L4,“-”,与式(I)或前文中的定义相同;/>是单链或双链的DNA,RNA,mRNA,siRNA,miRNA,或piRNA;X5的定义与X1相同;Y和Y’是O,S,NH或CH2.
在另一个实施例中,一种,两种或多种不同功能的分子或药物与IgG抗体偶联,优选在轻链和重链之间的一对巯基(通过还原二硫键),两条重链之间的上部巯基和两条重链之间的下部巯基特异性偶联,如以下结构ST1,ST2,ST3,ST4,ST5,ST6,ST7或ST8所示:
其中X1,X1’,X2,X2’,X3,X3’,X4,X4’,L1,L1’,L2,L2’,L3,L3’,L4,L4’,和T的定义与式(I)中X1相同;另外,X1,X1’,X2,X2’,X3,X3’,X4和X4’可以缺省。
在另一个实施方案中,包含治疗有效量的式(II)的偶联物或本专利申请描述的任何偶联物的药物组合物可以与其他治疗剂,如有效治疗或预防癌症或自身免疫疾病或传染病的化学治疗剂,放射疗法,免疫治疗剂,自身免疫病症剂,抗感染剂或其他偶联物协同给药。协同剂优选自以下一种或几种药物:阿巴西普(Orencia),醋酸阿比特龙 ,对乙酰氨基酚/氢可酮,阿达木单抗,阿法替尼二马来酸盐/>Alectinib(Alecensa),alemtuzumab/>阿维A酸/>曲妥珠单抗emtansine(KadcylaTM),安非他命混合盐(苯丙胺/右旋安非他命或Adderall XR),阿那曲唑阿立哌唑,阿扎那韦,Atezolizumab(Tecentriq,MPDL3280A),阿托伐他汀,阿昔替尼/>AZD9291,Belinostat(BeleodaqTM),贝伐单抗(A/>),Bortezomib(PS-341;Velcade,Neomib,Bortecad),Cabazitaxel/>Cabozantinib(Come-triqTM),贝沙罗汀/>Blinatumomab(BlincytoTM),Bortezomib/>波舒替尼/>brentuximab vedotin/>布地奈德,布地奈德/福莫特罗,丁丙诺啡,卡培他滨,carfilzomib/>塞来昔布,赛替尼(LDK378/Zykadia),西妥昔单抗/>Ciclosporin,Cinacalcet,Crizotinib(Xalkori),Cobimetinib(Cotellic),达比加群,达拉菲尼/>Daratumumab(Darzalex),Darbepoetinalfa,Darunavir,甲磺酸伊马替尼/>达沙替尼/>Denileukin,Diftitox/>Denosumab/>Depakote,Dexamethasone,右兰索拉唑,右旋哌甲酯,Dinutuximab(UnituxinTM),多西环素,度洛西汀,Durvalumab(MEDI4736),Elotuzumab(Empliciti),Emtricitabine/Rilpivirine/Tenofovir地索普西富马酸盐,Emtricitbine/替诺福韦/依法韦仑,依诺肝素,Enzalutamide/>依泊汀α,厄洛替尼/>埃索美拉唑,艾司佐匹克隆,依那西普,依维莫司/>依西美坦依维莫司/>依泽替米贝,依泽替米贝/辛伐他汀,非诺贝特,非格司亭,芬戈莫德,丙酸氟替卡松,氟替卡松/沙美特罗,氟维司群/>吉非替尼格拉替雷,醋酸戈舍瑞林(Zoladex),伊替替尼,伊马替尼(格列卫),伊布替莫单抗tiuxetan/>Ibrutinib(ImbruvicaTM),Idelalisib/>英夫利西单抗,Iniparib,门冬胰岛素,地特胰岛素,甘精胰岛素,赖脯胰岛素,干扰素β1a,干扰素β1b,拉帕替尼/>伊匹单抗/>异丙托溴铵沙丁胺醇,Ixazomib(Ninlaro),醋酸兰瑞肽(/> Depot),Ixazomi/>Kanuma,醋酸兰瑞肽(SomatulineDepot),来那度胺/>Lenvatinib(LenvimaTM),来曲唑/>左旋甲状腺素,利多卡因,利奈唑胺,利拉鲁肽,Lisdexamfetamine,MEDI4736(AstraZeneca,Celgene),美金刚,哌醋甲酯,美托洛尔,莫达非尼,莫米松,Necitumumab(Portrazza),NilotinibNiraparib,Nivolumab/>澳法木单抗/>Obinutuzumab(GazyvaTM),澳拉帕尼(LynparzaTM),澳美沙坦,澳美沙坦/氢氯噻嗪,澳马珠单抗,澳米加-3脂肪酸乙酯,澳司他韦,Osimertinib(或Mereletinib,Tagrisso),羟考酮,Palbociclib/>帕利珠单抗,帕尼单抗/>Panobinostat/>帕唑帕尼派姆单抗/>培美曲塞(Alimta),帕妥珠单抗(PerjetaTM),肺炎球菌结合疫苗,Pomalidomide/>普瑞巴林,普萘洛尔,喹硫平,雷贝拉唑,镭223氯化物/>雷洛昔芬,拉替拉韦,雷莫芦单抗/>Ranibizumab,瑞格菲尼/>利妥昔单抗/> ,利伐沙班,罗米地辛/>罗苏伐他汀,鲁索替尼磷酸盐(JakafiTM),沙丁胺醇,司维拉姆,西地那非,Siltuximab(SylvantTM),西他列汀,西他列汀/二甲双胍,索利那新,Sonidegib(LDE225,Odomzo),索拉非尼/>舒尼替尼/>他达拉非,他莫昔芬,Telaprevir,Talazoparib,Temsirolimus/> 替诺福韦/恩曲他滨,睾酮凝胶,沙利度胺(Immunoprin,Talidex),噻托溴铵,托瑞米芬/>Trametinib/>曲妥珠单抗,Trabectedin(Ecteinascidin743,Yondelis),Trifluridinetipiracil(Lonsurf,TAS-102),维甲酸/>优特克单抗,缬沙坦,凡德他尼/>威罗菲尼/>Venetoclax(Venclexta),伏立诺他/>阿柏西普/>Zostavax以及它们的类似物、衍生物、药学上可接受的盐、载体、稀释剂或赋形剂,或其组合。
通过本专利申请的连接体偶联的药物/细胞毒性剂,可以是本专利申请中描述的药物/分子的任何类似物和/或衍生物。药物/细胞毒剂领域的专业技术人员可以理解,本发明所述的药物/细胞毒剂均可以被修饰,只要获得的化合物仍保留起始化合物的特异性和/或活性。本领域技术人员还会知道,可以使用这些化合物来代替本文所述的药物/细胞毒性剂。因此,本发明的药物/细胞毒性剂包括本文所述化合物的类似物和衍生物。
所有引用的参考文献以及下面的实施例中的全部参考文献都完整明确地并入了本文。
实施例
在以下实施例中对本发明进行了进一步描述,这些实施例并不旨在限制本发明的保护范围。本发明申请的中的细胞系,除非另有说明,都是根据美国典型培养物保藏中心(ATCC)或Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH,Braunschweig,Germany(DMSZ)或中国上海细胞培养研究所规定的条件,保存在培养物中。除非另有说明,否则细胞培养基是从Invitrogen Corp.获得的。商业途径获得所有无水溶剂在氮气下储存在Sure-seal瓶中。所有其他试剂和溶剂均以最高等级购买,无需进一步纯化即可使用。用Varain PreStar HPLC进行制备型HPLC分离。在Varian Mercury 400MHz仪器上记录NMR光谱。化学位移(δ)以百万分之一(ppm)为单位,以四甲基硅烷为基准,以0.00表示,偶联常数(J)以Hz表示。质谱数据在配备Waters Acquity UPLC分离模块和Acquity TUV检测器的Waters Xevo QTOF质谱仪上获得。
实施例1.1,2-双(2-(叔丁氧基)-2-氧代乙基)肼-1,2-二甲酸二叔丁酯(38)的合成
向二叔丁基肼-1,2-二甲酸酯(37)(8.01g,34,4mmol)的DMF(150mL)溶液中加入NaH(60%在矿物油中,2.76g,68.8mmol)。在室温下搅拌30分钟后,加入2-溴乙酸叔丁酯(14.01g,72.1mmol)。将混合物搅拌过夜,加入甲醇(3mL)淬灭,浓缩,用乙酸乙酯(100mL)和水(100mL)稀释,分层,水层用乙酸乙酯(2×50mL)萃取。合并有机层,用硫酸镁干燥,过滤,浓缩,并通过硅胶柱层析(乙酸乙酯/己烷1:5至1:3)纯化,得到标题化合物(12.98g,82%收率),为无色油状物。MS ESI m/z C22H41N2O8[M+H]+计算值461.28,实测值461.40。
实施例2.2,2’-(肼-1,2-二基)二乙酸(39)的合成。
向1,2-双(2-(叔丁氧基)-2-氧代乙基)肼-1,2-二甲酸二叔丁酯(6.51g,14.14mmol)的1,4-二恶烷(40mL)溶液中加入盐酸(12M,10mL)。将混合物搅拌30分钟,用二恶烷(20mL)和甲苯(40mL)稀释,浓缩并与二恶烷(20mL)和甲苯(40mL)共浓缩至干,得到用于下一步的粗品,无需进一步纯化(2.15g,103%收率,~93%纯度)。MS ESI m/z C4H9N2O4[M+H]+计算值149.05,实测值149.40。
实施例3.2,2’-(1,2-双((E)-3-溴丙烯酰基)肼-1,2-二基)二乙酸(36)的合成
向2,2’-(肼-1,2-二基)二乙酸(1.10g,7.43mmol)的四氢呋喃(50mL)和Na H2PO4(0.1M,80mL,pH 6.0)溶液中加入(E)-3-溴丙烯酰溴(5.01g,23.60mmol)。将混合物搅拌6小时,浓缩并在硅胶柱上纯化,用含有3%甲酸的水/乙腈(1:9)洗脱,得到标题化合物(2.35g,77%收率,~93%纯度)。MS ESI m/z C10H11Br2N2O6[M+H]+计算值412.89,实测值413.50。
实施例4.2,2’-(1,2-双((E)-3-溴丙烯酰基)肼-1,2-二基)二乙酰氯(41)的合成
向2,2’-(1,2-双((E)-3-溴丙烯酰基)肼-1,2-二基)二乙酸(210mg,0.509mmol)的二氯乙烷(15mL)溶液中加入(COCl)2(505mg,4.01mmol),然后加入0.040mL DMF。在室温下搅拌2小时后,将混合物浓缩并与二氯乙烷(2×20mL)和甲苯(2×15mL)共浓缩至干,得到标题粗产物(不稳定)(245mg,107%收率),无需进一步纯化,直接用于下一步骤。MS ESI m/zC10H9Br2Cl2N2O4[M+H]+计算值448.82,450.82,452.82,454.82,测定值448.60,450.60,452.60,454.60.。
实施例5.2,8-二氧代-1,5-氧杂环辛烷-5-羧酸叔丁酯(47)的合成
在4℃下,1小时内,向3,3’-氮杂二苯基丙酸(42)(10.00g,62.08mmol)的氢氧化钠(1.0M,300mL)溶液中加入二碳酸二叔丁酯(22.10g,101.3mmol)的四氢呋喃(200mL)溶液。添加后,将混合物在4℃下搅拌2小时。用0.2M H3PO4小心地将混合物酸化至pH~4,真空浓缩,用二氯甲烷萃取,用无水硫酸钠干燥,浓缩并用快速硅胶色谱法纯化,用AcOH/MeOH/二氯甲烷(0.01:1:5)洗脱,得到3 3’-((叔丁氧基羰基)氮杂二基)二丙酸(46)(13.62g,84%收率)。ESI MS m/z C11H19NO6[M+H]+,实测值262.27,实测值262.40。
在0℃下,向3,3’-((叔丁氧基羰基)氮杂二基)二丙酸(8.0g,30.6mmol)的二氯甲烷(500mL)溶液中加入五氧化二磷(8.70g,61.30mmol)。将混合物在0℃下搅拌2小时,然后在室温下搅拌1小时,通过短硅胶柱过滤,并用乙酸乙酯/二氯甲烷(1:6)冲洗柱。浓缩滤液,用乙酸乙酯/正己烷打浆,得到标题化合物(47)(5.64g,74%收率)。ESI MS m/z C11H17NO5[M+H]+计算值244.11,实测值244.30。
实施例6.2,5-二氧代吡咯烷-1-基丙酸酯(61)的合成
将丙酸(5.00g,71.4mmol),NHS(9.01g,78.3mmol)和EDC(20.0g,104.1mmol)加入二氯甲烷(150mL),然后和DIPEA(5mL,28.7mmol)搅拌过夜,浓缩并通过硅胶柱层析(乙酸乙酯/正己烷1:4)纯化,得到标题化合物(9.30g,79%产率),为无色油状物。1H-NMR(500MHz,CDCl3)δ2.68(s,1H),2.61(s,4H).MS ESI m/z C7H5NaNO4[M+Na]+计算值190.02,实测值190.20。
实施例7.2-丙醇酰肼羧酸叔丁酯的合成(88)
将丙炔酸(5.00g,71.4mmol),肼基羧酸叔丁酯(9.45g,71.5mmol)和EDC(20.0g,104.1mmol)加入二氯甲烷(150mL)和DIPEA(5mL,28.7mmol)并搅拌过夜,浓缩并通过硅胶柱层析法(乙酸乙酯/正己烷1:5)纯化,得到标题化合物(7.92g,84%产率),为无色油状物。1H-NMR(500MHz,CDCl3)δ8.76(m,2H),2.68(s,1H),1.39(s,9H).MS ESI m/z C5H12NaN2O2[M+Na]+计算值为155.09,实测值155.26。
实施例8.丙炔酰肼盐酸盐(89)的合成
将2-丙醇酰肼羧酸叔丁酯(4.01g,30.35mmol)溶解于1,4-二恶烷(12mL)中并与4mL浓盐酸在4℃搅拌30分钟,用二恶烷(30mL)和甲苯(30mL)稀释,并在真空下浓缩。将粗品在硅胶柱上使用含甲醇(5%至10%)和1%甲酸的二氯甲烷溶液作为洗脱液纯化,得到标题化合物(2.11g,83%收率),ESI MS m/z C3H5N2O[M+H]+,计算值85.03,实测值85.30。
实施例9.(S,E)-2-甲基-N-(3-甲基丁-2-基)丙烷-2-磺酰胺(186)的合成
在室温,N2下,向(S)-2-甲基丙烷-2-亚磺酰胺(100g,0.825mol,1.0eq.)的四氢呋喃(1L)溶液中加入Ti(OEt)4(345mL,1.82mol,2.2eq.)和甲基-2-丁酮(81mL,0.825mol,1.0eq.)。将反应混合物回流16小时,然后冷却至室温并倒在冰水中。过滤混合物,之后用乙酸乙酯洗涤滤饼。分离有机层,用无水硫酸钠干燥并浓缩,得到残余物,将其通过真空蒸馏(15-20torr,95℃)纯化,得到标题产物(141g,90%收率),为黄色油状物。1H-NMR(500MHz,CDCl3)δ2.54–2.44(m,1H),2.25(s,3H),1.17(s,9H),1.06(dd,J=6.9,5.1Hz,6H).MS ESIm/z C9H19NaNOS[M+Na]+计算值212.12;实测值212.11。
实施例10.(2S,3S)-2-叠氮基-3-甲基戊酸(177)的合成
在0℃,向NaN3(20.0g,308mmol)的水(50mL)和二氯甲烷(80mL)的混合物中缓慢加入Tf2O(10mL,59.2mmol,2.0eq.)。然后在0℃下搅拌2小时,之后分出有机相,水相用二氯甲烷(2×40mL)萃取。将合并的有机相用饱和碳酸氢钠溶液洗涤并留用。将三氟甲磺酸叠氮化物的二氯甲烷溶液加入(L)-异亮氨酸(4.04g,30.8mmol,1.0eq.),K2CO3(6.39g,46.2mmol,1.5eq.),CuSO4.5H2O(77.4mg,0.31mmol,0.01eq.)的水(100mL)和甲醇(200mL)混合物中。将混合物在室温下搅拌16小时后减压除去有机溶剂,水相用水(250mL)稀释,用浓盐酸酸化至pH6,用磷酸盐缓冲液(0.25M,pH6.2,250mL)稀释。将水层用乙酸乙酯(5×100mL)洗涤以除去磺酰胺副产物,然后用浓盐酸酸化至pH 2,用乙酸乙酯(3×150mL)萃取。将合并的有机层用无水硫酸钠干燥,过滤并浓缩,得到标题产物(4.90g,99%收率),为无色油状物。1H-NMR(500MHz,CDCl3)δ12.01(s,1H),3.82(d,J=5.9Hz,1H),2.00(ddd,J=10.6,8.6,5.5Hz,1H),1.54(dqd,J=14.8,7.5,4.4Hz,1H),1.36–1.24(m,1H),1.08–0.99(m,3H),0.97–0.87(m,3H).
实施例11.D-N-甲基哌啶酸的合成
向D-哌啶酸(10.0g,77.4mmol,1.0eq.)的甲醇(100mL)溶液中加入甲醛(37%水溶液,30.8mL,154.8mmol,2.0eq.),然后加入Pd/C(10wt%,1.0g)。将反应混合物在H2(1atm)下搅拌过夜,然后通过硅藻土过滤,用甲醇洗涤滤垫。减压浓缩滤液,得到标题化合物(10.0g,90%收率),为白色固体。
实施例12.(R)-1-甲基哌啶-2-羧基五氟苯基酯的合成
将D-N-甲基哌啶酸(2.65g,18.5mmol)溶于乙酸乙酯(50mL)中,然后加入五氟苯酚(3.75g,20.4mmol)和DCC(4.21g,20.4mmol)。将反应混合物在室温下搅拌16小时,然后通过Celite过滤。将滤垫用10mL乙酸乙酯洗涤。滤液可立即使用而无需进一步纯化或浓缩。
实施例13.2,2-二乙氧基乙硫基酰胺(180)的合成
在室温下将2,2-二乙氧基乙腈(100g,0.774mol,1.0eq.)与(NH4)2S水溶液(48%,143mL,1.05mol,1.36eq.)在甲醇(1.5L)中混合。搅拌16小时后,浓缩反应混合物,将残余物溶于二氯甲烷中,用饱和NaHCO 3溶液和盐水洗涤,用无水硫酸钠干燥并浓缩。将残余物用石油醚和二氯甲烷的溶剂混合物打浆。过滤后,收集所需的标题产物,为白色固体(100g,79%收率)。1H-NMR(500MHz,CDCl3)δ7.81(d,J=71.1Hz,2H),5.03(s,1H),3.73(dq,J=9.4,7.1Hz,2H),3.64(dq,J=9.4,7.0Hz,2H),1.25(t,J=7.1Hz,6H).
实施例14.2-(二乙氧基甲基)噻唑-4-羧酸乙酯(182)的合成
向2,2-二乙氧基乙硫基酰胺(100g,0.61mol,1.0eq.)和溴丙酮酸乙酯(142mL,1.1mol,1.8eq.)的EtOH(1L)溶液中加入90g分子筛将混合物回流1小时(内部温度约60℃),然后在旋转浓缩仪上除去乙醇,将残余物溶于二氯甲烷。滤出固体,浓缩滤液,并通过柱层析(石油醚/乙酸乙酯5:1-3:1)纯化,得到标题化合物(130g,82%产率),为黄色油状物。
实施例15.2-甲酰基噻唑-4-羧酸乙酯(183)的合成
向2-(二乙氧基甲基)噻唑-4-羧酸酯(130g,0.50mol)的丙酮(1.3L)溶液中加入2N盐酸(85mL,0.165mol,0.33eq.)。将反应混合物回流(内部温度约60℃),TLC分析反应液,直至原料完全耗尽(约1-2小时)。减压除去丙酮,将残余物溶于二氯甲烷(1.3L)中,用饱和碳酸氢钠溶液,水和盐水洗涤,然后经无水硫酸钠干燥。过滤溶液并减压浓缩。用石油醚和乙醚重结晶纯化粗产物,得到标题化合物,为白色固体(40g,43%收率)。1H-NMR(500MHz,CDCl3)δ10.08–10.06(m,1H),8.53–8.50(m,1H),4.49(q,J=7.1Hz,2H),1.44(t,J=7.1Hz,3H).MS ESI m/z C7H8NO3S[M+H]+实测值186.01;计算值186.01。
实施例16.2-((R,E)-3-(((S)-叔丁基亚磺酰基)亚氨基)-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯(187)的合成
在-78℃,N2下,向二异丙胺(121mL,0.86mol,4.0eq.)的无水四氢呋喃(300mL)溶液中加入正丁基锂(2.5M,302mL,0.76mol,3.5eq.)。将反应混合物在30分钟内升温至0℃,然后冷却回-78°。加入含(S,E)-2-甲基-N-(3-甲基丁-2-基)丙烷-2-磺酰胺(57g,0.3mol,1.4eq.)的四氢呋喃(200mL)溶液。将反应混合物搅拌1小时,然后逐滴加入含有ClTi(OiPr)3(168.5g,0.645mol,3.0eq.)的四氢呋喃(350mL)溶液。搅拌1小时后,滴加溶解在四氢呋喃(175mL)中的2-甲酰基噻唑-4-羧酸乙酯(40g,0.215mol,1.0eq.),并将所得反应混合物搅拌2小时。TLC分析显示反应完成。用乙酸和四氢呋喃(v/v1:4,200mL)的混合物淬灭反应,然后倒入冰水中,用乙酸乙酯(4×500mL)萃取。将有机相用水和盐水洗涤,用无水硫酸钠干燥,过滤并浓缩。通过柱层析(二氯甲烷/乙酸乙酯/石油醚2:1:2)纯化残余物,得到标题化合物(60g,74%产率),为无色油状物。1H-NMR(500MHz,CDCl3)δ8.13(s,1H),6.63(d,J=8.2Hz,1H),5.20–5.11(m,1H),4.43(q,J=7.0Hz,2H),3.42–3.28(m,2H),2.89(dt,J=13.1,6.5Hz,1H),1.42(t,J=7.1Hz,3H),1.33(s,9H),1.25–1.22(m,6H).MS ESI m/zC16H26NaN2O4S2[M+Na]+的计算值397.13,实测值397.11.
实施例17.2-((1R,3R)-3-((S)-1,1-二甲基乙基亚磺酰胺基)-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯(188)的合成
将2-((R,E)-3-(((S)-叔丁基亚磺酰基)亚氨基)-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯(23.5g,62.7mmol)溶于四氢呋喃(200mL)中,冷却至-45℃。缓慢加入Ti(OEt)4(42.9mL,188mmol,3.0eq.)。添加完成后,将混合物搅拌1小时,然后分批加入NaBH4(4.75g,126mmol,2.0eq.)。将反应混合物在-45℃下搅拌3小时。TLC分析显示仍有一些起始原料。用乙酸/四氢呋喃(v/v 1:4,25mL)淬灭反应,然后加入EtOH(25mL)。将反应混合物倒入冰(100g)中并升温至室温。用硅藻土过滤后,分层有机相,用水和盐水洗涤,用无水硫酸钠干燥,过滤并浓缩。通过柱层析(乙酸乙酯/石油醚1:1)纯化残余物,得到标题产物(16.7g,71%产率),为白色固体。1H-NMR(500MHz,CDCl3)δ8.10(s,1H),5.51(d,J=5.8Hz,1H),5.23–5.15(m,1H),4.41(q,J=7.0Hz,2H),3.48–3.40(m,1H),3.37(d,J=8.3Hz,1H),2.29(t,J=13.0Hz,1H),1.95–1.87(m,1H),1.73–1.67(m,1H),1.40(t,J=7.1Hz,3H),1.29(s,9H),0.93(d,J=7.3Hz,3H),0.90(d,J=7.2Hz,3H).MS ESI m/z C16H28NaN2O4S2[M+Na]+计算值为399.15,实测值为399.14。
Example 18.2-((1R,3R)-3-氨基-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯盐酸盐(189)的合成
在0℃下,向2-((1R,3R)-3-((S)-1,1-二甲基乙基亚磺酰胺基)-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯(6.00g,16.0mmol,1.0eq.)的乙醇(40mL)溶液中缓慢加入4N盐酸的二恶烷溶液(40mL)。使反应升温至室温。搅拌2.5小时,然后浓缩,用石油醚打浆。收集白色固体标题化合物(4.54g,92%收率)。
实施例19.2-((1R,3R)-3-((2S,3S)-2-叠氮基-3-甲基戊酰氨基)-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯(190)的合成
将(2S,3S)-2-叠氮基-3-甲基戊酸(5.03g,28.8mmol,2.0eq.)溶解在四氢呋喃(120mL)中并冷却至0℃,向其中依次加入NMM(6.2mL,56.0mmol,4.0)和氯甲酸异丁酯(3.7mL,28.8mmol,2.0eq.)。在0℃下搅拌30分钟并在室温下搅拌1.0小时,然后冷却回0℃。分批加入2-((1R,3R)-3-氨基-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯盐酸盐(4.54g,14.7mmol,1.0eq.)。在0℃下搅拌30分钟后,将反应升温至室温。并搅拌2小时。在0℃加入水以淬灭反应,并将所得混合物用乙酸乙酯萃取三次。将合并的有机层用1N盐酸,饱和碳酸氢钠和盐水洗涤,经无水硫酸钠干燥,过滤并浓缩。通过柱层析(0-30%乙酸乙酯/石油醚)纯化残余物,得到白色固体(4.55g,74%收率)。
实施例20.2-((1R,3R)-3-((2S,3S)-2-叠氮基-3-甲基戊酰氨基)-4-甲基-1-((三乙基甲硅烷基)氧基)戊基)噻唑-4的合成-羧酸盐(191)
在0℃下,向2-((1R,3R)-3-((2S,3S)-2-叠氮基-3-甲基戊酰氨基)-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯(5.30g,12.8mmol,1.0eq.)的二氯甲烷(50mL)溶液中加入咪唑(1.75g,25.6mmol,2.0eq.),然后加入三乙基氯硅烷(4.3mL,25.6mmol,2.0eq.)。将反应混合物在一小时内升温至室温,再搅拌一小时。将盐水加入反应混合物中,分离有机层,水层用乙酸乙酯萃取。将合并的有机相干燥,过滤,减压浓缩,并通过柱层析法纯化,用15-35%乙酸乙酯/石油醚溶液梯度洗脱,得到标题产物(6.70g,99%收率),为白色固体。1H-NMR(500MHz,CDCl3)δ8.12(s,1H),6.75(d,J=8.0Hz,1H),5.20–5.12(m,1H),4.44(q,J=7.0Hz,2H),4.06–3.97(m,1H),3.87(d,J=3.8Hz,1H),2.14(d,J=3.8Hz,1H),2.01–1.91(m,3H),1.42(t,J=7.1Hz,3H),1.34–1.25(m,2H),1.06(d,J=6.8Hz,3H),1.00–0.93(m,18H),0.88(dd,J=19.1,6.8Hz,6H).MS ESI m/z C24H44N5O4SSi[M+H]+计算值526.28,实测值526.28。
实施例21.2-((1R,3R)-3-((2S,3S)-2-叠氮基-N,3-二甲基戊酰氨基)-4-甲基-1-((三乙基甲硅烷基)氧基)戊基)的合成噻唑-4-羧酸酯(192)的合成
将2-((1R,3R)-3-((2S,3S)-2-叠氮基-3-甲基戊酰氨基)-4-甲基-1-((三乙基甲硅烷基)氧基)戊基)噻唑-4-羧酸乙酯(5.20g,9.9mmol,1.0eq.)的四氢呋喃(50mL)的溶液冷却至-45℃并加入KHMDS(1M甲苯溶液,23.8mL,23.8mmol,2.4eq.)。将所得混合物在-45℃下搅拌20分钟。然后加入碘甲烷(1.85mL,29.7mmol,3.0eq.),并将反应混合物在4.5小时内升温至室温,此时用EtOH(10mL)淬灭反应。将粗产物用乙酸乙酯(250mL)稀释,并用盐水(100mL)洗涤。用乙酸乙酯(3×50mL)萃取水层。将有机层干燥,过滤,浓缩并通过柱层析法纯化,用15-35%乙酸乙酯/石油醚溶液梯度洗脱,得到标题产物(3.33g,63%收率),为浅黄色油状物。1H-NMR(500MHz,CDCl3)δ8.09(s,1H),4.95(d,J=6.6Hz,1H),4.41(q,J=7.1Hz,2H),3.56(d,J=9.5Hz,1H),2.98(s,3H),2.27–2.06(m,4H),1.83–1.70(m,2H),1.41(t,J=7.2Hz,3H),1.29(ddd,J=8.9,6.8,1.6Hz,3H),1.01(d,J=6.6Hz,3H),0.96(dt,J=8.0,2.9Hz,15H),0.92(d,J=6.6Hz,3H),0.90(d,J=6.7Hz,3H).MS ESI m/z C25H46N5O4SSi[M+H]+计算值540.30,,实测值540.30。
实施例22.2-((3S,6R,8R)-3-((S)-仲丁基)-10,10-二乙基-6-异丙基-5-甲基-1-((R)-乙酯的合成1-甲基吡啶-2-基)-1,4-二氧代-9-氧杂-2,5-二氮杂-10-硅十二烷-8-基)噻唑-4-羧酸乙酯的合成
将干燥的Pd/C(10wt%,300mg)和2-((1R,3R)-3-((2S,3S)-2-叠氮基-N,3-二甲基戊酰胺基)-4-甲基-1-乙基将((三乙基甲硅烷基)氧基)戊基)噻唑-4-羧酸酯(3.33g,6.61mmol)加入(R)-全氟苯基1-甲基哌啶-2-羧酸酯的乙酸乙酯溶液中。将反应混合物在氢气环境下搅拌27小时,然后通过硅藻土塞过滤,用乙酸乙酯洗涤滤垫。浓缩合并的有机部分,并通过柱层析法纯化,用0-5%甲醇的乙酸乙酯溶液梯度洗脱,得到标题产物(3.90g,86%收率)。MS ESI m/z C32H59N4O5SSi[M+H]+计算值639.39,实测值639.39。
实施例23.2-((1R,3R)-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰胺基)-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯的合成
将2-((3S,6R,8R)-3-((S)-仲丁基)-10,10-二乙基-6-异丙基-5-甲基-1-((R)-1-甲基哌啶-2)-1,4-二氧代-9-氧杂-2,5-二氮杂-10-硅杂十八碳-8-基)噻唑-4-羧酸酯(3.90g,6.1mmol)溶于脱氧的乙酸/水/四氢呋喃(v/v/v 3:1:1,100mL)中,并在室温下持续搅拌48小时。然后浓缩反应物并通过柱层析((2:98至15:85甲醇/乙酸乙酯)纯化,得到标题化合物(2.50g,两步收率72%)。C26H45N4O5S[M+H]+的计算值525.30,实测值525.33。
实施例24.2-((1R,3R)-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰胺基)-1-羟基-4-甲基戊基)噻唑-4-羧酸的合成
在0℃,将LiOH水溶液(0.4N,47.7mL,19.1mmol,4.0eq.)加入2-((1R,3R)-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)-戊酰胺基)-1-羟基-4-甲基戊基)噻唑-4-羧酸酯(2.50g,4.76mmol,1.0eq.)的二恶烷溶液(47.7mL)中。将反应混合物在室温下搅拌2小时后浓缩。柱层析纯化(100%二氯甲烷然后二氯甲烷/甲醇/NH4OH 80:20:1洗脱),得到标题化合物(2.36g,99%收率),为无定形固体。MS ESI m/z C24H41N4O5S[M+H]+计算值497.27,实测值497.28。
实施例25.2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰胺基)-4-甲基戊基)噻唑-4-羧酸的合成
在0℃下,向2-((1R,3R)-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰胺基)-1-羟基-4-甲基戊基)噻唑-4-羧酸(2.36g,4.75mmol)的吡啶(50mL)溶液中缓慢加入乙酸酐(2.25mL,24mmol)。将反应混合物在2小时升温至室温并在室温下持续搅拌24小时。浓缩反应物,并通过反相HPLC(C18柱,10-90%乙腈/水)纯化残余物,得到标题化合物(2.25g,88%产率),为无定形白色固体。MS ESI m/z C26H43N4O6S[M+H]+计算值539.28,实测值539.28.
实施例26.(1R,3R)-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰胺基)-4-甲基-1-(4-(全氟苯甲酰基)噻唑-2-基)乙酸戊酯(294)的合成
在0℃下,向2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基-哌啶-2-甲酰胺基)戊酰胺的溶液)4-甲基戊基)噻唑-4-羧酸(86mg,0.16mmol,1.0eq.)的二氯甲烷(2mL)溶液中加入五氟苯酚(44mg,0.24mmol,1.5eq.)和N,N’-二异丙基碳二亚胺(0mg,22mg,0.175mmol,1.1eq.)。将反应混合物升温至室温并搅拌过夜。在减压下除去溶剂后,将反应混合物用乙酸乙酯(2mL)稀释,然后经硅藻土过滤。浓缩滤液,得到标题化合物,不经进一步纯化直接使用。
实施例27.3-(2-(2-(2-羟基乙氧基)乙氧基)乙氧基)丙酸叔丁酯的合成
向2,2’-(乙烷-1,2-二基双(氧基))二乙醇(55.0mL,410.75mmol,3.0eq.)的无水四氢呋喃(200mL)溶液中加入钠(0.1g)。搅拌混合物直至钠块消失,然后滴加丙烯酸叔丁酯(20.0mL,137.79mmol,1.0eq.)。将混合物搅拌过夜,然后在0℃下用盐酸溶液(20.0mL,1N)淬灭。通过旋转浓缩除去四氢呋喃,加入盐水(300mL)并将所得混合物用乙酸乙酯(3×100mL)萃取。将有机层用盐水(3×300mL)洗涤,经无水硫酸钠干燥,过滤并浓缩,得到无色油状物(30.20g,79.0%产率),其不经进一步纯化而直接使用。MS ESI m/z C13H27O6[M+H]+计算值278.1729,实测值278.1730.
实施例28.3-(2-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)乙氧基)丙酸叔丁酯的合成
在0℃下,向3-(2-(2-(2-羟基乙氧基)乙氧基)乙氧基)丙酸叔丁酯(30.20g,108.5mmol,1.0eq.)和TsCl(41.37g,217.0mmol,2.0eq.)的无水二氯甲烷(220mL)溶液中加入TEA(30.0mL,217.0mmol,2.0eq.)。将混合物在室温下搅拌过夜,然后用水(3×300mL)和盐水(300mL)洗涤,经无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(3:1正己烷/乙酸乙酯)纯化得到无色油状物(39.4g,收率84.0%)。MS ESI m/z C20H33O8S[M+H]+计算值433.1818,实测值433.2838.
实施例29.3-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)丙酸叔丁酯的合成
将3-(2-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)乙氧基)丙酸叔丁酯(39.4g,91.1mmol,1.0eq.)溶解于无水DMF(100mL),接着加入NaN3(20.67g,316.6mmol,3.5eq.)。将混合物在室温下搅拌过夜。加入水(500mL)并用乙酸乙酯(3×300mL)萃取。将合并的有机层用水(3×900mL)和盐水(900mL)洗涤,用无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(5:1正己烷/乙酸乙酯)纯化,得到浅黄色油状物(23.8g,85.53%收率)。MS ESI m/zC13H25O3N5Na[M+Na]+计算值326.2,实际值326.2.
实施例30.3-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)丙酸叔丁酯的合成
将Raney-Ni(7.5g,悬浮在水中)用水(三次)和异丙醇(三次)洗涤,并与化合物147(5.0g,16.5mmol)在异丙醇中混合。将混合物在室温下H2气球环境中持续搅拌16小时,然后用硅藻土垫过滤,用异丙醇洗涤垫。浓缩滤液并通过柱层析(5-25%甲醇/二氯甲烷)纯化,得到浅黄色油状物(2.60g,57%收率)。MS ESI m/z C18H23NO2Na[M+Na]+计算值309.1729,实测值309.1967。
实施例31.2-(2-(二苄基氨基)乙氧基)乙醇(298)的合成
将2-(2-氨基乙氧基)乙醇(21.00g,200mmol,1.0eq.)和K2CO3(83.00g,600mmol,3.0eq.)混合于乙腈(350mL),接着加入苄溴(57.0mL,480mmol,2.4eq.))。将混合物回流过夜。加入水(1L)并用乙酸乙酯(3×300mL)萃取。将合并的有机层用盐水(1000mL)洗涤,经无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(4:1正己烷/乙酸乙酯)纯化,得到无色油状物(50.97g,89.2%产率)。MS ESI m/z C18H23NO2Na[M+Na]+计算值为309.1729,,实测值309.1967。
实施例32.3-(2-(2-(二苄基氨基)乙氧基)乙氧基)丙酸叔丁酯(300)的合成
向2-(2-(二苄基氨基)乙氧基)乙醇(47.17g,165.3mmol,1.0eq.),丙烯酸叔丁酯(72.0mL,495.9mmol,3.0eq.)和n-Bu4NI(6.10g,16.53mmol,0.1eq.)和二氯甲烷(560mL)的混合物中加入氢氧化钠溶液(300mL,50%)。将混合物搅拌过夜。分离有机层,水层用乙酸乙酯(3×100mL)萃取。将有机层用水(3×300mL)和盐水(300mL)洗涤,经无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(7:1正己烷/乙酸乙酯)纯化,得到无色油状物(61.08g,89.4%收益率)。MS ESI m/z C25H36NO4[M+H]+计算值414.2566,实测值414.2384.
实施例33.3-(2-(2-氨基乙氧基)乙氧基)丙酸叔丁酯(301)的合成
在氢化瓶中,向3-(2-(2-(二苄基氨基)乙氧基)乙氧基)丙酸叔丁酯(20.00g,48.36mmol,1.0eq.)的四氢呋喃(30mL)和甲醇(60mL)溶液中加入Pd/C(2.00g,10wt%,50%水)。将混合物振荡过夜,通过Celite过滤(助滤剂),浓缩滤液,得到无色油状物(10.58g,93.8%收率)。MS ESI m/z C11H24NO4[M+H]+计算值234.1627,实测值234.1810。
实施例34.3-(2-(2-羟基乙氧基)乙氧基)丙酸叔丁酯的合成
向2,2’-氧代二乙醇(19.7mL,206.7mmol,3.0eq.)的无水四氢呋喃(100mL)溶液中加入钠(0.1g)。搅拌混合物直至钠块消失,然后滴加丙烯酸叔丁酯(10.0mL,68.9mmol,1.0eq.)。将混合物搅拌过夜,加入盐水(200mL)并用乙酸乙酯(3×100mL)萃取。将有机层用盐水(3×300mL)洗涤,经无水硫酸钠干燥,过滤,浓缩并通过SiO2柱层析(1:1正己烷/乙酸乙酯)纯化,得到无色油状物(8.10g,49.4%收率)。MS ESI m/z C11H23O5[M+H]+的计算值235.1467,实测值235.1667。
实施例35.3-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)丙酸叔丁酯的合成
在0℃下,向3-(2-(2-羟基乙氧基)乙氧基)丙酸叔丁酯(6.24g,26.63mmol,1.0eq.)和TsCl(10.15g,53.27mmol,2.0eq.)的无水二氯甲烷(50mL)溶液中加入吡啶(4.3mL,53.27mmol,2.0eq.)。将混合物在室温下搅拌过夜,然后用水(100mL)洗涤,水层用二氯甲烷(3×50mL)萃取。将合并的有机层用盐水(300mL)洗涤,经无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(5:1正己烷/乙酸乙酯)纯化,得到无色油状物(6.33g,61.3%产率)。MS ESI m/z C18H27O7S[M+H]+计算值389.1556,实测值389.2809。
实施例36.3-(2-(2-叠氮基乙氧基)乙氧基)丙酸叔丁酯的合成
向3-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)丙酸叔丁酯(5.80g,14.93mmol,1.0eq.)的无水DMF(20mL)溶液中加入NaN3(5.02g,77.22mmol),5.0eq.)。将混合物在室温下搅拌过夜,加入水(120mL)并用乙酸乙酯(3×50mL)萃取。将合并的有机层用水(3×150mL)和盐水(150mL)洗涤,用无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(5:1正己烷/乙酸乙酯)纯化,得到无色油状物(3.73g,产率69.6%)。MS ESI m/z C11H22O3N4Na[M+H]+计算值260.1532,实测值260.2259。
实施例37.3-(2-(2-氨基乙氧基)乙氧基)丙酸叔丁酯的合成
将3-(2-(2-叠氮基乙氧基)乙氧基)丙酸叔丁酯(0.18g,0.69mmol)溶于甲醇(3.0mL,含60μL浓盐酸)中并与Pd/C(10wt%,20mg)氢化30分钟。将催化剂通过硅藻土垫过滤,用甲醇洗涤硅藻土垫。浓缩滤液,得到无色油状物(0.15g,93%收率)。ESI m/z C11H24NO4[M+H]+的计算值234.16,实测值234.14。
实施例38.3-(2-(2-叠氮基乙氧基)乙氧基)丙酸
将3-(2-(2-叠氮基乙氧基)乙氧基)丙酸叔丁酯(2.51g,9.68mmol)溶解于1,4-二恶烷(30mL)中并与10mL浓盐酸在室温下搅拌35分钟,用EtOH(30mL)和甲苯(30mL)稀释,并在真空下浓缩。将粗品在硅胶上使用甲醇/二氯甲烷(5%至10%)(含1%甲酸)纯化,得到标题化合物(1.63g,83%收率),ESI MS m/z C7H12N3O4[M-H]-计算值202.06,实测值202.30。
实施例39.2,5-二氧代吡咯烷-1-基3-(2-(2-叠氮基乙氧基)乙氧基)丙酸酯的合成
向3-(2-(2-叠氮基乙氧基)乙氧基)丙酸(1.60g,7.87mmol)的30mL的二氯甲烷溶液中边搅拌边加入NHS(1.08g,9.39mmol)和EDC(3.60g,18.75mmol)。8小时后,TLC分析显示反应完成,将反应混合物浓缩并在硅胶上使用乙酸乙酯(5%至10%)在二氯甲烷中的混合物作为洗脱液纯化,得到标题化合物(1.93g,产率82%)。ESI MS m/z C11H17N4O6[M+H]+,计算值301.11,实际值301.20.
实施例40.(S)-15-叠氮基-5-异丙基-4,7-二氧代-10,13-二氧杂-3,6-二氮杂十五烷-1-酸的合成
向(S)-2-(2-氨基-3-甲基丁酰胺基)乙酸(Val-Gly)(1.01g,5.80mmol)的DMA(50mL)和NaH2PO4(50mL,pH 7.5)溶液中加入2,5-二氧代吡咯烷-1-基3-(2-(2-叠氮基乙氧基)乙氧基)丙酸酯(1.90g,6.33)。将混合物搅拌4小时,真空浓缩,在硅胶上使用甲醇/二氯甲烷(5%至15%,含有0.5%乙酸)混合物作为洗脱液纯化,得到标题化合物(1.52g,73%)。ESI MS m/z C14H26N5O6[M+H]+,计算值360.18,实测值360.40。
实施例41.(S)-2,5-二氧代吡咯烷-1-基15-叠氮基-5-异丙基-4,7-二氧代-10,13-二氧杂-3,6-二氮杂十五烷-1-酸的合成
向(S)-15-叠氮基-5-异丙基-4,7-二氧代-10,13-二氧杂-3,6-二氮杂十五烷-1-酸(1.50g,4.17mmol)的二氯甲烷(40mL)溶液中加入NHS(0.88g,7.65mmol)和EDC(2.60g,13.54mmol)。搅拌8小时后,TLC分析显示反应完成,将反应混合物浓缩并在硅胶上使用乙酸乙酯/二氯甲烷(5%-20%)作为洗脱液纯化,得到标题化合物(1.48g,产率78%)。ESI MSm/z C18H29N6O8[M+H]+,计算值457.20,实测值457.50。
实施例42.4-(((苄氧基)羰基)氨基)丁酸的合成
将4-氨基丁酸(7.5g,75mmol)和氢氧化钠(6g,150mmol)的水(40mL)溶液冷却至0℃,并滴加CbzCl(16.1g,95mmol)的四氢呋喃(32mL)溶液。滴加1小时后,将反应物升温至室温并搅拌3小时。真空除去四氢呋喃,通过加入6N盐酸将水溶液的pH调节至1.5。用乙酸乙酯萃取,有机层用盐水洗涤,干燥并浓缩,得到标题化合物(16.4g,92%收率)。MS ESI m/zC12H16NO5[M+H]+计算值238.10,实测值238.08。
实施例43.4-(((苄氧基)羰基)氨基)丁酸叔丁酯的合成
向4-(((苄氧基)羰基)氨基)丁酸(16.4g,69.2mmol)和t-BuOH(15.4g,208mmol)的二氯甲烷(100mL)溶液中加入DMAP(0.8g,6.56mmol)和DCC(17.1g,83mmol)。在室温下搅拌过夜,过滤反应物并浓缩滤液。将残余物溶于乙酸乙酯中,用1N盐酸,盐水洗涤,用无水硫酸钠干燥。浓缩并通过柱层析法纯化(10至50%乙酸乙酯/正己烷),得到标题化合物(7.5g,37%收率).MS ESI m/z C16H23NO4Na[M+Na]+计算值316.16,实测值316.13。
实施例44.4-氨基丁酸叔丁酯的合成
将4-(((苄氧基)羰基)氨基)丁酸叔丁酯(560mg,1.91mmol)溶解在甲醇(50mL)中,并与Pd/C催化剂(10wt%,100mg)混合,然后氢化(1atm)并在室温下保持3小时。滤除催化剂,真空除去所有挥发物,得到标题化合物(272mg,90%收率)。MS ESI m/z C8H18NO2[M+H]+计算值160.13,实际值160.13.。
实施例45.2-(三苯基亚正膦基)丙酸叔丁酯(206)的合成
将2-溴丙酸叔丁酯(15.5g,74.1mmol,1.0eq.)和三苯基膦(19.4g,74.1mmol,1.0eq.)在无水乙腈(45mL)中混合并在室温下搅拌18小时。减压除去乙腈,加入甲苯,使白色沉淀物析出。然后倒出甲苯,将白色固体溶解在二氯甲烷(100mL)中,并转移到分液漏斗中。向漏斗中加入10%氢氧化钠(100mL),震荡后有机层立即变黄。分离有机层,水层用二氯甲烷(30mL)萃取一次。合并二氯甲烷层并用盐水(50mL)洗涤一次,然后经无水硫酸钠干燥,过滤并浓缩,得到内鎓盐,为黄色固体(16.8g,58%)。
实施例46.(S)-3-(4-(苄氧基)苯基)-2-((叔丁氧基羰基)氨基)丙酸甲酯(203)的合成
向Boc-L-Tyr-OMe(20.0g,67.7mmol,1.0eq.),K2CO3(14.0g,101.6mmol,1.5eq.)和KI(1.12g,6.77mmol,0.1eq.)的丙酮(100mL)混合物中缓慢加入苄溴(10.5mL,81.3mmol,1.2eq.)。然后将混合物回流过夜。加入水(250mL)并将反应混合物用乙酸乙酯(3×100mL)萃取。将合并的有机层用盐水(300mL)洗涤,经无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(4:1正己烷/乙酸乙酯)纯化,得到标题化合物,为白色固体(26.12g,99%收率)。1H-NMR(500MHz,CDCl3)δ7.44–7.41(m,2H),7.41–7.36(m,2H),7.35–7.30(m,1H),7.04(d,J=8.5Hz,2H),6.93–6.89(m,2H),5.04(s,2H),4.97(d,J=7.7Hz,1H),4.55(d,J=6.9Hz,1H),3.71(s,3H),3.03(dd,J=14.4,5.7Hz,2H),1.44(d,J=18.6Hz,10H).MS ESI m/zC22H27NO5Na[M+Na]+计算值408.18,实测值408.11.
实施例47.(S)-(1-(4-(苄氧基)苯基)-3-氧代丙烷-2-基)氨基甲酸叔丁酯(204)的合成
在1小时内,在-78℃下,向(S)-3-(4-(苄氧基)苯基)-2-((叔丁氧基羰基)氨基)-丙酸甲酯(26.1g,67.8mmol,1.0eq.)的无水二氯甲烷(450mL)中加入DIBAL(1.0M正己烷溶液,163mL,2.2eq.)。将混合物在-78℃下搅拌3小时,然后用50mL乙醇猝灭。逐滴加入1N盐酸直至达到pH4。将所得混合物升温至0℃。进行分层,水层进一步用乙酸乙酯(3×100mL)萃取。将合并的有机溶液用盐水洗涤,用无水硫酸钠干燥并浓缩。用石油醚/乙酸乙酯打浆并过滤,得到标题化合物,为白色固体(18.3g,76%收率)。MS ESI m/z C22H27NO5Na[M+Na]+计算值378.11,实际值378.11.
实施例48.(S,Z)-5-(4-(苄氧基)苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸叔丁酯(207)的合成
向(S)-(1-(4-(苄氧基)苯基)-3-氧代丙烷-2-基)氨基甲酸叔丁酯(0.84g,2mmol,1.0eq.)的无水二氯甲烷(50mL)溶液中加入2-(三苯基-亚膦基)丙酸叔丁酯(1.6g,4mmol,2.0eq.),在室温下搅拌1.5小时,TLC分析显示反应完成。通过柱层析(10-50%乙酸乙酯/正己烷)纯化,得到标题化合物(1.16g,98%收率)。
实施例49.(4R)-4-((叔丁氧基羰基)氨基)-5-(4-羟基苯基)-2-甲基戊酸叔丁酯的合成
将(S,Z)-5-(4-(苄氧基)苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸叔丁酯(467mg,1mmol)溶解在甲醇(30mL)中并在室温下和Pd/C催化剂(10wt%,250mg)混合并氢化反应(1atm)过夜。滤除催化剂,减压浓缩滤液,得到标题化合物(379mg,99%收率)。
实施例50.(4R)-4-((叔丁氧基羰基)氨基)-5-(4-羟基-3-硝基苯基)-2-甲基戊酸叔丁酯的合成
将(4R)-4-((叔丁氧基羰基)氨基)-5-(4-羟基苯基)-2-甲基戊酸叔丁酯(379mg,1mmol,1.0eq.)溶于四氢呋喃(20mL)中,加入亚硝酸叔丁酯(315mg,3mmol,3.0eq.)的四氢呋喃(2mL)溶液。在室温下搅拌3小时,然后倒入水中,用乙酸乙酯(2×50mL)萃取,合并的有机相用盐水(50mL)洗涤,用无水硫酸钠干燥,过滤并浓缩。通过柱层析(10-50%乙酸乙酯/正己烷)纯化,得到标题化合物(300mg,71%收率)。
实施例51.(4R)-5-(3-氨基-4-羟基苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸叔丁酯(210)的合成
将(4R)-4-((叔丁氧基羰基)氨基)-5-(4-羟基-3-硝基苯基)-2-甲基-戊酸叔丁酯(200mg,0.47mmol)溶于乙酸乙酯(30mL)中并与Pd/C催化剂(10wt%,100mg)混合,然后在室温下氢化(1atm)2小时,滤除催化剂并在真空下除去所有挥发物,得到标题化合物(185mg,99%)。
或者,将(4R)-4-((叔丁氧基羰基)氨基)-5-(4-羟基-3-硝基苯基)-2-甲基戊酸叔丁酯(56mg,0.132mmol)溶于乙酸乙酯(20mL)中。在室温下与Pd/C催化剂(10wt%,50mg)混合并氢化(1atm)3小时。滤除催化剂,真空除去所有挥发物,得到标题化合物(52mg,99%收率)。MS ESI m/z C21H35N2O5[M+H]+计算值395.25,实际值395.26.
实施例52.(4R)-4-((叔丁氧基羰基)氨基)-5-(4-((叔丁基二甲基甲硅烷基)氧基)-3-硝基苯基)-2-甲基戊酸叔丁酯的合成
向(4R)-4-((叔丁氧基羰基)氨基)-5-(4-羟基-3-硝基苯基)-2-甲基戊酸叔丁酯(424mg,1mmol)的二氯甲烷(20mL)溶液中加入咪唑(408mg,6mmol)和叔丁基氯二甲基硅烷(602mg,4mmol)。将所得溶液在室温下搅拌3小时。然后,将反应混合物用盐水(50mL)洗涤,经无水硫酸钠干燥,浓缩并通过柱层析(10%至30%乙酸乙酯/正己烷)纯化,得到标题化合物(344mg,64%收率)。
实施例53.(4R)-5-(3-氨基-4-((叔丁基二甲基甲硅烷基)氧基)苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸叔丁酯(215)的合成
将(4R)-4-((叔丁氧基羰基)氨基)-5-(4-((叔丁基二甲基甲硅烷基)氧基)-3-硝基苯基)-2-甲基戊酸叔丁酯(200mg,0.37mmol)溶解于乙酸乙酯(30mL),与Pd/C催化剂(10wt%,100mg)混合并在室温下氢化(1atm)2小时滤除催化剂,真空除去所有挥发物,得到标题化合物(187mg,99%收率)。
实施例54.(S)-2-(羟甲基)吡咯烷-1-羧酸叔丁酯的合成
将溶解在50mL四氢呋喃中的Boc-L-脯氨酸(10.0g,46.4mmol)冷却至0℃,小心地加入BH3的四氢呋喃溶液(1.0M,46.4mL)。将混合物在0℃下搅拌1.5小时,然后倒入冰水中并用乙酸乙酯萃取。将有机层用盐水(50mL)洗涤,经无水硫酸钠干燥,并在减压下浓缩,得到标题化合物(8.50g,91%产率),为白色固体。1H-NMR(500MHz,CDCl3)δ3.94(dd,J=4.9,2.7Hz,2H),3.60(ddd,J=18.7,11.9,9.3Hz,2H),3.49–3.37(m,1H),3.34–3.23(m,1H),2.06–1.91(m,1H),1.89–1.69(m,2H),1.65–1.51(m,1H),1.49–.40(m,9H).
实施例55.(S)-2-甲酰基吡咯烷-1-羧酸叔丁酯的合成
向(S)-2-(羟甲基)吡咯烷-1-羧酸叔丁酯(13.0g,64.6mmol)的二甲基亚砜(90mL)的溶液中加入三乙胺(40mL),搅拌15分钟。将混合物在冰浴上冷却,并在40分钟内分批加入三氧化硫-吡啶络合物(35.98g,226mmol)。将反应升温至室温并搅拌2.5小时。加入冰(250g)后,将混合物用二氯甲烷(150mL×3)萃取。将有机相用50%柠檬酸溶液(150mL),水(150mL),饱和碳酸氢钠溶液(150mL)和盐水(150mL)洗涤,经无水硫酸钠干燥。在真空中除去溶剂,得到标题醛(10.4g,81%收率),为稠油状物,且不经进一步纯化而使用。1H-NMR(500MHz,CDCl3)δ9.45(s,1H),4.04(s,1H),3.53(dd,J=14.4,8.0Hz,2H),2.00–1.82(m,4H),1.44(d,J=22.6Hz,9H).
实施例56.(4R,5S)-4-甲基-5-苯基-3-丙酰基恶唑烷-2-酮的合成
在-78℃,N2条件下,向正丁基锂的正己烷(21.6mL,2.2M,47.43mmol)溶液中滴加4-甲基-5-苯基恶唑烷-2-酮(8.0g,45.17mmol)的四氢呋喃(100mL)溶液。将溶液在-78℃保持1小时,然后缓慢加入丙酰氯(4.4mL,50.59mmol)。将反应混合物升温至-50℃,搅拌2小时,然后加入饱和氯化铵溶液(100mL)淬灭。真空除去有机溶剂,用乙酸乙酯(3×100mL)萃取所得溶液。用饱和碳酸氢钠溶液(100mL)和盐水(100mL)洗涤有机层,用无水硫酸钠干燥,过滤并真空浓缩。通过柱层析(20%乙酸乙酯/正己烷)纯化残余物,得到标题化合物,为稠油状物(10.5g,98%收率)。1H-NMR(500MHz,CDCl3)δ7.45–7.34(m,3H),7.30(d,J=7.0Hz,2H),5.67(d,J=7.3Hz,1H),4.82–4.70(m,1H),2.97(dd,J=19.0,7.4Hz,2H),1.19(t,J=7.4Hz,3H),0.90(d,J=6.6Hz,3H).
实施例57.(S)-叔丁基2-((1R,2R)-1-羟基-2-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基恶唑烷-3-基)-3-氧代丙基)吡咯烷-1-羧酸叔丁酯的合成
在0℃下,向(4R,5S)-4-甲基-5-苯基-3-丙酰基恶唑烷-2-酮(9.40g,40.4mmol)的二氯甲烷(60mL)溶液中加入三乙胺(6.45mL,46.64mmol),然后加入1M二丁基硼三氟甲磺酸酯的二氯甲烷(42mL,42mmol)溶液。将混合物在0℃下搅拌45分钟,冷却至-70℃,然后在30分钟内缓慢加入(S)-2-甲酰基吡咯烷-1-羧酸叔丁酯(4.58g,22.97mmol)的二氯甲烷(40mL)溶液。将反应混合物在-70℃下搅拌2小时,0℃下搅拌1小时,并在室温下搅拌15分钟,然后用磷酸盐缓冲溶液(pH 7,38mL)淬灭。在低于10℃下加入甲醇-30%H2O2溶液(2:1,100mL),搅拌20分钟后,加入水(100mL)并将混合物真空浓缩。向残余物中加入更多的水(200mL),用乙酸乙酯(3×100mL)萃取混合物。用1N KHSO4(100mL),碳酸氢钠溶液(100mL)和盐水(100mL)洗涤有机层,用无水硫酸钠干燥并真空浓缩。通过快速柱层析(10%-50%乙酸乙酯/正己烷)纯化残余物,得到标题化合物,为白色固体(7.10g,71%收率).1H-NMR(500MHz,CDCl3)δ7.39(dt,J=23.4,7.1Hz,3H),7.30(d,J=7.5Hz,2H),5.67(d,J=7.1Hz,1H),4.84–4.67(m,1H),4.08–3.93(m,3H),3.92–3.84(m,1H),3.50(d,J=9.0Hz,1H),3.24(d,J=6.7Hz,1H),2.15(s,1H),1.89(dd,J=22.4,14.8Hz,3H),1.48(d,J=21.5Hz,9H),1.33(d,J=6.9Hz,3H),0.88(d,J=6.4Hz,3H).
实施例58.(S)叔丁基2-(-(1R,2R)-1-甲氧基-2-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基恶唑烷-吡啶-3-基)-3-氧代丙基)吡咯烷-1-羧酸叔丁酯的合成
在N2下,向(S)-叔丁基2-((1R,2R)-1-羟基-2-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基恶唑烷-3-基)-3-氧代丙基)吡咯烷-1-甲酸(5.1g,11.9mmol)和分子筛( 5g)的混合物中加入无水二氯乙烷(30mL)。将混合物在室温下搅拌20分钟并冷却至0℃,加入质子海绵(6.62g,30.9mmol),然后加入三甲基氧鎓四氟硼酸盐(4.40g,29.7mmol)。在0℃下继续搅拌2小时,在室温下搅拌48小时。过滤反应混合物,浓缩滤液,并通过柱层析(20-70%乙酸乙酯/正己烷)纯化,得到标题化合物,为白色固体(1.80g,35%收率)。1H-NMR(500MHz,CDCl3)δ7.46–7.27(m,5H),5.65(s,1H),4.69(s,1H),3.92(s,1H),3.83(s,1H),3.48(s,3H),3.17(s,2H),2.02–1.68(m,5H),1.48(d,J=22.3Hz,9H),1.32(t,J=6.0Hz,3H),0.91–0.84(m,3H).
实施例59.(S)-叔丁基(2R,3R)-3-((S)-1-(叔丁氧基羰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酸的合成
在0℃下,在5分钟内向(S)-叔丁基2-((1R,2R)-1-甲氧基-2-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基恶唑烷-3-基)-3-氧代丙基)吡咯烷-1-甲酸-(3)-氧代丙基)吡咯烷-1-甲酸酯(1.80g,4.03mmol)的四氢呋喃(30mL)和水(7.5mL)溶液中加入30%H2O2(1.44mL,14.4mmol)。然后加入LiOH(0.27g,6.45mmol)的水溶液(5mL)。在0℃下搅拌3小时后,加入1N亚硫酸钠(15.7mL)并将混合物升温至室温且搅拌过夜。真空除去四氢呋喃,水相用二氯甲烷(3×50mL)洗涤,除去恶唑烷酮助剂。用1N盐酸将水相酸化至pH 3并用乙酸乙酯(3×50mL)萃取。用盐水(50mL)洗涤有机层,用无水硫酸钠干燥,过滤并真空浓缩,得到标题化合物,为无色油状物(1.15g,98%收率)。1H-NMR(500MHz,CDCl3)δ3.99–3.74(m,2H),3.44(d,J=2.6Hz,3H),3.23(s,1H),2.60–2.45(m,1H),1.92(tt,J=56.0,31.5Hz,3H),1.79–1.69(m,1H),1.58–1.39(m,9H),1.30–1.24(m,3H).
实施例60.(4S,5S)-乙基4-((叔丁氧基羰基)氨基)-5-甲基-3-氧代庚酸乙酯的合成
向用冰冷却的N-Boc-L-异亮氨酸(4.55g,19.67mmol)的四氢呋喃(20mL)溶液中加入1,1’-羰基二咪唑(3.51g,21.63mmol)。待气体停止产生后,将所得混合物升温至室温,搅拌3.5小时。
5℃下,向新制备的异丙基溴化镁的四氢呋喃(123mmol,30mL)溶液中滴加预冷至(0℃)的丙二酸单乙酯(6.50g,49.2mmol)溶液。然后将混合物在室温下搅拌1.5小时。将该烯醇镁溶液在冰水浴上冷却,并在1小时内通过双头针向其中加入咪唑化物溶液。将所得混合物在0℃下搅拌30分钟,然后在室温下搅拌64小时。通过加入10%柠檬酸水溶液(5mL)淬灭反应混合物,并用另外的10%柠檬酸水溶液(110mL)酸化至pH 3。用乙酸乙酯(3×150mL)萃取混合物。将有机萃取液用水(50mL),饱和碳酸氢钠水溶液(50mL)和饱和氯化钠水溶液(50mL)洗涤,用无水硫酸钠干燥,并真空浓缩。残留物通过硅胶柱层析纯化,用乙酸乙酯/正己烷(1:4)作为洗脱液,得到标题化合物(5.50g,93%收率)。1H-NMR(500MHz,CDCl3)δ5.04(d,J=7.8Hz,1H),4.20(p,J=7.0Hz,3H),3.52(t,J=10.7Hz,2H),1.96(d,J=3.7Hz,1H),1.69(s,2H),1.44(s,9H),1.28(dd,J=7.1,2.9Hz,3H),0.98(t,J=6.9Hz,3H),0.92–0.86(m,3H).
实施例61.(3R,4S,5S)-4-((叔丁氧基羰基)氨基)-3-羟基-5-甲基庚酸乙酯的合成
在-60℃下向(4S,5S)-4-((叔丁氧基羰基)氨基)-5-甲基-3-氧代庚酸乙酯(5.90g,19.83mmol)的乙醇(6mL)溶液中一次性加入硼氢化钠(3.77g,99.2mmol)。将反应混合物在-55℃下搅拌5.5小时,然后用10%柠檬酸水溶液(100mL)淬灭。用另外的10%柠檬酸水溶液将所得溶液酸化至pH 2,然后用乙酸乙酯(3×100mL)萃取。用饱和氯化钠水溶液(100mL)洗涤有机物,用无水硫酸钠干燥,并真空浓缩。通过柱层析(10-50%乙酸乙酯/正己烷)纯化残余物,得到标题化合物,为非对映异构体(2.20g,37%收率)和两种非对映异构体的混合物(2.0g,34%收率,约9:1比率)。1H-NMR(500MHz,CDCl3)δ4.41(d,J=9.3Hz,1H),4.17(tt,J=7.1,3.6Hz,2H),4.00(t,J=6.9Hz,1H),3.55(dd,J=11.7,9.3Hz,1H),2.56–2.51(m,2H),2.44(dd,J=16.4,9.0Hz,1H),1.79(d,J=3.8Hz,1H),1.60–1.53(m,1H),1.43(s,9H),1.27(dd,J=9.3,5.0Hz,3H),1.03–0.91(m,7H).
实施例62.(3R,4S,5S)-4-((叔丁氧基羰基)氨基)-3-羟基-5-甲基庚酸的合成
向(3R,4S,5S)-4-((叔丁氧基羰基)氨基)-3-羟基-5-甲基庚酸乙酯(2.20g,7.20mmol)的乙醇(22mL)溶液中加入1N氢氧化钠(7.57mL,7.57mmol)。将混合物在0℃下搅拌30分钟,然后在室温下搅拌2小时,通过加入1N盐酸水溶液将所得溶液酸化至pH4,然后用乙酸乙酯(3×50mL)萃取。将有机萃取液用1N硫酸氢钾水溶液(50mL)和饱和氯化钠水溶液(50mL)洗涤,用无水硫酸钠干燥,并真空浓缩,得到化合物(1.90g,95%收率)。1H-NMR(500MHz,CDCl3)δ4.50(d,J=8.7Hz,1H),4.07(d,J=5.5Hz,1H),3.59(d,J=8.3Hz,1H),2.56–2.45(m,2H),1.76–1.65(m,1H),1.56(d,J=7.1Hz,1H),1.45(s,9H),1.26(t,J=7.1Hz,3H),0.93(dd,J=14.4,7.1Hz,6H).。
实施例63.(3R,4S,5S)-4-((叔丁氧基羰基)(甲基)氨基)-3-甲氧基-5-甲基庚酸的合成
向(3R,4S,5S)-4-((叔丁氧基羰基)氨基)-3-羟基-5-甲基庚酸(1.90g,6.9mmol)的四氢呋喃(40mL)溶液中加入氢化钠(在0℃下,60%矿物油中,1.93g,48.3mmol)。搅拌1小时后,加入碘甲烷(6.6mL,103.5mmol)。在0℃下继续搅拌40小时,然后加入饱和碳酸氢钠水溶液(50mL),接着加入水(100mL)。将混合物用乙醚(2×50mL)洗涤,并将水层用1N硫酸氢钾水溶液酸化至pH 3,然后用乙酸乙酯(3×50mL)萃取。将合并的有机萃取液用5%硫代硫酸钠水溶液(50mL)和饱和氯化钠水溶液(50mL)洗涤,用无水硫酸钠干燥,真空浓缩,得到标题化合物(1.00g,48%收率)。1H-NMR(500MHz,CDCl3)δ3.95(d,J=75.4Hz,2H),3.42(d,J=4.4Hz,3H),2.71(s,3H),2.62(s,1H),2.56–2.47(m,2H),1.79(s,1H),1.47(s,1H),1.45(d,J=3.3Hz,9H),1.13–1.05(m,1H),0.96(d,J=6.7Hz,3H),0.89(td,J=7.2,2.5Hz,3H).
实施例64.Boc-N-Me-L-Val-OH的合成
在0℃下,向BOC-L-缬氨酸-OH(2.00克,9.2mmol)和碘甲烷(5.74mL,92mmol)的无水四氢呋喃(40mL)溶液中加入氢化钠(3.68克,92mmol)。将反应混合物在0℃下搅拌1.5小时,然后升温至室温并搅拌24小时。用冰水(50mL)淬灭反应,加入水(100mL)后,将反应混合物用乙酸乙酯(3×50mL))洗涤,将水溶液酸化至pH 3,然后用乙酸乙酯(3×50mL)萃取。将合并的有机相用无水硫酸钠干燥并浓缩,得到白色固体Boc-N-Me-Val-OH(2.00g,94%产量).1H-NMR(500MHz,CDCl3)δ4.10(d,J=10.0Hz,1H),2.87(s,3H),2.37–2.13(m,1H),1.44(d,J=26.7Hz,9H),1.02(d,J=6.5Hz,3H),0.90(t,J=8.6Hz,3H).
实施例65.(S)-2-((1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙烷-2-基)氨基叔丁酯的合成甲基)-2-甲基-3-氧代丙基)吡咯烷-1-羧酸叔丁酯的合成
在0℃下,向(2R,3R)-3-((S)-1-(叔丁氧基羰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酸(100mg,0.347mmol)和L-苯丙氨酸甲酯盐酸盐(107.8mg,0.500mmol)的DMF(5mL)溶液中加入氰基膦酸二乙酯(75.6μL,0.451mmol),然后加入三乙胺(131μL,0.94mmol)。将反应混合物在0℃下搅拌2小时,然后升温至室温并搅拌过夜。然后将反应混合物用乙酸乙酯(80mL)稀释,用1N硫酸氢钾水溶液(40mL),水(40mL),饱和碳酸氢钠水溶液(40mL)和饱和氯化钠水溶液(40)洗涤。用无水硫酸钠干燥,真空浓缩。通过柱层析(15-75%乙酸乙酯/正己烷)纯化残余物,得到标题化合物(130mg,83%产率),为白色固体。1H-NMR(500MHz,CDCl3)δ7.28(dd,J=7.9,6.5Hz,2H),7.23(t,J=7.3Hz,1H),7.16(s,2H),4.81(s,1H),3.98–3.56(m,5H),3.50(s,1H),3.37(d,J=2.9Hz,3H),3.17(dd,J=13.9,5.4Hz,2H),3.04(dd,J=14.0,7.7Hz,1H),2.34(s,1H),1.81–1.69(m,2H),1.65(s,3H),1.51–1.40(m,9H),1.16(d,J=7.0Hz,3H).
实施例66.用三氟乙酸除去Boc官能团的一般步骤
向N-Boc氨基酸(1.0mmol)的二氯甲烷(2.5mL)溶液中加入三氟乙酸(1.0mL)。在室温下搅拌1-3小时后,将反应混合物真空浓缩。与甲苯共浓缩得到脱保护的产物,其不经任何进一步纯化即可使用。
实施例67.(S)-甲基-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((叔丁氧基羰基)(甲基)氨基)-3-甲氧基-5-甲基庚基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸乙酯的合成
在0℃下,向(S)(叔丁基-2-((1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙烷-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-羧酸乙酯(0.29mmol)的Boc-去保护产物和(3R,4S,5S)-4-((叔丁氧基羰基)(甲基)氨基)-3-甲氧基-5-甲基庚酸(96.6mg,0.318mmol)的DMF(5mL)溶液中加入氰基膦酸二乙酯(58μL,0.347mmol),然后加入Et3N(109μL,0.78mmol)。将反应混合物在0℃下搅拌2小时,然后升温至室温并搅拌过夜。将反应混合物用乙酸乙酯(80mL)稀释,用1N硫酸氢钾水溶液(40mL),水(40mL),饱和碳酸氢钠水溶液(40mL)和饱和氯化钠水溶液(40mL)洗涤。用无水硫酸钠干燥并真空浓缩。通过柱层析(15-75%乙酸乙酯/正己烷)纯化残余物,得到标题化合物(150mg,81%产率),为白色固体。LC-MS(ESI)m/z C34H55N3O8[M+H]+计算值634.40,实测值634.40。
实施例68.(S)-2-甲基-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((叔丁氧基羰基)氨基)-N,3-二甲基丁酰胺)-3-甲氧基-5-甲基庚基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸乙酯的合成
在0℃下,向(S)-甲基2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((叔丁氧基羰基))(甲基)氨基)-3-甲氧基-5-甲基庚酰基)-吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯的去Boc保护的产物(0.118mmol)和Boc-Val-OH(51.8mg,0.236mmol))的二氯甲烷(5mL)溶液中加入BroP(70.1mg,0.184mmol),然后加入二异丙基乙胺(70μL,0.425mmol)。将混合物置于避光处并在0℃下搅拌30分钟,然后在室温下搅拌2天,将反应混合物用乙酸乙酯(80mL)稀释,用1N硫酸氢钾水溶液(40mL),水(40mL),饱和碳酸氢钠水溶液(40mL)和饱和氯化钠水溶液(40mL)洗涤。用无水硫酸钠干燥并真空浓缩,通过柱层析(20-100%乙酸乙酯/正己烷)纯化残余物,得到标题化合物为白色固体(67mg,77%产率)。LC-MS(ESI)m/zC39H64N4O9[M+H]+计算值733.47,实测值733.46.
实施例69.(S)-甲基2-((2R,3R)-3-((S)-1-((6S,9S,12S,13R)-12-((S)-仲丁基)-6,9-二异丙基-13-甲氧基2,2,5,11四甲基-4,7,10-三氧代-3-氧杂-5,8,11-三氮十五烷-15酰基)吡咯烷-2-基))-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(221)的合成
在0℃下,向(S)-甲基2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4
-((S)-2)-((叔丁氧基羰基)氨基)-N,3-二甲基丁酰胺基)-3-甲氧基-5-甲基庚酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯的去Boc产物(0.091mmol)和Boc-N-Me-Val-OH(127mg,0.548mmol)的DMF(5mL)溶液中加入氰基膦酸二乙酯(18.2μL,0.114mmol),然后加入N-甲基吗啉(59μL,0.548mmol)。将反应混合物在0℃下搅拌2小时,然后升温至室温并搅拌过夜。将反应混合物用乙酸乙酯(80mL)稀释,用1N硫酸氢钾水溶液(40mL),水(40mL),饱和碳酸氢钠水溶液(40mL)和饱和氯化钠水溶液(40mL)洗涤。用硫酸钠干燥,真空浓缩。通过柱层析(20-100%乙酸乙酯/正己烷)纯化残余物,得到标题化合物为白色固体(30mg,39%产率)。LC-MS(ESI)m/z C45H75N5O10[M+H]+计算值846.55,实际值:846.56.
实施例70.(S)-甲基2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-二甲基-2-((S)-3-甲基-2-(甲基氨基)丁酰氨基)丁酰氨基)-3-甲氧基-5-甲基-庚基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙(222)的合成
在室温下,向(S)甲基-(2R,3R)-3-((S)-1-((6S,9S,12S,13R)-12-((S)-仲丁基)-6,9-二异丙基-13-甲氧基-2,2,5,11-四甲基-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十五烷-15酰基)吡咯烷-2-基)3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(75.0mg,0.0886mmol)的二氯甲烷溶液(5mL)中加入三氟乙酸(2mL)。在室温下搅拌1小时,将反应混合物真空浓缩并与甲苯共浓缩得到去保护的标题产物,其无需进一步纯化即可使用。
实施例71.3,3’-(苄基氮杂二基)二丙酸二叔丁酯(227)的合成
将苯基甲胺(2.0mL,18.29mmol,1.0eq.)和丙烯酸叔丁酯(13.3mL,91.46mmol,5.0eq.)的混合物在80℃下回流过夜,然后浓缩。通过硅胶柱层析(20:1正己烷/乙酸乙酯)纯化粗产物,得到标题化合物,为无色油状物(5.10g,77%收率)。ESI MS m/z C21H34NO4[M+H]+计算值364.2,实际值364.2.1H-NMR(400MHz,CDCl3)δ7.38–7.21(m,5H),3.58(s,2H),2.76(t,J=7.0Hz,4H),2.38(t,J=7.0Hz,4H),1.43(s,17H).
实施例72.3,3’-氮杂二基丙酸二叔丁酯(228)的合成
在氢化瓶中,向3,3’-(苄基氮杂二基)二丙酸二叔丁酯(1.37g,3.77mmol,1.0eq.)的甲醇(10mL)溶液中加入Pd/C(0.20g,10wt%,50%水)。将混合物在H2下振荡过夜,然后通过硅藻土垫过滤。浓缩滤液,得到标题化合物,为无色油状物(1.22g,89%收率)。ESI MS m/z C14H28NO4[M+H]+计算值274.19,实际值274.20.
实施例73.3,3’-(丙酰基偶氮二基)二丙酸二叔丁酯(229)的合成
在0℃下,向3,3’-氮杂二丙基丙酸二叔丁酯(1.22g,4.45mmol,1.0eq.)和丙炔酸(0.468g,6.68mmol,1.5eq.)的无水DMF(100mL)溶液中加入PyBrop(2.49g,5.34mmol,1.2eq.)和DIPEA(2.32mL,13.4mmol,3.0eq.)。将反应在0℃下搅拌10分钟,然后升温至室温并搅拌1.5小时。加入水(500mL)并将混合物用乙酸乙酯(6×200mL)萃取。将合并的有机层用水(4×600mL)和盐水(600mL)洗涤,用无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(4:1石油醚/乙酸乙酯)纯化,得到标题化合物,为淡黄色油状物(1.00克,产率82%)。ESI MSm/z C17H28NO5[M+H]+计算值326.18,实际值326.208.。
实施例74.3,3’-(丙酰基氮杂二基)二丙酸(230)的合成
在室温下向3,3’-(丙酰基偶氮二基)二丙酸二叔丁酯(0.078g,0.240mmol,1.0eq.)的二氯甲烷(3mL)溶液中加入TFA(1mL)并搅拌反应物30分钟,然后用无水甲苯稀释,浓缩,重复该操作3次,得到淡黄色油状的标题化合物(0.051g,>100%收率)。ESI MS m/z C9H12NO5[M+H]+214.06,计算值214.06,实测值214.06。
实施例75.(3R,4S,7S,10S,13S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-((1R),2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,13-三甲基-6,9,12,15-四氧代-18-丙二酰基-2-氧杂-5,8,11,14,18-五氮杂苯甲酸-21-酸(231)的合成
在0℃下,向3,3’-(丙酰基氮杂二基)二丙酸(0.051g,0.240mmol,6.5eq.)和(S)-甲基2-((2R,3R)-3-((S)-1-(3R,4S,5S)-4-((S)-2-((S)-2-((S)-2-氨基-N-甲基-丙酰胺基)-3-甲基丁酰胺基)-N,3-二甲基丁酰胺基)-3-甲氧基-5-甲基-庚酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(0.030g,0.0368mmol,1.0eq.)的无水DMF(3mL)溶液中加入PyBrop(0.021g,0.0442mmol,1.2eq.)和DIPEA(0.019mL,0.110mmol,3.0eq.)。将反应在0℃下搅拌10分钟,然后升温至室温并搅拌1.0小时。加入两滴水,浓缩混合物,并用制备HPLC(C18柱,流动相A:水,流动相B:乙腈,从20%B至80%B,50分钟)纯化。合并组分并冻干,得到无色油状物标题化合物(21mg,57%收率)。ESI MS m/z C55H89N8O13[M+H]+计算值1069.64,实测值1069.66.
实施例76.(S)-甲基2-((2R,3R)-3-((S)-1-((14S,17S,20S,23S,24R)-23-((S)-仲丁基)-17,20二异丙基24甲氧基14,16,22三甲基6,12,15,18,21-五氧代-9-丙炔酰基-2-氧杂5,9,13,16,19,22-六氮杂二十六烷-26-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(233)的合成
在0℃下,向(3R,4S,7S,10S,13S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-(1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,13-三甲基-6,9,12,15-四氧代-18-丙烯酰基-2-氧杂-5,8,11,14,18-五氮杂二十一烷-21-酸(0.008g,0.00791mmol,1.0eq.)和2-甲氧基乙胺(0.006g,0.0791mmol,10.0eq.)的无水DMF(2mL)溶液中加入PyBrop(0.004g,0.00870mmol,1.1eq.)和DIPEA(0.004mL,0.00267mmol,3.0eq.)。将反应物在0℃下搅拌10分钟,然后升温至室温并搅拌1.0h。滴加两滴水,将混合物用制备型HPLC纯化(C18柱,流动相A:水,流动相B:乙腈,50分钟内从20%B到80%B)。合并组分并冻干,得到无色油状标题化合物(7.0mg,83%产率)。ESI MS m/z C55H89N8O13[M+H]+计算值1069.64,实测值1069.66.
实施例77.(S)-甲基2-((2R,3R)-3-((S)-1-((81S,84S,87S,90S,91R)-90-((S)-仲丁基)-1-羟基84,87二异丙基91甲氧基81,83,89三甲基73,79,82,85,88-五氧唑-76丙炔酰基-3,6,9,12,15-18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69-二十三氧-72,76,80,83,86,89-六氮杂九十三-93-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(237)的合成
在0℃下,向(3R,4S,7S,10S,13S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-(1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧乙基)-5,11,13-三甲基-6,9,12,15-四氧-18-丙烯酰基-2-氧杂-5,8,11,14,18-五氮杂二十一-21-酸(0.021g,在0.0208mmol,1.0eq.)和HO-PEG24-NH2(0.027g,0.0250mmol,1.2eq.)的无水DMF(3mL)溶液中加入PyBrop(0.010g,0.0218mmol,1.05eq。)和DIPEA(0.011mL,0.0624mmol,3.0eq.)。将反应在0℃下搅拌10分钟,然后升温至室温并搅拌1.0小时。加入两滴水,用制备HPLC(C18柱,流动相A:水,流动相B:乙腈,从20%B至80%B,50分钟)纯化。合并组分并冻干,得到标题化合物,为无色油状物(35mg,81%收率),ESI MS m/z C100H179N8O36[M+H]+计算值2068.23,实测值2068.25。
实施例78.4-(2-(((苄氧基)羰基)氨基)丙烷酰胺基丁酸叔丁酯(251)的合成
在0℃下,向4-氨基丁酸叔丁酯(1.00g,6.28mmol,1.0eq.)和Z-L-丙氨酸(2.10g,9.42mmol,1.5eq.的无水二氯甲烷(50mL)溶液中加入HATU(3.10g,8.164mmol,1.3eq.)和TEA(2.6mL,18.8mmol,3.0eq.)。将反应在0℃下搅拌10分钟,然后升温至室温并搅拌过夜。将混合物用二氯甲烷稀释,然后用水和盐水洗涤,经无水硫酸钠干燥,浓缩,并通过硅胶柱层析(10:3石油醚/乙酸乙酯)纯化,得到标题化合物,为无色油状物(1.39g,61%产率)。ESIMS m/z C19H29N2O5Na[M+H]+计算值387.2,实测值387.2。
实施例79.4-(2-氨基丙酰胺基)丁酸叔丁酯(252)的合成
在氢化瓶中,向4-(2-(((苄氧基)羰基)氨基)丙酰胺基)丁酸叔丁酯(1.39g,3.808mmol,1.0eq.)的甲醇(12mL)溶液中加入Pd/C(0.20g,10wt%,10%水)。将混合物振荡2小时,然后通过硅藻土(助滤剂)过滤,浓缩,得到标题化合物,为浅黄色油状物(0.838g,95%收率)。ESI MS m/z C11H23N2O3[M+H]+计算值231.16,实测值231.15。
实施例80.3-(2-(2-(二苄基氨基)乙氧基)乙氧基)丙酸(254)的合成
在室温下,向3-(2-(2-(二苄基氨基)乙氧基)乙氧基)丙酸叔丁酯(2.3g,5.59mmol,1.0eq.)的二氯甲烷(10mL)溶液中加入TFA(5mL)。搅拌90分钟后,将反应混合物用无水甲苯稀释并浓缩,重复该操作三次,得到标题化合物,为浅黄色油状物(2.0g,理论收率),直接用于下一步。ESI MS m/z C21H28NO4[M+H]+计算值358.19,实测值358.19。
实施例81.五氟苯基3-(2-(2-(二苄基氨基)乙氧基)乙氧基)-丙酸酯(255)的合成
在0℃下,向3-(2-(2-(二苄基氨基)乙氧基)乙氧基)丙酸(2.00g,5.59mmol,1.0eq.)的无水二氯甲烷(30mL)溶液中加入DIPEA直至pH为中性,然后加入五氟苯酚(1.54g,8.38mmol,1.5eq.)和DIC(1.04mL,6.70mmol,1.2eq.)。10分钟后,将反应升温至室温并搅拌过夜。将混合物过滤,浓缩并通过SiO2柱层析(15:1石油醚/乙酸乙酯)纯化,得到标题化合物,为无色油状物(2.10g,72%收率)。ESI MS m/z C27H27F5NO4[M+H]+计算值524.2,实测值524.2。
实施例82.2-苄基-13-甲基-11,14-二氧代-1-苯基-5,8-二氧杂-2,12,15-三氮杂十九烷-19-酸叔丁酯的合成(256)
在0℃下,向4-(2-氨基丙酰胺基)丁酸叔丁酯(0.736g,3.2mmol,1.0eq.)和五氟苯基3-2-(2-(二苄基氨基)乙氧基)乙氧基)丙酸酯(2.01g,3.84mmol,1.2eq.)的无水DMA(20mL)溶液中加入DIPEA(1.7mL,9.6mmol,3.0eq.)。在0℃下搅拌10分钟。将反应升温至室温并搅拌过夜。加入水(100mL)并将混合物用乙酸乙酯(3×100mL)萃取。将合并的有机层用水(3×200mL)和盐水(200mL)洗涤,用无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(25:2二氯甲烷/甲醇)纯化,得到标题化合物,为无色油(1.46克,80%产率)。ESI MS m/zC32H48N3O6[M+H]+计算值570.34,实测值570.33。
实施例83.2-苄基-13-甲基-11,14-二氧代-1-苯基-5,8-二氧杂-2,12,15-三氮杂十九烷-19-酸(257)的合成
在室温下,向2-苄基-13-甲基-11,14-二氧代-1-苯基-5,8-二氧杂-2,12,15-三氮杂十九烷-19-酸叔丁酯(0.057g,0.101mmol)的二氯甲烷(3mL)溶液中加入TFA(1mL)并搅拌40分钟。用无水甲苯稀释反应物,然后浓缩。重复该操作三次,得到标题化合物,为无色油状物(0.052g,理论产量),将其直接用于下一步骤。ESI MS m/z C28H40N3O6[M+H]+计算值514.28,实测值514.28。
实施例84.(2S)-2-((2R,3R)-3-((2S)-1-((21S,24S,27S,28R)-2-苄基-27-((S)-仲丁基)-21,24-二异丙基-28甲氧基13,20,26-三甲基-11,14,19,22,25-五氧唑-1-苯基-5,8-二氧杂-2,12,15,20,23,26-六氮杂三十-30-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(258)的合成
在0℃下,向2-苄基-13-甲基-11,14-二氧代-1-苯基-5,8-二氧杂-2,12,15-三氮杂十九烷-19-酸(0.052g,0.101mmol,1.5eq.)和已合成的(S)-甲基2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-二甲基-2)-((S)-3-甲基-2-(甲基氨基)-丁酰氨基)丁酰氨基)-3-甲氧基-5-甲基-庚基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯丙酸盐(0.050g,0.0671mmol,1.0eq.)的无水二氯甲烷(5mL)溶液中加入BrOP(0.034g,0.0872mmol,1.3eq.)和DIPEA(0.035mL,0.201mmol,3.0eq.)。搅拌10分钟后。在0℃下,将反应升温至室温并搅拌过夜。加入两滴水,浓缩混合物,并在HPLC(C18柱,流动相A:水,流动相B:乙腈,20%B至80%B,50分钟)上纯化。合并组分并冻干,得到标题化合物,为无色油状物(60mg,72%收率)。ESIMS m/z C68H105N8O13[M+H]+计算值1241.77,实测值1241.77。
实施例85.(2S)-2-((2R,3R)-3-((2S)-1-((19S,22S,25S,26R)-1-氨基-25-((S)-仲丁基)-19,22-二异丙基-26-甲氧基-11,18,24-三甲基-9,12,17,20,23-五杂氧-3,6-二氧杂-10,13,18,21,24-五氮二十八烷-28-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(259)的合成
在氢化瓶中,向(2S)-甲基2-((2R,3R)-3-((2S)-1-((21S,24S,27S,28R)-2-苄基-27-((S)-仲丁基)-21,24-二异丙基-28-甲氧-13,20,26-三甲基-11,14,19,22,25-五杂氧-1-苯基-5,8-二氧杂-2,12,15,20,23,26-六氮杂三十烷-30-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(0.030g,0.0288mmol,1.0eq.)的甲醇(3mL)溶液加入Pd/C(0.050g,10wt%,10%水)和一滴6N盐酸。将混合物振荡2小时,然后通过硅藻土(助滤剂)过滤,浓缩,得到标题化合物,为浅黄色油状物(0.030g,>100%收率)。ESI MS m/zC54H93N8O13[M+1]+计算值1061.67,实测值1061.69。
实施例86.4-丙氨基丁酸叔丁酯的合成
在室温下,向4-氨基丁酸叔丁酯(0.500g,3.14mmol,1.0eq.)和丙炔酸(0.330g,4.71mmol,1.5eq.)的无水二氯甲烷(60mL)中溶液中加入DCC(0.972g,4.71mmol,1.5eq.)。将反应物搅拌3小时,然后过滤,浓缩并通过硅胶柱层析(15:1二氯甲烷/甲醇)纯化,得到标题化合物,为黄色油状物(0.489g,74%收率)。ESI MS m/z C11H18NO3Na[M+H]+计算值234.1,实测值234.1。
实施例87.4-丙氨基丁酸的合成
在室温下,向4-丙基氨基丁酸叔丁酯(0.498g,2.32mmol,1.0eq.)的二氯甲烷(3mL)溶液中加入TFA(1mL)并将反应物搅拌2小时,然后用无水甲苯稀释并且浓缩。重复该操作三次,得到标题化合物,为浅黄色油状物(0.051g,>100%收率),将其直接用于下一步骤。ESI MS m/z C7H10NO3[M+H]+计算值156.1,实测值156.1。
实施例88.3,3’-((4-丙酰基氨基丁酰基)氮杂二基)二丙酸二叔丁酯的合成
在0℃下,向4-丙酰基氨基丁酸(0.360g,2.32mmol,1.2eq.)和3,3’-氮杂二羟基丙酸二叔丁酯(0.528g,1.93mmol,1.0eq.)的无水二氯甲烷(15mL)溶液中,加入PyBrop(0.990g,2.22mmol,1.1eq.)和DIPEA(1.0mL,5.80mmol,3.0eq.)。10分钟后,将反应升温至室温并搅拌过夜。然后将混合物用二氯甲烷稀释,用水和盐水洗涤,经无水硫酸钠干燥,浓缩,并通过硅胶柱层析(5:2石油醚/乙酸乙酯)纯化,得到标题化合物,为黄色油状物(0.367g,46%产量)。ESI MS m/z C21H35N2O6[M+H]+计算值411.2,实测值411.3。
实施例89.3,3’-((4-丙酰胺基丁酰基)氮杂二基)二丙酸的合成
在室温下,向3,3’-((4-丙酰胺丁醇)氮杂环己基)二丙酸二叔丁基酯(0.367g,0.895mmol,1.0eq.)的二氯甲烷(3mL)溶液中加入TFA(1mL)。将反应物搅拌3小时,然后用无水甲苯稀释并浓缩。重复该操作三次,得到标题化合物,为浅黄色油状物(0.266g,>100%收率),将其直接用于下一步骤。ESI MS m/z C13H19N2O6[M+H]+计算值299.1,实测值299.1。
实施例90.(3R,4S,7S,10S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-((1R,2R))-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,1-三甲基-6,9,12,17,20,30-六氧-33-(4-丙二醇酰胺丁醇)-2,23,26-三氧杂-5,8,11,16,19,29,33-七氮杂三十六烷-36-酸(260)的合成
在0℃下,向(2S)-甲基2-((2R,3R)-3-((2S)-1-((19S,22S,25S,26R)-1-氨基-25-((S)-仲丁基)-19,2-二异丙-26-甲氧基-11,18,24-三甲基-9,12,17,20,23-五氧-3,6-二氧杂-10,13,18,21,24-五氮杂二十八烷-28-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(0.030g,0.0288mmol,1.0eq.)和3,3’-((4-丙酰胺基丁酰基)氮杂二基)二丙酸(0.026g,0.0865mmol,3.0eq.)的无水DMF(3mL)溶液中的中加入PyBrop(0.017g,0.0374mmol,1.3eq.)和DIPEA(0.035mL,0.064mmol,3.0eq.)。在0℃下搅拌10分钟。将反应升温至室温并搅拌1小时,加入两滴水,浓缩混合物,并用HPLC(C18柱,流动相A:水,流动相B:乙腈,20%B至80%B,50分钟)纯化。合并组分并冻干,得到标题化合物,为无色油状物(18.1mg,47%收率)。ESI MS m/z C67H109N10O18[M+H]+计算值1341.784,实测值1341.81。
实施例91.(S)-2-((2R,3R)-3-((S)-1-((5S,8S,11S,14S,15R)-14-((S)-仲丁基)-8,11-二异丙基-15-甲氧-5,7,1-三甲基-3,6,9,12-四氧-1-苯基-2-氧杂-4,7,10,13-四氮杂十七烷-17-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸甲基酯(263)的合成
在0℃下,向MMAF-OMe(0.132g,0.178mmol,1.0eq.)和Z-L-丙氨酸(0.119g,0.533mmol,3.0eq.)的无水二氯甲烷(10mL)溶液中加入HATU(0.135g,依次加入0.356mmol,2.0eq.)和NMM(0.12mL,1.07mmol,6.0eq.)。将反应在0℃下搅拌10分钟,然后升温至室温并搅拌过夜。将混合物用二氯甲烷稀释,用水和盐水洗涤,经无水硫酸钠干燥,浓缩,并通过硅胶柱层析(20:1二氯甲烷/甲醇)纯化,得到标题化合物,为白色泡沫状固体(0.148g,88%收率))。ESI MS m/z C51H79N6O11[M+H]+的计算值951.6,实测值951.6。
实施例92.(S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S))-2-((S)-2-氨基-N-甲基丙酰胺基)-3-甲基丁酰胺基)-N,3-二甲基丁酰胺)-3-甲氧基-5-甲基庚基)吡咯烷-2-基)-3-甲氧基-2-(甲基丙酰胺基)-3-苯基丙酸甲基酯(264)的合成
在氢化瓶中,向(S)-2-((2R,3R)-3-((S)-1-((5S,8S,11S,14S,15R)-14-((S)-仲丁基)-8,11-二异丙-甲氧基-5,7,13-三甲基-3,6,9,12-四氧-1-苯基-2-氧杂-4,7,10,13-四氮杂十七烷-17-将酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基-丙酸甲基酯(0.148g,0.156mmol,1.0eq.)的甲醇(5mL)溶液加入Pd/C(0.100g,10wt%,50%水)。将混合物振荡5小时,然后通过硅藻土垫过滤。浓缩滤液,得到标题化合物,为白色泡沫状固体(0.122g,96%收率)。ESI MS m/z C43H73N6O9[M+H]+817.5,计算值817.5,实测值817.5。
在0℃下,向(E)-3-溴丙烯酸(0.15g,1mmol),DMAP(0.15g,1.2mmol)和DCC(0.21g,1mmol)的二氯甲烷(10mL)溶液中加入3-(2-(2-氨基乙氧基)乙氧基)丙酸叔丁基酯(0.23g,1mmol)。将反应混合物升温至室温并搅拌过夜。浓缩粗产物,并通过硅胶柱层析法用乙酸乙酯/二氯甲烷梯度纯化,得到标题产物(0.31g,85%收率)。ESI MS m/z C14H25BrNO5[M+H]+:计算值366.08,实测值366.08。
实施例94.(E)-3-(2-(2-(3-溴丙烯酰氨基)乙氧基)乙氧基)丙酸(303)的合成
在0℃下,将(E)-3-(2-(3-溴丙烯酰胺基)乙氧基)乙氧基)丙酸叔丁酯(0.31g,0.84mmol)溶解在甲酸(4mL)中,然后加入水(2mL)。将反应混合物升温至室温并搅拌过夜。浓缩粗产物,不经进一步纯化直接用于下一步。ESI MS m/z C10H17BrNO5[M+H]+:计算值310.02,实测值310.03。
实施例95.(E)-2,5-二氧代吡咯烷-1-基3-(2-(2-(3-溴丙烯酰氨基)乙氧基)乙氧基)丙酸酯(304)的合成
将(E)-3-(2-(2-(3-溴丙烯酰胺基)乙氧基)乙氧基)丙酸(0.12g,0.39mmol),NHS(0.067g,0.58mmol)和EDC(0.11g,0.58mmol)溶解在二氯甲烷(10mL)中并将混合物在室温下搅拌过夜,浓缩并通过硅胶柱层析法纯化,得到标题产物(0.13g,82%收率)。ESI MS m/zC14H20BrN2O7[M+H]+:计算值407.04,实测值407.04。
实施例96.(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶)-2-甲酰氨基)戊基)-4-甲基戊基)噻唑-4-甲酰氨基)-5-(3-(3-(2-(2-((E)-3-溴丙烯氨基)乙氧基)乙氧基)丙酰氨基)-4-羟基苯基)-2-甲基戊酸(306)的合成
向(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰氨基)-4-甲基戊基)噻唑-4-甲酰氨基)-5-(3-氨基-4-羟基苯基)-2-甲基戊酸(305)(Huang Y.等,Med Chem.#44,249th ACS National Meeting,Denver,CO,Mar.22~26,2015;WO2014009774)(50mg,0.066mmol),(E)-2,5-二氧代吡咯烷-1-基3-(2-(2-(3-溴代丙烯酰胺(乙氧基)丙酸酯(60mg,0.148mmol)的DMA(3mL)溶液中加入NaH2PO4(17.8mg,0.15mmol)。将混合物在室温下搅拌过夜,浓缩并通过反相HPLC纯化,用乙腈/水梯度洗脱,得到标题产物(22.6mg,33%收率)。ESI MS m/z C48H73BrN7O12S[M+H]+:计算值1052.41,实测值1052.40。
实施例97.3-(2-(2-丙酰胺基乙氧基)乙氧基)丙酸叔丁酯(320)的合成
将3-(2-(2-氨基乙氧基)乙氧基)丙酸叔丁酯(466mg,2mmol)和丙炔酸(210mg,3mmol)溶解在二氯甲烷(50mL)中,加入DCC(618mg,3mmol)。将所得溶液在室温下搅拌3小时后浓缩。通过柱层析(10%至100%乙酸乙酯/正己烷)纯化,得到标题化合物(400mg,70%)。ESI MS m/z 286.17([M+H]+)。
实施例98.3-(2-(2-丙酰氨基乙氧基)乙氧基)丙酸(321)的合成
将3-(2-(2-丙酰胺基乙氧基)乙氧基)丙酸叔丁酯(200mg,0.7mmol)溶于二氯甲烷(5mL)中,向其中加入甲酸(7mL)。将所得溶液在38℃下搅拌过夜。真空除去所有挥发物,得到标题化合物(160mg,>100%收率)。ESI MS m/z 230.11([M+H]+)。
实施例99.2,5-二氧代吡咯烷-1-基3-(2-(2-丙酰胺基乙氧基)-乙氧基)丙酸酯的合成(322)
将NHS(115mg,1mmol)和EDC(192mg,1mmol)加入到3-(2-(2-丙酰胺基乙氧基)乙氧基)丙酸(149mg,0.65mmol)的二氯甲烷(15mL)溶液中。在室温下搅拌过夜,浓缩反应物并通过柱层析(0%至10%甲醇/二氯甲烷)纯化,得到标题化合物(180mg,85%)。ESI MS m/z327.11([M+H]+)。
实施例100.(4R)-4-((叔丁氧基羰基)氨基)-5-(4-羟基-3-(3-(2-(2-丙酰氨基乙氧基)乙氧基)丙酰胺基)苯基)-2-甲基戊酸酯(323)的合成
向2,5-二氧代吡咯烷-1-基3-(2-(2-丙酰胺基乙氧基)乙氧基)丙酸酯(90mg,0.276mmol)和5-(3-氨基-4-羟基苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸丁酯(109mg,0.276mmol)的乙醇(7.5mL)溶液中加入NaH2PO4(0.1M,1.5mL)。在室温下搅拌所得溶液24小时。真空除去所有挥发物,并通过柱层析(30%至100%乙酸乙酯/正己烷)纯化残余物,得到标题化合物(160mg,96%)。ESI MS m/z 606.34([M+H]+)。
实施例101.(4R)-4-氨基-5-(4-羟基-3-(3-(2-(2-丙酰胺基乙氧基)-乙氧基)丙酰胺基)苯基)-2-甲基戊酸(324)的合成
将(4R)-4-(叔丁氧基羰基)氨基)-5-(4-羟基-3-(3-(2-(2-丙酰胺基-乙氧基)乙氧基)丙酰胺基)苯基)-2-甲基戊酸叔丁酯(40mg,0.066mmol)溶解在二氯甲烷(3mL)中并与TFA(3mL)在室温下搅拌2小时。真空除去所有挥发物,得到标题化合物(29mg,99%)。ESI MSm/z 450.23([M+H]+)。
实施例102.(4R)-4-(2-((6S,9R,11R)-6-((S)-仲丁基)-9-异丙基-2,3,3,8-四甲基-4,7,13-三氧-12-氧-2,5,8-三氮十四烷-11-基)噻唑-4-甲酰氨基)-5-(4-羟基-3-(3-(2-(2-丙酰胺乙氧基)乙氧基)丙酰胺基)苯基)-2-甲基戊酸(325)的合成
将(4R)-4-氨基-5-(4-羟基-3-(3-(2-(2-丙酰胺基乙氧基)-乙氧基)丙酰胺基)-苯基)-2-甲基戊酸(30mg,0.066mmol)和五氟苯基2-((6S,9R,11R)-6-((S)-仲丁基)-9-异丙基-2,3,3,8-四甲基-4,7,13-三氧-12-氧杂-2,5,8-三氮杂十四烷-11-基)噻唑-4-羧酸酯(46mg,0.066mmol)溶解在DMA(3mL)中。然后加入DIPEA(10mg,0.078mmol)并在室温下搅拌1.5小时。真空除去溶剂,并将残余物在制备型HPLC(C18柱,10-90%乙腈/水)上纯化,得到标题化合物(15mg,24%)。ESI MS m/z 958.47([M+H]+)。
实施例103.(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶)-2-甲酰胺基)戊酰氨基)-4-甲基戊基)噻唑-4-甲酰胺基)-5-(3-(3-(2-(2-叠氮基乙氧基)乙氧基)丙酰胺基)-4-羟基苯基)-2-甲基戊酸(335)的合成
在2小时内分四次向(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰氨基)-4-甲基戊基)噻唑-4-甲酰氨基)-5-(3-氨基-4-羟基苯基)-2-甲基戊酸(100mg,0.131mmol)的DMA(10mL)和NaH2PO4缓冲溶液(pH 7.5,1.0M,0.7mL)的混合物中加入2,5-二氧代吡咯烷-1-基3-(2-(2-叠氮基乙氧基)乙氧基)丙酸酯(80.0mg,0.266mmol)。将混合物搅拌过夜,浓缩并在C18制备HPLC上纯化,用80%水/甲醇至10%水/甲醇洗脱45分钟,得到标题化合物(101.5mg,82%收率)。LC-MS(ESI)m/zC45H70N9O11S[M+H]+:计算值944.48,实测值944.70。
实施例104.(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基)-哌啶-2-甲酰氨基)戊基)-4-甲基戊基)噻唑-4-甲酰氨基)-5-(3-(3-(2-(2-氨基乙氧基)乙氧基)丙酰氨基)-4-羟基苯基)-2-甲基戊酸(336)的合成
在氢化瓶中,向(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰氨基)-4-甲基戊基)噻唑-4-甲酰胺基)-5-(3-(3-(2-(2-叠氮基乙氧基)乙氧基)丙酰胺基)-4-羟基苯基)-2-甲基戊酸(100.0mg,0.106mmol)含有0.1%盐酸的甲醇(25mL)溶液中加入Pd/C(25mg,10wt%,50%水)。将空气抽空并导入35psi H2后,将混合物振荡4小时。通过硅藻土过滤,浓缩滤液,在制备HPLC(C18,3.0×25cm,25mL/min)上纯化,用85%水/甲醇至15%水/甲醇洗脱45分钟,得到标题化合物(77.5mg,79%)。LC-MS(ESI)m/z C45H72N7O11S[M+H]+计算值918.49,实测值918.60。
实施例105.(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶)-2-甲酰氨基)戊基)-4-甲基戊基)噻唑-4-甲酰氨基)-5-(3-((3R,4S,7S,10S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-((1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,18-三甲基6,9,12,17,20,30,36-七氧-33-(5-氧代庚-6-炔基)-2,23,26,40,43-五氧杂-5,8,11,16,19,29,33,37-八氮杂四十六酰胺基)-4-羟基苯基)-2-甲基戊酸(338)的合成
向3R,4S,7S,10S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-((1R,2R))-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,18-三甲基-6,9,12,17,20,30-六氧代-33-(4-丙烯酰胺丁酰基-2,23,26-三氧杂5,8,11,16,19,29,33-七氮杂六氮杂三十六烷-36-酸(0.018g,0.0134mmol)的二氯甲烷(5mL)悬浮液中加入五氟苯酚(3.7mg,0.0201mmol)和DIC(2.0mg,0.0161mmol)。在室温下搅拌4小时,用硅藻土过滤。浓缩滤液并溶于DMF(1mL)中,之后加入(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基-哌啶-2-甲酰氨基)戊胺酰胺)-4-甲基戊基)噻唑-4-甲酰氨基)-5-(3-(3-(2-(2-氨基乙氧基)乙氧基)丙酰氨)-4-羟基苯基)-2-甲基戊酸(13.5mg,0.0147mmol)的无水DMF(2mL)溶液。在0℃下搅拌2小时,将混合物浓缩并在HPLC上纯化(C18柱,流动相A:水,流动相B:乙腈,50%时从20%B至80%B)。合并组分并冻干,得到标题化合物,为无色油状物(8.9mg,30%收率)。ESI MS m/zC112H176N16O28S[M+H]+计算值2226.26,实测值2226.48。
实施例106.(2S,4R)-甲基-4-羟基吡咯烷-2-羧酸甲酯盐酸的合成
在0至4℃下,向反式-4-羟基-L-脯氨酸(15.0g,114.3mmol)的无水甲醇(250mL)溶液中滴加氯化亚砜(17mL,231mmol)。将所得混合物在室温下过夜搅拌。浓缩,用乙醇/正己烷重结晶,得到标题化合物(18.0g,87%收率)。ESI MS m/z 168.2([M+Na]+)。
实施例107.(2S,4R)-1-叔丁基2-甲基-4-羟基吡咯烷-1,2-二羧酸酯的合成
向反式-4-羟基-L-脯氨酸甲酯(18.0g,107.0mmol)的甲醇(150mL)和碳酸氢钠溶液(2.0M,350mL)的混合物中加入Boc2O(30.0g,137.6mmol)在4小时内分为三份。再搅拌4小时后,将反应混合物浓缩至约350mL并用乙酸乙酯(4×80mL)萃取。将合并的有机层用盐水(100mL)洗涤,干燥的(硫酸镁),过滤,浓缩并通过硅胶柱层析(1:1正己烷/乙酸乙酯)纯化,得到标题化合物(22.54g,86%收率)。ESI MS m/z 268.2([M+Na]+)。
实施例108.(S)-1-叔丁基2-甲基4-氧代吡咯烷-1,2-二羧酸酯的合成
通过Dess-Martin氧化制备标题化合物可参考:Franco Manfre等J.Org.Chem.1992,57,2060-2065。此外,也可使用Swern的氧化,操作步骤如下:将(COCl)2(13.0mL,74.38mmol)的二氯甲烷(350mL)溶液冷却至-78℃,加入无水DMSO(26.0mL)。将溶液在-78℃下搅拌15分钟,然后将(2S,4R)-1-叔丁基2-甲基-4-羟基吡咯烷-1,2-二甲酰基酯(8.0g,32.63mmol)的二氯甲烷(100mL)溶液加入。在-78℃下搅拌2小时后,滴加三乙胺(50mL,180.3mmol),将反应溶液升温至室温。将混合物用NaH2PO4溶液稀释(1.0M,400mL),分层,用二氯甲烷(2×60mL)萃取水层,合并有机层,用硫酸镁干燥,过滤,浓缩并通过硅胶柱层析(7:3正己烷/乙酸乙酯)纯化,得到标题化合物(6.73g,85%收率)。ESI MS m/z 266.2([M+Na]+)。
实施例109.(S)-1-叔丁基2-甲基-4-亚甲基吡咯烷-1,2-二羧酸酯的合成
在0℃下,向溴化甲基三苯基鏻(19.62g,55.11mmol)的四氢呋喃(150mL)悬浮液中加入叔丁醇钾(6.20g,55.30mmol)的无水四氢呋喃(80mL)溶液。在0℃下搅拌2小时后,将得到的黄色叶立德加入到(S)-1-叔丁基2-甲基4-氧代吡咯烷-1,2-二甲酸酯(6.70g,27.55mmol)的四氢呋喃(40mL)溶液中。在室温下搅拌1小时,浓缩反应混合物,用乙酸乙酯(200mL)稀释,用水(150mL),盐水(150mL)洗涤,经硫酸镁干燥,浓缩并在硅胶柱层析上纯化(9:1正己烷/乙酸乙酯),得到标题化合物(5.77g,87%收率)。EI MS m/z 264([M+Na]+)。
实施例110.(S)-甲基4-亚甲基吡咯烷-2-羧酸甲酯盐酸盐的合成
在4℃下,向(S)-1-甲基-4-亚甲基吡咯烷-1,2-二甲酸叔丁酯(5.70g,23.63mmol)的乙酸乙酯(40mL)溶液中加入盐酸(12M,10mL)。将混合物搅拌1小时,用甲苯(50mL)稀释,浓缩,之后用乙醇/正己烷重结晶,得到标题化合物,为盐酸盐形式(3.85g,92%收率)。EIMS m/z 142.2([M+H]+)。
实施例111.4-(苄氧基)-3-甲氧基苯甲酸的合成
向4-羟基-3-甲氧基苯甲酸(50.0g,297.5mmol)的乙醇(350mL)和氢氧化钠溶液(2.0M,350mL)的混合物中加入苄溴(140.0g,823.5mmol)。将混合物在65℃下搅拌8小时,浓缩,与水(2×400mL)共浓缩至约400mL,用6N盐酸酸化至pH 3.0。过滤收集固体,用乙醇重结晶,在45℃下真空干燥,得到标题化合物(63.6g,83%收率)。ESI MS m/z 281.2([M+Na]+)。
实施例112.4-(苄氧基)-5-甲氧基-2-硝基苯甲酸的合成
向4-(苄氧基)-3-甲氧基苯甲酸(63.5g,246.0mmol)二氯甲烷(400mL)和乙酸(100mL)溶液中加入发烟硝酸(25.0mL,528.5mmol)。将混合物搅拌6小时,浓缩,用乙醇结晶,在40℃下真空干燥,得到标题化合物(63.3g,85%收率)。ESI MS m/z 326.1([M+Na]+)。
实施例113.(S)-甲基1-(4-(苄氧基)-5-甲氧基-2-硝基苯甲酰基)-4-亚甲基吡咯烷-2-羧酸甲酯的合成
将催化量的DMF(30μl)加入到4-(苄氧基)-5-甲氧基-2-硝基苯甲酸(2.70g,8.91mmol)和草酰氯(2.0mL,22.50mmol)的无水二氯甲烷溶液中,将所得混合物在室温下搅拌2小时。用旋转浓缩仪除去过量的二氯甲烷和草酰氯。在N2条件下,0℃将乙酰氯重新悬浮在新鲜的二氯甲烷(70mL)中,并缓慢加入到预混合的(S)-4-亚甲基吡咯烷-2-羧酸甲酯盐酸盐(1.58g,8.91mmol)和Et3N(6mL)的二氯甲烷溶液中。将反应混合物升温至室温,继续搅拌8小时。除去二氯甲烷和Et3N后,将残余物在水和乙酸乙酯(70/70mL)之间分配。用乙酸乙酯(2×60mL)进一步萃取水层。将合并的有机层用盐水(40mL)洗涤,干燥(硫酸镁)并浓缩。用快速硅胶柱层析(2:8正己烷/乙酸乙酯)纯化残余物,得到标题化合物(2.88g,76%收率)。EI MS m/z 449.1([M+Na]+)。
实施例114.(S)-1-(4-(苄氧基)-5-甲氧基-2-硝基苯甲酰基)-4-亚甲基吡咯烷-2-甲醛的合成
在-78℃和N2条件下,剧烈搅拌(S)-1-(4-(苄氧基)-5-甲氧基-2-硝基苯甲酰基)-4-亚甲基吡咯烷-2-羧酸甲酯(2.80g,6.57mmol)的无水二氯甲烷(60mL)溶液并滴加DIBAL-H(在二氯甲烷中的1N,10mL)。将混合物再搅拌90分钟后,加入2mL甲醇和5%盐酸(10mL)淬灭反应。将所得混合物升温至0℃,分离各层,水层进一步用二氯甲烷(3×50mL)萃取。将合并的有机层用盐水洗涤,干燥(硫酸镁)并浓缩。用快速硅胶柱层析(95:5CHCl3/甲醇)纯化残余物,得到标题化合物(2.19g,84%收率)。EIMS m/z 419.1([M+Na]+)。
实施例115.(S)-8-(苄氧基)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]-吡咯并[1,2-a]氮杂卓-5(11aH)-酮的合成
将(S)-1-(4-(苄氧基)-5-甲氧基-2-硝基苯甲酰基)-4-亚甲基吡咯烷-2-甲醛(2.18g,5.50mmol)和Na2S2O4(8.0g,45.97mmol)的四氢呋喃(60mL)和水(40mL)的混合物在室温下搅拌20小时。在高真空下除去溶剂。将残余物重新悬浮在甲醇(60mL)中,逐滴加入盐酸(6M)直至达到pH~2。将所得混合物在室温下搅拌1小时,去除甲醇后用乙酸乙酯(100mL)稀释。用饱和NaHCO3水溶液和盐水洗涤乙酸乙酯溶液,干燥(硫酸镁)并浓缩。用快速硅胶柱层析(97:3CHCl3/甲醇)纯化残余物,得到标题化合物(1.52g,80%)。EIMS m/z 372.1([M+Na]+)。
实施例116.(S)-8-羟基-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]-吡咯并[1,2-a]氮杂卓-5(11aH)-酮的合成
在0℃下,向(S)-8-(苄氧基)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]-吡咯并[1,2-a]氮杂卓-5(11aH)-酮(1.50g,4.32mmol)的二氯甲烷(70mL)溶液中加入25mL的CH3SO3H。将混合物在0℃下搅拌10分钟,然后在室温下搅拌2小时。用二氯甲烷稀释,用冷的1.0N碳酸氢钠调节pH至4并过滤。用二氯甲烷(3×60mL)萃取水层。合并有机层,用无水硫酸钠干燥,过滤,浓缩并在硅胶柱层析(甲醇/二氯甲烷1:15)上纯化,得到811mg(73%收率)标题产物。EI-MS m/z 281.1([M+Na]+)。
实施例117.(11aS,11a’S)-8,8’-(戊烷-1,5-二基双(氧))双(7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]的合成吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮)的合成
向搅拌的Cs2CO3(0.761g,2.33mmol)的丁酮(8mL)悬浮液中加入(S)-8-羟基-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯[1,2-a]氮杂-5(11aH)-酮(401mg,1.55mmol)和1,5-二碘戊烷(240mg,0.740mmol)。将混合物在室温下搅拌过夜,浓缩,并在硅胶柱上纯化(乙酸乙酯/二氯甲烷1:10),得到337mg(78%收率)标题产物。EI MS m/z 607.2([M+Na]+)。
实施例118.(S)-7-甲氧基-8-((5-(((S)-7-甲氧-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢)-1H-苯并[e]吡咯并[1,2-α][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯[1,2-a][1,4]二氮杂-5(11aH)-酮(340)的合成。
在0℃下,向(11aS,11a’S)-8,8’-(戊烷-1,5-二基双(氧))双(7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯烷[1,2-a][1,4]二氮杂-5(11aH)-酮)(150mg,0.256mmol)的无水二氯甲烷(1mL)和无水乙醇(1.5mL)的溶液中加入硼氢化钠的甲氧基乙醚(85μl,0.5M,0.042mmol)混合物。5分钟后除去冰浴,将混合物在室温下搅拌3小时,然后冷却至0℃,用饱和氯化铵淬灭,用二氯甲烷稀释,并分层。将有机层用盐水洗涤,用无水硫酸钠干燥,通过硅藻土过滤并浓缩。通过反相HPLC(C18,乙腈/水)纯化残余物。用二氯甲烷萃取相应的组分并浓缩,得到标题化合物(64.7mg,43%),MS m/z 609.2([M+Na]+),625.3([M+K]+)和627.2([M+Na+H2O]+);得到完全还原的化合物(16.5mg,11%),MS m/z 611.2([M+Na]+),627.2([M+K]+),629.2([M+Na+H2O]+);回收未反应的原料(10.2mg,7%),MS m/z 607.2([M+Na]+),625.2([M+Na+H2O]+)。
实施例119.(S)-8-((5-(((S)-10-(3-(2-(2-叠氮基乙氧基)乙氧基)丙酰基)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮(341)的合成
向(S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢)-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮(60.0mg,0.102mmol)和2,5-二氧代吡咯烷-1-基3-(2-(2-叠氮基乙氧基)乙氧基)丙酸酯(40.5mg,0.134mmol)的二氯甲烷(5mL)的混合物中加入EDC(100.5mg,0.520mmol)。将混合物在室温下搅拌过夜,浓缩并在硅胶柱上纯化(乙酸乙酯/二氯甲烷,1:6),得到63.1mg(81%收率)标题产物。ESI MS m/zC40H50N7O9[M+H]+计算值772.36,实测值772.30。
实施例120.(S)-8-((5-(((S)-10-(3-(2-(2-氨基乙氧基)乙氧基)丙酰基)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮(342)的合成
向(S)-8-((5-(((S)-10-(3-(2-(2-叠氮基乙氧基)乙氧基)丙酰基)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a六氢-1H-苯并[e]吡咯并[1,2-α][1,4]二氮杂-8-基)氧基)戊基)氧基)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮(60mg,0.078mmol)的四氢呋喃(5mL)和Na2HSO4缓冲溶液(pH 7.5,1.0M,0.7mL)的混合物中加入PPh3(70mg,0.267mmol)。将混合物在室温下搅拌过夜,浓缩并在C18制备HPLC上纯化,用水/乙腈(在35分钟内从90%水至35%水)洗脱,在高真空下干燥后得到45.1mg(79%收率)标题产物。ESI MS m/z C40H52N5O9[M+H]+计算值746.37,实测值746.50。
实施例121.(2S)-甲基2-((2R,3R)-3-((2S)-1-((37S,40S,43S,44R)-43-((S)-仲丁基)-37,40二异丙基44甲氧基-1-((S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-1,2,3,4-5,11a四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧代-2,3,4-11,11A-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-29,36,42-三甲基-1,11,17,27,30,35,38,41-八氧代-14-(4-丙酰胺丁酰基)-4,7,21,24-四氧杂-10,14,18,28,31,36,39,42-八氮杂四十六烷-46-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(343)的合成
向(3R,4S,7S,10S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-((1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,18三甲基6,9,12,17,20,30-八氧代-33-(4-丙酰胺丁酰基)-2,23,26-三氧杂5,8,11,16,19,29,33-七氮杂三十六烷-36-酸(0.018g,0.0134mmol)和(S)-8-((5-(((S)-10-(3-(2-(2-氨基乙氧基)乙氧基)丙酰基)基)-7-甲氧基-2-亚甲基-5-氧代2,3,5,10,11,11a六氢-1H-苯并[e]吡咯并[1,2-α][1,4]二氮杂-8-基)氧基)戊基)氧)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-α][1,4]二氮杂-5(11aH)酮(11.0mg,0.0145mmol)的无水DMF(3mL)溶液中加入EDC(0.020g,0.104mmol)。在室温下搅拌4小时后,将混合物浓缩并在HPLC上纯化(C18柱,流动相A:水,流动相B:乙腈,50分钟内从20%B至80%B)。合并组分并冻干,得到标题化合物,为无色油状物(15.2mg,55%收率)。ESI MS m/zC107H157N15O26[M+H]+计算值2069.14,实测值2069.42。
实施例122.(S)-2-(3-(2-(2-叠氮基乙氧基)乙氧基)丙酰胺基)-N-(2-((S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-苯并[e]吡咯[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧代2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-2-氧代乙基)-3-甲基丁酰胺(351)
向(S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮(60.0mg,0.102mmol)和(S)-15-叠氮基-5-异丙基-4,7-二氧代-10,13-二氧杂-3,6-二氮杂十五烷-1-甲酸(45.1mg,0.125mmol)的二氯甲烷(7mL)溶液中加入BrOP(120.1mg,0.309mmol)。将混合物在室温下搅拌过夜,浓缩并在硅胶柱上纯化(乙酸乙酯/二氯甲烷,1:6),得到71.4mg(77%收率)标题产物。ESI MS m/z C47H62N9O11[M+H]+计算值928.45,实测值928.60。
实施例123.(S)-2-(3-(2-(2-氨基乙氧基)乙氧基)丙酰胺基)-N-(2-((S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-2-氧代乙基)-3-甲基丁酰胺(352)
向(S)-2-(3-(2-(2-叠氮基乙氧基)乙氧基)丙酰胺基)-N-(2-((S)-7-甲氧基-8-((5-(((S-7-甲氧基-2-亚甲基-5-氧代2,3,5,11a-四氢-1H-苯并[e]吡咯[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-2-氧代乙基)-3-甲基丁酰胺(63mg,0.068mmol)的四氢呋喃(5mL)和NaH2PO4缓冲溶液(pH 7.5,1.0M,0.7mL)的混合物中加入PPh3(70mg,0.267mmol)。将混合物在室温下搅拌过夜,浓缩并在C18制备HPLC上纯化,用水/乙腈(从90%水至35%水,35分钟)洗脱,在高真空下干燥后得到46.5mg(76%收率)标题产物。ESI MS m/z C47H64N7O11[M+H]+,902.46,实测值902.60。
实施例124.(2S)-2-((2R,3R)-3-((2S)-1-((5S,43S,46S,49S,50R)-49-((S)-仲丁基)-5,43,46-三异丙基-50-甲氧基-1-((S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)-戊基)氧基)-2-亚甲基-5-氧代-2,3,11,11a四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-35,42,48-三甲基-1,4,7,17,23,33,36,41,44,47-十二氧-20-(4-丙酸酰胺-丁酰基)-10,13,27,30-四氧-3,6,16,20,24,34,37,42,45,48-十氮杂五十二烷-52-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(353)
向(3R,4S,7S,10S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-((1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)-吡咯烷-1-基)-2-氧代乙基)-5,11,18三甲-6,9,12,17,20,30-六氧代-33-(4-丙酸酰胺-丁酰基)-2,23,26-三氧杂-5,8,11,16,19,29,33-七氮杂三十六烷-36-酸(18.0mg,0.0134mmol)和(S)-2-(3-(2-(2-氨基乙氧基)乙氧基)丙酰胺基)-N-(2-(2-)(S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a四氢-1H-苯并[e]-吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]将吡咯并-[1,2-a][1,4]二氮杂-10(5H)-基)-2-氧代乙基)-3-甲基丁酰胺(13.0mg,0.0144mmol)的无水DMF(3mL)溶液中加入EDC(0.020克,0.104mmol)。在室温下搅拌4小时后,将混合物浓缩并在HPLC上纯化(C18柱,流动相A:水,流动相B:乙腈,50分钟内从20%B至80%B)。合并组分并冻干,得到标题化合物,为无色油状物(18.1mg,47%收率)。ESI MS m/z C114H170N17O28[M+H]+计算值2225.23,实测值2226.22。
实施例125.(2S)-2-((2R,3R)-3-((2S)-1-((5S,37S,40S,43S,44R)-43-((S)-仲丁基)-5,37,40-三异丙基-44-甲氧基-1-((S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-29,36,42-三甲基-1,4,7,14,20,27,30,35,38,41-十二氧-17-(4-丙醇酰氨基丁酰基)-10,24二氧杂-3,6,13,17,21,28,31,36,39,42-十氮杂四十六烷-46-酰基))吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(354)
在石英管里,向pH 7.5的1.0mL 20mg/mL赫赛汀中,加入1.0mL 100mM NaH2PO4,pH7.5缓冲液和TCEP(25μL,20mM水溶液)。在25℃下搅拌孵育30分钟后,加入(2S)-甲基2-((2R,3R)-3-((2S)-1-((5S,37S,40S,43S,44R)-43-((S)-仲丁基)-5,37,40-三异丙基-44-甲氧基-1-((S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-29,36,42-三甲基-1,4,7,14,20,27,30,35,38,41-十二氧-17-(4-丙醇酰氨基丁酰基)-10,24二氧杂3,6,13,17,21,28,31,36,39,42-十氮杂四十六烷-46-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯353(27μL,20mM DMA溶液)。将混合物在15℃冷却,并在UV365nm(100W,光通量为~20W/m2,用邻硝基苯甲醛测量,Willett,K.和Hites,R.,J.Chem.Educ.,2000,77,900)照射4~6小时,然后加入DHAA(135μL,50mM)。从冷却器中取出石英管后,将混合物在室温下培养过夜,然后在G-25柱上纯化,用100mM NaH2PO4,50mM NaCl pH 6.0-7.5缓冲液洗脱,得到14.8mg偶联物(在2.73mL缓冲液中,74%产率)。药物/抗体比(DAR)通过UPLC-QTOF质谱确定为2.60(双药)或5.18(分别计算MMAF和PBD时)。SEC HPLC分析(TosohBioscience,Tskgel G3000SW,7.8mm ID×30cm,0.5mL/min,100分钟)单体含量94~99%和SDS-PAGE显示为单一条带。
实施例126.(S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-二甲基-2)-((S)-3-甲基-2-(甲氨基)丁酰氨基)丁酰胺基)-3-甲氧基-5-甲基庚酰基)-吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(356)的合成
将(S)-甲基2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-二甲基-2-((S)-3-甲基-2-(甲基氨基)丁酰氨基)丁酰胺基)-3-甲氧基-5-甲基-庚酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(25mg,0.030mmol)与浓盐酸(0.3mL)的1,4-二恶烷(0.9mL)混合物在室温下搅拌35分钟。将混合物用乙醇(1.0mL)和甲苯(1.0mL)稀释,浓缩并与乙醇/甲苯(2:1)共浓缩,得到标题化合物,为白色固体(22mg,~100%收率),其不经进一步纯化即用于下一步。LC-MS(ESI)m/z C39H66N5O8[M+H]+计算值732.48,实测值732.60。
实施例127.(2S)-2-((2R,3R)-3-((2S)-1-((11S,14S,17S)-1-叠氮基-17-((R)-仲丁基))-11,1-二异丙基-18-甲氧基-10,16-二甲基-9,12,15-三氧代-3,6-二氧杂-10,13,16-三氮杂二十烷-20-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(357)的合成
在两小时内,分四份向(S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-二甲基-2-((S)-3-甲基-2-(甲氨基)丁酰氨基)丁酰氨基)-3-甲氧基-5-甲基庚酰基)-吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸粗品(22毫克,0.030mmol)的DMA(0.8mL)和NaH2PO4缓冲溶液(pH 7.5,1.0M,0.7mL)的混合物中加入2,5-二氧代吡咯烷-1-基3-(2-(2-叠氮基乙氧基)乙氧基)丙酸盐(18.0mg,0.060mmol)。将混合物搅拌过夜,浓缩并在硅胶柱(CH3OH/二氯甲烷/HOAc 1:8:0.01)上纯化,得到标题化合物(22.5mg,82%收率)。LC-MS(ESI)m/z C46H77N8O11[M+H]+计算值917.56,实测值917.60。
实施例128.(2S)-2-((2R,3R)-3-((2S)-1-((11S,14S,17S)-1-氨基-17-((R)-仲丁基))-11,14二异丙基-18-甲氧基-10,16-二甲基-9,12,15-三氧代-3,6-二氧杂-10,13,16-三氮杂二十烷-20-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(358)的合成
在氢化瓶里,向(2S)-2-((2R,3R)-3-((2S)-1-((11S,14S,17S)-1-叠氮基-17-((R)-仲丁基)-11,14二异丙基-18-甲氧基-10,16-二甲基-9,12,15-三氧代-3,6-二氧杂-10,13,16-三氮杂环氧乙烷-20-酰基)吡咯烷-2-基)-3-的甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(22.0mg,0.024mmol)的甲醇(5mL)溶液中加入Pd/C(5mg,10wt%,50%水)。将空气抽空并充入25psi H2,将混合物振荡4小时,通过硅藻土过滤。浓缩滤液,得到标题产物(~20mg,92%收率),其不经进一步纯化直接用于下一步。ESI MS m/z C46H79N6O11[M+H]+计算值891.57,实测值891.60。
实施例129.(2S)-2-((2R,3R)-3-((2S)-1-((3R,4S,7S,10S,48S,51S,54S,55R)-4,54-二((S)-仲丁基)-7,10,48,51-四异丙基-55-甲氧基-3-(2-((S)-2-((1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,18,47,53-五甲基-6,9,12,17,20,30,36,46,49,52-六氧代-33-(4-丙酰胺丁酰基)-2,23,26,40,43-五氧杂-5,8,11,16,19,29,33,37,47,50,53-十一氮杂五十七烷-57-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(359)的合成
向(3R,4S,7S,10S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-((1R,2R))-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,18-三甲基-6,9,12,17,20,30-六氧代-33-(4-丙醇酰氨基丁酰基)-2,23,26-三氧杂-5,8,11,16,19,29,33-七氮杂三十六烷-36-甲酸(0.018g,0.0134mmol)的二氯甲烷(5mL)的悬浮液中加入五氟苯酚(3.7mg,0.0201mmol)和DIC(2.0mg,0.0161mmol)。在室温下搅拌4小时,用硅藻土过滤。浓缩滤液并溶于DMF(1mL)中,之后加入(2S)-2-((2R,3R)-3-((2S)-1-((11S,14S,17S)-1-氨基-17-((R)-仲丁基)-11,14二异丙基-18-甲氧基-10,16-二甲基-9,12,15-三氧代-3,6-二氧杂-10,13,16-三氮杂二十-20-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(13.1mg,0.0147mmol)的无水DMF(2mL)溶液。在室温下搅拌2小时后,将混合物浓缩并在HPLC上纯化(C18柱,流动相A:水,流动相B:乙腈,从20%B至80%B在50分中内)。合并组分并冻干,得到标题化合物,为无色油状物(17.8mg,60%收率)。ESI MS m/z C113H184N16O28[M+H]+计算值2214.35,实测值2214.36。
实施例130.(S)-2-((2R,3R)-3-((S)-1-((6S,9S,12S,13R)-12-((S)-仲丁基)-6,9-二异丙基-13-甲氧基-2,2,5,11-四甲基-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十五烷-15-酰基)吡咯烷-2基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸的合成
向(S)-(2R,3R)-3-((S)-1-((6S,9S,12S,13R)-12-((S)-仲丁基)-(S)-6,9-二异丙基-13-甲氧基2,2,5,1-1四甲基-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十五烷-15酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(30mg,0.035mmol)的四氢呋喃(1.0mL)溶液中加入LiOH水溶液(1.0M,0.8mL)。将混合物在室温下搅拌35分钟,用0.5MH3PO4中和至pH 6,浓缩并在硅胶柱上纯化(CH3OH/二氯甲烷/HOAc 1:10:0.01),得到标题化合物(25.0mg,85%收率)。LC-MS(ESI)m/z C44H74N5O10[M+H]+计算值832.54,实测值832.60。
实施例131.(S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-二甲基-2)-((S)-3-甲基-2-(甲氨基)丁酰氨基)丁酰胺基)-3-甲氧基-5-甲基庚酰基)-吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(356)的合成
向(S)-2-((2R,3R)-3-((S)-1-((6S,9S,12S,13R)-12-((S)-仲丁基)-6,9二异丙基-13-甲氧基-2,2,5,11-四甲基-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十五烷-15-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(25mg,0.030mmol)的二恶烷(2.0mL)溶液中加入盐酸(12.0M,0.6mL)。将混合物在室温下搅拌30分钟,用二恶烷(4mL)和甲苯(4mL)稀释,浓缩并用C18 HPLC纯化,用甲醇和水洗脱(200mm×Φ20mm,9mL/min,40分钟从5%甲醇至40%甲醇),得到标题化合物(20.0mg,90%收率)。LC-MS(ESI)m/z C39H66N5O8[M+H]+计算值732.48,实测值732.90。
实施例132.4-(((苄氧基)羰基)氨基)丁酸的合成
将4-氨基丁酸(7.5g,75mmol)和氢氧化钠(6g,150mmol)的水(40mL)溶液冷却至0℃并滴加CbzCl(16.1g,95mmol)的四氢呋喃(32mL)溶液。搅拌1小时后,使反应升温至室温,搅拌3小时。真空除去四氢呋喃,通过加入6N盐酸将水溶液的pH调节至1.5。用乙酸乙酯萃取,有机层用盐水洗涤,干燥并浓缩,得到标题化合物(16.4g,92%收率)。MS ESI m/zC12H16NO5[M+H]+计算值238.10,实测值238.08。
实施例133.4-(((苄氧基)羰基)氨基)丁酸叔丁酯的合成
向4-(((苄氧基)羰基)氨基)丁酸(16.4g,69.2mmol)和t-BuOH(15.4g,208mmol)的二氯甲烷(100mL)溶液中加入DMAP(0.8g,6.56mmol)和DCC(17.1g,83mmol)。在室温下搅拌过夜,过滤反应物并浓缩滤液。将残余物溶于乙酸乙酯中,用1N盐酸,盐水洗涤,用无水硫酸钠干燥。浓缩并通过柱层析法纯化(10至50%乙酸乙酯/正己烷),得到标题化合物(7.5g,37%收率)。MS ESI m/z C16H23NO4Na[M+Na]+计算值316.16,实测值316.13。
实施例134.4-氨基丁酸叔丁酯的合成
将4-(((苄氧基)羰基)氨基)丁酸叔丁酯(560mg,1.91mmol)溶解在甲醇(50mL)中,并与Pd/C催化剂(10wt%,100mg)混合,然后在室温下氢化(1atm)3小时。滤除催化剂,真空除去所有挥发物,得到标题化合物(272mg,90%收率)。MS ESI m/z C8H18NO2[M+H]+计算值160.13,实测值160.13。
实施例135.2,2-二丙酰氨基乙酸(373)的合成。
向2,2-二氨基乙酸(2.0g,22.2mmol)的乙醇(15mL)和50mM NaH2PO4缓冲液(25mL,pH 7.5)的混合物中加入2,5-二氧代吡咯烷-1-基丙酸酯(9.0g,53.8mmol)。将混合物搅拌8小时,浓缩,用0.1M盐酸酸化至pH 3.0,用乙酸乙酯(3×30mL)萃取。合并有机层,用无水硫酸钠干燥,过滤,浓缩并在硅胶柱上纯化,用甲醇/二氯甲烷(1:10to 1:6)洗脱,得到标题化合物(3.27g,76%收率)。1H-NMR(CDCl3)11.8(br,1H),8.12(d,2H),6.66(m,1H),2.66(s,2H)。ESI MS m/z C8H6N2O4[M+H]+计算值195.03,实测值195.20。
实施例136.2,2-二丙基氨基乙酸全氟苯酯(421)的合成
在室温下,将2,2-二丙基氨基乙酸(2.01g,10.31mmol),五氟苯酚(2.08g,11.30mmol),DIPEA(1.00mL,5.73mmol)和EDC(4.01g,20.88mmol)的二氯甲烷(100mL)溶液搅拌过夜,浓缩并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1:15to 1:8)洗脱,得到标题化合物(3.08g,83%收率)。1H-NMR(CDCl3)8.10(d,2H),6.61(m,1H),2.67(s,2H)。ESI MS m/zC14H6F5N2O4[M+H]+计算值361.02,实测值361.20。
实施例137.(S)-2-((S)-2-(2,2-二丙酰氨基乙酰氨基)丙酰氨基)-丙酸(423)的合成
向(S)-2-((S)-2-氨基丙酰胺基)丙酸(422)(1.10g,6.87mmol)的DMA(18mL)和50mM NaH2PO4缓冲液(pH 7.5,30mL)的混合物中加入2,2-二丙酰氨基乙酸五氟苯基酯(3.00g,8.33mmol)。将混合物搅拌14小时,浓缩,用0.1M盐酸酸化至pH 3.0,用乙酸乙酯(3×40mL)萃取。合并有机层,用无水硫酸钠干燥,过滤,浓缩并在硅胶柱上纯化,用甲醇/二氯甲烷(1:10to 1:5)洗脱,得到标题化合物(1.80g,78%收率)。ESI MS m/z C14H17N4O6[M+H]+计算值337.11,实测值337.30。
实施例138.(S)-2,5-二氧代吡咯烷-1-基2-((S)-2-(2,2-二丙酰氨基-乙酰氨基)丙酰胺基)丙酸酯(424)的合成
将(S)-2-((S)-2-(2,2-二丙酰氨基乙酰胺基)丙酰胺基)-丙酸(1.01g,3.00mmol),NHS(0.41g,3.56mmol),DIPEA(0.40mL,2.29mmol)和EDC(1.51g,7.86mmol)的二氯甲烷(50mL)溶液在室温下搅拌过夜,浓缩并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1:15to 1:7)洗脱,得到标题化合物(1.05g,81%收率)。ESI MS m/z C18H20N5O8[M+H]+计算值434.12,实测值434.40。
实施例139.(4R)-5-(4-乙酰氧基-3-硝基苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸叔丁酯的合成
在0℃下,向化合物190(107.1mg,0.252mmol)的二氯甲烷(4.0mL)溶液中依次加入乙酸酐(0.11mL,1.17mmol)和三乙胺(0.16mL)。然后将反应升温至室温,搅拌1小时,用二氯甲烷稀释,之后用水和盐水洗涤,用无水硫酸钠干燥,过滤并浓缩。通过柱层析(0-15%乙酸乙酯/石油醚)纯化残余物,得到无色油状物(120.3mg,>100%收率)。MS ESI m/z C23H35N2O8[M+H]+计算值467.23,实测值467.23。
实施例140.(4R)-5-(4-乙酰氧基-3-氨基苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸叔丁酯的合成
将苯基腈348(120.3mg,0.258mmol)溶于乙酸乙酯(5mL)和乙酸(0.5mL)中。向其中加入Pd/C(10wt%,10mg)并将混合物在氢气中室温下搅拌30分钟。然后通过硅藻土垫过滤,用乙酸乙酯洗涤垫。浓缩滤液,并通过柱层析(0-25%乙酸乙酯/石油醚)纯化,得到黄色油状物(120.9mg,>100%产率)。MS ESI m/z C23H37N2O6[M+H]+4计算值437.26,实测值437.28。
实施例141.(4R)-5-(3-(4-(((苄氧基)羰基)氨基)丁酰氨基)-4-((叔丁基二甲基甲硅烷基)氧基)苯基)-4-((叔丁氧基羰基)乙酯的合成基)氨基)-2-甲基戊酸乙酯
将2,5-二氧代吡咯烷-1-基4-(((苄氧基)羰基)氨基)丁酸酯(0.396克,1.2mmol)和(4R)-乙基-5-(3-氨基-4-羟基苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸酯(0.44g,1.2mmol)溶解在乙醇(10mL)中,并加入磷酸盐缓冲溶液(pH=7.5,0.1M,2mL)。将反应混合物在室温下搅拌过夜,然后减压除去溶剂,残余物用硅胶柱层析纯化,得到标题产物(0.485g,70%)。ESI MS m/z C31H44N3O8[M+H]+计算值586.31,实测值586.31。
实施例142.(4R)-5-(3-(4-氨基丁酰氨基)-4-((叔丁基二甲基甲硅烷基)氧基)苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸乙酯的合成
将(4R)-5-(3-(4-(((苄氧基)羰基)氨基)丁酰氨基)-4-((叔丁基二甲基-甲硅烷基)氧基)苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸酯(0.35g,0.5mmol)溶解在甲醇(5mL)中,然后加入Pd/C(10wt%,35mg)。将反应混合物在室温H2气球下搅拌过夜,然后通过硅藻土过滤,将滤液减压浓缩,得到标题产物(0.22g,79%收率)。ESI MS m/z C29H52N3O6Si[M+H]+计算值566.35,实测值566.35。
实施例143.2-((6S,9S,12R,14R)-9-((S)-仲丁基)-14-羟基-6,12-二异丙基-2,2,5,11-四甲基-4,7,10-三氧-3-氧杂-5,8,11-三氮杂十四烷-14-基)噻唑-4-羧酸(381)的合成
向Boc-N-Me-L-Val-OH(33mg,0.14mmol)的乙酸乙酯溶液中加入五氟苯酚(39mg,0.21mmol)和DCC(32mg,0.154mmol)。将反应混合物在室温下搅拌16小时,然后通过硅藻土垫过滤,用乙酸乙酯洗涤滤垫。浓缩滤液并重新溶解在DMA(2mL)中,然后加入2-((1R,3R)-3-((2S,3S)-2-氨基-N,3-二甲基戊酰胺基)-1-羟基-4-甲基戊基)噻唑-4-羧酸(52mg,0.14mmol)和DIPEA(48.5μL,0.28mmol)。将反应混合物在室温下搅拌24小时,然后浓缩并通过反相HPLC(C18柱,10-100%乙腈/水)纯化,得到标题化合物(40.2mg,49%收率)。ESI MSm/z C28H49N4O7S[M+H]+585.32,实测值585.32。
实施例144.2-((6S,9S,12R,14R)-9-((S)-仲丁基)-6,12-二-异丙基-2,2,5,11-四甲基-4,7,10,16-四氧代-3,15-二氧杂-5,8,11-三氮杂十七烷-14-基)噻唑-4-羧酸的合成
在0℃下,将2-((6S,9S,12R,14R)-9-((S)-仲丁基)-14-羟基-6,12-二异丙基-2,2,5,11-四甲基-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十七烷-14-基)噻唑-4-羧酸(40mg,0.069mmol)溶于吡啶(8mL)中,向其中加入乙酸酐(20.4mg,0.2%)mmol)并将反应混合物升温至室温并搅拌过夜。浓缩混合物并通过硅胶柱层析纯化,用二氯甲烷/甲醇梯度洗脱,得到标题产物(48.1mg,~100%产率)。ESI MS m/z C30H51N4O8S[M+H]+计算值627.33,实测值627.33。
实施例145.(4R)-4-(2-((6S,9S,12R,14R)-9-((S)-仲丁基)-6,12-二异丙基-2,2,5,11-四甲基-4,7,10,16-四氧代-3,15-二氧杂-5,8,11-三氮杂十七烷-14-基)噻唑-4-甲酰胺基)-2-甲基-5-苯基戊酸的合成
向2-((6S,9S,12R,14R)-9-((S)-仲丁基)-6,12-二-异丙基-2,2,5,11-四甲基-4,7的10,16-四氧代-3,15-二氧杂-5,8,11-三氮杂十七烷-14-基)噻唑-4-羧酸(48.1mg,0.077mmol)的乙酸乙酯溶液中加入五氟苯酚(21.2mg,0.115mmol)和DCC(17.4mg,0.085mmol)。将反应混合物在室温下搅拌16小时,然后通过硅藻土垫过滤,用乙酸乙酯洗涤滤垫。浓缩滤液并重新溶解在DMA(4mL)中,然后加入(4R)-4-氨基-2-甲基-5-苯基戊酸(20.7mg,0.1mmol)和DIPEA(26.8μL,0.154mmol)。将反应混合物在室温下搅拌24小时,然后浓缩并通过反相HPLC(C18柱,10-100%乙腈/水)纯化,得到标题化合物(63mg,~100%产率)。ESI MS m/z C42H66N5O9S[M+H]+计算值816.45,实测值816.45。
例146(4R)-4-(2-((3S,6S,9R,11R)-6-((S)-仲丁基)-3,9-二异丙基-8-甲基-4,7,13-三氧-12-氧杂-2,5,8-三氮杂十四烷-11-基)噻唑-4-甲酰胺基)-2-甲基-5-苯基戊酸盐酸盐(474)的合成
将(4R)-4-(2-((6S,9S,12R,14R)-9-((S)-仲丁基)-6,12-二异丙基-2,2,5,11-四甲基-4,7,10,16-四氧代-3,15-二氧杂-5,8,11-三氮杂十七烷-14-基)噻唑-4-甲酰胺基)-2-甲基-5-苯基戊酸(60mg,0.073mmol)的乙酸乙酯(3mL)溶液和HCl(0.8mL,12M)搅拌30分钟,并用甲苯(5mL)和二恶烷(5mL)稀释。浓缩混合物,与二恶烷(5mL)和甲苯(5mL)共浓缩至干,得到标题产物(57.1mg,103%产率),不经进一步纯化用于下一步。ESI MS m/zC37H58N5O7S[M+H]+计算值716.40,实测值716.60。
实施例147.(4R)-4-(2-((4R,6R,9S,12S,15S,18S)-9-((S)-仲丁基)-6,12-二异丙-7,13,15,18-四甲基-2,8,11,14,17,20,23-七氧杂-21-丙炔酰胺基-3-氧杂-7,10,13,16,19,22-六氮杂二十五烷-24-炔-4-基)噻唑-4-甲酰胺基)-2-甲基-5-苯基戊酸(475)的合成
向化合物474(25mg,0.034mmol)的DMA(2mL)和0.1M Na2HPO4(pH8.0,1mL)的混合物中,在3小时内分三批加入化合物424(23.1mg,0.053mmol),然后再搅拌12小时。浓缩混合物,并通过反相HPLC(200mm×10mm,C18柱,10-100%乙腈/水,40分钟,8mL/min)纯化,得到标题化合物(30.0mg,85%收率)。ESI MS m/z C51H71N9O12S[M+H]+计算值1034.49,实测值1034.90。
实施例148.(S)-2-((2R,3R)-3-((S)-1-((8S,11S,14S,17S,20S,21R)-20-((S)-仲丁基)-14,17-二异丙基-21-甲氧基-8,11,13,19-四甲基-3,6,9,12,15,18-六氧杂-5-丙炔酰胺基-4,7,10,13,16,19-六氮杂二十三烷-1-炔-23-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(477)的合成
向化合物356(20mg,0.027mmol)的DMA(2mL)和0.1M Na2HPO4的混合物(pH 8.0,1mL)中,在3小时内分3次加入化合物424(20.1mg,0.046mmol)。然后将混合物再搅拌12小时。浓缩混合物,并通过反相HPLC(200mm×10mm,C18柱,10-100%乙腈/水,40分钟,8mL/min)纯化,得到标题化合物(22.1mg,78%收率)。ESI MS m/z C53H80N9O13[M+H]+计算值1050.58,实测值1050.96。
实施例149.(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶)-2-甲酰氨基)戊酰胺)-4-甲基戊基)噻唑-4-甲酰氨基)-5-(4-羟基-3-(3-(2-(2-((双(2-丙炔酰肼基)磷酰基)氨基)乙氧基)乙氧基)-丙酰胺基)苯基)-2-甲基戊酸(480)的合成
在0℃下,向化合物89(16.1mg,0.132mmol)的四氢呋喃(5mL)和DIPEA(10μl,0.057mmol)的混合物中加入POCl3(10.1mg,0.0665mmol)。在0℃下搅拌20分钟后,将混合物升温至室温并继续搅拌4小时。然后向混合物中加入化合物336(60mg,0.065mmol)和DIPEA(20μl,0.114mmol)。将混合物在50℃搅拌过夜,浓缩,并通过反相HPLC(200mm×10mm,C18柱,10-100%乙腈/水,40分钟,8mL/min)纯化,得到标题化合物(23.1mg,32%收率)。ESI MS m/z C51H76N11O14PS[M+H]+1130.50,计算值1130.50,实测值1131.20。
实施例150.(2S)-2-((2R,3R)-3-((2S)-1-((11S,14S,17S,18R)-17-((S)-仲丁基)-11,14-二异丙基-18-甲氧基-10,16-二甲-9,12,15-三氧代-1-((双(2-丙炔酰肼基)磷酰基)氨基)-3,6-二氧杂-10,13,16-三氮杂二十烷-20-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(482)的合成
在0℃下,向化合物89(16.1mg,0.132mmol)的四氢呋喃(5mL)和DIPEA(10μl,0.057mmol)的混合物中加入POCl3(10.1mg,0.0665mmol)。在0℃下搅拌20分钟后,将混合物升温至室温并继续搅拌小时。然后向混合物中加入化合物358(60mg,0.067mmol)和DIPEA(20μl,0.114mmol)。将混合物在50℃搅拌过夜,浓缩,并通过反相HPLC(200mm×10mm,C18柱,10-100%乙腈/水,40分钟,8mL/min)纯化,得到标题化合物(25.6mg,34%收率)。ESI MS m/z C52H84N10O14P[M+H]+计算值1103.58,实测值1104.10。
实施例151.(2S,2’S)-2,2’-((13,14-双((E)-3-溴丙烯酰基)-11,16-二氧代-4,7,20,23-四氧杂-10,13,14,17-四氮杂二十六烷-1,26-二酰基)双(氮烷二基))双(N-(2-((S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧代2,3,11,11a四氢-1H-苯并[e]吡咯并[1,2-α][1,4]二氮杂-10(5H)-基)-2-氧代乙基)-3-甲基丁酰胺)(497)的合成
将化合物352(25.1mg,0.0278mmol),化合物36(11.50mg,0.0279mmol)和EDC(15mg,0.078mmol)的DMA(2mL)溶液搅拌过夜,浓缩,并通过反相HPLC纯化(200mm×10mm,C18柱,10-100%乙腈/水,40分钟,8mL/min),得到标题化合物(23.8mg,39%收率)。ESI MS m/zC104H133Br2N16O26[M+H]+计算值2179.79,实测值2180.50[M+H]+,219780[M+H2O+H]+,2215.81[M+2H2O+H]+。
实施例152.化合物499的合成
将化合物259(26.1mg,0.0246mmol),化合物36(10.20mg,0.0247mmol)和EDC(15mg,0.078mmol)的DMA(2mL)溶液搅拌过夜,浓缩,并通过反相HPLC纯化(200mm×10mm,C18柱,10-100%乙腈/水,40分钟,8mL/min),得到标题化合物(27.6mg,45%收率)。ESI MS m/zC118H190Br2N18O30[M+H]+计算值2498.23,实测值2499.50。
实施例153.偶联物232,234,238,261,307,326,339,344或360的制备。
从化合物物231,233,237,260,306,325,338,343或359分别制备偶联物232,234,238,261,308,327,339,344或360的方法,类似于实施例125中所描述的从化合物353制备偶联物354的方法。
实施例154.制备偶联物235,239,307,327,339,345,355,361,476,478,481,483,498或500的一般方法
向赫赛汀(pH 6.0~8.0,10mg/mL,2.0mL)中分别加入NaH2PO4(pH 6.5~8.5,100mM,0.70~2.0mL)缓冲液,TCEP(14-35μL,20mM水溶液)和化合物231,233,237,306,325,343,353,359,475,477,480,482,497或499(14-28μL,20mM DMA溶液,化合物497和498加入14-18μL)。将混合物在室温下孵育4-18小时,然后加入DHAA(135μL,50mM)。在室温下孵育过夜后,将混合物在G-25柱上纯化,用100mM NaH2PO4,50mM NaCl pH 6.0~7.5缓冲液洗脱,得到在13.4~15.8mL缓冲液中的12.8~18.1mg偶联化合物235,239,307,327,339,345,355,361,476,478,481,483,498或500(60%~91%产率)。偶联物235,239,307,327,339,345,355,361,476,478,481或483的药物/抗体比(DAR)为2.1~4.2,偶联物498或者500的DAR为2.6~5.3,DAR通过UPLC-QTOF质谱确定。通过SEC HPLC(Tosoh Bioscience,TskgelG3000SW,7.8mm ID×30cm,0.5mL/min,100min)分析单体含量为94%至99%,SDS-PAGE显示为单一条带。
实施例155.与T-DM1相比,偶联物232,234,235,238,239,261,307,308,326,327,339,344,345,354,355,360,361,476,478,481,483,498或500的体外细胞毒性评价:
用于细胞毒性测定的细胞系是NCI-N87,一种人胃癌细胞系;细胞在含有10%FBS的RPMI-1640中生长。为了进行测定,将细胞(180μL,6000个细胞)加入到96孔板中的每个孔中,并在37℃,5% CO2下温育24小时。之后在合适的细胞培养基(总体积0.2mL)中用各种浓度的测试化合物(20μL)处理细胞。对照孔含有细胞和培养基但无测试化合物。在37℃,5%CO2下,将板孵育120小时。然后将MTT(5mg/mL)加入孔中(20μL),在37℃下,将板温育1.5小时。小心地除去培养基,然后加入DMSO(180μL)。振荡15分钟后,在490nm和570nm处测量吸光度(参比滤光片620nm)。根据下式计算抑制率:抑制率%=[1-(样品-空白)/(对照-空白)]×100。
细胞毒性结果(IC50):
实施例156.体内抗肿瘤活性(携带NCI-N87异种移植肿瘤的BALB/c裸鼠)
在人体胃癌N-87细胞系肿瘤异种移植模型上评价偶联物232,308,327,339,476,483和500以及T-DM1的体内活性。在5周龄雌性BALB/c裸鼠(54只动物)右肩下区域皮下接种0.1mL无血清培养基中的N-87癌细胞(5×106细胞/小鼠)。使肿瘤生长8天至平均尺寸135mm3。然后将动物随机分成9组(每组6只动物)。第一组小鼠作为对照组,并注射磷酸盐缓冲盐水(PBS)。6组以5mg/kg的剂量分别静脉注射偶联物232,308,327,476,483和T-DM1。剩余的2组以4mg/Kg的剂量分别静脉注射偶联物339和500。每4天测量肿瘤的三个维度,并使用公式“肿瘤体积=1/2(长×宽×高)”计算肿瘤体积。同时还测量动物的体重。当满足以下任何一个标准时,处死小鼠:(1)体重减轻超过治疗前体重的20%,(2)肿瘤体积大于2000mm3,(3)病得太重,不能进食和饮水,或(4)皮肤坏死。如果没有可感知的肿瘤,则认为小鼠无肿瘤。
结果绘制在图45中。所有8个偶联物均未引起动物体重减轻。对照组的动物由于肿瘤体积大于2200mm3且病重在第56天被杀死。测试的7种偶联物表现出比T-DM1更好的抗肿瘤活性。偶联物476,483,339和500组中的所有动物(6/6)在第14天至第52天完全没有可测量的肿瘤。相比之下,5mg/kg剂量的T-DM1不能消除肿瘤,仅抑制肿瘤生长31天。5mg/kg剂量的偶联物232,308和327不能完全根除肿瘤。抑制肿瘤生长数据如下:
偶联物 | 肿瘤生长延迟期 |
T-DM1 | 31days |
308 | 39days |
327 | 46days |
232 | 52days |
476 | 65days |
483 | 66days |
339 | 66days |
500 | 67days |
Claims (43)
1.结构为式Formula(I)和(II)的连接体:
其中,
Lv1和Lv2表示相同或不同的,可被巯基取代的离去基团。这些离去基团选自卤化物(例如氟化物,氯化物,溴化物和碘化物),甲磺酰基(mesyl),甲苯磺酰基(tosy l),三氟甲基磺酰基(triflate),硝基苯氧基,N-琥珀酰亚胺基氧基(NHS),苯氧基;二硝基苯氧基;五氟苯氧基,四氟苯氧基,三氟苯氧基,二氟苯氧基,单氟苯氧基,五氯苯氧基,1H-咪唑-1-基,氯苯氧基,二氯苯氧基,三氯苯氧基,四氯苯氧基,N-(苯并三唑基)氧基,2-乙基-5-苯基异恶唑-3'-磺酰基,苯基恶二唑-磺酰基(-sulfone-OD A),2-乙基-5-苯基异恶唑-基,苯基恶二唑基(ODA),恶二唑基,或者与下列缩合剂产生的中间分子:1-乙基-(3-二甲基氨基丙基)碳二亚胺(EDC)、二环己基碳二亚胺(DCC)、N,N'-二异丙基碳二亚胺(DIC)、N-环己基-N'-(2-吗啉代-乙基)碳二亚胺甲基对甲苯磺酸盐(CMC或CME-CDI)、1,1'-羰基二咪唑(CDI)、氧-(苯并三唑-1-)基)-N,N,N’,N’-四甲基脲四氟硼酸盐(TBTU)、N,N,N',N'-四甲基-氧-(1H-苯并三唑-1-基)-六氟磷酸铵(HBTU)、(苯并三唑-1-基氧基)三(二甲基氨基)-六氟磷酸盐(BOP)、(苯并三唑-1-基氧基)三吡咯烷基六氟磷酸盐(PyBO P)、氰基膦酸二乙酯(DEPC)、氯-N,N,N',N'-四甲基甲脒六氟磷酸盐、1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶3-氧六氟磷酸盐(HATU)、1-[(二甲氨基)(吗啉代)亚甲基]-1H-[1,2,3]三唑并[4,5-b]吡啶-1-鎓3-氧六氟磷酸盐(HDMA)、2-氯-1,3-二甲基-咪唑六氟磷酸盐(CIP)、六氟磷酸氯代吡咯烷酮鎓(PyCloP)、氟-N,N,N',N'-双(四亚甲基)甲脒六氟磷酸盐(BTFFH)、N,N,N',N'-四甲基-S-(1-氧代-2-吡啶基)硫脲六氟磷酸盐、氧-(2-氧代-1(2H)吡啶基)-N,N,N',N'-四甲基脲四氟硼酸盐(TPTU)、S-(1-氧代-2-吡啶基)N,N,N',N'-四甲基硫脲四氟硼酸盐、氧-[(乙氧基羰基)-氰基甲基氨基]-N,N,N',N'-六氟磷酸四甲基脲(HOTU)、(1-氰基-2-乙氧基-2-氧代乙基氨基氧基)二甲氨基-吗啉代-六氟磷酸盐(COMU)、氧-(苯并三唑-1-基)-N,N,N',N'-双(四亚甲基)六氟磷酸盐(HBPyU)、N-芐基-N'-环己基-碳二亚胺(有或没有聚合物结合)、二吡咯烷基(N-琥珀酰亚胺基氧基)碳鎓六氟磷酸盐(HSPyU)、氯二吡咯烷基六氟磷酸盐(PyClU)、2-氯-1,3-二甲基咪唑四氟硼酸盐(CIB)、(苯并三唑-1-基氧基)二呱啶碳六氟磷酸盐(HBPipU)、氧-(6-氯苯并三唑-1-基)-N,N,N',N'-四甲基脲四氟硼酸盐(TCTU)、溴代(二甲基氨基)-六氟磷酸盐(BroP)、丙基膦酸酐(PPACA、)、2-吗啉代乙基异氰化物(MEI)、N,N,N',N'-四甲基-氧-(N-琥珀酰亚胺基)六氟磷酸盐(HSTU)、2-溴-1-乙基-吡啶鎓四氟硼酸盐(BEP)、氧-[(乙氧基羰基)氰基-亚甲基氨基]-N,N,N',N'-四甲基脲四氟硼酸盐(TOTU)、4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉氯化物(MMTM、DMTMM)、N,N,N',N'-四甲基-氧-(N-琥珀酰亚胺基)脲四氟硼酸(TSTU)、氧-(3,4-二氢-4-氧代-1,2,3-苯并三嗪-3-基)-N,N,N’,N’-四甲基脲四氟硼酸盐(TDBTU)、1,1'-(偶氮二羰基)-二呱啶(ADD)、二-(4-氯芐基)偶氮二羧酸酯(DCAD)、偶氮二羧酸二叔丁酯(DBAD)、偶氮二羧酸二异丙酯(DIAD)、偶氮二羧酸二乙酯(DEAD)。
Y是能够与药物或细胞毒性剂反应形成二硫化物,醚,酯,硫醚,硫酯,肽,腙,氨基甲酸酯,碳酸酯,胺(二级,三级或四级),亚胺,环杂烷基,杂芳基,烷基肟或酰胺键的官能团;Y选自以下结构:
N-羟基琥珀酰亚胺酯基;/>马来酰亚胺基;/>单取代马来酰亚胺基;/>二取代马来酰亚胺基;/>单取代的琥珀酰亚胺基;/>二取代琥珀酰亚胺基;醛基;/>乙烯基磺酰基;丙烯酰基;/>2-(甲苯磺酰氧基)乙酰基;2-(甲磺酰氧基)乙酰基;/>2-(硝基苯氧基)乙酰基;/>2-(二硝基苯基)乙酰基;2-(氟代苯氧基)-乙酰基;/>2-(二氟苯氧基)-乙酰基;/>2-(((三氟甲基)-磺酰)氧基)乙酰基;/>酮或醛基;/>2-(五氟苯氧基)乙酰基;/>甲基砜苯基恶二唑(ODA)苯基;/>酸酐,/>烷氧基氨基;/>叠氮基,/>炔基,或/>酰肼,其中X1'为F,Cl,Br,I或Lv3;X2'是O,NH,N(R1)或CH2;R3和R5独立地为H,R1,芳基,杂芳基或芳香基团,其中一个或几个H原子被-R1,-卤素,-OR1,-SR1,-NR1R2,-NO2,-S(O)R1,-S(O)2R1,或-COOR1取代;Lv3是离去基团,选自硝基苯氧基,N-琥珀酰亚胺基氧基(NHS),苯氧基;二硝基苯氧基;五氟苯氧基,四氟苯氧基,二氟苯氧基,单氟苯氧基,五氯苯氧基,三氟甲基磺酰基,咪唑基,二氯苯氧基,四氯苯氧基,1-羟基苯并三唑基,甲苯磺酸基,甲磺酸基,2-乙基-5-苯基异恶唑-3'-磺酸基,自身形成,或与其它酸酐形成的酸酐,例如乙酸酐,甲酸酐,或与多肽缩合试剂作用产生的或Mitsunobu反应的中间体。
R1可以缺省,或者可以选自C1-C8(1-8个碳原子)烷基;C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或含2-8个碳原子的酯,醚或酰胺;或含有1-8个氨基酸的肽;或具有式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p是0至约1000的整数,或其上述基团的组合。
T为CH2,NH,NHNH,N(R3),N(R3)N(R3’),O,S,C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;含有1~4氨基酸单位的肽,优选自天冬氨酸,谷氨酸,精氨酸,组氨酸,赖氨酸,丝氨酸,苏氨酸,天冬酰胺,谷氨酰胺,半胱氨酸,硒代半胱氨酸,酪氨酸,苯丙氨酸,甘氨酸,脯氨酸,色氨酸,丙氨酸;或以下结构之一:
X1,X2,X3,X4,X5,X6,X1’,X2’和X3’独立地选自NH;NHNH;N(R3);N(R3)N(R3’);O;S;C1-C6烷基;C2-C6杂烷基,烷基环烷基,杂环烷基的;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或1~8个氨基酸;其中R3和R3'独立地为H;C1-C8烷基;C2-8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或含1-8个碳原子的酯,醚或酰胺;或具有式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p是0至约1000的整数,或其上述基团的组合。
m1,m2,m3,m4和m5是独立的选自1到10的整数,优选1到4。
L1和L2是相同或不同,独立地选自O,NH,S,NHNH,N(R3),N(R3)N(R3'),如式(OCH2CH2pOR3、(OCH2CH(CH3))pOR3、NH(CH2CH2O)pR3、NH(CH2CH(CH3)O)pR3、N[(CH2CH2O)pR3][(CH2CH2O)p'R3']、(OCH2CH2)pC(=O)X1R3或CH2CH2(OCH2CH2)pC(=O)X1R3的聚乙烯氧单元,其中p和p'独立地是选自1至约1000的整数,或其组合;C1-C8烷基;C2-8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;其中X1,R3和R3'如前文所定义。
L1或L2可以含有自我毁灭或非自我毁灭的组分、肽单元(1~8天然或非天然氨基酸)、腙键、二硫化物、酯、肟、酰胺或硫醚键。自我毁灭单元选自对氨基芐基氨甲酰基(PAB),2-氨基咪唑-5-甲醇的衍生物、杂环PAB同系物、β-葡糖苷酸、以及邻或对氨基芐基缩醛。
自我毁灭型连接体单元具有以下结构之一:
其中,*标记的是额外的间隔体或可释放的连接体、或细胞毒性剂、和/或结合分子(CBA)的连接点;X1、Y1、Z2和Z3独立地为NH、O或S;Z1为H、NHR1、OR1、SR1、COX1R1,其中X1和R1如前文所定义;v为0或1;U1为H、OH、C1-C6烷基、(OCH2CH2)n、F、Cl、Br、I、OR5、SR5、NR5R5’、N=NR5、N=R5、NO2、SOR5R5’、SO2R5、SO3R5、OSO3R5、PR5R5’、POR5R5’、PO2R5R5’、OPO(OR5)(OR5’)或OCH2PO(OR5(OR5’),其中R5和R5'独立地选自H、C1-C8烷基;C2-C8烯基、炔基、杂烷基或氨基酸;C3-C8芳基、杂环、碳环、环烷基、杂环烷基、杂芳烷基、烷基羰基或糖苷;或药学上的阳离子盐。
非自我毁灭的组分选自以下结构:
其中,*标记的是额外的间隔体或可释放的连接体、或细胞毒性剂、和/或结合分子的连接点;X1、Y1、U1、R5、R5’如前文所定义;r为0-100;m和n独立地为0-6;或者,L1,L2,X1,X2,X3,X1’,X2’和X3’独立地可以缺省。
2.结构如式(III),(IV),(V),(VI),(VII),(VIII)或(IX)的细胞结合剂-药物偶联物:
其中:
n是1~20;T与结构式(I)中描述的相同。
Cb,Cb’,Cb”,Cb”’代表相同或不同的细胞结合剂/分子或免疫治疗蛋白,优选抗体或抗体片段。
Drug,Drug’,和Drug”表示相同或不同的细胞毒性剂,或治疗药物,或免疫治疗蛋白质,或用于增强细胞结合剂的结合或稳定的功能分子,或者细胞表面受体结合配体,其应用本专利申请的桥接剂,经由R1与细胞结合剂连接,R1含有C1-C8烷基;C2-C8亚烷基,亚烯基,亚炔基,芳基,醚,聚氧亚烷基,酯,胺,亚胺,多胺,肼,腙,酰胺,脲,氨基脲,卡巴肼,烷氧基胺,氨基甲酸,氨基酸,肽,酰氧基胺,异羟肟酸,二硫化物,硫醚,硫酯,氨基甲酸酯,碳酸酯,杂环,杂烷基,杂芳基,烷氧基或上述基团组合。表示单键或双键。
m1,m1’,m1”,m2,m2’,m2”,m3,m4,m5,m4’,m5’,m4”,m5”,m4”’,m5”’,m4””和m5””独立地是1到10的整数。
X1,X1’,X1”,X1”’和X2””独立地选自NH;NHNH;N(R3);N(R3)N(R3’);O;S;C1-C6烷基;C2-C6杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或1~8个氨基酸;其中R3和R3’独立地为H;C1-C8烷基;C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基、杂芳基;1-8个碳原子的酯、醚或酰胺;或如式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p为从0到1000的整数;或以上的组合。此外,X1,X1’,X1”,X1”’和X2””可以独立地缺省。
R1,R1’,和R1”相同或不同,选自C1-C8烷基;C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基、杂芳基;2-8个碳原子的酯、醚或酰胺;或如式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p为从0到1000的整数;或以上的组合。
L1,L1’,L1”,L1”’,L2,L2’,L2”和L2”’相同或不同,其定义与权利要求1中的L1和L2相同。L1,L1’,L1”,L1”’,L2,L2’,L2”和L2”’可以由一个或者多个连接体单元组成。连接体单元选自6-马来酰亚胺基己酰基(“MC”),马来酰亚胺丙酰基(“MP”),缬氨酸-瓜氨酸(“val-cit”或“vc”),丙氨酸-苯丙氨酸(“ala-phe”或“af”),对氨基苄氧基酰基(“PAB”),4-硫代戊酰基(“SPP”),4-(N-马来酰亚胺甲基)环己烷-1酰基(“MCC”),(4-乙酰基)氨基-苯酰基(“SIAB”),4-硫代丁酰基(“SPDB”),4-硫代-2-羟基磺酰基-丁酰基(“2-磺基-SPDB”),作为一个或多个重复乙烯氧基-CH2C水-单元(“EO”或“PEO”)。
3.结构如式(X),(XI),(XII),(XIII),(XIV),(XV)或(XVI)的化合物:
其中R1,R1’,R1”,R2,X1,X1’,X1”,L1,L1’,L1”,L2,L2’,L2”,Cb,m1,m1’,m1”,m2,m2’,m2”,m3,m4,m5,m4’,m5’,m4”和m5”的定义与权利要求2中相同。
其中Y,Y’,和Y”的定义与权利要求1中的Y相同。
Y,Y’和Y”独立地是二硫化物,马来酰亚胺基,卤代乙酰基,烷氧基胺,叠氮基,酮,醛,肼,炔烃,N-羟基琥珀酰亚胺酯,或苯酚,二硝基苯酚,五氟苯酚,四氟苯酚,二氟苯酚,单氟苯酚,五氯苯酚,咪唑,氯酚,四氯苯酚,1-羟基苯并三唑形成的羧基酯;甲苯磺酸酯;甲磺酸酯;三氟甲磺酸酯;2-乙基-5-苯基异恶唑-3'-磺酸酯。Y,Y'和Y”可以独立地与细胞毒性剂反应,形成二硫化物,硫醚,腙,酰胺,烷氧基,氨基甲酸酯,酯,醚键或杂芳环。
5.权利要求2中所述的结构式为(III),(IV),(V)或(VI)的偶联物,是由权利要求4中的结构式为(XVII)或(XVIII)的化合物在波长为190-390nm的UV光的
辅助下与细胞结合分子中的一对巯基缩合而制备。
6.权利要求3所述的结构式为(X),(XI),(XII)或(XIII)的偶联物,是由权利要求1中的结构式为(I)或(II)的化合物在波长为190-390nm的UV光的辅助下与细胞结合分子中一对巯基缩合而制备。
7.权利要求2或权利要求3所述的化合物,与连接体连接的细胞结合剂/分子的一对巯基
是细胞结合剂的链间二硫键被还原所得,还原剂选自二硫苏糖醇(DTT),二硫赤藓糖
醇(DTE),二硫代丁胺(DTBA),L-谷胱甘肽(GSH),三(2-羧乙基)膦(TCE
P),2-巯基乙胺(β-MEA)或/和β-巯基乙醇(β-ME,2-ME)。
8.权利要求2或4的偶合物中的Drug,Drug’和Drug”独立地选自:
1)化疗剂:
a)烷基化剂,选自氮芥:氯苯那普,氯普那嗪,环磷酰胺,达卡巴嗪,雌二醇氮芥,异环磷酰胺,氮芥,盐酸二甲氧胺,氧化二氮芥,盐酸氨氯地平,麦考酚酸,卫矛醇,哌泊溴烷,新氮芥,苯芥胆甾醇,松龙苯芥,噻替哌,曲磷胺对,尿嘧啶;CC-1065
(包括其阿多来新,卡折来新和比折来新合成类似物);多卡霉素(包括合成类似物K
W-2189和CBI-TMI);苯并二氮卓二聚体(例如吡咯并苯二氮卓(PBD)或托美霉素,吲哚并苯并二氮卓,咪唑并苯并噻二氮卓或恶唑烷并苯并二氮卓的二聚体);亚硝基脲
(卡莫司汀,洛莫司汀,氯化梭菌素,福莫司汀,尼莫司汀,拉莫司汀);烷基磺酸盐
(白消安,硫丹,硫丹和硫磺);三氮烯(达卡巴嗪);含铂化合物(卡铂,顺铂,奥沙利铂);吖丙啶类,如苯并二氢吡喃酮,卡洛酮,美妥替派和乌雷多巴;乙烯亚胺和甲基三聚氰胺,包括六甲蜜胺,三亚乙基三胺,三乙基磷酰胺,三亚乙基硫代磷酰胺和三羟甲基甲基胺;
b)植物生物碱:选自长春花生物碱(长春新碱,长春碱,长春地辛,长春瑞滨,去甲长春碱);类紫杉醇(紫杉醇,多西紫杉醇)及其类似物;美登素(DM1,DM2,DM3,DM4,美登素和安沙霉素)及其类似物;cryptophycin(特别是cryptophycin 1和cr yptophycin 8);埃博霉素,软珊瑚醇,迪莫利德,草苔虫内酯,海兔毒素,澳瑞他汀,tubulysin,cephalostatin,pancratistatin,sarcodictyin,海绵抑制素;
c)DNA拓扑异构酶抑制剂,选自依托泊苷替尼(9-氨基喜树碱,喜树碱,克立那托,道诺霉素,依托泊苷,磷酸依托泊苷,伊立替康,米托蒽醌,诺消灵,视黄酸(视黄醇),替尼泊苷,拓扑替康,9-硝基喜树碱(RFS 2000));丝裂霉素(丝裂霉素C);
d)抗代谢物,选自抗叶酸剂,DHFR抑制剂(甲氨蝶呤,曲麦克特,二甲叶酸,蝶罗呤,氨喋呤(4-氨基苯甲酸)或其他叶酸类似物);IMP脱氢酶抑制剂(麦考酚酸,噻唑呋林,利巴韦林,EICAR);核糖核苷酸还原酶抑制剂(羟基脲,去铁胺);嘧啶类似物,尿嘧啶类似物(安西他滨,阿扎胞苷,6-氮尿嘧啶,卡培他滨(希罗达),卡莫氟,阿糖胞苷,双脱氧尿苷,去氧氟尿苷,依诺他滨,5-氟尿嘧啶,氟尿苷,ratitrexe d(Tomudex);胞嘧啶类似物(阿糖胞苷,胞嘧啶阿拉伯糖苷,氟达拉滨);嘌呤类似物(硫唑嘌呤,氟达拉滨,巯嘌呤,硫胺素,硫鸟嘌呤);叶酸补充剂,如弗洛林酸;
e)激素疗法剂,选自受体拮抗剂,抗雌激素(甲地孕酮,雷洛昔芬,他莫昔芬),LHRH兴奋剂(戈斯他林,醋酸亮丙瑞林);抗雄激素药(比卡鲁胺,氟他胺,卡鲁司酮,丙酸倍他雄酮,表雄甾醇,戈舍瑞林,亮丙瑞林,美替利定,尼鲁米特,睾内酯,曲洛司坦及其他雄激素抑制剂);维甲类化合物,维生素D3类似物(CB1093,EB1089KH1060,胆钙化醇,麦角钙化甾醇);光动力疗法剂(维替泊芬,酞菁,光敏剂Pc4,去甲氧基-竹红菌素A);细胞因子(干扰素-α,干扰素-γ,肿瘤坏死因子(TNF),含TNF的人蛋白);
f)激酶抑制剂,选自BIBW 2992(抗-EGFR/Erb2),伊马替尼,吉非替尼,哌加他尼,索拉非尼,达沙替尼,舒尼替尼,厄洛替尼,尼洛替尼,拉帕替尼,阿西替尼,帕唑帕尼,凡德他尼,E7080(抗VEGFR2),mubritinib,普纳替尼(AP24534),bafeti nib(INNO-406),bosutinib(SKI-606),卡博替尼,维莫德吉,iniparib,鲁索利替尼,CYT387,阿西替尼,tivozanib,索拉非尼,贝伐单抗,西妥昔单抗,曲妥珠单抗,雷珠单抗,帕尼单抗,伊斯平斯;
g)聚(ADP核糖)聚合酶(PARP)抑制剂,如奥拉帕里、尼拉帕里、尼帕里、他拉唑帕里、维利帕里、维利帕里、CEP 9722(Cephalon)、E7016(Eisai)、BGB-290(BeiGene)、3-氨基苯甲酰胺;
h)抗生素,选自烯二炔类抗生素(选自加利车霉素,加利车霉素γ1,δ1,α1和β1,达因霉素,包括达因霉素A和脱氧米霉素,埃斯培拉霉素,卡达霉素,C-1027,maduro peptin以及新制癌菌素发色团和相关色蛋白烯二炔抗生素发色团),aclacinomysins,放线菌素,安曲霉素,重氮丝氨酸,博来霉素,卡诺霉素,卡拉霉素,洋红霉素,嗜癌素,阿霉素,阿霉素,吗啉代阿霉素,2-吡咯啉阿霉素和脱氧柔红霉素,表柔比星,阿柔比星,伊达比星,马可霉素,霉素,霉酚酸,洛匹霉素,培洛霉素,培洛霉素,嘌呤霉素,三铁阿霉素,阿霉素,链脲霉素,链脲佐菌素,杀结核菌素,乌苯美司,净司他丁,佐柔比星;
i)聚酮化合物(番荔素),bullatacin和bullatacinone,吉西他滨,环氧酶素(如卡菲偌米布),硼替佐米,沙利度胺,来那度胺,pomalidomide,tosedostat,zybrestat,PLX4032,STA-9090,Stimuvax,allovectin-7,Xegeva,Provenge,Yervoy,异戊二烯化抑制剂(如洛伐他汀),多巴胺能神经毒素(如星形孢菌素),放线菌素(如放线菌素D,更生霉素),博莱霉素(如博来霉素A2,博莱霉素B2,培洛霉素),蒽环类抗生素(如柔红霉素),阿霉素(亚德里亚霉素),伊达比星,表柔比星,吡柔比星,佐柔比星,米托蒽醌,MDR抑制剂(如维拉帕米),Ca2+ATP酶抑制剂(如毒胡萝卜素),组蛋白去乙酰酶抑制剂(伏立诺他,罗米地辛,帕比司他,丙戊酸,Mocetinostat(MG CD0103),Belinostat,PCI-24781,恩替诺特,SB939,Resminostat,Givinostat,AR-42,CUDC-101,萝卜硫素,曲古抑菌素A);塞来昔布,格列酮类,表没食子儿茶素没食子酸酯,双硫仑,Salinosporamide A;抗肾上腺药物,如氨鲁米特,米托坦,曲洛司坦,醋葡醛内酯,醛磷酰胺,氨基乙酰丙酸,安吖啶,阿拉伯糖苷,bestrabucil,比生群,edatraxate,defofamine,美可辛,地吖醌,依氟鸟氨酸(DFMO),elfomithine,依利醋铵,乙基葡糖酸,硝酸镓,胞嘧啶,羟基脲,伊班膦酸盐,香菇多糖,氯尼达明,米托胍腙,米托蒽醌,莫哌达醇,二胺硝吖啶,喷司他丁,蛋氨氮芥,吡柔比星,鬼臼酸,2-乙肼,甲基苄肼,哌嗪二酮丙烷,根霉素,西佐,螺环锗,细格孢氮杂酸,三亚胺醌,三氯三乙胺,单端孢霉烯(特别是T-2毒素,疣孢菌素A,杆孢菌素A和anguidine),聚氨酯,siRNA,反义药物。
2)自身免疫疾病药物:环孢菌素,环孢菌素A,氨基己酸,硫唑嘌呤,溴隐亭,苯丁酸氮芥,氯喹,环磷酰胺,皮质类固醇(例如安西奈德,地塞米松,曲安奈德,丙酸倍氯米松,DHEA,依那西普,羟基氯喹,英夫利昔单抗,美洛昔康,甲氨蝶呤,麦考酚酸酯,泼尼松,西罗莫司,他克莫司。
3)抗感染性疾病药物:
a)氨基糖苷类:阿米卡星,阿司米星,庆大霉素(奈替米星,西索米星,异帕米星),潮霉素B,卡那霉素(阿米卡星,阿贝卡星,氨基去氧卡那霉素,地贝卡星,妥布霉素),新霉素(framycetin,巴龙霉素,核糖霉素),奈替米星,壮观霉素,链霉素,妥布霉素,甲基姿苏霉素;
b)酰胺醇类:叠氮氯霉素,氯霉素,氟苯尼考,甲砜霉素;
c)安沙霉素:格尔德霉素,除莠霉素;
d)碳青霉烯类:比阿培南,多利培南,厄他培南,亚胺培南/西司他丁,美罗培南,帕尼培南;
e)头孢烯:碳头孢烯(洛拉卡比),头孢乙腈,氯氨苄青霉素,头孢拉定,头孢羟氨,头孢洛宁,头孢噻啶,头孢噻吩或头孢金素,头孢氨苄,头孢来星,头孢孟多,头孢匹林,羟胺唑头孢菌素,氟唑头孢菌素,孢西酮,唑啉头孢菌素,头孢拉宗,头孢卡品,头孢达肟,头孢吡,头孢克肟,头孢西丁,头孢罗齐,头孢甲氧环烯胺,头孢替唑,头孢呋辛,头孢克肟,头孢地尼,头孢托仑,头孢吡,头孢他美,头孢甲肟,头孢地嗪,头孢尼西,头孢哌酮,头孢雷特,头孢噻肟,噻乙胺唑头孢菌素,头孢唑兰,头孢氨苄,头孢咪唑,头孢匹胺,头孢匹罗,头孢泊肟,头孢罗齐,头孢喹诺,头孢磺啶,头孢他啶,头孢特仑,头孢布腾,头孢噻林,头孢唑肟,头孢吡普,头孢曲松,头孢呋辛,头孢唑南,头霉素(头孢西丁,头孢替坦,头孢氰唑),氧(碳)头孢烯(氟氧头孢,头孢);
f)糖肽:博来霉素,万古霉素(奥利万星,特拉万星),替考拉宁(达巴万星),雷莫拉宁;
g)甘氨酰环素:如替加环素;
h)β-内酰胺酶抑制剂:青霉烷(舒巴坦,他唑巴坦),氧青霉烷(克拉维酸);
i)林可酰胺:克林霉素,林可霉素;
j)脂肽:达托霉素,A54145,钙依赖性抗生素(CDA);
k)大环内酯类:阿奇霉素,克霉素,克拉霉素,地红霉素,红霉素,氟雷霉素,交沙霉素,酮内酯(泰利霉素,塞红霉素),麦迪霉素,米卡霉素,竹桃霉素,利福霉素(异烟肼、利福平,利福布丁,利福喷汀),罗匹霉素,罗红霉素,大观霉素,螺旋霉素,他克莫司(FK506),醋竹桃霉素,泰利霉素;
l)单环胺:氨曲南,替吉莫南;
m)恶唑烷酮类:利奈唑胺;
n)青霉素类:阿莫西林,氨苄青霉素(匹氨西林,海洛西林,巴氨西林,氨苄青霉素,阿霉素),阿替代西林,阿洛西林,苄青霉素,苄星青霉素苄青霉素,苄星青霉素苯氧甲基青霉素,克洛西林,普鲁卡因青霉素(美替西林),美洛西林,甲氧西林,萘夫西林,苯唑西林,醋甲西林,青霉素,非奈西林,苯氧基甲基青霉素,哌拉西林,氨苄西林,磺苯西林,替莫西林,替卡西林;
o)多肽:杆菌肽,粘菌素,多粘菌素B;
p)喹诺酮类:阿拉曲沙星,巴洛沙星,环丙沙星,克林沙,达氟沙星,二氟沙星,依诺沙星,恩诺沙星,加雷沙星,加替沙星,吉米沙星,格帕沙星,卡诺曲伐沙星,左氧氟沙星,洛美沙星,麻保沙星,莫西沙星,那氟沙星,诺氟沙星,奥比沙星,氧氟沙星,培氟沙星,曲伐沙星,格帕沙星,西他沙星,司帕沙星,替马沙星,托沙星,曲伐沙星;
q)链阳性菌素:普那霉素,奎奴普丁/达福普汀;
r)磺胺类药物:磺胺类药物:磺胺类药物,磺胺嘧啶,磺胺嘧啶,磺胺嘧啶,柳氮磺胺吡啶,磺胺异恶唑,三苯氧胺,甲氧苄氨嘧啶-磺胺甲恶唑(复方新诺明);
s)类固醇抗菌药物:如夫西地酸;
t)四环素类:强力霉素,金霉素,氯米西环素,地美环素,雷莫昔林,美西环素,美他环素,米诺环素,土霉素,青霉素V钾哌四环素,吡咯烷甲基四环素,四环素,甘氨酰环素(如替加环素);
u)其他类型的抗生素:番荔枝素,胂凡纳明,细菌萜醇抑制剂(杆菌),DANAL/AR抑制剂(环丝氨酸),dictyostatin,圆皮海绵内酯,软珊瑚醇,埃博霉素,乙胺丁醇,依托泊苷,法罗培南,夫西地酸,呋喃唑酮,异烟肼,laulimalide,甲硝唑,莫匹罗星,NAM合成抑制剂(例如磷霉素),呋喃妥因,紫杉醇,普兰西霉素,吡嗪酰胺,奎奴普丁/达福普汀,利福平(利福平),他唑巴坦替硝唑,乌菊花素。
4)抗病毒药物:
a)进入/融合抑制剂:阿帕韦洛,马拉韦罗,vicriviroc,gp41(恩夫韦肽),PRO 140,CD4(艾巴利珠单抗);
b)整合酶抑制剂:雷特格韦,elvitegravir,globoidnan A;
c)成熟抑制剂:bevirimat,vivecon;
d)神经氨酸酶抑制剂:奥司他韦,扎那米韦,帕拉米韦;
e)核苷和核苷酸:阿巴卡韦,阿昔单韦,阿德福韦,阿莫西韦,阿昔单抗,溴夫定,西多福韦,克拉夫定,地塞米松,去羟肌苷(ddI),elvucitabine,恩曲他滨(FTC),恩替卡韦,泛昔洛韦,氟拉西林(5-FU),3’-氟取代的2’,3’-脱氧核苷类似物(如3,3’-氟-2′,3′-双脱氧胸苷(FLT)和3’-氟-2’,3’-双脱氧鸟苷(FLG),福米韦生,9-鸟嘌呤,碘苷,拉米夫定(3TC),1-核苷(例如β-1-胸苷和β-1-2'-脱氧胞苷),喷昔洛韦,racivir,利巴韦林,迪替丁,司他夫定(d4T),塔利巴韦林(viramidine),替比夫定,替诺福韦,三氟尿苷伐昔洛韦,缬更昔洛韦,扎西他滨(ddC),齐多夫定(AZT);
f)非核苷类:金刚烷胺,阿替吡啶,卡普韦林,二芳基嘧啶(依曲韦林,rilpivirine),地拉夫定,二十二烷醇,乙米韦林,依法韦仑,膦甲酸(磷酰基甲酸),咪喹莫特,聚乙二醇干扰素,洛韦胺,洛德腺苷,甲吲噻腙,奈韦拉平,NOV-205,长效干扰素α,鬼臼毒素,利福平,金刚乙胺,瑞喹莫德(R-848),醋胺金刚烷;
g)蛋白酶抑制剂:安普那韦阿扎那韦,boceprevir,darunavir,福沙那韦,印地那韦,洛匹那韦,奈非那韦,普来可那立,利托那韦,沙奎那韦,telaprevir(VX-950),替拉那韦;
h)其它类型的抗病毒药物:抗氧化酶,阿比朵尔,卡拉诺莱德,ceragenin,氰维林-n,二芳基嘧啶,表没食子儿茶素没食子酸酯(EGCG),膦甲酸,格里菲辛,taribavirin(viramidine),羟基脲,KP-1461,米替福新,普来可那立,混成抑制剂,利巴韦林,seliciclib。
5)放射性同位素,选自3H,11C,14C,18F,32P,35S,64Cu,68Ga,86Y,99Tc,111In,123I,124I,125I,131I,133Xe,177Lu,211At或213Bi。
6)发色分子,发色分子可以吸收一种光,如紫外光,荧光,红外光,近红外光或可见光;发色分子包括黄色素,红细胞,虹彩色素,白细胞,黑色素和蓝绿色素的一类或一个亚类,荧光分子(吸收光后再发光的荧光化学物质)的一类或一个亚类,视觉光转导分子的一类或一个亚类,光子分子的一类或一个亚类,冷光分子的一类或一个亚类和荧光素化合物的一类或一个亚类。非蛋白质有机荧光团选自:氧杂蒽衍生物(荧光素,罗丹明,俄勒冈绿,伊红和德克萨斯红);花青衍生物(花青,吲哚羰花青,氧杂花青,硫代花青和部花青);方酸衍生物和环取代的方酸,包括Seta,SeTau和Square染料;萘衍生物(丹酰和氟硅酸钠衍生物);香豆素衍生物;恶二唑衍生物(吡啶基恶唑,硝基苯并恶唑和苯并恶二唑);蒽衍生物(蒽醌类,包括DRAQ5,DRAQ7和CyTRAK橙);芘衍生物(级联蓝等);恶嗪衍生物(尼罗红,尼罗蓝,甲酚紫,恶嗪170等);吖啶衍生物(黄醇黄素,吖啶橙,吖啶黄等);芳基甲胺衍生物(金胺,结晶紫,孔雀石绿)和四吡咯衍生物(卟吩,酞菁,胆红素)。
以下荧光化合物的任何类似物和衍生物:CF染料(Biotium),DRAQ和CyTRAK探针(BioS-tatus),BODIPY(Invitrogen),Alexa Fluor(Invitrogen),DyLight Fluor(ThermoScientific,Pierce),Atto和Tracy(Sigma Aldrich),FluoProbes(Interchi m),Abberior染料(Abberior),DY和MegaStokes染料(Dyomics),Sulfo Cy染料(Cyandye),HiLyte Fluor(AnaSpec),Seta,SeTau和Square染料(Biosearch Techno logies),SureLight染料(APC,RPEPerCP,Phycobilisomes)(Columbia Biosciences),APC,APCXL,RPE,BPE(Phyco-Biotech),别藻蓝蛋白(APC),氨基胭脂蛋白,APC-Cy7偶联物,BODIPY-FL,Cascade Blue,Cy2,Cy3,Cy3.5,Cy3B,Cy5,Cy5.5,Cy7,荧光素,FluorX,羟基香豆素,丽丝胺罗丹明B,萤光黄,Me-甲氧基香豆素,NBD,Pacific Blue,Pacific Orange,PE-Cy5偶联物,PE-R-藻红蛋白(PE),Red 613,Seta-555-Azide,Seta-555-DBCO,Seta-555-NHS,Seta-580-NHS,Seta-680-NHS,Seta-AP C-780,Seta-PerCP-680,Seta-R-PE-670,SeTau-380-NHS,SeTau-405-马来酰亚胺,SeT au-405-NHS,SeTau-425-NHS,SeTau-647-NHS,Texas Red,TRITC,TruRed,X-Rhodamine,7-AAD(7-氨基放线菌素D,CG-选择性的),吖啶橙,色霉素A3,CyTRAK橙(Biostatus),DAPI,DRAQ5,DRAQ7,溴化乙锭,Hoechst33258,Hoechst33342,LDS 751,光辉霉素,碘化丙啶(PI),SYTOX蓝,SYTOX绿,SYTOX橙,噻唑橙,TO-PRO,菁染料单体,TOTO-1,TO-PRO-1,TOTO-3,TO-PRO-3,YOSeta-1,YOY O-1。可以与本发明的连接体相连,用于研究细胞的荧光化合物,选自下列化合物或其衍生物:DCFH(2',7'-二氯二氢荧光素,氧化形式),DHR(二氢罗丹明123,氧化形式,光催化氧化),Fluo-3(AM酯,pH>6),Fluo-4(AM酯,pH7.2),Indo-1(AM酯,低/高钙(Ca 2+)),SNARF(pH 6/9),别藻蓝蛋白(APC),AmCyan1(四聚体,Clontech),AsRed2(四聚体,Clontech),蓟绿(单体,MBL),Azurite,B-藻红蛋白(BPE),Cerulean,CyPet,DsRed单体(Clontech),DsRed2(RFP,Clontech),EBFP,EBFP2,ECFP,EGFP(弱二聚体,Clontech),Emerald(弱二聚体,Invitrogen),EYFP(弱二聚体,Clontech),GFP(S65A突变),GFP(S65C突变),GFP(S65L突变)GFP(Y66H突变),GFP(Y66W突变),GFPuv,HcRed1,J-Red,Katusha,Kusabira Orange(单聚体,MBL),mCFP,mCherry(单体,MBL),mKate(TagFP635,单体,Evrogen),mKeima-Red(单体,MBL),mKO,mOrange,mPlum,mRaspberry,mRFP1(单体,Tsien实验室),mStrawberry,mTFP1,mTurquoise2,P3(藻胆体复合物),多甲藻黄素-叶绿素-蛋白质复合物(PerCP),R-phycoerythrin(RPE),T-Sapphire,TagCFP(二聚体,Evrogen),TagGFP(二聚体,Evrogen),TagRFP(二聚体,Evrogen),TagYFP(二聚体,Evrogen),tdTomato(串联二聚体),Topaz,TurboFP602(二聚体,Evrogen),TurboFPP635(二聚体,Evrogen),TurboGFP(二聚体,Evrogen),TurboRFP(二聚体,Evrogen),TurboYFP(二聚体,Evrogen),Venus,野生型GFP型,YPet,ZsGreen1(四聚体,Clontech),ZsYellow1(四聚体,Clontech)。
7)细胞偶合配体或受体激动剂,可选自:叶酸衍生物;谷氨酸脲衍生物;生长抑素及其类似物(选自奥曲肽(Sandostatin)和兰瑞肽(Somatuline));芳香磺酰胺;垂体腺苷酸环化酶激活肽(PACAP)(PAC1);血管活性肠肽(VIP/PACAP)(VPAC1,VPAC2);黑素细胞刺激素(α-MSH);胆囊收缩素(CCK)/胃泌素受体激动剂;Bombesins(Gly-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2等)/胃泌素释放肽(GRP);神经降压素受体配体(NTR1,NTR2,NTR3);物质P(NK1受体)配体;神经肽Y(Y1-Y6);归巢肽包括RGD(Arg-Gly-Asp),NGR(Asn-Gly-Arg),二聚体和多聚体环状RGD肽(cRGDfV等),TAASGVRSMH和LTLRWVGLMS(硫酸软骨素蛋白多糖NG2受体的配体)和F3肽;细胞穿透肽(CPPs);肽激素,如促黄体激素释放激素(LHRH)激动剂和拮抗剂,和促性腺激素释放激素(GnRH)激动剂,通过靶向卵泡刺激素(FSH)和黄体生成素(LH)以及睾酮生成起作用,选自布舍瑞林(Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-NHEt),戈那瑞林(Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2),戈舍瑞林(Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-AzGly-NH2),组氨瑞林(Pyr-His-Trp-Ser-Tyr-D-His(N-benzyl)-Leu-Arg-Pro-NHEt),醋酸亮丙瑞林(Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt),那法瑞林(Pyr-His-Trp-Ser-Tyr-2Nal-Leu-Arg-Pro-Gly-NH2),曲普瑞林(Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2),那法瑞林,德舍瑞林,阿巴瑞克(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-isopropylLys-Pro-DAla-NH2),西曲瑞克(Ac-D-2Nal-D-4-chloro-Phe-D-3-(3-pyridyl)Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2),加瑞克(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-4-aminoPhe(L-hydroorotyl)-D-4-aminoPhe(carba-moyl)-Leu-isopropylLys-Pro-D-Ala-NH2)和加尼瑞克(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-Tyr-D-(N9,N10-diethyl)-homoArg-Leu-(N9,N10-diethyl)-homoArg-Pro-D-Ala-NH2);模式识别受体(PRR),选自Toll样受体(TLR)配体,C型凝集素和Nodlike受体(NLRs)配体;降钙素受体激动剂;整合素受体及其受体亚型(选自αVβ1,αVβ3,αVβ5,αVβ6,α6β4,α7β1,αLβ2,αIIbβ3)激动剂,选自GRGDSPK,环(RGDfV)(L1)和它的衍生物(环(-N(Me)R-GDfV),环(R-Sar-DfV),环(RG-N(Me)D-fV),环(RGD-N(Me)fV),环(RGDf-N(Me)V-)(西仑吉肽);纳米抗体(VHH衍生物(骆驼科动物Ig));结构域抗体(dAb,VH或VL结构域的衍生物);双特异性T细胞接头(BiTE,双特异性双抗体);双重亲和力重定向剂(DART,双特异性双抗体);四价串联抗体(TandAb,二聚双特异性双抗体);Anticalin(Lipocalins的衍生物);Adnectin(10th FN3(Fibronectin));设计的锚蛋白重复蛋白(DARPins);Avimers;EGF受体和VEGF受体激动剂。
8)任何上述药物的药学上可接受的盐,酸或衍生物。
9.根据权利要求2所述的偶合物,其特征在于所述的Drug,Drug’,或Drug”是发色分子且偶合物可用于检测,监测或研究细胞偶合的相互作用和/或功能,和/或偶合物与靶细胞的相互作用。
10.根据权利要求2所述的偶合物,其特征在于所述Drug,Drug’,或Drug”中的一种,两种或全部独立地是聚(乙二醇)(PEG),聚(丙二醇),环氧乙烷或环氧丙烷的共聚物,或它们类似物的分子量为44Daltons至300kDa,并且当向哺乳动物给药时,这些聚合物用于延长细胞结合分子的半衰期。
11.根据权利要求2所述的偶合物,其特征在于所述Drug,Drug’,或Drug”中的一种,两种或全部独立地是细胞偶合配体或细胞受体激动剂,或细胞受体偶合分子,并且所述偶合物作为靶向导体/导向器将偶合物递送至恶性细胞,或调节或共酮刺激所需的免疫应答,或改变信号通路。
12.根据权利要求2或4的偶合物,其特征在于所述的Drug,Drug’,或Drug”选自微管蛋白抑制剂,加利车霉素,奥瑞他汀,美登素类,CC-1065类似物,柔红霉素和多柔比星化合物,taxanoids(紫杉烷类),隐藻菌素埃坡霉素,苯并二氮杂二聚体(包括吡咯并苯并二氮杂二聚体(PBD),托美霉素二聚体,蒽霉素二聚体,吲哚并苯并二氮杂二聚体,咪唑并苯并二氮杂二聚体,或恶唑烷基苯并二氮杂二聚体及其衍生物),加利霉素和烯二炔类抗生素,放线菌素,鹅膏毒肽,鹅膏蕈碱,重氮丝氨酸,博来霉素,表柔比星,他莫昔芬,伊达比星,多拉司他汀/澳瑞他汀衍生物(包括单甲基澳瑞他汀E,MMAE,MMAF,澳瑞他汀PYE,澳瑞他汀TP,澳瑞他汀2-AQ,6-AQ,EB(AE B),EFP(AEFP)及其类似物),多卡霉素,格尔德霉素,氨甲喋呤,塞替派,长春地辛,长春新碱,半米塔林,nazumamides,microginins,radiosumin,alterobactins,mi crosclerodermins,theonellamides,esperamicins,siRNA,miRNA,piRNA,溶核酶和/或其药学上可接受的盐,酸,和/或它们的任何上述分子的类似物衍生物。
13.根据权利要求2或3的偶合物,其特征在于所述细胞偶合剂/分子,Cb,Cb'或Cb”独立地选自抗体,蛋白质,维生素(选自叶酸),肽,聚合物胶束,脂质体,基于脂蛋白的药物载体,纳米颗粒药物载体,树枝状聚合物和上述用细胞偶合配体包覆的分子,或其上述组合。
14.根据权利要求2或3或13的偶联物,其中所述细胞偶合剂/分子,Cb,Cb'或Cb”独立地选自抗体,抗体样蛋白,全长抗体(多克隆抗体,单克隆抗体,抗体二聚体,抗体多聚体或多特异性抗体(选自双特异性或三特异性抗体));单链抗体,与靶细胞偶合的抗体片段,单克隆抗体,单链单克隆抗体,或与靶细胞偶合的单克隆抗体片段,嵌合抗体,与靶细胞偶合的嵌合抗体片段,结构域抗体,与靶细胞偶合的结构域抗体片段,复原面抗体,表面重构单链抗体,或与靶细胞偶合的表面重构抗体片段,人体抗体或表面重构抗体,人源化单链抗体,或与靶细胞偶合的人源化抗体片段,抗独特型(抗Id)抗体,CDR,双抗体,三抗体,四抗体,小抗体,前抗体(probody),小免疫蛋白(SI P),淋巴因子,激素,维生素,生长因子,集落刺激因子,营养转运分子,大分子量蛋白质,纳米粒子或用抗体或大分子量蛋白质修饰的聚合物。
15.根据权利要求2或3或13的偶合物,其特征在于细胞偶合剂/分子,Cb,Cb'或Cb”是分子或试剂其能够对抗肿瘤细胞,微生物感染细胞,寄生虫感染细胞,自身免疫疾病细胞,活化肿瘤细胞,骨髓细胞,活化T细胞,影响B细胞或黑素细胞,或表达一种或多种下列抗原的细胞或受体CD3,CD4,CD5,CD6,CD7,CD8,CD9,CD10,CD11a,CD11b,CD11c,CD12w,CD14,CD15,CD16,CDw17,CD18,CD19,CD20,CD21,CD22,CD23,CD24,CD25,CD26,CD27,CD28,CD29,CD30,CD31,CD32,CD33,CD34,CD35,CD36,CD37,CD38,CD39,CD40,CD41,CD42,CD43,CD44,CD45,CD46,CD47,CD48,CD49b,CD49c,CD51,CD52,CD53,CD54,CD55,CD56,CD58,CD59,CD61,CD62E,CD62L,CD62P,CD63,CD66,CD68,CD69,CD70,CD72,CD74,CD79,CD79a,CD79b,CD80,CD81,CD82,CD83,CD86,CD87,CD88,CD89,CD90,CD91,CD95,CD96,CD98,CD100,CD103,CD105,CD106,CD109,CD123,CD117,CD120,CD125,CD126,CD127,CD133,CD134,CD135,CD137,CD138,CD141,CD142,CD143,CD144,CD147,CD151,CD147,CD152,CD154,CD156,CD158,CD163,CD166,.CD168,CD174,CD180,CD184,CD w186,CD194,CD195,CD200,CD200a,CD200b,CD209,CD221,CD227,CD235a,CD240,CD262,CD271,CD274,CD276(B7-H3),CD303,CD304,CD309,CD326,4-1BB,5AC,5T4(Trophoblast糖蛋白,TPBG,5T4,Wnt-活化抑制因子1或WAIF1 1或WAIF1),腺癌抗原,AGS-5,AGS-22M6,激活素受体激酶1,AFP,AKAP-4,ALK,α整合素,α整合素,αvβ6,氨基肽酶N,淀粉样蛋白β,雄激素受体,促血管新生蛋白因子2,促血管新生蛋白因子3,膜联蛋白A1,炭疽毒素保护性抗原,抗转移蛋白受体,AOC3(VAP-1),B7-H3,炭疽杆菌,BAFF(B细胞活化因子),BCMA,B淋巴瘤细胞,蛙皮素,BORIS,C5,C242抗原,CA125(糖抗原125,MUC16),CA-IX(或CAIX,碳酸酐酶9),CALLA,CanAg,犬红斑狼疮IL31,碳酸酐酶IX,心肌肌凝蛋白,CCL11(C-C片段趋化因子11),CC R4(C-C趋化因子受体4,CD194),CCR5,CD3E(ε),CEA(癌胚抗原),CEA CAM3,CEACAM5(癌胚抗原),CFD(因子D),Ch4D5,胆囊收缩素2(CCK2R),CLDN18(Claudin-18),丛生因子A,CRIPTO,FCSF1R(集落刺激因子1受体,CD115),CSF2(集落刺激因子2,粒细胞-巨噬细胞集落刺激因子(GM-CSF)),CTLA4(细胞毒性T淋巴细胞相关蛋白4),CTAA16.88肿瘤抗原,CXCR4(CD184),C-X-C趋化因子受体4,环状ADP核糖核酸酶,细胞周期蛋白B1,CYP1B1,巨细胞病毒,巨细胞病毒糖蛋白B,Dabigatran,DLL4(类Δ配体4),DPP4(双肽-肽酶4),DR5(死亡受体5),大肠杆菌shiga毒素类型-1,大肠杆菌shiga毒素类型-2,ED-B,EGFL7(类EGF结构域蛋白7),EGFR,EGFRII,EGFRvIII,内皮因子(CD105),内皮素B受体,内毒素,EpCAM(上皮细胞粘附分子),EphA2,Episialin,ERBB2(表皮生长因子受体2),ERBB3,ERG(TMPRSS2 ETS融合基因),大肠杆菌,ETV6-AML,FAP(成纤维细胞活化蛋白α),FCGR1,甲胎蛋白,纤维蛋白IIβ链,纤连蛋白额外结构域-B,FOLR(叶酸受体),叶酸受体α,叶酸水解酶,Fos相关抗原1,呼吸道合胞病毒的F蛋白,卷曲的受体,岩藻糖GM1,GD2神经节苷脂,G-28(细胞表面抗原糖脂),GD3独特型,GloboH,Glypican 3,N-羟乙酰神经氨酸,GM3,GMCSF受体α链,生长分化因子8,GP100,GPNMB(跨膜糖蛋白NMB),GUCY2C(鸟苷酸环化酶2C),鸟苷酸环化酶C(GC-C),肠鸟苷酸环化酶,鸟苷酸环化酶C受体,热稳定肠毒素受体(hSTAR),热休克蛋白,血凝素,乙肝表面抗原,乙型肝炎病毒,HER1(人类表皮生长因子受体1),HER2,HER2/neu,HER3(ERBB-3),Ig G4,HGF/SF(肝细胞生长因子/分散因子),HHGFR,HIV-1,组蛋白复合物,HLA-DR(人类白细胞抗原),HLA-DR10,HLA-DRB,HMWMAA,人类绒毛膜促性腺激素,HNGF,人类分散因子受体激酶,HPV E6/E7,Hsp90,hTERT,ICAM-1(细胞间粘附分子1),独特型,IGF1R(IGF–1,类胰岛素生长因子1受体),IGHE,IFN-γ,流感血凝素,IgE,IgE Fc区,IGHE,IL–1,IL-2R(白介素2受体),IL–4,IL-5,IL–6,IL-6R(白介素6受体),IL-9,IL–10,IL–12,IL-13,IL-17,IL-17A,IL-20,IL-22,IL-23,IL31RA,ILGF2(类胰岛素生长因子2),整合蛋白(α4、αIIbβ3、αvβ3、α4β7、α5β1、α6β4、α7β7、αllβ3、α5β5、αvβ5),干扰素γ诱导蛋白质,ITGA2,ITG B2,KIR2D,LCK,Le,Legumain,Lewis-Y抗原,LFA-1(淋巴细胞功能相关抗原1,CD11a),LHRH,LINGO-1,脂磷壁酸,LIV1A,LMP2,LTA,MAD-CT-1,MAD-CT-2,MAGE-1,MAGE-2,MAGE-3,MAGE A1,MAGE A3,MAGE 4,MART1,MCP-1,MIF(巨噬细胞迁移抑制因子,或糖基抑制因子(GIF)),MS4A1(跨膜4结构域亚家族A成员1),MSLN(间皮素),MUC1(粘蛋白1,细胞表面相关(MU C1)或多态性上皮粘蛋白(PEM)),MUC1-KLH,MUC16(CA125),MCP1(单核细胞趋化蛋白1),MelanA/MART1,ML-IAP,MPG,MS4A1,MYCN,髓磷脂相关糖蛋白,Myostatin,NA17,NARP-1,NCA-90(粒细胞抗原),Nectin-4(ASG-22ME),NGF,神经细胞凋亡调控蛋白酶1,NOGO-A,Notch受体,核仁素,Neu致癌基因产物,NY-BR-1,NY-ESO-1,OX-40,OxLDL(氧化低密度脂蛋白),OY-TE S1,P21,p53非突变体,P97,PAP,抗(N-羟乙酰神经氨酸)抗体偶合部位,PAX3,PAX5,PCSK9,PDCD1(PD-1、程序性细胞死亡蛋白1,CD279),PDGF-Rα(α血小板源生长因子受体),PDGFR-β,PDL-1,PLAC1,类PLAP睾丸碱性磷酸酶,血小板衍生生长因子受体β,磷酸钠联合转运体,PMEL 17,聚唾液酸,蛋白酶3(PR1),前列腺癌,PS(磷脂酰丝氨酸),前列腺癌细胞,铜绿假单胞菌,PSMA,PSA,PSCA,狂犬病病毒糖蛋白,RHD(Rh多肽1(RhPI),CD240),Rhesus因子,RANKL,RhoC,Ras突变,RGS5,ROBO4,呼吸道合胞病毒,RON,肉瘤易位断点,SART3,Sclerostin,SLAMF7(SLAM成员7),Selectin P,SDC1(多配体蛋白聚糖1),系统性红斑狼疮(a),生长调节素C,SIP(1-磷酸鞘氨醇),生长激素抑制素,精子蛋白17,SSX2,STEAP1(6-跨膜上皮前列腺抗原1),STEAP2,STn,TAG-72(肿瘤相关糖蛋白),存活素,T细胞受体,T细胞跨膜蛋白。
16.根据权利要求13的肿瘤细胞,其特征在于所述的肿瘤细胞选自淋巴瘤细胞,骨髓瘤细胞,肾细胞,乳腺癌细胞,前列腺癌细胞,卵巢癌细胞,结肠直肠癌细胞,胃癌细胞,鳞状细胞癌,小细胞肺癌细胞,没有小细胞肺癌细胞,睾丸癌细胞,恶性细胞,或任何以不受管制,可以加快的速度生长和分裂以引起癌症的细胞。
17.根据权利要求1,2,3或4的化合物连接体,其特征在于连接体的组分L1,L1’,L1”,L1”’,L2,L2’,L2”和L2”’是独立选自由一种或多种,或重复或其组合组成的组,具有以下结构的组分:
对氨基苄氧羰基(PAB),4-硫代戊(SPP),/>4-硫代丁酸(SPDB),/>4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯(MCC),马来酰亚胺(ME),/>4-硫代-2-羟基磺酰基-丁酸(2-Sulfo-SPDB),/>芳基硫醇(PySS),/>(4-乙酰基)氨基苯甲酸酯(SIAB),/>氧苄硫基,/>氨基苄硫基,二氧苄硫基,/>二氨基苄硫基,氨氧基苄硫基,
烷氧基氨基(AOA),/>乙烯(EO),/>4-甲基-4-硫代-戊(MPDP),/>三唑,/>二硫代,/>烷基砜,烷基磺酰胺基,/>砜双酰胺,/>磷酸二酰胺,烷基磷酸酰胺,/>次膦酸,/>N-甲基膦酰胺酸,N,N'-二甲基膦-酰胺酸,/>N,N'-二甲基磷酰胺,肼,/>乙脒;/>肟,/>乙酰基乙酰肼,/>氨基乙基胺,/>氨基乙基-氨基乙基-胺,和L-或D-,含有1-20个氨基酸的天然或非天然肽,
18.根据权利要求1,2,3或4的所述的化合物的连接体,其特征在于连接体的组分,L1,L1’,L1”,L1”’,L2,L2’,L2”和L2”’是独立选择自由一种或多种,或重复或其组合组成的组,具有以下结构的组分:
-(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t-,-(CR5R6)m(CR7R8)n(Aa)r(OC H2CH2)t-,-(Aa)r-(CR5R6)m(CR7R8)n(OCH2CH2)t-,-(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t-,-(CR5R6)m-(CR7=CR8)(CR9R10)n(Aa)t(OCH2CH2)r
-,-(CR5R6)m(NR11CO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r-,-(CR5R6)m(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-,-(CR5R6)m(CO)(Aa)t-(CR9R10)n(OCH2CH2)r-,-(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-,-(CR5R6)m-(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-,-(CR5R6)m(CO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-(CR5R6)m-苯基-CO(Aa)t(CR7R8)n-,-(CR5R6)m-呋喃-CO(Aa)t(CR7R8)n-,-(CR5R6)m-恶唑-CO(Aa)t(CR7R8)n-,
-(CR5R6)m-噻唑基-CO(Aa)t(CCR7R8)n-,-(CR5R6)t-噻吩-CO(CR7R8)n-,-(CR5R6)t-咪唑-CO-(CR7R8)n-,-(CR5R6)t-吗啉-CO(Aa)t-(CR7R8)n-,-(CR5R6)t哌嗪-CO(Aa)t-(CR7R8)n-,-(CR5R6)t-N-甲基哌嗪-CO(Aa)t-(CR7R8)n-,
-(CR5R)m-(Aa)t苯基-,-(CR5R6)m-(Aa)t呋喃-,-(CR5R6)m-恶唑(Aa)t-,
-(CR5R6)m-噻唑(Aa)t-,-(CR5R6)m-噻吩-(Aa)t-,-(CR5R6)m-咪唑(Aa)t-,
-(C R5R6)m-吗啉-(Aa)t-,-(CR5R6)m-哌嗪-(Aa)t-,-(CR5R6)m-N-甲基哌嗪-(Aa)t-,
-K(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t-,-K(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t-,-K(Aa)r-(CR5R6)m(CR7R8)n(OCH2CH2)t-,-K(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t-,-K(CR5R6)m-(CR7=CR8)(CR9R10)n(Aa)t(OCH2CH2)r-,-K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m(CO)(Aa)t-(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m-(OCO)(Aa)t(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-,-K-(CR5R6)m(CO)(Aa)t(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m-苯基-CO(Aa)t(CR7R8)n-,-K-(CR5R6)m-呋喃-CO(Aa)t-(CR7R8)n-,-K(CR5R6)m-恶唑-CO(Aa)t(CR7R8)n-,-K(CR5R6)m-噻唑-CO(Aa)t-(CR7R8)n-,-K(CR5R6)t-噻吩-CO(CR7R8)n-,-K(CR5R6)t咪唑-CO-(CR7R8)n-,-K(CR5R6)t吗啉-CO(Aa)t(CR7R8)n-,-K(CR5R6)t哌嗪-CO(Aa)t-(CR7R8)n-,-K(CR5R6)t-N-甲基哌嗪CO(Aa)t(CR7R8)n-,-K(CR5R)m(Aa)t苯基,-K-(CR5R6)m-(Aa)t呋喃-,-K(CR5R6)m-(Aa)t-,-K(CR5R6)m-恶唑(Aa)t-,-K(CR5R6)m--噻唑-(Aa)t-,-K(CR5R6)m-咪唑(Aa)t-,-K(CR5R6)m-吗啉(Aa)t-,-K(CR5R6)m-哌嗪-(Aa)tG,-K(CR5R6)mN-甲基哌嗪(Aa)t-;其中m,Aa,m,和n如上所描述;t和r分别为0–100;R3,R4,R5,R6,R7,和R8分别选自H;卤化物;C1~C8烷基;C2~C8芳基,烯基,炔基,醚,酯,胺或酰胺,其任选被一个或多个卤化物取代,CN,NR1R2,CF3,OR1,Aryl,杂环,S(O)R1,SO2R1,-CO2H,-SO3H,-OR1,-CO2R1,-CONR1,-PO2R1R2,-PO3H或P(O)R1R2R3;K是NR1,-SS-,-C(=O)-,-C(=O)NH-,-C(=O)O-,-C=NH-O-,-C=N-NH-,-C(=O)NH-NH-,O,S,Se,B,Het(具有C3-C8的杂环或杂芳环),或含有1-20个氨基酸的肽。
20.根据权利要求2所述的偶合物,其特征在于Drug,Drug’,或Drug”是微管蛋白抑制剂类似物,式(II)的偶合物选自T01,T02,T03,T04,T05,T06,T07,T08,T09,T10,T11,T12,T13,T14,T15,T16,T17和T18的结构如下:
其中n,m1,m2,X1,X2,L1,L2,L3,R1,R2,R3,R4,and R5与权利要求1或权利要求2中的定义相同;mAb是抗体,或细胞连接分子;Z3是H,OP(O)(OM1)(OM2),OOCCH3,OCH2OP(O)(OM1)(OM2),OSO3M1,R1,或O-糖苷(葡萄糖苷,半乳糖苷,甘露糖苷,葡萄糖醛酸苷,异香糖苷,果糖苷,等),NH-糖苷,S-糖苷或CH2-糖苷;另外,两个Rs:R1R2,R2R3,R1R3或R3R4可以形成烷基,芳基,杂芳基,杂烷基或烷基环烷基的3~8元环状环;X3为H,CH3或X1'R1',其中X1'为NH,N(CH3),NHNH,O或S,R1'为H或C1-C8的直链或支链烷基,芳基,杂芳基,杂烷基,烷基环烷基,酰氧基胺;R3'是直链或支链烷基的H或C1-C6;p为0-2000;M1和M2独立地为H,Na,K,Ca,Mg,NH4,NR1R2R3;Drug1是另一种选自权利要求8的微管溶素类似物或细胞毒性剂。此外,R1'可以是权利要求8中定义的细胞毒性剂。
24.根据权利要求2所述的偶合物,其特征在于Drug,Drug’,或Drug”是CC-1065类似物和/或多卡米类似物,偶合物选自CC01,CC02和CC03的结构如下:
26.根据权利要求2所述的偶合物,其特征在于Drug,Drug’,或Drug”是一种奥瑞他汀或多拉司他汀类似物,该共轭化合物选自Au01,Au02,Au03,Au04,Au05,Au06,Au07,Au08,Au09,Au10,Au11,A12和Au13的结构如下:
其中n,m1,m2,X1,X2,R1,R2,R3,R4和R5与权利要求1或权利要求2中定义的相同;mAb是抗体或细胞结合分子;L1,L2,L3,L4,和L5在权利要求1中独立地定义为L1;Z3'为H,OP(O)(OM1)(OM2),OOCCH3,OCH2OP(O)(OM1)(OM2),OSO3M1,R1,或O-糖苷(包括葡萄糖苷,半乳糖苷,甘露糖苷,葡萄糖醛酸苷/葡萄糖苷),alloside,果糖苷等),NH-糖苷,S-糖苷或CH2-糖苷;另外,两个Rs:R1R2,R2R3,R1R3或R3R4可以形成烷基,芳基,杂芳基,杂烷基或烷基环烷基的3~8元环状环;X3为H,CH3或X1'R1',其中X1'为NH,N(CH3),NHNH,O或S,R1'为H或C1-C8的直链或支链烷基,芳基,杂芳基,杂烷基,烷基环烷基,酰氧基胺;R3'是直链或支链烷基的H或C1-C6;p为0-2000;M1和M2独立地为H,Na,K,Ca,Mg,NH4,NR1R2R3;另外,R1',Drug1和Drug2可以是权利要求8中定义的细胞毒性剂。
27.根据权利要求2所述的偶合物,其特征在于Drug,Drug’或Drug”,偶合物是苯并二氮杂类似物的二聚体,选自PB01,PB02,PB03,PB04,PB05,PB06,PB07,PB08,PB09,PB10和PB11的结构。
28.根据权利要求2所述的偶合物,其特征在于Drug,Drug’,或Drug”是鹅膏毒肽类似物,偶合物选自下面的Am01,Am02,Am03,Am04的结构:
30.根据权利要求2所述的偶联物,其特征在于Drug,Drug’,或Drug”是细胞偶合配体或细胞受体激动剂及其类似物,所述偶合物选自如下结构:LB01(叶酸偶合物偶合物),LB02(PMSA配体偶合物),LB03(PMSA配体偶合物),LB04(生长抑素偶合物),LB05(奥曲肽,生长抑素类似物偶合物),LB06(Lanreotide,生长抑素类似物偶合物),LB07(Vapreotide(Sanvar),Somatostatin类似物)偶合物),LB08(CAIX配体偶合物),LB09(CAIX配体偶合物),LB10(胃泌素释放肽受体(GRPr),MBA偶合物),LB11(促黄体激素释放激素(LH-RH)配体和GnRH偶合物),LB12(黄体生成激素释放激素(LH-RH)和GnRH配体偶合物),LB13(GnRH拮抗剂,Abarelix偶合物),LB14(钴胺素,维生素B12类似物偶合物),LB15(钴胺素,维生素B12类似物偶合物),LB16(用于αvβ3)整合素受体,环状RGD五肽偶联物),LB17(杂双用于VEGF受体的价格肽配体偶合物,LB18(神经介素B偶合物),LB19(用于G蛋白偶联受体的铃蟾肽偶合物),LB20(用于Toll样受体的TLR2偶合物),LB21(用于雄激素受体),LB22
(用于αv整合素受体的西仑吉肽/环(-RGDfV-)偶合物,LB23(氟氢可的松偶合物),LB24(地塞米松偶合物),LB25(丙酸氟替卡松偶合物),LB26(丙酸倍氯米松),LB27(曲安奈德偶合物),LB28(泼尼松偶联物),LB29(泼尼松龙偶联物),LB30(甲基强的松龙偶联物),LB31(伊伐替康类似物),LB33(克唑替尼类似物),LB34(硼替佐米类似物),LB35(卡非佐米类似物),LB36(卡非佐米)模拟),LB37(亮丙瑞林类似物),LB38(曲普瑞林类似物),LB39(利拉鲁肽类似物),LB40
(Semaglutide类似物)和LB41(利西拉来类似物),它们显示在以下结构中:
其中n,m1,m2,X1,X2,L1,L2,R1,R2,R3,和R4与权利要求1或权利要求2所定义的相同;其中mAb是抗体或细胞结合分子;L1,L2,L3,L4,和L5在权利要求1中独立地定义为L1;;X3是CH2,O,NH,NHC(O),NHC(O)NH,C(O),OC(O),OC(O)(NR3),R1,NHR1,NR1,C(O)R1或缺省;X4 isCH2,C(O),C(O)NH,C(O)N(R1),R1,NHR1,NR1,C(O)R1或C(O)O;M1和M2独立的选自H,Na,K,Ca,Mg,NH4,NR1R2R3;R1’和R3’独立的选自H或直链或支链烷基的C1-C6;p是0-2000.此外,R1’可以是权利要求8中定义的细胞毒性剂。此外,R1可以缺省且R2可以是H。
31.根据权利要求2所述的偶合物,其特征在于Drug,Drug’,或Drug”是DNA,RN A,mRNA,小干扰RNA(siRNA),微小RNA(miRNA)或PIWI相互作用RNA(pi RNA),所述偶联物选自以下SI-1,SI-2,SI-3,SI-4,SI-5或SI-6的结构。
32.根据权利要求2所述的偶合物,其特征在于权利要求6的两种或更多种不同的功能分子可以通过权利要求1的式(I)或(II)或权利要求4的式(XVII)或(XVIII)与细胞连接分子偶联。
33.根据权利要求32所述的偶合物,其特征在于可选自以下结构之一,Z01,Z02,Z02,Z04,Z05,Z06,Z07,Z08,Z09,Z10,Z12,Z13,Z14,Z15,Z16,Z17和Z18:
34.根据权利要求2,3,13,14,15,19,20,21,22,23,24,25,26,27,28,29,30,31,32或33的偶合物,其中特征在于细胞偶连接分子/试剂选自IgG抗体,单克隆抗体或IgG抗体样蛋白,偶合物含有权利要求8中的一种或两种或多种相同或不同功能的分子或的细胞毒性剂与一对硫醇通过还原轻链和重链之间的细胞结合分子/试剂的二硫键,两条重链之间的二硫键和两条重链之间的二硫键特异性偶联,如下面的结构ST1所示,ST2,ST3,ST4,ST5,ST6,ST7,ST8,ST9,ST10,ST11,ST12,ST13或ST14。
35.根据权利要求34的偶合物,其特征在于细胞毒剂选自微管溶素,美登木素生物碱,紫杉烷类(taxanes),CC-1065类似物,柔红霉素和多柔比星化合物,苯并二氮杂二聚体(选自吡咯并苯并二氮杂卓(PBD)的二聚体,托美霉素,氨茴霉素,吲哚并苯并二氮杂二聚体,咪唑并苯并二氮杂二聚体,或者恶唑烷苯并二氮杂卓),加利霉素和烯二炔类抗生素,放线菌素,鹅膏蕈碱(amatoxins),重氮丝氨酸,博来霉素,表柔比星,他莫昔芬,伊达比星,多拉司他汀,,澳瑞他汀衍生物(例如,单甲基澳瑞他汀E,MMAE,MMAF,澳瑞他汀PYE,澳瑞他汀TP,澳瑞他汀2-AQ,6-AQ,EB(AEB)和EFP(AEFP),多卡霉素,噻替派,长春地辛,半米塔林,nazumamides,microginins,radiosumins,alterobactins,microsclerodermins,theonellamides,esperamici ns,PNU-159682及其上述类似物和衍生物。
37.根据权利要求2所述的偶合物,其特征在于所述的偶合物具有式2-1,2-2,2-3,2-4,2-5,2-6,2-7,2-8,2-9,2-10,2-11,2-12,2-13,2-14,2-15,2-16,2-17,2-18,2-19,2-20,2-21,2-22,2-23,2-24,2-25,2-26,2-27,2-28,2-29,2-30,2-31,2-32,2-33,2-34,2-35,F2-1,F2-2,F2-3,F2-4,F2-5,F2-6,F2-7,F2-8,F2-9,F2-10,F2-11,F2-12,F2-13,F2-14,F2-15,F2-16,F2-17,F2-18,F2-19,F2-20,F2-21,F2-22,F2-23,F2-24,F2-25,F2-26,F2-27,F2-28,F2-29,F2-30,F2-31,F2-32,F2-33,F2-34,F2-35,F2-36,F2-37,F2-38,F2-39,F2-40,F2-41,F2-42,F2-43,28,32,53,55,64,69,70,78,86,95,97,103,111,116,117,124,127,141,144,147,155,167,173,220,
232,234,235,238,239,261,268,273,281,289,293,296,307,308,313,318,326,327,339,344,345,354,355,360,361,371,377,379,381,391,393,395,404,411,418,420,428,430,432,434,439,443,452,458,463,467,470,473,476,478,481,483,494,496,498,500,506和508如图所示:
38.根据权利要求4所述的化合物,其特征在于具有式4-1,4-2,4-3,4-4,4-5,4-6,4-7,4-8,4-9,4-10,4-11,4-12,4-13,4-14,4-15,4-16,4-17,17,27,31,44,52,54,63,68,77,80,82,85,87,92,94,96,100,102,110,115,123,126,140,143,145,153,166,172,219,231,233,237,260,267,272,280,288,292,295,306,312,314,325,338,343,353,359,370,376,378,380,390,392,394,403,410,417,419,427,429,431,433,438,442,451,457,462,466,469,472,475,477,480,482,493,495,497,499,505和507如图所示:
39.一种药物组合物包含治疗有效量的权利要求2,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35或37的偶合物,及药学上可接受的盐,载体,稀释剂或赋形剂或其组合,其特征在于可用于治疗或预防癌症,或自身免疫疾病或传染病。
40.根据权利要求2,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,37,或39所述的偶合物,其特征在于具有体外,体内或离体细胞杀伤活性。
41.根据权利要求2,3,4,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,33,34,36,37,或38所述的化合物,其特征在于链接体组分,R1,R2,L,L1,L1’,L1”,L1”’,L2,L2’,L2”L3,L4,和L5可被蛋白酶独立的切割。
42.一种药物组合物包含claim 2,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,37,或39中具有有效治疗效果的偶合物,其特征在于与化学治疗剂,放射疗法,免疫治疗剂,自身免疫病症剂,抗感染剂或其他偶合物同时施用,用于协同有效地治疗或预防癌症,或自身免疫疾病或传染病。
43.根据权利要求42所述的协同剂,其特征在于所述的协同剂选自以下药物中的一种或几种:Abatacept(Orencia),醋酸阿比特龙对乙酰氨基酚/氢可酮,阿杜单抗,阿达木单抗,ADXS31-142(Advaxis'),ADXS-HER2(Advaxis'),阿法替尼二马来酸盐alemtuzumab/>阿维A酸(Panretin),曲妥珠单抗emtansine(KadcylaTM),苯丙胺混合盐(苯丙胺/右旋安非他命或Adderall XR),阿那曲唑阿立哌唑,阿扎那韦,Atezolizumab(MPDL3280A),阿托伐他汀,阿昔替尼(Inlyta),Avelumab,belinostat(BeleodaqTM),贝伐单抗/> CabazitaxelCabozantinib(Come-triqTM),贝沙罗汀/>blinatumomab(BlincytoTM),Bortezomib/>波舒替尼/>brentuximab vedotin布地奈德,布地奈德/福莫特罗,丁丙诺啡,卡培他滨,carfilzomib塞来昔布,赛替尼(LDK378/Zyka-dia),西妥昔单抗(Cetuximab),Ciclosporin,Cinacalcet,crizotinib/>Cosentyx,CTL019,达比加群,达拉菲尼/>Daratumumab(Darzalex),Darbepoetin alfa,Darunavir,甲磺酸伊马替尼达沙替尼/>denileukin diftitox/>DenosumabDepakote,右兰索拉唑,右旋哌甲酯,地塞米松,Dignitana DigniCap冷却系统,Dinutuximab(UnituxinTM),多西环素,度洛西汀,Duvelisib,elotuzumab,Emtricitabine/Ril-pivirine/Tenofovir disoproxil富马酸盐,Emtricitbine/替诺福韦/依法韦仑,依诺肝素,Enzalutamide/>依泊汀α,厄洛替尼/>埃索美拉唑,艾司佐匹克隆,依那西普,依维莫司/>依泽替米贝,依泽替米贝/辛伐他汀,非诺贝特,非格司亭,芬戈莫德,丙酸氟替卡松,氟替卡松/沙美特罗,氟维司群gazyva,吉非替尼/>格拉替雷,醋酸戈舍瑞林(Zoladex),伊替替尼,伊马替尼(格列卫),伊布替莫单抗tiuxetan/>ibrutinib(ImbruvicaTM),idelalisib/>英夫利西单抗,伊尼帕利布,门冬胰岛素,地特胰岛素,甘精胰岛素,胰岛素赖脯胰岛素,干扰素β1a,干扰素β1b,拉帕替尼/> 伊匹单抗异丙托溴铵/沙丁胺醇,Ixazomi/>Kanuma,醋酸兰瑞肽(Somatuline Depot),来那度胺,来那度胺/>甲磺酸仑尼替尼(LenvimaTM),来曲唑(Lema),左旋甲状腺素,左旋甲状腺素,利多卡因,利奈唑胺,利拉鲁肽,Lisdexamfetamine,LN-144(Lion Biotech.),MEDI4736(Astra Zeneca,Celgene),美金刚,哌醋甲酯,美托洛尔,Mekinist,莫达非尼,莫米松,Nilotinib/>niraparib,Nivolumab/>奥法木单抗(Arzerra),obinutuzumab(GazyvaTM),奥拉帕尼(LynparzaTM),奥美沙坦,奥美沙坦/氢氯噻嗪,奥马珠单抗,奥米加-3脂肪酸乙酯,奥司他韦,羟考酮,palbociclib/>帕利珠单抗,帕尼单抗/>panobinostat帕唑帕尼/> 派姆单抗/>培美曲塞(Alimta),帕妥珠单抗(PerjetaTM),肺炎球菌偶合疫苗,pomalidomide/>普瑞巴林,ProscaVax,普萘洛尔,奎硫平,雷贝拉唑,镭223氯化物/>雷洛昔芬,拉替拉韦,雷莫芦单抗/> Ranibizumab,瑞格菲尼/>利妥昔单抗/>利伐沙班,罗米地辛/>罗苏伐他汀,鲁索替尼磷酸盐(JakafiTM),沙丁胺醇,司维拉姆,西地那非,siltuximab(SylvantTM),西他列汀,西他列汀/二甲双胍,索利那新,索拉尼单抗,索拉非尼/>舒尼替尼/>他达拉非,他莫昔芬,Tafinlar,Telaprevir,temsirolimus/>替诺福韦/恩曲他滨,睾酮凝胶,沙利度胺(Immuno-prin,Talidex),噻托溴铵,托瑞米芬/>trametinib/> 曲妥珠单抗,维甲酸/>优特克单抗,缬沙坦,veliparib,凡德他尼/>威罗菲尼/>伏立诺他/>ziv-阿柏西普/> Zostavax及其类似物,衍生物,药学上可接受的盐,载体,稀释剂或赋形剂,或其组合。/>
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