CN101784550B - 包含新型茅屋霉素衍生物的细胞毒性剂及其治疗用途 - Google Patents
包含新型茅屋霉素衍生物的细胞毒性剂及其治疗用途 Download PDFInfo
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- CN101784550B CN101784550B CN200880103551.3A CN200880103551A CN101784550B CN 101784550 B CN101784550 B CN 101784550B CN 200880103551 A CN200880103551 A CN 200880103551A CN 101784550 B CN101784550 B CN 101784550B
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- tetrahydrochysene
- pyrrolo
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Abstract
本发明涉及包含连接物的新型茅屋霉素衍生物。其还涉及包含经由该茅屋霉素衍生物的连接物上存在的连接基共价连接到细胞结合剂上的一种或更多种所述茅屋霉素衍生物的缀合物分子。其还涉及该茅屋霉素衍生物和该缀合物分子的制备。
Description
发明领域
本发明涉及新型茅屋霉素衍生物及其作为细胞毒性剂的治疗用途。该治疗用途是通过将茅屋霉素衍生物化学连接到细胞结合剂上而以靶向方式将该茅屋霉素衍生物输送至特定细胞群落的结果。本发明还涉及包含化学连接到任选改性的细胞结合剂上的一种或更多种所述茅屋霉素衍生物的缀合物分子。
发明背景
许多报道已尝试用单克隆抗体-药物缀合物特异性靶向肿瘤细胞(Sela等人,Immuno-conjugates,189-216(C.Vogel,ed.1987);Ghose等人,Targeted Drugs 1-22(E.Goldberg,ed.1983);Diener等人,AntibodyMediated delivery systems,1-23(J.Rodwell,ed.1988);Pietersz等人,Antibody Mediated delivery systems,25-53(J.Rodwell,ed.1988);Bumol等人,Antibody Mediated delivery systems,55-79(J.Rodwell,ed.1988);G.A.Pietersz & K.Krauer,2,J.Drug Targeting,183-215(1994);R.V.J.Chari,31 Adv.Drug Delivery Revs.,89-104(1998);W.A.Blattler & R.V.J.Chari,Anticancer Agents,Frontiers in Cancer Chemotherapy,317-338,ACS Symposium Series 796;和I.Ojima等人eds,American ChemicalSociety 2001;J.M.Lambert,5 Current Opinion in Pharmacology,543-549(2005);P.R.Hamann,15 Expert Opinion on Therapeutics Patents,1087-1103(2005))。本文列举的所有参考文献和专利经此引用并入本文。
细胞毒性药物,如甲氨蝶呤、柔毛霉素、阿霉素、长春新碱、长春碱、美法仑、丝裂霉素C和苯丁酸氮芥已缀合到各种鼠科单克隆抗体上。在一些情况下,药物分子通过中间载体分子,如血清白蛋白(Garnett等人,46,Cancer Res.2407-2412(1986);Ohkawa等人23,Cancer Immunol.Immunother.81-86(1986);Endo等人,47 Cancer Res.1076-1080(1980))、葡聚糖(Hurwitz等人,2 Appl.Biochem.25-35(1980);Manabi等人,34 Biochem.Pharmacol.289-291(1985);Dillman等人,46 Cancer Res.,4886-4891(1986);Shoval等人,85,Proc.Natl.Acad.Sci,8276-8280(1988))、或聚谷氨酸(Tsukada等人,73,J.Natl.Cane.Inst,721-729(1984);Kato等人,27J.Med.Chem.,1602-1607(1984);Tsukada等人,52,Br.J.Cancer,111-116(1985))连接到抗体分子上。
多种连接物(linker)技术已用于制备这类免疫缀合物,已经研究了可裂解和不可裂解的连接物。然而,在大多数情况下,只有在可使用可裂解连接物由该缀合物在靶位置以未改性形式释放药物分子的情况下才能观察到该药物的高细胞毒素潜力。
然而,体外细胞毒性试验已经揭示,抗体-药物缀合物不仅杀死抗原-阳性细胞,还杀死附近的其它细胞,与它们表面上的抗原表达无关。这种现象被称作旁效应(bystander effect)。在抗-CanAg抗体huC242与美登类化合物(maytansinoids)和与CC1065类似物的缀合物中观察到这种效应(Erickson等人,66 Cancer Res.,4426-4433(2006);Kovtun等人,66 Cancer Res.,3214-3221(2006))。迄今只有经由可裂解键,如可还原的二硫化物键连接的缀合物表现出旁效应(bystander)细胞毒性,而经由不可还原的硫醚连接物连接的缀合物没有表现出旁效应。
连接到靶向剂,如抗体上的高效细胞毒性效应分子可以在该缀合物的细胞内加工后产生强效药物衍生物。如果生成的细胞代谢物表现出不想要或不容易控制的副作用,这可能成问题。为了控制抗体-药物缀合物的毒性,使用不可裂解的连接物是非常有益的。
大多数抗体-药物缀合物的另一主要缺点是,由于靶向抗原的数量有限和癌症抑制(cancerostatic)药物,如甲氨蝶呤、柔毛霉素和长春新碱的相对缓和的细胞毒性,它们不能将足够浓度的药物输送至靶位置。为了实现显著细胞毒性,大量药物分子必须直接或通过聚合载体分子连接到抗体上。然而,这种严重改性的抗体通常表现出受损的与靶抗原的结合和从血流中快速体内清除。因此,替代方案是使用有效得多的药物分子,如下面公开的那些。
不可裂解的连接物也已用于缀合。它们在放射性免疫治疗用途中特别有意义。这也已用于将毒素连接到单克隆抗体上,如对于具有MAb9.2.27的假单胞菌属外毒素,使用异双官能团马来酰亚胺琥珀酰亚胺基4-(N-马来酰亚氨基甲基)环己烷-1-羧酸酯(SMCC)(EP 306943)。MAb毒素缀合物对阳性细胞系的体外特异性经证实比相应的二硫化物键缀合物高,因此在小鼠模型中毒性较低。当使用不可裂解的连接物时,非特异性毒性显著降低。在靶向HER2(ErbB)的曲妥单抗(trastuzumab)(赫赛汀)的情况下已经使用这种不可裂解的连接物。HERR2是关键靶,正研究最大限度提高使用MAbs抑制这种受体的效果的方法。一种方法旨在通过使曲妥单抗(赫赛汀)偶联到化疗剂上来增大其效力,由此能够在细胞层面实施细胞毒性治疗(Ranson和Sliwkowski,63(Suppl.1)Oncology,17-24(2002))。
存在其它形式的SMCC试剂,例如水溶性4-(N-马来酰亚氨基甲基)环己烷-1-羧酸磺基琥珀酰亚胺酯(磺基-SMCC)也已用在缀合反应中。其它不可裂解的连接物特别包括N-琥珀酰亚胺基-S-乙酰基硫代乙酸酯(SATA)、SATA-SMCC、2-亚氨基噻唑(2IT)和2IT-SMCC(Foulon等人,10,Bioconjugate Chem.,867-876(1999))。也已经使用包含卤代乙酰基部分的交联试剂并包括N-琥珀酰亚胺基-4-(碘乙酰基)-氨基苯甲酸酯(SIAB)、N-琥珀酰亚胺基碘乙酸酯(SIA)、N-琥珀酰亚胺基溴乙酸酯(SBA)和N-琥珀酰亚胺基3-(溴-乙酰氨基)丙酸酯(SBAP)。这些交联试剂构成衍生自卤代乙酰基部分的不可裂解的连接物。
尽管有归因于药物分子的如上报道的困难,已经报道了包含细胞结合部分和被称作美登类化合物的细胞毒性药物类型的有用细胞毒性剂(USP 5,208,020、USP 5,416,064和R.V.J.Chari,31 Advanced DrugDelivery Reviews 89-104(1998))。类似地,也已经报道了包含细胞结合部分和有效抗肿瘤抗体CC-1065的类似物和衍生物的有用细胞毒性剂(USP 5,475,092、USP 5,585,499和USP 6,756,397)。
茅屋霉素衍生物是吡咯并[1,4]苯并二氮杂(PBD)——通过在DNA小沟中共价结合到鸟嘌呤的N2上来发挥其生物学性质的已知类型的化合物。PBD包括许多小沟结合剂,如安曲霉素、新茴霉素(neothramycin)和DC-81。然而,由于其对正常细胞的非特异性毒性,茅屋霉素抗癌活性有限。因此需要提高茅屋霉素化合物的治疗活性和减小非特异性毒性作用。本发明人已经表明,通过将茅屋霉素化合物连接到细胞结合剂上而靶向输送该化合物,可以满足这种需要。另外,需要开发在水溶液中可溶和稳定的茅屋霉素衍生物。此外,与细胞结合剂的缀合物中使用时,茅屋霉素不够有效。
最近,已经公开了若干新PBD衍生物及其在临床前模型中的抗癌活性(WO00/12508和WO2005/085260)。然而,最初的人体临床试验表明,基于可施用于人体的极低剂量,这类化合物是剧毒的(I.Puzanov,Proc.AACR-NCl-EORTC International Conference,Philadelphia,USA2005,Abstract#B117)。因此,需要提供表现出较低副作用且不损失细胞毒性活性的备选衍生物。
现有技术
国际申请WO 2007/085930和WO 2008/010101描述了可通过连接物连接到细胞结合剂上的茅屋霉素衍生物,但该连接物不是如对本发明的化合物所定义的连接物。
文章“Tetrahedron Letters,第29卷,N°40,第5105-5108页”描述了无任何连接物的茅屋霉素衍生物ref.(13)-(15)。
国际申请WO 2005/085250描述了通式PBD-A-Y-X-(Het)na-L-(Het)nb-L-(Het)nc-T-(Het′)nd-L-(Het′)ne-L-(Het′)nf-X′-Y′-A′-PBD’的PBD二聚物,其中Het和Het′是式-J-G-J’或J’-G-J-的氨基-亚杂芳基,其中G是任选取代的亚杂芳基,na-nf是0至5的整数,L可以是β-丙氨酸、甘氨酸、4-氨基丁酸或单键。X和X’都是-NH-或-C(=O)-,且Y和Y’是二价基团以使HY为烷基、杂环基或芳基或单键。A和A’选自O、S、NH或单键。T是式-NH-Q-NH-或-C(=O)-Q-C(=O)-的二价连接物,其中Q是二价基团以使QH是烷基、杂环基或芳基(任选取代)。根据该通式的化合物都包含-NH-或-C(=O)-作为X和X’,以及-NH-Q-NH-或-C(=O)-Q-C(=O)-,这不是本发明的化合物的情况。
国际申请WO 2005/023814描述了在氮原子N10上被包含桥-X-R”-X-的R10-COO-保护的PDBs二聚物,其中R”是任选被一个或更多个杂原子NH、O或S***的亚芳基和/或芳环,且X是O、S或NH。没有提到在桥-X-R”-X-上的连接物。此外,本发明的化合物没有在N10上被保护。
文章“European Journal of Medicinal Chemistry,第40卷,N°7,第641-654页”描述了PBD的二聚物ref.(38)-(40),其不包含任何与本发明的化合物一样的连接物。
文章“Expert opinion;Monoclonal antibody-drug conjugates”,Ashleypublications,第15卷,N°9,2005,第1087-1103页,ISSN:1354-3774没有描述本发明的化合物,文章“Cancer Res.2006,66(8),第4426-4433页”描述了连接到细胞结合剂上的美登类化合物。
发明概述
本发明涉及包含连接物的权利要求1至30的新型茅屋霉素衍生物。其还涉及包含经由该茅屋霉素衍生物的连接物上存在的连接基共价连接到细胞结合剂上的一种或更多种所述茅屋霉素衍生物的缀合物分子。其还涉及该茅屋霉素衍生物和该缀合物分子的制备。
发明详述
定义
·Alk代表烷基、烯或炔;
·“烷基”是指脂族烃基,其可以是在链中具有1至20个碳原子的直链或支链,或是具有3至10个碳原子的环状的。优选的烷基在链中具有1至12个碳原子。“支链”是指一个或更多个低碳烷基,如甲基、乙基或丙基连接到直链烷基链上。示例性烷基包括甲基、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、环戊基和环己基;
·“烯”是指含有碳-碳双键的脂族烃基,其可以是在链中具有2至15个碳原子的直链或支链。优选的链烯基在链中具有2至12个碳原子;更优选在链中具有大约2至4个碳原子。示例性链烯基包括乙烯基、丙烯基、正丁烯基、异丁烯基、3-甲基丁-2-烯基、正戊烯基、庚烯基、辛烯基、壬烯基、癸烯基;
·“炔”是指含有碳-碳三键的脂族烃基,其可以是在链中具有2至15个碳原子的直链或支链。优选的炔基在链中具有2至12个碳原子;更优选在链中具有2至4个碳原子。示例性炔基包括乙炔基、丙炔基、正丁炔基、2-丁炔基、3-甲基丁炔基、正戊炔基、庚炔基、辛炔基和癸炔基;
·“卤素原子”是指氟、氯、溴或碘原子;优选氟和氯原子。
·“芳基”是指具有6至14个碳原子,优选6至10个碳原子的芳族单环或多环烃环系。示例性芳基包括苯基或萘基;
·“Het”是指杂环或杂芳基;
·术语“杂环”或“杂环基”是指饱和、部分不饱和或不饱和的、非芳族稳定的3至14,优选5至10元单、二或多环,其中该环的至少一个成员是杂原子。通常,杂原子包括,但不限于,氧、氮、硫、硒和磷原子。优选的杂原子是氧、氮和硫。合适的杂环也公开在The Handbookof Chemistry and Physics,第76版,CRC Press,Inc.,1995-1996,第2-25至2-26页中,其公开内容经此引用并入本文。
优选的非芳族杂环基包括,但不限于,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、二氧杂环己环基、二氧戊环基、哌啶基、哌嗪基、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pyrinidinyl、二氢噻喃基、氮杂环庚烷基以及与苯基稠合产生的稠合体系;
·术语“杂芳基”或芳族杂环是指5至14元,优选5至10元芳族杂、单、二或多环。实例包括吡咯基、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、***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、异噁唑基、吡啶基-N-氧化物以及与苯基缩合形成的稠合体系;
·“烷基、”“环烷基”、“链烯基”、“炔基”、“芳基”、“杂芳基”、“杂环”等还涉及通过除去两个氢原子而形成的相应的“亚烷基、”“亚环烷基”、“亚烯基”、“亚炔基”、“亚芳基”、“亚杂芳基”、“亚杂环基”等;
·“不可裂解的连接物”是指适合将所述茅屋霉素衍生物共价连接到细胞结合剂上的任何基团,其中所述基团不含二硫化物基团、酸不稳定基团、光不稳定基团、肽酶不稳定基团和酯酶不稳定基团。优选地,所述“不可裂解的连接物”包含末端羧基或酰胺基或其前体。该连接物在该缀合物分子在细胞内内化和该细胞结合剂的可能蛋白水解后的细胞内加工过程中不裂解;
·术语“可连接到细胞结合剂上”是指该茅屋霉素衍生物包含适合将所述衍生物键合到细胞结合剂上的至少一个连接物(其又包含连接基)或其前体;优选的连接基是羧基、酰胺键或其前体;
·术语“连接到细胞结合剂上”是指该缀合物分子包含至少一种经由合适的连接基键合到细胞结合剂上的茅屋霉素衍生物,或其前体;优选的连接基是不可裂解键或其前体;
·给定基团的“前体”是指可通过任何脱保护、化学改性或偶联反应产生该基团的任何基团;
·“患者”是指动物,例如用于饲养、陪伴或保存用途的有价值动物,或优选人类或儿童,其患有或有可能会患有一种或更多种本文所述的疾病和病症;
·“治疗有效量”是指有效预防、减轻、消除、治疗或控制本文所述的疾病和病症的症状的本发明的化合物的量。术语“控制”是指其中可能减缓、中断、遏制或停止本文所述的疾病和病症的进展的所有过程,但不一定是指完全消除所有疾病和病症症状,并且旨在包括预防性治疗;
·“药物上可接受的”是指在合理的医学判断范围内适合与人和动物的组织接触而没有过度毒性、刺激、过敏响应或其它与合理的效益/风险比率相称的问题并发症的那些化合物、材料、赋形剂、组合物或剂型。
·“药物上可接受的盐”是指所述化合物的衍生物,其中母体化合物通过制备其酸性或碱性盐来改性。药物上可接受的盐包括例如由无毒性无机或有机酸形成的母体化合物的常规无毒盐或季铵盐。例如,这类常规无毒盐包括由无机酸,如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸和类似物生成的盐;和由有机酸,如乙酸、丙酸、琥珀酸、酒石酸、柠檬酸、甲磺酸、苯磺酸、葡糖酸、谷氨酸、苯甲酸、水杨酸、甲苯磺酸、草酸、富马酸、马来酸、乳酸和类似物制成的盐。其它加成盐包括铵盐,如氨丁三醇、甲葡胺、吡咯乙醇(epolamine)等,金属盐,如钠、钾、钙、锌或镁。本发明的药物上可接受的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,这类盐可通过使这些化合物的游离酸或碱形式与化学计算量的合适碱或酸在水或在有机溶剂或两者的混合物中反应来制备。通常,非水介质,如醚、乙酸乙酯、乙醇、异丙醇或乙腈是优选的。合适的盐的名单可见于Remington’sPharmaceutical Sciences,第17版,Mack Publishing Company,Easton,PA,1985,第1418页,其公开内容经此引用并入本文。
·“治疗”是指逆转、减轻、抑制该术语指向的失调症或病症的进展或防止该失调症或病症或这类失调症或病症的一个或更多个症状。
·“治疗有效量”是指有效预防或治疗本文所述的病理症状的本发明的化合物/药物的量;
·“药用”或“药物上可接受的”是指适当施用于动物或人类时不产生不利、过敏或其它不适当的反应的分子体和组合物;
·“药物上可接受的赋形剂”包括任何载体、稀释剂、佐剂或赋形剂,如防腐剂或抗氧化剂、填料、崩解剂、润湿剂、乳化剂、悬浮剂、溶剂、分散介质、涂料、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂,和类似物。这类介质和试剂用于药物活性物质是本领域中公知的。任何常规介质或试剂除了与活性成分不相容外,都可考虑用在该治疗组合物中。辅助活性成分也可以作为合适的治疗组合掺入该组合物中。
茅屋霉素衍生物
本发明基于新型茅屋霉素衍生物的合成,其保持高细胞毒性并且可以用不可裂解的连接物有效连接到细胞结合剂上,这种缀合物在肿瘤细胞杀灭中表现出高效力。之前已经表明,使用可裂解的连接,如二硫化物键连接高度细胞毒性药物与抗体确保在细胞内释放完全活性药物,这类缀合物以抗原特异性方式是细胞毒性的(US 6,340,701;US 6,372,738;US 6,436,931)。然而,现有技术揭示,极难在不降低它们的细胞毒性潜力的情况下改性现有药物。本发明通过用化学部分改性所公开的茅屋霉素衍生物来克服这一问题。结果,所公开的新型茅屋霉素衍生物保存且在一些情况下甚至提高茅屋霉素衍生物的细胞毒性效力。细胞结合剂-茅屋霉素衍生物复合物使得茅屋霉素衍生物的细胞毒性作用完全以靶向方式仅作用于不想要的细胞,因此避免由于损害非靶向的健康细胞而引起的副作用。因此,本发明提供可用于消除要被杀死或溶解的带病或异常细胞,如肿瘤细胞(尤其是实体瘤细胞)的药剂。
茅屋霉素
本发明的细胞毒性剂包含一种或更多种经由不可裂解的连接基任选可连接或已连接到细胞结合剂上的茅屋霉素衍生物。该连接基是通过常规方法共价键合到茅屋霉素衍生物上的化学基团的一部分。
根据一个方面,本发明涉及式(I)的茅屋霉素衍生物:
其中:
----代表任选的单键;
前提是,当代表单键时,U和U’相同或不同,独立地代表H,W和W’相同或不同,独立地选自OH、醚如-OR、酯(例如乙酸酯),如-OCOR或-COOR、碳酸酯如-OCOOR、氨基甲酸酯如-OCONRR’、环氨基甲酸酯以使N10和C11是环的一部分、脲如-NRCONRR’、硫代氨基甲酸酯如-OCSNHR、环硫代氨基甲酸酯以使N10和C11是环的一部分、-SH、硫化物如-SR、亚砜如-SOR、砜如-SOOR、磺酸酯如-SO3 -、磺酰胺如-NRSOOR’、胺如-NRR’、任选环胺以使N10和C11是环的一部分、羟胺衍生物如-NROR’、酰胺如-NRCOR’、叠氮基如-N3、氰基-CN、卤化物(Hal)、三烷基或三芳基鏻;优选地,W和W’相同或不同并且是-OH、-OMe、-OEt、-NHCONH2、-SMe;
·R1、R2、R1’、R2’相同或不同且独立地选自H、卤化物或任选被一个或更多个Hal、CN、NRR’、CF3、OR、芳基、Het、S(O)qR取代的烷基,或R1和R2以及R1’和R2’一起形成分别含有基团=B和=B’的双键。
优选地,R1和R2以及R1’和R2’一起形成分别含有基团=B和=B’的双键。
·B和B’相同或不同且独立地选自任选被一个或更多个Hal、CN、NRR’、CF3、OR、SR、SOR、SO2R、芳基、Het取代的链烯基,或B和B’代表氧原子。
优选B=B’。
更优选B=B’==CH2或=CH-CH3,
·X、X’相同或不同且独立地选自一个或更多个-O-、-S-、-NR-、-(C=O)-、-SO-、-SO2-;
优选X=X’。
更优选X=X’=0。
·A、A’相同或不同且独立地选自烷基或链烯基,各自任选被一个或更多个Hal、CN、NRR’、CF3、OR、SR、SOR、SO2R、芳基、Het、烷基、链烯基取代。
优选A=A’。更优选A=A’=直链未取代烷基。
·Y、Y’相同或不同且独立地选自H、OR;
优选Y=Y’。
更优选Y=Y′=O烷基,更优选O甲基。
·T是-NR-或4至10元芳基、环烷基、杂环、杂芳基或直链或支链烷基,各自被一个或更多个不可裂解的连接物取代并任选被Hal、CN、NRR’、CF3、R、OR、SOR或SO2R中的一个或更多个取代。
·n、n’相同或不同,是0或1;
·q是0、1或2;
根据另一方面,该茅屋霉素衍生物具有下式(I’):
其中R1、R1’、R2、R2’、W、W、U、U’、Y、Y’、X、X’、A、A’、n、n’如上所述,T是-NR-或4至10元芳基、环烷基、杂环、杂芳基或直链或支链烷基,各自被一个或更多个式-G-D-(Z)p-C(=O)-Z’R”的连接物取代并任选被Hal、CN、NRR’、CF3、R、OR、SOR、SO2R中的一个或更多个取代。
桥连基-X-An-T-A’n’-X’-不含任何-NH-C(=O)-连接。
该连接物具有下式:
-G-D-(Z)p-C(=O)-Z’R”
其中:
·G是单键、双键或三键、-O-、-S-或-NR-;
·D是单键或-E-、-E-NR-、-E-NR-F-、-E-O-、-E-O-F-、-E-NR-CO-、-E-CO-NR-、-E-NR-CO-F-、-E-CO-NR-F-、-E-CO-、-CO-E-、-E-CO-F、-E-S-、-E-S-F-、-E-NR-CS-、-E-CS-NR-、-E-NR-CS-F-、-E-CS-NR-F-;
·E和F相同或不同且独立地选自直链或支链-(OCH2CH2)i烷基(OCH2CH2)j-、-烷基(OCH2CH2)i-烷基-、-(OCH2CH2)j-、-(OCH2CH2)i环烷基(OCH2CH2)j-、-(OCH2CH2)i杂环(OCH2CH2)j-、-(OCH2CH2)i芳基(OCH2CH2)j-、-(OCH2CH2)i杂芳基(OCH2CH2)j-、-烷基-(OCH2CH2)i烷基(OCH2CH2)j-、-烷基-(OCH2CH2)i-、-烷基-(OCH2CH2)i环烷基(OCH2CH2)j-、-烷基(OCH2CH2)i杂环(OCH2CH2)j-、-烷基-(OCH2CH2)i芳基(OCH2CH2)j-、-烷基(OCH2CH2)i杂芳基(OCH2CH2)j-、-环烷基-烷基-、-烷基-环烷基-、-杂环-烷基-、-烷基-杂环-、-烷基-芳基-、-芳基-烷基-、-烷基-杂芳基-、-杂芳基-烷基-;
·i和j相同或不同,是整数且独立地选自0、1至2000;
·Z是直链或支链烷基、环烷基、芳基、杂芳基、杂环基、芳烷基、环烷基、杂芳烷基或杂环基烷基,任选被增溶官能团,如氨基、醚、磺酸基和羧酸基取代;
·p是0或1;
·-C(=O)-Z’R”是含羰基的官能团,其中
-Z’代表单键或-O-、-S-、-NR-且
-R”代表H、烷基、环烷基、芳基、杂芳基或杂环基,各自任选被一个或更多个Hal、CN、NRR′、CF3、R、OR、SOR、SO2R、芳基、Het取代;
R、R’相同或不同且独立地选自H、烷基、芳基,各自任选被Hal、CN、COOH、COOR、CONHR、CONRR’、NRR’、CF3、R、OR、SOR、SO2R、芳基、Het取代。
该连接物包含被不含任何可裂解基团,如二硫化物基团、酸不稳定基团、光不稳定基团、肽酶不稳定基团和酯酶不稳定基团的连接基封端的链。该末端连接基不含-S-V基团,其中V是H、硫醇保护基(如COR)、R20或SR20,R20是H、甲基、烷基,任选被环烷基、芳基、杂芳基或杂环基取代。该连接物不是WO 2007/085930或WO 2008/010101中公开的任一种。本发明的茅屋霉素衍生物的末端连接基优选是在侧链末端的羧基或酰胺基。该侧链可以是直链或支链的、芳族或杂环的。本领域普通技术人员可以容易地确定合适的侧链。优选的连接物由含有增溶官能团,如氨基、羟基、醚、磺酸基和羧酸基的直链构成。
T优选是4至10元芳基或杂芳基,更优选是苯基或吡啶基,其被一个或更多个所述连接物取代并任选被Hal、CN、NRR’、CF3、R、OR、SOR或SO2R中的一个或更多个取代。与苯基相比,吡啶基使该茅屋霉素衍生物在水溶液中的溶解度更高。更高的溶解度有助于制备与疏水抗体的缀合物分子,因为聚集体往往较少,这有助于提高该缀合物分子的收率。
该化合物的药物上可接受的盐、水合物或水合盐,或多晶型晶体结构以及旋光异构体、外消旋体、非对映体或对映体也构成本发明的一部分。当该化合物是离子(例如磺酸根)形式时,可能存在抗衡离子(例如Na+或K+)。
本发明涉及下列优选实施方案或它们的任何组合:
·G是单键或-O-;
·D是单键或-E-或-E-O-;
·D是-E-;
·E是直链或支链-烷基-或-Alk(OCH2CH2)i-;
·Z是直链或支链-烷基-;
·p是0;
·Z’是单键或O;
·Z’是O;
·R”是H或直链或支链-烷基-或任选取代的杂环基;
连接物的具体实例包括下列:
-(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ’R”、
-(CR13R14)t(OCH2CH2)yO(CR15R16)uCOZ’R”、
-(CR13R14)t(CR17=CR18)(CR15R16)u(OCH2CH2)yCOZ’R”、
-(CR13R14)t(NR19CO)(CR15R16)u(OCH2CH2)yCOZ’R”、
-(CR13R14)t(OCO)(CR15R16)u(OCH2CH2)yCOZ’R”、
-(CR13R14)t(CO)(CR15R16)u(OCH2CH2)yCOZ’R”、
-(CR13R14)t(CONR19)(CR15R16)u(OCH2CH2)yCOZ’R”、
-(CR13R14)t-苯基-CO(CR15R16)uCOZ’R”、-(CR13R14)t-呋喃基-CO(CR15R16)uCOZ’R”、-(CR13R14)t-噁唑基-CO(CR15R16)uCOZ’R”、-(CR13R14)t-噻唑基-CO(CR15R16)uCOZ’R”、-(CR13R14)t-噻吩基-CO(CR15R16)uCOZ’R”、-(CR13R14)t-咪唑基-CO(CR15R16)uCOZ’R”、-(CR13R14)t-哌嗪并-CO(CR15R16)uCOZ’R”、-(CR13R14)t-苯基-QCOZ’R”、-(CR13R14)t-呋喃基-QCOZ’R”、-(CR13R14)t-噁唑基-QCOZ’R”、-(CR13R14)t-噻唑基-QCOZ’R”、-(CR13R14)t-噻吩基-QCOZ’R”、-(CR13R14)t-咪唑基-QCOZ’R”、-(CR13R14)t-哌嗪并-QCOZ’R”、
-(C≡C)-(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ’R”、
-O(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ’R”、
-O(CR13R14)t(NR19CO)(CR15R16)u(OCH2CH2)yCOZ’R”、
-O(CR13R14)t(CR17=CR18)(CR15R16)u(OCH2CH2)yCOZ’R”、
-O-苯基-QCOZ’R”、-O-呋喃基-QCOZ’R”、-O-噁唑基-QCOZ’R”、-O-噻唑基-QCOZ’R”、-O-噻吩基-QCOZ’R”、-O-咪唑基-QSCOZ’R”、-O-吗啉并-QCOZ’R”、-O-哌嗪并-QCOZ’R”、
-OCO(CR13R14)t(NR19CO)(CR15R16)u(OCH2CH2)yCOZ’R”、
-OCO-(CR13R14)t(CR17=CR18)(CR15R16)u(OCH2CH2)yCOZ’R”、
-OCONR12(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ’R”、
-OCO-苯基-QCOZ’R”、-OCO-呋喃基-QCOZ’R”、-OCO-噁唑基-QCOZ’R”、-OCO-噻唑基-QCOZ’R”、-OCO-噻吩基-QCOZ’R”、-OCO-咪唑基-QCOZ’R”、-OCO-哌嗪并-QCOZ’R”、或
-CO(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ’R”、
-CO-(CR13R14)t(CR17=R18)(CR15R16)u(OCH2CH2)yCOZ’R”、
-CONR12(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ’R”、
-CO-苯基-QCOZ’R”、-CO-呋喃基-QCOZ’R”、-CO-噁唑基-QCOZ’R”、-CO-噻唑基-QCOZ’R”、-CO-噻吩基-QCOZ’R”、-CO-咪唑基-QCOZ’R”、-CO-哌嗪并-QCOZ’R”、-CO-哌啶子基-QCOZ’R”、
-NR19(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ’R”、
-NR19CO(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ’R”、
-NR19(CR13R14)t(CR17=CR18)(CR15R16)u(OCH2CH2)yCOZ’R”、
-NR19CO(CR13R14)t(CR17=CR18)(CR15R16)u(OCH2CH2)yCOZ’R”、
-NR19CONR12(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ’R”、
-NR19CONR12(CR13R14)t(CR17=CR18)(CR15R16)u(OCH2CH2)yCOZ’R”、
-NR19CO-苯基-QCOZ’R”-、-NR19CO-呋喃基-QCOZ’R”、-NR19CO-噁唑基-QCOZ’R”、-NR19CO-噻唑基-QCOZ’R”、-NR19CO-噻吩基-QCOZ’R”、-NR19CO-咪唑基-QCOZ’R”、-NR19CO-吗啉并-QCOZ’R”、-NR19CO-哌嗪并-QCOZ’R”、-NR19CO-哌啶子基-QCOZ’R”、-NR19-苯基-QCOZ’R”、-NR19-呋喃基-QCOZ’R”、-NR19-噁唑基-QCOZ’R”、-NR19-噻唑基-QCOZ’R”、-NR19-噻吩基-QCOZ’R”、-NR19-咪唑基-QCOZ’R”、-NR19-哌嗪并-QCOZ’R”、-NR19-哌啶子基-QCOZ’R”、-NR19CO-NR12-苯基-QCOZ’R”、-NR19CO-NR12-噁唑基-QCOZ’R”、-NR19CO-NR12-噻唑基-QCOZ’R”、-NR19CO-NR12-噻吩基-QCOZ’R”、-NR19CO-NR12-哌啶子基-QCOZ’R”、
-S(O)q(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ’R”、
-S(O)q(CR13R14)t(CR17=CR18)(CR15R16)u(OCH2CH2)yCOZ’R”、
-SCONR12(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ’R”、-SCO-哌嗪并-QCOZ’R”和-SCO-哌啶子基-QCOZ’R”,
其中:
·Q是直接键或具有1-10个碳原子的直链烷基或支链烷基或具有2至20个重复乙烯氧基单元的聚乙二醇间隔基;
·R19和R12相同或不同并且是具有1至10个碳原子的直链烷基、支链烷基或环烷基,或简单或取代芳基或杂环基,且R12还可以是H;
·R13、R14、R15和R16相同或不同并且是H或具有1至4个碳原子的直链或支链烷基;
·R17和R18是H或烷基;
·u是1至10的整数并且也可以是0;
·t是1至10的整数并且也可以是0;
·y是1至20的整数并且也可以是0。
该连接物更特别是:
·-(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ’R”;
·-(CR13R14)t(OCH2CH2)yO(CR15R16)uCOZ’R”;
·-O(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ’R”;
·-O(CR13R14)t(NR19CO)(CR15R16)u(OCH2CH2)yCOZ’R”;
·-(C≡C)-(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ’R”,
或下列之一
·-O(CR13R14)tCOZ’R”;
·-(OCH2CH2)yCOZ’R”;
·-(C≡C)-(CR13R14)tCOZ’R”;
·-O(CR13R14)t(NR19CO)(CR15R16)uCOZ’R”;
·-(CR13R14)t(OCH2CH2)yCOZ’R”。
一个化合物亚类包含下列化合物:
其中X、X’、A、A’、Y、Y’、T、n、n′如上定义。
另一亚类包含下列化合物:
其中Y、Y’、G、D、Z、p、Z’和R”如上定义,且M代表CH或N。如上所述,当M是N时,茅屋霉素衍生物在水溶液中的溶解度改进。
根据另一优选方面,本发明的化合物选自:
·3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸;
·3-(2-{2-[2-(2,6-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-哌啶-4-氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸;
·N-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙基]-N-甲基-琥珀酰胺酸;
·(2-{2-[2-(2-{3-[3,5-双-(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-基氧甲基)-苯基]-丙氧基}-乙氧基)乙氧基]-乙氧基}-乙氧基)-乙酸;
·(3-{2-[2-(2-{3-[3,5-双-(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-基氧甲基)-苯基]-丙氧基}-乙氧基)乙氧基]-乙氧基}-乙氧基)-丙酸;
以及相应的酯或N-羟基琥珀酰亚胺基酯,
或它们的药物上可接受的盐、水合物或水合盐,或这些化合物的多晶型晶体结构或它们的旋光异构体、外消旋体、非对映体或对映体。
通式(I)或(I’)的化合物的几何异构体和立体异构体也是本发明的一部分。
该茅屋霉素衍生物的N10、C11双键已知在水、醇、硫醇、伯或仲胺、脲和其它亲核体存在下容易以可逆方式转化成相应的亚胺加合物。这种过程是可逆的,容易在脱水剂存在下,在非质子有机溶剂中在真空中或在高温下再生相应的茅屋霉素衍生物(Z.Tozuka,36,J.Antibiotics,276(1983)。因此,本发明也提供通式(II)的茅屋霉素衍生物的可逆衍生物:
其中A、X、Y、n、T、A’、X’、Y’、n’、R1、R2、R1’、R2’如式(I)或(I’)中所定义,W和W’相同或不同,选自OH、醚如-OR、酯(例如乙酸酯),如-OCOR、-COOR、碳酸酯如-OCOOR、氨基甲酸酯如-OCONRR’、环氨基甲酸酯以使N10和C11是环的一部分、脲如-NRCONRR’、硫代氨基甲酸酯如-OCSNHR、环硫代氨基甲酸酯以使N10和C11是环的一部分、-SH、硫化物如-SR、亚砜如-SOR、砜如-SOOR、磺酸酯如-SO3 -、磺酰胺如-NRSOOR’、胺如-NRR’、任选环胺以使N10和C11是环的一部分、羟胺衍生物如-NROR’、酰胺如-NRCOR’、-NRCONRR’、叠氮基如-N3、氰基、卤素、三烷基或三芳基鏻、氨基酸衍生基团。优选地,W和W’相同或不同并且是OH、OMe、OEt、NHCONH2、SMe。式(II)的化合物因此可以被视为溶剂合物,当溶剂是水时,包括水;这些溶剂合物特别可用。
关于该化合物的制备
该化合物可以通过采用或修改下述方法或技术人员会认识到的其变体合成。适当的修改和替代是本领域技术人员显而易见和公知的或容易从科学文献中获得,这类方法可见于R.C.Larock,ComprehensiveOrganic Transformations,Wiley-VCH Publishers,1999。
要认识到,本发明的化合物可含有一个或更多个不对称取代的碳原子,可以以旋光或外消旋形式分离。因此,意在包含一结构的所有手性、非对映、外消旋形式和所有几何异构形式,除非明确指明特定的立体化学或异构形式。如何制备和分离这类旋光形式是本领域中公知的。例如,立体异构体的混合物可通过标准技术分离,包括但不限于,外消旋形式的拆分、正相、反相和手性色谱法、优先盐形成、重结晶等,或通过由手性原料手性合成,或通过目标手性中心的有意合成。
在下述反应中,可能必须保护最终产品中需要的反应性官能团,例如羟基、氨基、亚氨基、硫基或羧基,以避免它们不合意地参与反应。可以根据标准实践使用常规保护基团,例如参见T.W.greene和P.G.M.Wuts,Protective Groups in Organic Chemistry,第3版,John Wiley andSons,1999;J.F.W.,McOmie,Protective Groups in Organic Chemistry,Plenum Press,1973。
一些反应可以在碱存在下进行。对用于这种反应的碱的性质没有特别限制,在这类反应中常规使用的任何碱在此都同样使用,只要其对该分子的其它部分没有不利影响。合适的碱的实例包括:氢氧化钠、碳酸钾、三乙胺、碱金属氢化物,如氢化钠和氢化钾;烷基锂化合物,如甲基锂和丁基锂;和碱金属醇盐,如甲醇钠和乙醇钠。
通常,反应在合适的溶剂中进行。可以使用各种溶剂,只要其对该反应或所涉及的试剂没有不利影响。合适的溶剂的实例包括:烃,其可以是芳族、脂族或脂环族烃,如己烷、环己烷、苯、甲苯和二甲苯;酰胺,如二甲基甲酰胺;醇,如乙醇和甲醇,和醚,如二***和四氢呋喃。
反应可以在宽的温度范围内进行。通常,可以在-20℃至150℃(更优选大约室温至100℃)的温度下进行该反应。该反应所需的时间也可根据许多因素,尤其是反应温度和试剂性质而广泛变化,。然而,如果反应在上述优选条件下进行,3小时至20小时的时间通常是足够的。
由此制成的化合物可通过常规方法从反应混合物中回收。例如,该化合物可通过从反应混合物中馏出溶剂来回收,或如果需要,在从反应混合物中馏出溶剂后,将残余物倒入水中,随后用水不混溶的有机溶剂萃取,并从萃出物中馏出溶剂。另外,如果需要,产物可通过各种公知技术进一步提纯,例如重结晶、再沉淀或各种色谱技术,尤其是柱色谱法或制备薄层色谱法。
第一途径
根据第一途径,其中T包含末端羧基的化合物的制备方法包括将下式的化合物脱保护的步骤:
代表性的脱保护反应是式(I)的化合物的水解,其中T’对应于T,其中末端羧基是酯形式。所述水解反应通常在碱性条件下,在有机或无机碱,如LiOH存在下进行,然后加入有机或无机酸,如盐酸。
这些化合物可以通过式(IV)、(IV’)和(V)的相应化合物的偶联获得:
其中Lg是离去基团,如卤素、-OMs(甲磺酸根)、-OTs(甲苯磺酸根)或-OPPh3 +(在Mitsunobu反应中形成的中间体)。
式(IV)和(IV’)的化合物通常是已知的,如WO 00/12508、WO00/12507、WO 2005/040170、WO 2005/085260中所公开,或可购得,和/或可通过全合成获得(M.mori等人,42Tetrahedron,3793-3806,1986)或通过链霉菌种生产,特别是根据法国专利FR 1,516,743的方法,或通过采用或修改实施例中给出的示例性方法来制备。
式(V)的化合物可由式HO-An-T’-A’n’-OH(VI)的相应化合物获得。反应通常在PPh3和CHal4存在下进行,或通过与磺酰氯(甲磺酰氯)在碱,如三乙胺或氢氧化钾,优选三乙胺存在下反应进行。
式(VI)的化合物可由式HO-An-T”-A’n’-OH(VII)的相应化合物获得,其中T”是T的前体基团。T的前体基团是指可通过任何脱保护、化学改性或偶联产生T的任何基团。T优选通过T’与补充部分的偶联获得,其中T’和补充部分包含可彼此反应的官能团,例如T’包括羟基官能团,补充部分包括溴官能团。下面描述这种反应的代表性实例:
通常,这种反应在碳酸钾存在下进行。
式(VII)的化合物可购得或通过修改或采用已知方法或根据实施例制造。
下面给出这种途径的示例性的非限制图式:
第二途径
根据第二途径,该化合物可由式(III)的相应化合物获得:
其中Y、Y’、X、A、A’、X’、n、n’、W、W’、U、U’、----、R1、R2、R1’、R2’如上定义且T”是T的任选被护的前体基团。T的前体基团是指可通过化学改性或偶联产生T的任何基团。T优选通过T’与相应补充部分的偶联获得,其中T’和补充部分包含可彼此反应的官能团,例如T’包括胺官能团,补充部分包含酸官能团。通常,这种反应在N-羟基琥珀酰亚胺和HOBT(N-羟基苯并***)存在下进行。
式(III)的化合物可以由式(IV)、(IV’)和(V’)的相应化合物的偶联获得:
其中Lg是离去基团,如卤素或-OMs、-OTs或-OPPh3 +(在Mitsunobu反应中形成的中间体)。
式(V’)的化合物可由式HO-An-T”-A’n’-OH(VII)的相应化合物获得,其中T”是T’的任选被护的前体基团。这种反应通常在PPh3和CHal4存在下进行,或通过羟基官能团的甲磺酰化进行。式(VII)的化合物可购得或通过修改或采用已知方法或根据实施例制造。
第三途径:
根据第三途径,可以通过环化式(VIII)的相应化合物来制备具有对称结构(R1=R1’,R2=R’2且Y=Y’)的化合物:
其中Y、X、X’、A、A’、n、n’、R1、R2、T如上定义。通常,这种反应在如次硫酸钠(Na2S2O4)之类的试剂存在下,在适当的溶剂,如THF/水混合物中进行,然后加入MeOH和AcCl。
式(VIII)的化合物可以由式(IX)的相应化合物获得:
这种反应在如二异丁基氢化铝(DIBAL-H)之类的试剂存在下,在适当的溶剂,如甲苯中进行。式(IX)的化合物可由式(X)和(XI)的相应化合物的偶联获得:
通常,这种反应通过向(X)中加入在适当的溶剂,如DMF中的如草酰氯之类的试剂,然后加入在适当的溶剂,如THF中的(XI)来进行。
下面给出这种途径的示例性非限制性图式:
上述反应可以由技术人员通过采用或修改下文实施例中例举的方法来进行。此外,本文所述的方法可以包括分离任何最终或中间产物的附加步骤。这可以由技术人员通过任何已知的常规方法,例如上述回收方法进行。原料产品可购得或可通过采用或修改任何已知方法或实施例中所述的方法来获得。该合成也可作为多组分反应的一锅法进行。
关于缀合物分子
本发明还涉及包含经由连接物的连接基化学连接到细胞结合剂上的至少一种茅屋霉素衍生物的缀合物分子。该化学连接优选是共价键。所述缀合物包含经由该茅屋霉素衍生物的连接物的连接基共价连接到细胞结合剂上的一种或更多种本发明的茅屋霉素衍生物。作为代表性实例,所述缀合物包含经由连接物的末端-CO-ZR”基团共价连接到细胞结合剂上的本发明的茅屋霉素衍生物。所述连接基共价连接细胞结合剂与茅屋霉素衍生物的连接物。
优选地,该连接物经由对例如细胞结合剂的分别来自还原的二硫化物键和赖氨酸残基的硫醇和氨基官能团呈反应性的官能团连接到细胞结合剂上。更特别地,所述衍生物经由-CO-基团连接到所述细胞结合剂的赖氨酸残基的氨基官能团上,从而形成酰胺键。
细胞结合剂可以是任何种类,包括肽类和非肽类。通常,这些可以是抗体(尤其是单克隆抗体)或含有至少一个结合位点的抗体片段、淋巴因子、激素、生长因子、营养传递分子(例如铁传递蛋白)或任何其它细胞结合分子或物质。可用的细胞结合剂的更具体实例包括:单克隆抗体;嵌合抗体;人源化抗体;全人抗体;单链抗体;抗体片段,如Fab、Fab’、F(ab’)2和Fv{Parham,131J.Immunol.2895-2902(1983);Spring等人,113J.Immunol.470-478(1974);Nisonoff等人,89Arch.Biochem.Biophys.230-244(1960)};干扰素;肽;淋巴因子如IL-2、IL-3、IL-4、IL-6;激素如胰岛素、TRH(促甲状腺释放素)、MSH(促黑素)、类固醇激素如雄激素和***;生长因子和集落刺激因子如EGF、TGFα、胰岛素类生长因子(IGF-I、IGF-II)G-CSF、M-CSF和GM-CSF {Burgess,5Immunology Today 155-158(1984)};维生素如叶酸和铁传递蛋白{O′Keefe等人,260J.Biol.Chem.932-937(1985)}。
术语“细胞结合剂”还包括改性细胞结合剂,其中所述细胞结合剂通过改性剂改性以改进所述细胞结合剂对茅屋霉素衍生物的连接物的连接基的反应性。
单克隆抗体技术能以特异性单克隆抗体形式生产极其选择性的细胞结合剂。本领域中特别公知的是通过用相关抗原,如完整靶细胞、由靶细胞分离的抗原、全病毒、削弱的全病毒和病毒蛋白质如病毒壳体蛋白质免疫小鼠、大鼠、仓鼠或任何其它哺乳动物而产生单克隆抗体的制造技术。
适当的细胞结合剂的选择是取决于靶向的特定细胞群落的选择问题,但通常优选单克隆抗体,只要可获得适当的单克隆抗体。例如,单克隆抗体MY9是鼠科IgG1抗体,其特异性结合到CD33抗原上{J.D.Griffin等人8Leukemia Res.,521(1984)},如果靶细胞表达CD33,如在急性骨髓性白血病(ALM)中那样,则其可以使用。类似地,单克隆抗体抗-B4是鼠科IgG1,其结合到B细胞上的CD19抗原上{Nadler等人,131J.Immunol.244-250(1983)},如果靶细胞是B细胞或表达此抗原的患病细胞时,如在非霍奇金淋巴瘤或慢性成淋巴细胞白血病中那样,则其可以使用。如上所述,MY9和抗-B4抗体可以是鼠科、嵌合、人源化或全人的。
另外,结合到骨髓细胞上的GM-CSF可用作来自急性骨髓性白血病的患病细胞的细胞结合剂。结合到活化T-细胞上的IL-2可用于预防移植物排异、用于治疗和预防移植物抗宿主病、用于治疗急性T细胞白血病。结合到黑素细胞上的MSH可用于治疗黑素瘤。
可用于制备该缀合物分子的合适的单克隆抗体的实例可以是hu2H11(ATCC以PTA-7662为名注册)、WO 2004/043344中描述的huMy9-6之一、WO 2005/009369中描述的huDS6或WO 2008/047242、WO 2005/061541或WO 02/16101中描述的一种。
该茅屋霉素衍生物可以经由酰胺型官能团连接到抗体或其它细胞结合剂上。优选地,合成该衍生物以含有羧酸官能团,随后使一种或更多种含羧酸的衍生物各自经由酰胺键共价连接到该细胞结合剂上。
本发明的代表性缀合物是抗体-茅屋霉素衍生物、抗体片段-茅屋霉素衍生物表皮生长因子(EGF)-茅屋霉素衍生物、促黑素(MSH)-茅屋霉素衍生物、促甲状腺素(TSH)-茅屋霉素衍生物、***-茅屋霉素衍生物、***类似物-茅屋霉素衍生物、雄激素-茅屋霉素衍生物、雄激素类似物-茅屋霉素衍生物和叶酸-茅屋霉素衍生物。该缀合物可以通过HPLC或通过凝胶过滤法提纯。
优选地,单克隆抗体-或细胞结合剂-茅屋霉素衍生物缀合物是如上所述经由酰胺键连接的那些,其能够输送茅屋霉素衍生物。可以使用茅屋霉素二聚物连接物末端的羧酸官能团的N-羟基琥珀酰亚胺衍生物制备缀合物。通过这种方法容易制备含有1至10种经由酰胺键连接的茅屋霉素衍生物药物的缀合物。
更具体地,抗体在含有0.05M磷酸钾、0.05M氯化钠和2mM乙二胺四乙酸(EDTA)的水性缓冲液(pH 8)中的8毫克/毫升浓度溶液用5倍摩尔过量的茅屋霉素二聚物的N-羟基琥珀酰亚胺衍生物在二甲基乙酰胺(DMA)中的溶液处理,以使缓冲液中的DMA最终浓度为20%。该反应混合物在室温(rt)下搅拌70分钟。提纯抗体-茅屋霉素衍生物缀合物并通过经由Sephadex G-25或Sephacryl S300或Superdex 200柱的凝胶过滤除去未反应药物和其它低分子材料。该样品还可以在pH 6.5缓冲液中透析整夜以进一步提纯产物。可通过测量在320nm和280nm的吸光率比率来测定每个抗体分子结合的茅屋霉素衍生物的数量。通过这种方法,经由酰胺键可连接平均1-10个茅屋霉素衍生物分子/抗体分子。
可以使用Liu等人,93Proc.Natl.Acad.Sci 8618-8623(1996)先前描述的方法测定结合对于与抗原表达细胞的结合亲合力的影响。茅屋霉素衍生物及其抗体缀合物对细胞系的细胞毒性可通过如Goldmacher等人,135J.Immunol.3648-3651(1985)中所述的细胞增殖曲线的反外推法测量。这些化合物对粘附细胞系的细胞毒性可通过如Goldmacher等人,102J.Cell Biol.1312-1319(1986)中所述的克隆化验测定。
本发明的代表性缀合物是茅屋霉素衍生物与抗体、抗体片段、表皮生长因子(EGF)、促黑素(MSH)、促甲状腺素(TSH)、***、***类似物、雄激素和雄激素类似物的缀合物。
下面描述衍生物和细胞结合剂的各种缀合物的制备的代表性实例。
酰胺连接物:例如,单克隆抗体MY9是鼠科IgG1抗体,其特异性结合到CD33抗原上{J.D.Griffin等人8Leukemia Res.,521(1984)},如果靶细胞表达CD33,如在急性骨髓性白血病(ALM)中那样,则其可以使用。类似地,单克隆抗体抗-B4是鼠科IgG1,其结合到B细胞上的CD 19抗原上{Nadler等人,131J.Immunol.244-250(1983)},如果靶细胞是B细胞或表达此抗原的患病细胞时,如在非霍奇金淋巴瘤或慢性成淋巴细胞白血病中那样,则其可以使用。
另外,结合到骨髓细胞上的GM-CSF可用作来自急性骨髓性白血病的患病细胞的细胞结合剂。结合到活化T-细胞上的IL-2可用于预防移植物排异、用于治疗和预防移植物抗宿主病、用于治疗急性T细胞白血病。结合到黑素细胞上的MSH可用于治疗黑素瘤。
使抗体或其它细胞结合剂与N-羟基-琥珀酰亚胺酸衍生物反应以制造酰胺连接的缀合物。
通过上述方法制成的缀合物可以通过标准色谱技术,如尺寸排阻法、吸附色谱法(包括但不限于离子交换、疏水相互作用色谱法、亲合色谱法、在陶瓷羟磷灰石上或在Porapak上的色谱法)或通过HPLC提纯。也可以通过透析或渗滤提纯。
优选地,单克隆抗体或细胞结合剂和本发明的衍生物之间的缀合物是如上所述经由酰胺键连接的那些。这类细胞结合性缀合物通过已知方法制备,如将具有羧酸官能团的可连接的药物分子改性以产生N-羟基-琥珀酰亚胺酸衍生物。所得活化的羧基随后将抗体的赖氨酸残基酰化以产生酰胺连接的缀合物。通过这种方法容易制备含有经由酰胺桥连接的1至10个衍生物的缀合物。
根据优选方面,该细胞结合剂是抗体,特别是单克隆抗体。根据本发明的另一优选方面,该细胞结合剂是抗原特异性抗体片段,如FV、Fab、Fab’或F(ab’)2。
关于缀合物分子的用途
本发明还涉及包含本发明的缀合物分子或如上定义的茅屋霉素衍生物以及药物上可接受的载体的药物组合物。
本发明还涉及杀死或抑制细胞,优选所选细胞群落生长的方法,包括使靶细胞或含有靶细胞的组织与有效量的药物组合物接触。所选细胞群落是癌细胞和/或增殖细胞。本发明还涉及治疗,优选选择性治疗癌症的方法,包括向需要治疗的患者施用有效量的该药物组合物。“选择性治疗癌症”是指杀死癌细胞和/或增殖细胞,且基本不杀死正常和/或非增殖细胞。
本发明还涉及如上定义的缀合物分子或茅屋霉素衍生物用于制备癌症治疗药物的用途。
抑制所选细胞群落生长的方法可体外、体内或离体(exvivo)实施。体外应用的实例包括处理细胞培养物以杀死除不表达靶抗原的所需变体外的所有细胞;或杀死表达不需要的抗原的变体。熟练技术人员容易确定非临床体外应用的条件。离体应用的实例包括在移植入同一患者体内之前处理自体同源骨髓以杀死患病细胞或恶性细胞:移植之前的骨髓处理以杀死感受态T细胞和防止移植物抗宿主病(GVHD)。可以如下进行临床离体处理,以在癌症治疗或自体免疫疾病治疗中的自体同源移植前从骨髓中除去肿瘤细胞或淋巴细胞,或以在移植前从异源骨髓或组织中除去T细胞和其它淋巴细胞从而预防GVHD。从患者或其它个体中收集骨髓,随后在含有血清的培养基中培养,向其中加入本发明的细胞毒性剂,浓度为约10μM至1pM,在约37℃培养约30分钟至约48小时。熟练技术人员容易确定浓度和培养时间(=剂量)的确切条件。在培养后,骨髓细胞用含血清的培养基洗涤,根据已知方法通过静脉内输注返回患者。在患者接受其它治疗,如在获取骨髓和处理过的细胞的再输注之间的ablative化疗或全身放射治疗过程的情况下,处理过的骨髓细胞用标准医学设备冷冻储存在液氮中。对于临床体内应用,本发明的细胞毒性剂以测试了无菌性和内毒素含量的溶液形式或以可再溶解在无菌水中以供注射的冻干固体形式供给。合适的缀合物给药制度如下。缀合物作为静脉推注剂每周给药持续6周。推注剂在50至400毫升生理盐水中给药,可以向该生理盐水中加入人血清白蛋白(例如0.5-1毫升人血清白蛋白浓溶液,100毫克/毫升)。剂量为每周大约50微克至100毫克/公斤体重,静脉内。在治疗后6周,患者可接受第二次治疗过程,关于给药途径、赋形剂、稀释剂、剂量、时间等的具体临床方案可由熟练技术人员根据临床状况确定。
可根据杀死所选细胞群落的体内或离体方法治疗的医学病症的实例包括任何类型的恶性肿瘤,包括例如肺癌、乳腺癌、结肠癌、***癌、肾癌、胰腺癌、卵巢癌和淋巴器官癌;黑素瘤;自体免疫疾病,如***性狼疮、风湿性关节炎和多发性硬化;移植排异,如肾移植排异、肝移植排异、肺移植排异、心脏移植排异和骨髓移植排异;移植物抗宿主病;病毒感染,如CMV感染、HIV感染、AIDS等;细菌感染;和寄生虫感染,如贾第鞭毛虫病、阿米巴病、血吸虫病和由本领域技术人员确定的其它疾病。
作为本领域技术人员的主治诊断医生可以通过使用常规技术和通过观察在类似情况下获得的结果容易地确定治疗有效量。在确定治疗有效量时,主治诊断医生考虑许多因素,包括但不限于:患者种类;体重、年龄和一般健康;所涉及的具体疾病;患病程度或疾病的严重性;个体患者的响应;给予的具体化合物;给药模式;给予的制剂的生物利用率特性;所选剂量制度;伴随药物治疗的使用;和其它相关情况。
实现所需生物效应所需要的量随许多因素而变,包括所用化合物的化学特性(例如疏水性)、化合物效力、疾病类型、患者所属的物种、患者病状、给药途径、该化合物通过所选途径的生物利用率,决定所需剂量、输送和给药方案的所有因素。
一般而言,本发明的化合物可以在含有0.1-10%w/v化合物的含水生理缓冲溶液中提供以用于肠道外给药。典型剂量范围是每天1微克/公斤至0.1克/公斤体重;优选剂量范围是每天0.01毫克/公斤至10毫克/公斤体重或在儿童中的相当剂量。所给药物的优选剂量可能取决于如下变量:疾病或失调症的类型和进展程度、特定患者的整体健康状况、所选化合物的相对生物学效力、化合物的配方、给药途径(静脉内、肌内、腹膜内、皮下或其它)、该化合物通过所选输送途径的药物动力学性质,以及给药速度(推注剂或连续输液)和时刻表(在给定时期内的重复数)。
该组合物可以方便地以单位剂型给药,并可以通过制药领域中公知的任何方法,例如Remington:The Science and Practice of Pharmacy,第20版;Gennaro,A.R.,Ed.;Lippincott Williams & Wilkins:Philadelphia,PA,2000中所述的方法制备。
用于肠道外给药的液体制剂包括无菌水性或非水溶液、悬浮液或乳状液。该液体组合物还可包括粘合剂、缓冲剂、防腐剂、螯合剂、增甜剂、香料和着色剂等。非水溶剂包括醇、丙二醇、聚乙二醇、植物油如橄榄油、和有机酯如油酸乙酯。水性载体包括醇和水的混合物、缓冲介质和盐水。特别地,生物相容的、可生物降解的交酯聚合物、交酯/乙交酯共聚物或聚氧乙烯-聚氧丙烯共聚物是可用的赋形剂以控制活性化合物的释放。静脉内赋形剂可包括液体和营养补充剂、电解质补充剂,如基于Ringer’s葡萄糖的那些,和类似物。这些活性化合物的其它可能可用的肠道外输送体系包括乙烯-乙酸乙烯酯共聚物粒子、渗透泵、可植入输注体系和脂质体。
附图
图1:实施例1的4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸甲酯的体外细胞毒性;
图2:实施例2的4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙酸甲酯的体外细胞毒性;
图3:实施例8的化合物8(IGP08)和9(IGP08-OMe)的体外细胞毒性效力;
图4代表实施例11的去糖基化的huMy9-6-4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酰基缀合物(通过UV,具有2.1Drug/Ab,即通过UV测得,每个抗体2.1个茅屋霉素衍生物)的质谱分析;
图5:实施例12的去糖基化的huB4-4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酰基缀合物(通过UV,4.48Drug/Ab)的质谱分析;
图6:实施例13的去糖基化的hu2H11-4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酰基缀合物(通过UV,3.74Drug/Ab)的MS分析;
图7:实施例14的huMy9-6-3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酰基缀合物(通过UV,4.8Drug/Ab)的MS分析;
图8:实施例15的hu2H11-3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酰基缀合物(通过UV,4.08Drug/Ab)的MS分析;
图9:去糖基化的huB4-IGP08(实施例18的化合物)的MS分析;
图10:裸huMy9-6和huMy9-6-IGP08(实施例18的化合物)与抗原CD33的对比结合性质;
图11:huB4-IGP08(实施例18的化合物)对Ramos(Ag-)和HL60/QC(Ag+)细胞的体外细胞毒性效力;
图12:实施例19的去糖基化的huB4-IGP08(通过UV,3.1Drug/Ab)的MS分析;
图13:huB4-IGP08(实施例19的化合物)对BJAB(Ag+)、Ramos(Ag+)和MOLT-4(Ag-)细胞的细胞毒性;
图14:裸huB4和huB4-IGP08(实施例19的化合物)的对比结合性质;
图15:实施例21的去糖基化的hu2H11-IGP13(通过UV,4.7Drug/Ab)的MS分析;
图16:hu2H11-IGP13(实施例21的化合物)对PC3(Ag+)、MDA-MB-231(Ag+)和SK-MEL-28(Ag-)细胞的细胞毒性;
图17:实施例5的3-(2-{2-[2-(2,6-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-吡啶-4-氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯的细胞毒性;
图18:实施例6的4-(2,6-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-吡啶-4-氧基)-丁酸甲酯的细胞毒性;
图19:实施例7的N-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙基]-N-甲基-琥珀酰胺酸甲酯的细胞毒性;
图20:来自实施例11的huMy9-6-4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酰基缀合物的体外细胞毒性数据;
图21:来自实施例12的huB4-4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酰基缀合物的体外细胞毒性数据;
图22:来自实施例13的hu2H11-4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酰基缀合物的体外细胞毒性数据;
图23:来自实施例14的huMy9-6-3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酰基缀合物的体外细胞毒性数据;
图24:来自实施例15的hu2H11-3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酰基缀合物的体外细胞毒性数据。
实验部分
方法A 1:高压液相色谱法-质谱法(LCMS)
使用Micromass MassLynx软件,在Waters Alliance HPLC上进行分析,其带有WATERS XBridge C18 3,5μm柱(100×3mm),用(A)甲醇和(B)水/0.1%甲酸的混合物以1.1毫升/分钟流速梯度洗脱(梯度:5%A:95%B经10分钟至95%A:5%B,95%A:5%B经1分钟降至5%A:95%B,5%A:95%B 2分钟);具有电喷雾(正和负电离)的Waters-Micromass Platform II光谱仪;直线二极管阵列(190-500nm);辅助检测器Sedere(France)型号SEDEX 85蒸发光散射(ELS)检测器。
方法A2:高压液相色谱法-质谱法(LCMS)
使用Micromass MassLynx软件,在Agilent 1100series HPLC上进行分析,其带有XBridge C18 2.5μm柱(50×3mm),用(A)乙腈和(B)水/0.1%甲酸的混合物以1.1毫升/分钟流速梯度洗脱(梯度:5%A:95%B经5分钟至100%A,100%A 0.5分钟,100%A经1分钟降至5%A:95%B,5%A:95%B 0.5分钟));带有电喷雾(正和负电离)的Waters-Micromass ZQ光谱仪;直线二极管阵列(210-254nm)。
方法A3:高压液相色谱法-质谱法(LCMS)
在Waters UPLC-SQD上进行分析,其带有在50℃下的ACQUITYBEH C18 1,7μm-2.1×50mm柱,用(A)H2O/0.1%甲酸和(B)CH3CN/0.1%甲酸的混合物以1毫升/分钟流速梯度洗脱(梯度:95%A:5%B经0.8分钟降至50%A:50%B,50%A:50%B经1.2分钟降至100%B,100%B 1.85分钟,100%B经1.95分钟升至95%A:5%B);电喷雾(正和/负电离)。
方法A4:高压液相色谱法-质谱法(LCMS)
在Waters ZQ光谱仪上进行分析,其带有在70℃下的XBridge C182.5μm柱(50×3mm),用(A)乙腈和(B)水/0.1%甲酸的混合物以0.9毫升/分钟流速梯度洗脱(梯度:5%A:95%B经5.3分钟至100%A,100%A 5.5分钟,5%A:95%B 6.3分钟));电喷雾(正和负电离)。
方法B:1H核磁共振(NMR)谱
在BRUKER AVANCE DRX-500、BRUKER AVANCE DRX-400光谱仪或BRUKER AVANCE DRX-300光谱仪上记录1H NMR谱。在BRUKER AVANCE DRX-300光谱仪上记录所报道的13C NMR谱。
方法C:化学电离(CI)质谱
使用WATERS GCT质谱仪(氨)记录CI质谱。
方法D:化学电离(CI)质谱;使用FINNIGAN SSQ 7000质谱仪(氨)记录CI质谱。
实施例1:4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸N-羟基琥珀酰亚胺酯可以如下制备:
向4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸(11.3毫克)在四氢呋喃(0.4毫升)中的悬浮液中加入N,N′-二琥珀酰亚胺基碳酸酯(7.7毫克)和N,N-二异丙基乙基胺(15.8微升)。在室温下2.5小时后,将乙酸乙酯(6毫升)添加到反应混合物中,该有机溶液用水(4毫升)然后用饱和氯化钠水溶液(5毫升)洗涤两次,经硫酸镁干燥并真空浓缩成残留物。该残留物通过硅胶色谱法提纯(Merck MiniVarioFlash 2.5g柱,Si6015-40微米),用MeOH(甲醇)(A)/DCM(二氯甲烷)(B)的混合物梯度洗脱(梯度:2%A:98%B至4%A:96%B)以获得4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸N-羟基琥珀酰亚胺酯(17.6毫克):LC/MS(方法A4):ES:m/z 846(M+H)+;停留时间(RT)=3.89分钟;1H NMR(400MHz,CDCI3-d1,δppm):δ=1.75(d,J=6.8Hz,6H);2.23(m,2H);2.73-2.87(m,6H);2.97(m,4H);3.84-3.95(m,2H);3.97(s,6H);4.06(m,2H);4.26(m,4H);5.14(d,J=12.4Hz,2H);5.21(d,J=12.4Hz,2H);5.62(m,2H);6.84(s,2H);6.96(s,2H);7.09(s,1H);7.53(s,2H);7.63(m,2H)。
4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸可以如下制备
向4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸甲酯(60毫克)在四氢呋喃(0.9毫升)中的溶液中加入MeOH(0.3毫升)、水(0.3毫升)和氢氧化锂水溶液(1M,87微升)。3小时后,该反应混合物用水(10毫升)稀释,通过添加盐酸水溶液1N,将pH值调节至2。水相用DCM(10毫升)萃取三次,合并的有机溶液经硫酸钠干燥,并真空浓缩成残留物。该残留物通过硅胶色谱法提纯(Merck SuperVarioFlash10g柱,SiOH 15-40微米),用DCM/MeOH/乙酸(100∶4∶0.5)的混合物洗脱以获得4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸:LC/MS(方法A2):ES:m/z=749MH+;m/z=375(M+2H)2+/2;RT=3.7min;1H N.M.R.(400MHz,DMSO-d6,δ以ppm计):δ=1.69(d,J=6.5Hz,6H);1.95(m,2H);2.39(t,J=6.5Hz,2H);2.91(m,2H);3.05(m,2H);3.83(s,6H);3.98(m,2H);4.01(t,J=6.5Hz,2H);4.10(m,4H);5.11(d,J=12.5Hz,2H);5.20(d,J=12.5Hz,2H);5.55(m,2H);从6.90至7.15(m,5H);7.34(s,2H);7.77(m,2H);12.1(m宽,1H)。
向4-(3,5-双-羟甲基-苯氧基)-丁酸甲酯(50毫克)和三乙胺(110微升)在THF(四氢呋喃)(1.4毫升)中的冷(0℃)溶液中加入甲磺酰氯(46微升)。1小时后,该反应混合物用DCM(10毫升)稀释并用水(5毫升)洗涤两次。该有机溶液经硫酸钠干燥,并真空浓缩成残留物。该残留物通过硅胶色谱法提纯(Merck SuperVarioFlash 10g柱,SiOH 15-40微米),用MeOH(A)/DCM(B)的混合物梯度洗脱(梯度:100%B降至5%A:95%B)以获得71.8毫克二-甲磺酸酯化合物。向茅屋霉素(80毫克)、碘化钾(49毫克)、碳酸钾(122毫克)在DMF(二甲基甲酰胺)(1毫升)中的混合物中加入二-甲磺酸酯化合物(71.8毫克)在DMF(1.6毫升)中的溶液。该反应混合物在30℃下搅拌16小时。加入水(12毫升),将所得固体过滤,用水洗涤并真空干燥以获得残留物。该残留物通过硅胶色谱法提纯(Merck SuperVarioFlash30g柱,SiOH 15-40微米),用MeOH(A)/DCM(B)的混合物梯度洗脱(梯度:100%B降至5%A:95%B)以获得4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]-苯并二氮杂e-5-酮-8-基氧甲基]-苯氧基)-丁酸甲酯(65.4毫克):LC/MS(方法A2):ES:m/z=763MH+;m/z=382(M+2H)2+/2;RT=4.0min;1H N.M.R.(500MHz,CDCl3-d1,δ以ppm计):1.75(d,J=6.5Hz,6H);2.11(m,2H);2.53(t,J=6.5Hz,2H);2.98(m,4H);3.69(s,3H);3.89(m,2H);3.97(s,6H);4.00(t,J=6.5Hz,2H);4.28(s宽,4H);5.12(d,J=12.5Hz,2H);5.19(d,J=12.5Hz,2H);5.61(m,2H);6.82(s,2H);6.92(s,2H);7.06(s,1H);7.52(s,2H);7.64(d,J=4,5Hz,2H)。
4-(3,5-双-羟甲基-苯氧基)-丁酸甲酯可以如下制备:
向3,5-双-羟甲基酚(Felder,D.;Gutierrez Nava,M.;del Pilar Carreon,M.;Eckert,J.F.;Luccisano,M.;Schall,C;Masson,P.;Gallani,J.L.;Heinrich,B.;Guillon,D.;Nierengarten,J.F.HeIv.Chimica Acta 2002,85,288)(200毫克)、碘化钾(50毫克)和碳酸钾(540毫克)在THF(2.5毫升)中的溶液中加入4-溴-丁酸甲酯(400微升)。该反应混合物在室温下搅拌20小时,然后滤出不可溶部分。将滤液真空浓缩,残留物通过硅胶色谱法提纯(Merck SuperVarioFlash 30g柱,Si60 15-40微米),用MeOH(A)/DMC(B)的混合物梯度洗脱(梯度:100%B降至5%A:95%B)以获得4-(3,5-双-羟甲基-苯氧基)-丁酸甲酯(53.5毫克):LC/MS(方法A2):ES:m/z=255MH+;m/z=237(M+H-H2O)+;RT=2.5min;1H N.M.R.(400MHz,DMSO-d6,δ以ppm计):δ=1.96(m,2H);2,47(t,J=6.5Hz,2H);3.61(s,3H);3.96(t,J=6.5Hz,2H);4.43(d,J=6.0Hz,4H);5.11(t,J=6.0Hz,2H);6.71(s,2H);6.82(s,1H)。
4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙酸可以根据4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸的制备程序,以4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙酸甲酯为原料制备:LC/MS(方法A2):ES:m/z=721MH+;m/z=361(M+2H)2+/2;RT=3.5min
4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙酸甲酯可以根据4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸甲酯的制备程序,以4-(3,5-双-羟甲基-苯氧基)-乙酸甲酯为原料制备:LC/MS(方法A2):ES:m/z=735MH+;m/z=368(M+2H)2+/2;RT=3.8min;1H N.M.R.(500MHz,CDCl3-d1,δ以ppm计):δ=1.76(d,J=6.5Hz,6H);2.96(m,4H);3.78(s,3H);3.88(m,2H);3.97(s,6H);4.27(s宽,4H);4.64(s,2H);5.13(d,J=12.5Hz,2H);5.19(d,J=12.5Hz,2H);5.60(m,2H);6.80(s,2H);6.96(s,2H);7.11(s,1H);7.53(s,2H);7.63(d,J=4.5Hz,2H)。
4-(3,5-双-羟甲基-苯氧基)-乙酸甲酯:
4-(3,5-双-羟甲基-苯氧基)-乙酸甲酯可以根据4-(3,5-双-羟甲基-苯氧基)-丁酸甲酯的制备程序,以4-溴-乙酸甲酯为原料制备:LC/MS(方法A2):ES:m/z=227MH+;m/z=209(M+H-H2O)+;RT=1.9min;1H N.M.R.(400MHz,DMSO-d6,δ以ppm计):δ=3.70(s,3H);4.43(d,J=6.0Hz,4H);4.74(s,2H);5.14(t,J=6.0Hz,2H);6.72(s,2H);6.88(s,1H)。
实施例3:3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸N-羟基琥珀酰亚胺酯:
3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸N-羟基琥珀酰亚胺酯可以根据4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸N-羟基琥珀酰亚胺酯的制备程序,以3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸为原料制备:LC/MS(方法A3):ES:m/z 964(M+H)+;RT=0.90min;1H NMR(500MHz,CDCl3-d1,δppm):δ=1.75(dd,J=6.7Hz,6H);2.82(m,4H);2.89(t,J=6.6Hz,2H);2.97(m,4H);3.57-4.23(m,16H);3.97(s,6H);4.27(m,4H);5.13(d,J=12.7Hz,2H);5.20(d,J=12.2Hz,2H);5.61(m,2H);6.82(s,2H);6.96(s,2H);7.07(s,1H);7.53(s,2H);7.64(d,J=4.4Hz,2H)。
3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸:
3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸可以根据4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸的制备程序,以3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯为原料制备:LC/MS(方法A3):ES:m/z 867(M+H)+;m/z 434(M+2H)2+/2;RT=0.84min;1H NMR(400MHz,CDCl3-d1,δppm):δ=1.76(dd,J=8.6,1.5Hz,6H);2.61(t,2H);2.94-3.00(m,4H);3.63-3.75(m,8H);3.80(t,J=6.5Hz,2H);3.85-3.95(m,4H);3.98(s,6H);4.17(t,J=4.9Hz,2H);4.27(br.s.,4H);5.14-5.21(m,2H);5.18(d,J=12.7Hz,2H);5.23(d,2H);5.23(d,J=12.7Hz,2H)5.62(td,J=4.5,2.2Hz,2H);6.88(d,J=0.5Hz,2H);6.97-7.02(m,2H);7.09(s,1H);7.54(s,2H);7.68(d,J=4.9Hz,2H)
3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯:
3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯可以根据4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸甲酯的制备程序,以3-(2-{2-[2-(3,5-双-羟甲基)-苯氧基]-乙氧基}-乙氧基)-乙氧基)-丙酸甲酯为原料制备:LC/MS(方法A3):ES:m/z881(M+H)+;m/z 441(M+2H)2+/2;RT=0.91min;1H NMR(400MHz,CDCl3-d1,δppm):δ=1.75(d宽,J=6.7Hz,6H);2.60(t,J=6.7Hz,2H);2.97(m,4H);3.54-4.21(m,16H);3.68(s,3H);3.97(s,6H);4.27(m,4H);5.13(d,J=12.2Hz,2H);5.21(d,J=12.2Hz,2H);5.61(m,2H);6.83(s,2H);6.96(s,2H);7.08(s,1H);7.53(s,2H);7.64(d,J=4.2Hz,2H)
3-(2-{2-[2-(3,5-双-羟甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯可以如下制备:
向3-(2-{2-[2-(3,5-双-羟甲基)-苯氧基]-乙氧基}-乙氧基)-乙氧基)-丙酸叔丁酯(607毫克)在DCM(8.7毫升)中的溶液中加入三氟乙酸(2.2毫升)。该反应混合物在室温下搅拌3天,然后真空浓缩,将所得残留物溶解在甲醇(5毫升)中。向该冷却的(0℃)甲醇溶液中加入在己烷中的(三甲基甲硅烷基)重氮甲烷2M(3.6毫升)直至留下黄色。然后加入乙酸(10微升)并将所得溶液真空浓缩成残留物。该残留物通过硅胶色谱法提纯(Analogix Super Flash SiO2 SF25-40g),用DCM(A)和MeOH(B)的混合物梯度洗脱(梯度:99%A:1%B降至90%A:10%B)以获得3-(2-{2-[2-(3,5-双-羟甲基)-苯氧基]-乙氧基}-乙氧基)-乙氧基)-丙酸甲酯(232毫克)。LC/MS(方法A3):ES:m/z 373(M+H)+;m/z 395(M+Na)+;RT=0.50min
3-(2-{2-[2-(3,5-双-羟甲基)-苯氧基]-乙氧基}-乙氧基}-乙氧基}-丙酸叔丁酯:
3-(2-{2-[2-(3,5-双-羟甲基)-苯氧基]-乙氧基}-乙氧基)-乙氧基)-丙酸叔丁酯可以根据4-(3,5-双-羟甲基-苯氧基)-丁酸甲酯的制备程序,以3-{2-[2-(2-溴-乙氧基)-乙氧基]-乙氧基}-丙酸叔丁酯(WO 2004/091542)为原料制备:LC/MS(方法A3):ES:m/z 415(M+H)+;m/z 432(M+NH4)+;RT=0.75min
实施例4:6-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯基)-己-5-炔酸N-羟基琥珀酰亚胺酯
6-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯基)-己-5-炔酸N-羟基琥珀酰亚胺酯可以根据4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸N-羟基琥珀酰亚胺酯的制备程序,以6-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯基)-己-5-炔酸为原料制备:LC/MS(方法A3):ES:m/z 854(M+H)+;RT=1.25min
6-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯基)-己-5-炔酸可以根据4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸的制备程序,以6-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯基)-己-5-炔酸甲酯为原料制备:LC/MS(方法A3):ES:m/z 757(M+H)+;RT=0.89min;1H NMR(400MHz,CDCl3-d1,δppm):δ=1.76(d,J=6.8Hz,6H);1.98(m,2H);2.55(m,4H);2.97(m,4H);3.91(m,2H);3.97(s,6H);4.27(m,4H);5.15(d,J=12.8Hz,2H);5.21(d,J=12.8Hz,2H);5.61(m,2H);6.88(s,2H);7.48(s,3H);7.53(s,2H);7.67(m,2H)
6-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯基)-己-5-炔酸甲酯可以根据4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸甲酯的制备程序,以6-(3,5-双-羟甲基-苯基)-己-5-炔酸甲酯为原料制备:LC/MS(方法A3):ES:m/z771(M+H)+;RT=1.00min;1H NMR(500MHz,CDCl3-d1,δppm):δ=1.75(d,J=6.6Hz,6H);1.93(m,2H);2.50(m,4H);2.96(m,4H);3.69(s,3H);3.90(m,2H);3.97(s,6H);4.27(m,4H);5.12(d,J=12.3Hz,2H);5.19(d,J=12.3Hz,2H);5.61(m,2H);6.81(s,2H);7.43(s,3H);7.54(s,2H);7.64(d,J=4.4Hz,2H)
6-(3,5-双-羟甲基-苯基)-己-5-炔酸甲酯如下制备:
向6-[3,5-双-(叔丁基-二甲基-甲硅烷氧基甲基)-苯基]-己-5-炔酸甲酯(140毫克)在无水四氢呋喃(0.3毫升)中的冷却(0℃)溶液中稍微加入四丁基氟化铵1M在THF中的溶液(716微升)。在室温下75分钟后,加入乙酸乙酯(20毫升),有机相用水(5毫升)洗涤三次并用饱和氯化钠水溶液(5毫升)洗涤一次,经硫酸钠干燥并真空浓缩成残留物。该残留物通过硅胶色谱法提纯(Merck SuperVarioFlash 15g柱,Si6015-40微米),用庚烷(A)/乙酸乙酯(B)的混合物梯度洗脱(梯度:50%A:50%B降至10%A:90%B)以获得浅黄色油状的6-(3,5-双-羟甲基-苯基)-己-5-炔酸甲酯(64.3毫克)。LC/MS(方法A3):ES:m/z263(M+H)+;RT=0.62min
6-[3,5-双-(叔丁基-二甲基-甲硅烷氧基甲基)-苯基]-己-5-炔酸甲酯可以如下制备
向1,3-双-羟甲基-5-碘代苯(Zeng,F.;Zimmerman,S.C.J.Am.Chem.Soc.1996,118(22),5326-5327)(1.7克)在二氯甲烷(10毫升)中的溶液中加入三乙胺(3.59毫升)、叔丁基二甲基甲硅烷基氯(2.91克)和DMF(2毫升)。1小时后,加入乙酸乙酯(200毫升),有机相用水(50毫升)洗涤三次并用饱和氯化钠水溶液(50毫升)洗涤一次,经硫酸镁干燥并真空浓缩成残留物(3.65克)。向前述残留物(200毫克)在DMF(0.90毫升)中的溶液中加入碘化铜(I)(7.7毫克)、二氯双(三苯基膦)钯(II)(28.5毫克)、5-己炔酸甲酯(102.4毫克)和三乙胺(113微升)。45分钟后,加入乙酸乙酯(40毫升),有机相用水(10毫升)洗涤三次并用饱和氯化钠水溶液(10毫升)洗涤一次,经硫酸镁干燥并真空浓缩成残留物。该残留物通过硅胶色谱法提纯(MerckSuperVarioFlash 30g柱,Si6015-40微米),用庚烷(A)/乙酸乙酯(B)的混合物梯度洗脱(梯度:100%A降至90%A:10%B)以获得黄色油状的6-[3,5-双-(叔丁基-二甲基-甲硅烷氧基甲基)-苯基]-己-5-炔酸甲酯(145.3毫克)。MS(方法C):Cl:m/z 494(M+NH4)+;1H N.M.R.(400MHz,DMSO-d6,δ以ppm计):δ=0.07(s,12H);0.89(s,18H);2.55-2.69(m,2H);3.63(s,3H);4.67(s,4H);7.15(s大,2H);7.28(s宽,1H)
实施例5:3-(2-{2-[2-(2,6-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-吡啶-4-氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯:
3-(2-{2-[2-(2,6-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-吡啶-4-氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯可以根据4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸甲酯的制备程序,以3-(2-{2-[2-(2,6-双-羟甲基-吡啶-4-氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯为原料制备:LC/MS(方法A3):ES:m/z882(M+H)+;m/z 441.5(M+2H)2+/2;RT=0.82min;1H NMR(400MHz,CDCl3-d1,δppm):δ=1.76(d,J=6.8Hz,6H);2.59(t,J=6.5Hz,2H);2.97(m,4H);3.58-3.72(m,9H);3.75(t,J=6.5Hz,2H);3.80-3.97(m,4H);4.00(s,6H);4.20(m宽,2H);4.27(m,4H);5.31-5.42(m,4H);5.61(m宽,2H);6.87(s,2H);7.02-7.15(m宽,2H);7.56(s,2H);7.65(d,J=4.4Hz,2H)
3-(2-{2-[2-(2,6-双-羟甲基-吡啶-4-氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯:
3-(2-{2-[2-(2,6-双-羟甲基-吡啶-4-氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯可以根据3-(2-{2-[2-(3,5-双-羟甲基)-苯氧基]-乙氧基}-乙氧基)-乙氧基)-丙酸甲酯的制备程序,以3-(2-{2-[2-(2,6-双-羟甲基-吡啶-4-氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸叔丁酯为原料制备:LC/MS(方法A3):ES:m/z 374(M+H)+;m/z 418(M+HCO2H-H)-;RT=0.31min
3-(2-{2-[2-(2,6-双-羟甲基-吡啶-4-氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸叔丁酯:
向4-(2-{2-[2-(2-叔丁氧基羰基-乙氧基)-乙氧基]-乙氧基}-乙氧基)-吡啶-2,6-二羧酸二乙酯(1.36克)在无水乙醇(72毫升)中的溶液中加入硼氢化钠(309毫克)和氯化钙(921毫克)。搅拌30分钟后,氢气释放停止,用水骤冷反应。减压浓缩后,加入氯化铵,水相用乙酸乙酯萃取三次。合并的有机溶液经硫酸镁干燥,并真空浓缩成残留物。该残留物通过硅胶色谱法提纯(Analogix Super Flash SiO2 SF25-80g),用DCM(A)和MeOH(B)的混合物梯度洗脱(梯度:100%A降至90%A:10%B)以获得3-(2-{2-[2-(2,6-双-羟甲基-吡啶-4-氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸叔丁酯(720毫克):LC/MS(方法A3):ES:m/z 416(M+H)+;RT=0.52min
4-(2-{2-[2-(2-叔丁氧基羰基-乙氧基)-乙氧基]-乙氧基}-乙氧基)-吡啶-2,6-二羧酸二乙酯:
向12-羟基-4,7,10-三氧杂癸酸叔丁酯(1.91毫升)在DCM(12.9毫升)中的冷却(0℃)溶液中加入三乙胺(1.13毫升),加入甲磺酰氯(622微升)。3小时后,将反应混合物真空浓缩成残留物,然后溶解在乙酸乙酯(13毫升)中。滤出不可溶部分,用乙酸乙酯(7毫升)洗涤两次,将合并的有机溶液真空浓缩成残留物(2.77克)。向1.64克该残留物在无水乙腈(10毫升)中的溶液中加入白屈氨酸二乙酯(Scrimin,P.;Tecilla,P.;Tonellato,U.;Vendrame,T.J.Org.Chem.1989,54,5988)(1克)和碳酸钾(2.88克)。回流24小时后,滤出不可溶部分并用乙酸乙酯洗涤。然后将有机相真空浓缩成残留物。该残留物通过硅胶色谱法提纯(Merck SuperVarioPrep 200g柱,Si6015-40微米),用DCM(A)和MeOH(B)的混合物梯度洗脱(梯度:100%A降至97%A:3%B)以获得4-(2-{2-[2-(2-叔丁氧基羰基-乙氧基)-乙氧基]-乙氧基}-乙氧基)-吡啶-2,6-二羧酸二乙酯(1.36克):LC/MS(方法A4):ES:m/z 500(M+H)+;m/z 522(M+Na)+;m/z 444(M-C4H8+H)+;RT=4.32min
实施例6:4-(2,6-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-吡啶-4-氧基)-丁酸N-羟基琥珀酰亚胺酯:
4-(2,6-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-吡啶-4-氧基)-丁酸N-羟基琥珀酰亚胺酯可以根据4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸N-羟基琥珀酰亚胺酯的制备程序,以4-(2,6-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-吡啶-4-氧基)-丁酸为原料制备:LC/MS(方法A3):ES:m/z 847(M+H)+;m/z 424(M+2H)2+/2;RT=0.80min;1H NMR(400MHz,CDCl3-d1,δppm):1.75(d宽,J=6.6Hz,6H);2.23(m宽,2H);2.76-2.89(m宽,6H);2.97(m宽,4H);3.91(m宽,2H);4.00(s宽,6H);4.14(m宽,2H);4.27(m宽,4H);5.28(m宽,4H);5.61(m宽,2H);6.87(s宽,2H);7.03(s宽,2H);7.56(s宽,2H);7.65(m宽,2H)
4-(2,6-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-吡啶-4-氧基)-丁酸盐酸盐:
4-(2,6-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-吡啶-4-氧基)-丁酸盐酸盐可以根据4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸的制备程序,以4-(2,6-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-吡啶-4-氧基)-丁酸甲酯为原料制备:LC/MS(方法A3):ES:m/z 750(M+H)+;m/z 375,5(M+2H)2+/2m/z 332,5(M-C4H6O2+2H)2+/2;RT=0.73min;1H NMR(400MHz,CDCl3-d1,δppm):δ=1.75(d,J=6.6Hz,6H);2.02(m,2H);2.42(m,2H);2.97(m,4H);3.83-4.14(m,4H);4.00(s,6H);4.27(m,4H);5.20-5.42(m,4H);5.61(m,2H);6.85(s,2H);6.94(s,2H);7.56(s,2H);7.63(m,2H)
4-(2,6-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-吡啶-4-氧基)-丁酸甲酯可以根据4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸甲酯的制备程序,以4-(2,6-双-羟甲基-吡啶-4-氧基)-丁酸甲酯为原料制备:LC/MS(方法A4):ES:m/z 764(M+H)+m/z 664(M-C5H8O2+H)+m/z 762(M-H)-RT=3.64min;1H NMR(500MHz,CDCl3-d1,δppm):δ=1.76(d,J=6.8Hz,6H);2.12(m,2H);2.50(t,J=7.3Hz,2H);2.97(m,4H);3.68(s,3H);3.90(m,2H);4.00(s,6H);4.07(m宽,2H);4.27(m,4H);5.29(m宽,4H);5.61(m,2H);6.86(s,2H);6.99(s宽,2H);7.56(s,2H);7.65(d,J=4.4Hz,2H)
4-(2,6-双-羟甲基-吡啶-4-氧基)-丁酸甲酯:
4-(2,6-双-羟甲基-吡啶-4-氧基)-丁酸甲酯可以根据3-(2-{2-[2-(3,5-双-羟甲基)-苯氧基]-乙氧基}-乙氧基)-乙氧基)-丙酸甲酯的制备程序,以4-(2,6-双-羟甲基-吡啶-4-氧基)-丁酸叔丁酯为原料制备:LC/MS(方法A3):ES:m/z 256(M+H)+RT=0.25min
4-(2,6-双-羟甲基-吡啶-4-氧基)-丁酸叔丁酯:
4-(2,6-双-羟甲基-吡啶-4-氧基)-丁酸叔丁酯可以根据3-(2-{2-[2-(2,6-双-羟甲基-吡啶-4-氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸叔丁酯的制备程序,以4-(3-叔丁氧基羰基-丙氧基)-吡啶-2,6-二羧酸二乙酯为原料制备:LC/MS(方法A4):ES:m/z 298(M+H)+;m/z 156(M-C8H14O2+H)+;RT=2.45min
4-(3-叔丁氧基羰基-丙氧基)-吡啶-2,6-二羧酸二乙酯:
4-(3-叔丁氧基羰基-丙氧基)-吡啶-2,6-二羧酸二乙酯可以根据4-(2-{2-[2-(2-叔丁氧基羰基-乙氧基)-乙氧基]-乙氧基}-乙氧基)-吡啶-2,6-二羧酸二乙酯的制备程序,以4-溴-丁酸叔丁基酯为原料制备:LC/MS (方法A4):ES:m/z 382(M+H)+m/z 404(M+Na)+m/z 785(2M+Na)+m/z 240(M-C8H14O2+H)+RT=4.65min
实施例7:N-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙基]-N-甲基-琥珀酰胺酸甲酯:
N-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙基]-N-甲基-琥珀酰胺酸甲酯可以根据4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸甲酯的制备程序,以N-[2-(3,5-双-羟甲基-苯氧基)-乙基]-N-甲基-琥珀酰胺酸甲酯为原料制备:LC/MS(方法A3):ES:m/z 834(M+H)+RT=0.87min;1HNMR(400MHz,CDCl3-d1,δppm):δ=1.75(d,J=6.6Hz,6H);2.54-3.21(m,11H);3.61-4.17(m,6H);3.69(s,3H);3.97(s,6H);4.27(m,4H);5.10-5.21(m,4H);5.61(m,2H);6.82(s,2H);6.91-6.95(m,2H);7.06-7.12(m,1H);7.53(s,2H);7.63(d,J=4.4Hz,2H)
N-[2-(3,5-双-羟甲基-苯氧基)-乙基]-N-甲基-琥珀酰胺酸甲酯可以如下制备:
向N-[2-(3,5-双-羟甲基-苯氧基)-乙基]-N-甲基-琥珀酰胺酸(225毫克)在甲醇(1毫升)中的冷却(0℃)溶液中加入在己烷中的(三甲基甲硅烷基)重氮甲烷2M(840微升)直至留下黄色。40分钟后,加入乙酸乙酯(5毫升)和乙酸(50微升),然后,1分钟后,加入碳酸氢钠的饱和水溶液直至pH=7。水相用乙酸乙酯萃取。合并的有机层用饱和氯化钠水溶液洗涤,经硫酸镁干燥并真空浓缩成残留物。该残留物通过硅胶色谱法提纯(Merck SuperVarioFlash 25g柱,Si6015-40微米),用DCM(A)/MeOH(B)的混合物梯度洗脱(梯度:98%A:2%B降至90%A:10%B)以获得N-[2-(3,5-双-羟甲基-苯氧基)-乙基]-N-甲基-琥珀酰胺酸甲酯(103毫克)。LC/MS(方法A3):ES:m/z 348(M+Na)+;m/z 326(M+H)+;m/z 308(M-H2O+H)+;RT=0.43min
N-[2-(3,5-双-羟甲基-苯氧基)-乙基]-N-甲基-琥珀酰胺酸可以如下制备:
N-[2-(3,5-双-羟甲基-苯氧基)-乙基]-N-甲基-琥珀酰胺酸可以根据N-[2-(3,5-双-羟甲基-苯氧基)-乙基]-琥珀酰胺酸的制备程序,以3,5-双-羟甲基-(2-甲基氨基-乙氧基)-苯为原料制备:LC/MS(方法A3):ES:m/z312(M+H)+;m/z 294(M-H2O+H)+;m/z 310(M-H)-;RT=0.35min
3,5-双-羟甲基-(2-甲基氨基-乙氧基)-苯盐酸盐
向1-(2-(叔丁氧基羰基)-甲基氨基-乙氧基)-3,5-双-(叔丁基-二甲基-甲硅烷氧基甲基)-苯(590毫克)在二氧杂环己烷(4毫升)中的溶液中加入盐酸4N在二氧杂环己烷中的溶液(3.3毫升)。在室温下15小时后,将所得固体过滤,用二氧杂环己烷洗涤并真空干燥以获得白色粉末状的3,5-双-羟甲基-(2-甲基氨基-乙氧基)-苯盐酸盐(240毫克)。LC/MS(方法A2):ES:m/z 212(M+H)+;RT=0.14min
1-(2-(叔丁氧基羰基)-甲基氨基-乙氧基)-3,5-双-(叔丁基-二甲基-甲硅烷氧基甲基)-苯可以如下制备:
向1-(2-叔丁氧基羰基氨基-乙氧基)-3,5-双-(叔丁基-二甲基-甲硅烷氧基甲基)-苯(270毫克)在四氢呋喃(5毫升)中的溶液中加入碘甲烷(70微升),并冷却反应混合物(0℃)。向该冷却溶液中加入氢化钠(68毫克)。1小时后,使温度升至室温。
16小时后,稍微加入THF和水的1∶1混合物(2毫升),然后加入柠檬酸直至pH=2。水相用乙酸乙酯萃取三次。合并的有机层用饱和氯化钠水溶液洗涤,经硫酸镁干燥并真空浓缩成残留物。该残留物通过硅胶色谱法提纯(Merck SuperVarioFlash 25g柱,Si60 15-40μm),用庚烷(A)/乙酸乙酯(B)的混合物梯度洗脱(梯度:100%A降至85%A:15%B)以获得1-(2-(叔丁氧基羰基)-甲基氨基-乙氧基)-3,5-双-(叔丁基-二甲基-甲硅烷氧基甲基)-苯(220毫克):LC/MS(方法A2):ES:m/z 562(M+Na)+;m/z 308(M+H-C5H8O2-OSiC6H16)+;RT=1.50min
1-(2-叔丁氧基羰基氨基-乙氧基)-3,5-双-(叔丁基-二甲基甲硅烷氧基甲基)-苯可以如下制备:
向1-(2-叔丁氧基羰基氨基-乙氧基)-3,5-双-(羟甲基)-苯(600毫克)在DMF(8毫升)中的冷却(0℃)溶液中加入叔丁基二甲基氯硅烷(913毫克)和三乙胺(936微升)。18小时后,加入水,水相用乙酸乙酯萃取两次。合并的有机层用饱和氯化钠水溶液洗涤,经硫酸镁干燥并真空浓缩以获得1-(2-叔丁氧基羰基氨基-乙氧基)-3,5-双-(叔丁基-二甲基-甲硅烷氧基甲基)-苯(1克):LC/MS(方法A2):ES:m/z548(M+Na)+;m/z 294(M+H-C5H8O2-OSiC6H16)+;RT=1,45min
图式1
图式2
化合物2:在0℃下经1小时向氢化锂铝(2.19克,54.8毫摩尔)在无水THF(50毫升)中的悬浮液中加入5-溴间苯二甲酸二甲酯(9.98克,36.5毫摩尔)在THF(100毫升)中的溶液。添加完成后,该混合物在室温下搅拌2小时。此后,加入150毫升THF。将该混合物再冷却至0℃,并用饱和NaCl水溶液骤冷。滤出白色沉淀物,固体用额外的THF(100毫升)进一步洗涤。合并的THF溶液用Na2SO4干燥,过滤并浓缩。用硅胶快速色谱法进一步提纯(95∶5CH2Cl2/CH3OH)以提供白色固体2(7.42克,95%)。
化合物3:将化合物2(3.36克,15.5毫摩尔)悬浮在无水CH2Cl2(31毫升)中。加入TBSCl(5.14克,34.1毫摩尔),然后加入咪唑(3.16克,46.5毫摩尔)。该混合物在室温下搅拌1小时。滤出白色沉淀物,滤液用旋转蒸发器浓缩。所得残留物通过快速色谱法提纯(硅胶,97∶3己烷/EtOAc)以获得无色油3(6.15克,89%):1H NMR(400MHz,CDCl3)δ=0.081(s,12H),0.92(s,18H),4.67(s,4H),7.18(s,1H),7.31(s,2H)。
化合物4:将含有化合物3(4.16克,9.36毫摩尔)、丙烯酸甲酯(1.3毫升,14.0毫摩尔)、Pd(OAc)2(105毫克,0.47毫摩尔)、P(邻甲苯基)3(285毫克,0.94毫摩尔)和Et3N(9毫升)在19毫升CH3CN的烧瓶在氩气氛下加热至回流16小时。冷却至室温后,加入冰水(20毫升)。该混合物用EtOAc(3×40毫升)萃取。合并的有机层用1N HCl、盐水洗涤,经Na2SO4干燥,并浓缩。残留物用快速色谱法进一步提纯(硅胶,97∶3己烷/EtOAc)以获得无色油4(3.91克,93%):1HNMR(400MHz,CDCl3)δ0.089(s,12H),0.93(s,18H),3.79(s,3H),4.72(s,4H),6.41(d,J=16Hz,1H),7.29(s,1H),7.34(s,2H),7.68(d,J=16Hz,1H).EIMS m/z 473([M]++Na)。
化合物5:4(2.54克,5.63毫摩尔)和Pd/C(563毫克)在55毫升EtOAc中的混合物在大气压下氢化30分钟。然后使该溶液通过C盐,固体用额外的EtOAc(25毫升)洗涤。将合并的EtOAc溶液浓缩以提供无色油5(2.55克,99+%),其足够纯净以用于下一步骤。1HNMR(400MHz,CDCl3)δ=0.067(s,12H),0.91(s,18H),2.60(t,J=8.0Hz,2H),2.92(t,J=8.0Hz,2H),3.65(s,3H),4.68(s,4H),7.00(s,2H),7.12(s,1H).EIMS m/z 475([M]++Na)。
化合物6:在0℃下,向5(1.48克,3.28毫摩尔)在无水THF(33毫升)中的溶液中加入8.2毫升的TBAF在THF中的1M溶液。在此室温下搅拌1小时后,向该混合物中加入饱和NH4Cl水溶液(30毫升)。该混合物用EtOAc(3×40毫升)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥并浓缩。残留物用快速色谱法进一步提纯(硅胶,95∶5DCM/CH3OH)产生无色油6(625毫克,85%),其在冷冻器中静置后凝固。1HNMR(400MHz,CDCl3)δ=2.59(t,J=8.0Hz,2H),2.91(t,J=8.0Hz,2H),3.63(s,3H),4.61(s,4H),7.08(s,2H),7.16(s,1H)。
化合物7:将二醇6(59毫克,0.26毫摩尔)溶解在DCM(2.6毫升)中。将该溶液冷却至0℃,并用Et3N(82微升,0.58毫摩尔)和MsCl(46微升,0.58毫摩尔)处理。该混合物在0℃下搅拌30分钟,并用冰水(2毫升)骤冷。分离层且水层用DCM(3×2毫升)进一步萃取。合并的DCM层用盐水洗涤,用Na2SO4干燥并浓缩。在高真空泵下进一步干燥提供浅黄色油7,其不经进一步提纯即直接用于下一步骤。
化合物8:向PBD单体(165毫克,0.64毫摩尔)和7(估计为0.26毫摩尔)在DMF(2.7毫升)中的混合物中相继加入K2CO3(147毫克,1.06毫摩尔)、KI(22毫克,0.13毫摩尔)和Bu4NI(49毫克,0.13毫摩尔)。该混合物在氩气下在室温下搅拌7小时。然后用高真空除去DMF。使该残留物在DCM和水之间分相,分离层。水层用DCM(3×3毫升)进一步萃取。合并的DCM层用盐水洗涤,干燥(Na2SO4)并浓缩。该残留物用硅胶色谱法提纯(25∶1,CH2Cl2/CH3OH),提供浅黄色玻璃状固体8(101毫克,54%)。EIMS m/z 763([M]++Na+2H2O),745([M]++Na+H2O),727([M]++Na)。
化合物9:在室温下向甲酯8(16毫克,0.023毫摩尔)在THF-MeOH-H2O(3∶1∶1,0.45毫升)中的搅拌溶液中加入1M LiOH水溶液(0.025毫升,1.1当量),通过TLC监测反应。3.5小时后,该混合物用H2O(5毫升)稀释,用1N HCl将pH值调节至2。该混合物随后用DCM(3×5毫升)萃取。合并的DCM层用盐水洗涤,经Na2SO4干燥,并浓缩。通过在硅胶上的快速色谱法进一步提纯(DCM∶MeOH∶AcOH=100∶4∶0.5)以提供所需酸9(8.2毫克,60%brsm),EIMS m/z 749([M]++Na+2H2O),731([M]++Na+H2O),713([M]++Na);以及少量(~2毫克)甲酯8。
化合物10:向酸9(8.2毫克,0.011毫摩尔)在CH2C12(1毫升)中的溶液中加入聚-DCC(38毫克,0.059毫摩尔)和N-羟基琥珀酰亚胺(NHS)(2.7毫克,0.024毫摩尔)。该混合物在室温下搅拌2小时,然后经小的C盐床过滤,用DCM洗涤,浓缩。所得残留物通过快速色谱法提纯(DCM∶MeOH/100∶3)以提供所需产物10(7毫克,81%)。EIMS m/z 874([M]++Na+2MeOH),842([M]++Na+MeOH),810([M]++Na)。
实施例9:(2-{2-[2-(2-{3-[3,5-双-(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-基氧甲基)-苯基]-丙氧基}-乙氧基)乙氧基]-乙氧基}-乙氧基)-乙酸N-羟基琥珀酰亚胺酯,化合物20
图式3
化合物12:将NaOH水溶液(50%,6.9毫升)添加到四乙二醇(68.08克,350毫摩尔)中。该混合物在室温下搅拌2小时,然后加入烯丙基碘(8毫升,87.6毫摩尔)。再搅拌24小时后,使该混合物在H2O和EtOAc(50/50毫升)之间分相。水层用EtOAc(5×30毫升)进一步萃取。合并的EtOAc层经Na2SO4干燥,并浓缩。残留物的快速色谱法(硅胶,己烷∶EtOAc 4∶6至0∶1)提供无色油12:1H NMR(400MHz,CDCl3)δ=2.44(br s,1H),3.63-3.71(m,16H),3.99-4.01(m,2H),5.13-5.17(m,1H),5.22-5.27(m,1H),5.84-5.92(m,1H);13CNMR δ61.8,69.4,70.4,70.59,70.61,70.63,72.2,72.5,117.0,134.8.EIMS m/z 257([M]++Na)。
化合物13:在氩气下,在0℃下向NaH(89毫克,2.2毫摩尔)在无水THF(2.5毫升)中的悬浮液中加入12(370毫克,1.58毫摩尔)在THF(5毫升)中的溶液。该混合物在此温度下搅拌30分钟,然后在室温下再搅拌30分钟。将该混合物再冷却至0℃,逐滴加入溴乙酸甲酯(0.29毫升,3.16毫摩尔)。在0℃下搅拌1小时后,移除冰浴,在室温下继续搅拌24小时。反应物经C盐过滤,浓缩滤液。残留物用快速色谱法进一步提纯(硅胶,1∶1己烷/EtOAc),产生浅黄色油13(220毫克):1H NMR(400MHz,CDCl3)δ=3.57-3.74(m,19H),3.98-4.0(m,2H),4.26(s,2H),5.15(d,J=10.4Hz,1H),5.24(dd,J=16,1.6Hz,1H),5.84-5.93(m,1H);13C NMRδ=51.7,68.6,69.4,70.56,70.60,70.62,70.9,72.2,117.0,134.8,170.9.EIMS m/z 329([M]++Na)。
化合物14:将含有在30毫升CH3CN中的化合物3(1.30克,2.92毫摩尔)、13(0.986克,3.220毫摩尔)、Pd(OAc)2(33毫克,0.15毫摩尔)、P(邻甲苯基)3(89毫克,0.29毫摩尔)和Et3N(2毫升)的烧瓶在氩气氛下加热至回流12小时。冷却至室温后,蒸发除去乙腈并加入乙酸乙酯(40毫升),使该混合物通过C盐,用乙酸乙酯漂洗并浓缩。残留物用快速色谱法进一步提纯(硅胶,6∶4己烷/EtOAc)以获得无色油14(1.02克):1H NMR(400MHz,CDCl3)δ=0.076(s,12H),0.92(s,18H),3.61-3.72(m,19H),4.14(s,2H),4.15-4.17(m,2H),4.69(s,4H),6.23-6.28(m,1H),6.57(d,J=16.0Hz,1H),7.16(s,1H),7.19(s,2H);13C NMR δ=-5.2,14.2,18.4,26.0,51.7,64.9,68.6,69.4,70.57,70.61,70.64,70.7,70.9,71.9,122.8,123.2,125.9,132.8,136.5,141.7,170.9.EIMS m/z 693([M]++Na)。
化合物15:将14(0.062克,0.092毫摩尔)和Pd/C(9毫克)在2.5毫升EtOAc中的混合物在大气压下氢化30分钟。然后使该溶液通过C盐,该固体用额外的EtOAc(10毫升)洗涤。将合并的EtOAc溶液浓缩以提供无色油15,其不经进一步提纯即使用。1H NMR(400MHz,CDCl3)δ=0.072(s,12H),0.92(s,18H),1.87-1.89(m,2H),2.64(t,J=8.0Hz,2H),3.43-3.70(m,21H),4.14(s,2H),4.68(s,4H),6.98(s,2H),7.10(s,1H).EIMS m/z 695([M]++Na)。
化合物16:在0℃下向来自前一步骤的15在无水THF(1.8毫升)中的溶液中加入0.23毫升TBAF在THF中的1M溶液。在此温度下搅拌1小时后,向该混合物中加入饱和NH4Cl水溶液(2毫升)。该混合物用EtOAc(3×5毫升)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥并浓缩。残留物用快速色谱法进一步提纯(硅胶,95∶5CH2Cl2/CH3OH)产生无色油16(27毫克,85%)。1H NMR(400MHz,CDCl3)δ=1.86-1.89(m,2H),2.66(t,J=8.0Hz,2H),3.40(t,J=6.4Hz,2H),3.50-3.70(m,19H),4.10(s,2H),4.61(s,4H),7.09(s,2H),7.13(s,1H)。EIMS m/z 467([M]++Na)。
化合物17:将二醇16(26.8毫克,0.06毫摩尔)溶解在DCM(1.2毫升)中。将该溶液冷却至0℃,并用Et3N(18.5微升,0.13毫摩尔)和MsCl(10.3微升,0.13毫摩尔)处理。该混合物在0℃下搅拌30分钟,并用冰水(2毫升)骤冷。分离层且水层用DCM(3×2毫升)进一步萃取。合并的DCM层用盐水洗涤,经Na2SO4干燥并浓缩。在高真空泵下进一步干燥提供浅黄色油17,其不经进一步提纯即直接用于下一步骤。EIMS m/z 623.1([M]++Na)。
化合物18:向PBD单体(40毫克,0.15毫摩尔)和来自前一步骤的17在DMF(1.57毫升)中的混合物中相继加入K2CO3(25毫克,0.18毫摩尔)和KI(10毫克,0.06毫摩尔)。该混合物在氩气下在室温下搅拌20小时。然后用高真空除去DMF。使该残留物在DCM和水之间分相,分离层。水层用DCM(3×3毫升)进一步萃取。合并的DCM层用盐水洗涤,干燥(Na2SO4)并浓缩。该残留物用硅胶色谱法提纯(25∶1,DCM/CH3OH)以提供浅黄色玻璃状固体18。EIMS m/z 1011.5([M]++Na+2CH3OH),979.5([M]++Na+CH3OH),947.5([M]++Na)。
化合物19:在室温下向甲酯18(16毫克,0.017毫摩尔)在THF-MeOH-H2O(3∶1∶1,0.7毫升)中的搅拌溶液中加入1M LiOH水溶液(0.019毫升,1.1当量),通过TLC(薄层色谱法)监测该反应。5小时后,该混合物用H2O(5毫升)稀释,用1N HCl将pH值调节至2。该混合物随后用DCM(3×5毫升)萃取。合并的DCM层用盐水洗涤,经Na2SO4干燥,并浓缩。通过在硅胶上的快速色谱法进一步提纯(DCM∶MeOH∶AcOH=100∶4∶0.5)以提供所需酸19。EIMS m/z 933.4([M]++Na)
化合物20:向酸19(5.9毫克,0.006毫摩尔)在CH2Cl2(1.0毫升)中的溶液中加入EDC(2毫克,0.0097毫摩尔)和NHS(1.0毫克,0.0084毫摩尔)。该混合物在室温下搅拌3小时,然后经小的C盐床过滤,用DCM洗涤,并浓缩提供所需产物10,其不经进一步提纯即使用,因为该材料据发现在二氧化硅提纯时分解。EIMS m/z 1030.4([M]++Na)。
实施例10:(3-{2-[2-(2-{3-[3,5-双-(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-基氧甲基)-苯基]-丙氧基}-乙氧基)乙氧基]-乙氧基}-乙氧基)-丙酸N-羟基琥珀酰亚胺酯,化合物31
图式4
化合物21:向四乙二醇(162毫升,940毫摩尔)在无水THF(500毫升)中的溶液中加入钠(215毫克,9.4毫摩尔)。在钠溶解时,加入丙烯酸叔丁酯(45毫升,310毫摩尔)。将该混合物在室温下搅拌20小时,并用8毫升1N HCl中和。除去溶剂后,使残留物在盐水和EtOAc之间分相。水层用EtOAc进一步萃取。合并的有机层用盐水洗涤,经Na2SO4干燥,并浓缩。所得残留物通过在硅胶上的快速色谱法提纯(己烷∶乙酸乙酯=4∶6)以提供所需酯21。1H NMR(400MHz,CDCl3)δ=1.41(s,9H),2.34(br.S,1H),2.47(t,J=6.4Hz,2H),3.56-3.71(m,18H).EIMSm/z 345([M]++Na)。
化合物22:将四丁基硫酸氢铵(1.27克,3.75毫摩尔)和NaOH(225毫克,5.63毫摩尔)在H2O(7毫升)中的溶液添加到21(1.20克,3.75毫摩尔)和烯丙基溴(0.48毫升,5.63毫摩尔)在DCM(14毫升)中的混合物中。将该两相体系剧烈搅拌45分钟。分离水层并用DCM萃取三次。将合并的DCM层浓缩。Et2O(15毫升)的加入导致四丁基溴化铵沉淀,将其过滤分离。滤液用盐水洗涤,经Na2SO4干燥,并浓缩。残留物用快速色谱法进一步提纯(硅胶,1∶1己烷/EtOAc)产生无色油22。1H NMR(400MHz,CDCl3)δ=1.42(s,9H),2.47(t,J=6.4Hz,2H),3.56-3.70(m,18H),4.00(m,2H),5.15(dq,J=6.0,1.2Hz,1H),5.25(dq,J=16,1.6Hz,1H),5.84-5.94(m,1H).EIMS m/z 385.2([M]++Na)。
化合物23:将化合物22(478毫克,1.32毫摩尔)在三氟乙酸(9毫升)中的溶液在室温下搅拌1.5小时,此时所有原材料消耗。在真空下除去TFA,借助甲苯将残留物进一步干燥。粗产物直接用于下一步骤。1H NMR(400MHz,CDCl3)δ=2.60(t,J=6.0Hz,2H),3.56-3.70(m,18H),4.01(d,J=5.6Hz,2H),5.16(dd,J=6.4,1.2Hz,1H),5.25(dd,J=16,1.6Hz,1H),5.84-5.94(m,1H).EIMS m/z 329.2([M]++Na)。
化合物24:用Cs2CO3(451毫克,1.38毫摩尔)和MeI(90微升,1.45毫摩尔)处理酸23在DMF中的溶液(6.6毫升)。该混合物在室温下搅拌2小时。随后在高真空下蒸发DMF。将残留物悬浮在EtOAc中,滤出固体。浓缩滤液。残留物用快速色谱法进一步提纯(硅胶,97∶3己烷/EtOAc)产生无色油24。1H NMR(400MHz,CDCl3)δ=2.58(t,J=6.4Hz,2H),3.56-3.70(m,18H),4.00(d,J=5.6Hz,2H),5.14(dd,J=6.4,1.2Hz,1H),5.24(dd,J=16,1.6Hz,1H),5.84-5.94(m,1H).EIMS m/z343.2([M]++Na)。
化合物25:将含有在3毫升CH3CN中的化合物3(0.066克,0.15毫摩尔)、24(0.05克,0.16毫摩尔)、Pd(OAc)2(1.7毫克,0.0074毫摩尔)、P(邻甲苯基)3(4.5毫克,0.015毫摩尔)和Et3N(0.1毫升)的烧瓶在氩气氛下加热至回流8小时。冷却至室温后,蒸发除去乙腈并加入乙酸乙酯(40毫升),使该混合物通过C盐,用乙酸乙酯漂洗。合并的有机层用盐水洗涤,经硫酸钠干燥并浓缩。残留物用快速色谱法进一步提纯(硅胶,6∶4己烷/EtOAc)以获得无色油25:1H NMR(400MHz,CDCl3)δ=0.076(s,12H),0.92(s,18H),2.57(t,J=6.4Hz,2H),3.57-3.68(m,20H),3.73(t,J=6.4Hz,2H),4.14(d,J=6.0Hz,2H),4.69(s,4H),6.23-6.29(m,1H),6.56(d,J=16.0Hz,1H),7.16(s,2H),7.19(s,1H).EIMSm/z 707.4([M]++Na)。
化合物26:将25(0.216克,0.31毫摩尔)和Pd/C(32毫克)在6.3毫升EtOAc中的混合物在大气压下氢化30分钟。然后使该溶液通过C盐,固体用额外的EtOAc(10毫升)洗涤。将合并的EtOAc溶液浓缩以提供无色油26,其不经进一步提纯即使用。1H NMR(400MHz,CDCl3)δ=0.071(s,12H),0.91(s,18H),1.87(m,2H),2.58(t,J=6.4Hz,2H),2.64(t,2H),3.44(t,J=6.4Hz,2H),3.54-3.67(m,20H),3.72(t,J=6.4Hz,2H),4.68(s,4H),6.98(s,2H),7.10(s,1H).EIMS m/z 709.4([M]++Na)。
化合物27:在0℃下向来自前一步骤的26在无水THF(3毫升)中的溶液中加入0.38毫升TBAF在THF中的1M溶液。在此温度下搅拌1小时后,向该混合物中加入饱和NH4Cl水溶液(2毫升)。该混合物用EtOAc(3×5毫升)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥并浓缩。残留物用快速色谱法进一步提纯(硅胶,95∶5CH2Cl2/CH3OH)产生无色油27。1H NMR(400MHz,CDCl3)δ=1.87(m,2H),2.56(t,J=6.4Hz,2H),2.69(t,J=7.2Hz,2H),3.42(t,J=6.4Hz,2H),3.54-3.67(m,20H),3.70(t,J=6.4Hz,2H),4.64(s,4H),7.12(s,2H),7.16(s,1H).EIMSm/z 481.3([M]++Na)。
化合物28:将二醇27(54毫克,0.126毫摩尔)溶解在DCM(2.4毫升)中。将该溶液冷却至0℃,用Et3N(41微升,0.29毫摩尔)和MsCl(23微升,0.29毫摩尔)处理。该混合物在0℃下搅拌30分钟,并用冰水(2毫升)骤冷。分离层,水层用CH2Cl2(3×2毫升)进一步萃取。合并的DCM层用盐水洗涤,经Na2SO4干燥并浓缩。在高真空泵下进一步干燥提供浅黄色油28,其不经进一步提纯即直接用于下一步骤。EIMS m/z 637.2([M]++Na)。
化合物29:向PBD单体(76毫克,0.29毫摩尔)和来自前一步骤的28在DMF(2.9毫升)中的混合物中相继加入K2CO3(49毫克,0.35毫摩尔)和KI(20毫克,0.12毫摩尔)。该混合物在氩气下在室温下搅拌20小时。然后用高真空除去DMF。使该残留物在DCM和水之间分相,分离层。水层用DCM(3×3毫升)进一步萃取。合并的DCM层用盐水洗涤,干燥(Na2SO4)并浓缩。该残留物用硅胶色谱法提纯(100∶3,DCM/CH3OH)以提供浅黄色玻璃状固体29。EIMS m/z 1025.6([M]++Na+2CH3OH),993.5([M]++Na+CH3OH),961.5([M]++Na)。
化合物30:在室温下向甲酯29(11.8毫克,0.012毫摩尔)在THF-MeOH-H2O(3∶1∶1,0.5毫升)中的搅拌溶液中加入1M LiOH水溶液(0.014毫升,1.1当量),通过TLC监测反应。5小时后,该混合物用AcOH(0.014毫摩尔)骤冷,并蒸发挥发物。通过在硅胶上的快速色谱法进一步提纯(DCM∶MeOH=95∶5)以提供所需酸30。EIMS m/z 947.5([M]++Na)
化合物31:向酸30(4.6毫克,0.005毫摩尔)在DCM(1.0毫升)中的溶液中加入作为偶联剂的EDC(1-乙基-3-(3-二甲基氨基丙基)碳二亚胺)(1.4毫克,0.0075毫摩尔)和NHS(0.74毫克,0.0065毫摩尔)。该混合物在室温下搅拌整夜,然后经小的C盐床过滤,用DCM洗涤并浓缩提供所需产物31。通过在硅胶上的快速色谱法进一步提纯(DCM∶MeOH=100∶3)提供所需NHS酯31。EIMS m/z1022.5([M]++Na)
实施例11:huMy9-6-4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酰基缀合物
huMy9-6抗体在含有0.05M磷酸钾和0.05M氯化钠的水性缓冲液(pH 8)中的1.45毫升浓度为6.4毫克/毫升的溶液用7.5倍摩尔过量的来自实施例1的4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)丁酸N-羟基琥珀酰亚胺酯在二甲基乙酰胺(DMA)中的9.5mM溶液处理,以使huMY9-6的最终浓度为5毫克/毫升且缓冲液中DMA的浓度为20%。该反应混合物在室温下搅拌195分钟,经MillexR-HV 0.45μM(PVDF DuraporeMillipore#SLHV013SL)过滤,随后加载到SuperdexTM 200制备级凝胶过滤柱(HiloadTM 16/60Column GE#17-1069-01)上,该柱已预先在含有0.010M磷酸盐、0.140M氯化钠的pH 6.5水性缓冲液中平衡。收集含结合的抗体的馏分,汇集,并在Vivaspin 2(10000MWCO HY Sartorius#VS02H02)上浓缩产生产物(1.8毫升)。使用对4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸甲酯(ε319nm=9087M-1cm-1和ε280nm=12166M-1cm-1)和huMy9-6抗体(ε280nm=206,539M-1cm-1)测得的消光系数分光光度检测最终缀合物。每分子抗体连接平均2.1个4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酰基部分(1.6毫克/毫升)。
huB4抗体在含有0.05M磷酸钾和0.05M氯化钠的水性缓冲液(pH8)中的3.4毫升浓度为8毫克/毫升的溶液用8倍摩尔过量的来自实施例1的4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)丁酸N-羟基琥珀酰亚胺酯在DMA中的11.5mM溶液处理,以使huB4的最终浓度为5.6毫克/毫升且缓冲液中DMA的浓度为20%。该反应混合物在室温下搅拌3小时,经MillexR-HV 0.45μM(PVDF Durapore Millipore#SLHV013SL)过滤,随后加载到SuperdexTM 200制备级凝胶过滤柱(HiloadTM 16/60Column GE#17-1069-01)上,该柱已预先在含有0.010M磷酸盐、0.140M氯化钠的pH 6.5水性缓冲液中平衡。收集含结合的抗体的馏分,汇集,并在Vivaspin 15R(10000MWCO HY Sartorius#VS02H02)上浓缩产生产物(5毫升)。使用对4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸甲酯(ε319nm=9087M-1cm-1和ε280nm=12166M-1cm-1)和huB4抗体(ε280nm=222,960M-1cm-1)测得的消光系数分光光度检测最终缀合物。每分子抗体连接平均4.48个4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酰基部分(1.49毫克/毫升)。
实施例13:hu2H11-4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酰基缀合物
hu2H11(参见WO 2008/010101;ATCC以目录号PTA-7662注册)抗体在含有0.05M磷酸钾和0.05M氯化钠的水性缓冲液(pH 8)中的3.45毫升浓度为5.1毫克/毫升的溶液用8倍摩尔过量的来自实施例1的4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)丁酸N-羟基琥珀酰亚胺酯在DMA中的10.5mM溶液处理,以使hu2H11的最终浓度为4.3毫克/毫升且缓冲液中DMA的浓度为20%。该反应混合物在室温下搅拌3小时,经MillexR-HV 0.45μM(PVDF Durapore Millipore#SLHV013SL)过滤,随后加载到SuperdexTM 200制备级凝胶过滤柱(HiloadTM 16/60Column GE#17-1069-01)上,该柱已预先在含有0.010M磷酸盐、0.140M氯化钠的pH 6.5水性缓冲液中平衡。收集含结合的抗体的馏分,汇集,并在Vivaspin 15R(10000MWCO HY Sartorius#VS02H02)上浓缩产生产物(2.2毫升)。使用对4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酸甲酯(ε319nm=9087M-1cm-1和ε280nm=12166M-1cm-1)和hu2H11抗体(ε280nm=208,380M-1cm-1)测得的消光系数分光光度检测最终缀合物。每分子抗体连接平均3.74个4-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-丁酰基部分(1.55毫克/毫升)。
实施例14:huMy9-6-3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酰基缀合物
huMy9-6抗体在含有0.05M N-(2-羟乙基)-哌嗪-N’-2-乙磺酸(HEPES)、0.05M氯化钠和2mM乙二胺四乙酸(EDTA)的水性缓冲液(pH 8)中的8.2毫升浓度为7.2毫克/毫升的溶液用10倍摩尔过量的来自实施例3的3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸N-羟基琥珀酰亚胺酯在DMA中的10.4mM溶液处理,以使huMY9-6的最终浓度为3毫克/毫升且缓冲液中DMA的浓度为20%。该反应混合物在室温下搅拌3小时,经MillexR-SV 5μM(PVDF Durapore Millipore#SLSV025SL)过滤,随后加载到SuperdexTM 200制备级凝胶过滤柱(HiloadTM 26/60Column GE#17-1071-01)上,该柱已预先在含有0.010M磷酸盐、0.140M氯化钠的pH 6.5水性缓冲液中平衡。收集含结合的抗体的馏分,汇集,并在AmiconUltra-15(Ultracel 10k Millipore#UFC901024)上浓缩产生产物(7毫升)。使用对3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯(ε319nm=7566M-1cm-1和ε280nm=7078M-1cm-1)和huMy9-6抗体(ε280nm=206,539M-1cm-1)测得的消光系数分光光度检测最终缀合物。每分子抗体连接平均4.80个3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酰基部分(3.44毫克/毫升)。
实施例15:hu2H11-3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酰基缀合物
hu2H11抗体在含有0.05M N-(2-羟乙基)-哌嗪-N’-2-乙磺酸(HEPES)、0.05M氯化钠和2mM乙二胺四乙酸(EDTA)的水性缓冲液(pH 8)中的13.2毫升浓度为4.7毫克/毫升的溶液用glycofurol和10倍摩尔过量的来自实施例3的3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸N-羟基琥珀酰亚胺酯在DMA中的10.6mM溶液处理,以使hu2H11的最终浓度为3毫克/毫升、缓冲液中glycofurol的浓度为10%且缓冲液中DMA的浓度为20%。该反应混合物在室温下搅拌3小时,经MillexR-SV 5μM(PVDF DuraporeMillipore#SLSV025SL)过滤,随后加载到SuperdexTM 200制备级凝胶过滤柱(HiloadTM 26/60Column GE#17-1071-01)上,该柱已预先在含有0.010M磷酸盐、0.140M氯化钠的pH 6.5水性缓冲液中平衡。收集含结合的抗体的馏分,汇集,并在Amicon Ultra-15(Ultracel 10k Millipore#UFC901024)上浓缩产生产物(3.6毫升)。使用对3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯(ε319nm=7566M-1cm-1和ε280nm=7078M-1cm-1)和hu2H11抗体(ε280nm=208,380M-1cm-1)测得的消光系数分光光度检测最终缀合物。每分子抗体连接平均4.08个3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酰基部分(1.33毫克/毫升)。
实施例16:hu2H11-6-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯基)-己-5-炔酰基缀合物
hu2H11抗体在含有0.05M磷酸钾和0.05M氯化钠的水性缓冲液(pH8)中的0.95毫升浓度为3.2毫克/毫升的溶液用8倍摩尔过量的来自实施例4的6-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯基)-己-5-炔酸N-羟基琥珀酰亚胺酯在DMA中的10.5mM溶液处理,以使hu2H11的最终浓度为2.5毫克/毫升且缓冲液中DMA的浓度为20%。该反应混合物在室温下搅拌4小时,经MillexR-HV 0.45μM(PVDF Durapore Millipore#SLHV013SL)过滤,随后加载到SuperdexTM 200制备级凝胶过滤柱(HiloadTM 16/60Column GE#17-1069-01)上,该柱已预先在含有0.010M磷酸盐、0.140M氯化钠的pH 6.5水性缓冲液中平衡。收集含结合的抗体的馏分,汇集,并在Amicon Ultra-4(Ultracel 10k Millipore#UFC801096)上浓缩产生产物(275微升)。使用对6-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯基)-己-5-炔酸甲酯(ε319=13594M-1cm-1和ε280=19416M-1cm-1)和hu2H11抗体(ε280nm=208,380M-1cm-1)测得的消光系数分光光度检测最终缀合物。每分子抗体连接平均1.75个6-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯基)-己-5-炔酰基部分(0.48毫克/毫升)。
实施例17:IGP-08-NHS储液制备
将IGP-08-NHS(实施例8的化合物10)的溶液新鲜制成基于787.81的分子量在DMA中的0.005M储液。使用在320纳米测得的基准消光系数(ε320=9137M-1cm-1)分光光度检测该储液。
实施例18:huMy9-6-IGP-08
选择与CD33抗原结合的huMy9-6抗体用于结合PBD衍生物。huMy9-6抗体在含有0.05M N-(2-羟乙基)-哌嗪-N’-2-乙磺酸(HEPES)和2mM乙二胺四乙酸(EDTA)的水性缓冲液(pH 8)中的浓度为5毫克/毫升的溶液用6倍摩尔过量的IGP-08-NHS(实施例8的化合物10)在DMA中的溶液处理,以使缓冲液中DMA的最终浓度为20%。该反应混合物在室温下搅拌120分钟,随后加载到Sephadex G25凝胶过滤柱(HiPrepTM 26/10Desalting Column GE#17-5087-01)上,该柱已预先在含有0.01M柠檬酸钠、0.135M氯化钠的pH 5.5水性缓冲液中平衡。收集含结合的抗体的馏分并汇集获得产物。汇集的样品在相同洗脱缓冲液(0.01M柠檬酸钠、0.135M氯化钠,pH 5.5)中透析整夜以进一步提纯产物。使用对实施例8的化合物8(ε320=9137M-1cm-1和ε280=7743M-1cm-1)和huMy9-6抗体(ε280nm=206,460M-1cm-1)测得的消光系数分光光度检测最终缀合物。每分子抗体连接平均4.5个PBD分子(实施例8的化合物9)。
实施例19:huB4-IGP-08
选择与人淋巴瘤细胞表面上优先表达的CD19抗原结合的Hu-Anti-B4抗体用于结合PBD衍生物。huB4抗体在含有0.05M磷酸钾、0.05M氯化钠和2mM乙二胺四乙酸(EDTA)的水性缓冲液(pH 7.1)中的浓度为8毫克/毫升的溶液用5倍摩尔过量的IGP-08-NHS(实施例8的化合物10)在二甲基乙酰胺(DMA)中的溶液处理,以使缓冲液中DMA的最终浓度为20%。该反应混合物在室温下搅拌70分钟,随后加载到Sephadex G25凝胶过滤柱(NAPTM Columns,GE#17-0852-02)上,该柱已预先在含有0.010M磷酸盐、0.140M氯化钠的pH 6.5水性缓冲液中平衡。收集含结合的抗体的馏分并汇集获得产物。汇集的样品在相同洗脱缓冲液(0.010M磷酸盐、0.140M氯化钠,pH 6.5)中透析整夜以进一步提纯产物。使用对实施例8的化合物8(ε320=9137M-1cm-1和ε280=7743M-1cm-1)和huB4抗体(ε280nm=222,960M-1cm-1)测得的消光系数分光光度检测最终缀合物。每分子抗体连接平均3.1个PBD分子(实施例8的化合物9)。
实施例20:IGP-13-NHS储液制备
将IGP-13-NHS(实施例10的化合物31)的溶液新鲜制成基于1022.1的分子量在DMA中的0.0062M储液。使用在320纳米测得的基准消光系数(ε320=9137M-1cm-1)分光光度检测该储液。
实施例21:hu2H11-IGP-13
选择与EpCAM抗原结合的Hu2H11抗体用于结合PBD衍生物。hu2H11抗体在含有0.05M N-(2-羟乙基)-哌嗪-N’-2-乙磺酸(HEPES)和2mM乙二胺四乙酸(EDTA)的水性缓冲液(pH 8)中的浓度为5毫克/毫升的溶液用8倍摩尔过量的IGP-13-NHS(实施例10的化合物31)在DMA中的溶液处理,以使缓冲液中DMA的最终浓度为15%。该反应混合物在室温下搅拌120分钟,随后加载到Sephadex G25凝胶过滤柱(HiPrepTM 26/10 Desalting Column GE#17-5087-01)上,该柱已预先在含有0.01M柠檬酸钠、0.135M氯化钠的pH 5.5水性缓冲液中平衡。收集含结合的抗体的馏分并汇集获得产物。汇集的样品在相同洗脱缓冲液(0.01M柠檬酸钠、0.135M氯化钠,pH 5.5)中透析整夜以进一步提纯产物。使用对实施例10的化合物29(ε320=9137M-1cm-1和ε280=7743M-1cm-1)和hu2H11抗体(ε280nm=215,525M-1cm-1)测得的消光系数分光光度检测最终缀合物。每分子抗体连接平均4.7个PBD分子(实施例10的化合物31)。
实施例22:结合试验
使用基于荧光的试验测定抗-B4抗体和其茅屋霉素缀合物在表达Ramos细胞的抗原上的相对结合亲合力。抗体-茅屋霉素缀合物和裸抗体以1×10-7M的起始浓度加入96孔圆底板中,用3倍系列稀释液滴定以使每一浓度都一式两份。Ramos细胞以每孔50,000个细胞添加到各个含有各种浓度的抗体或缀合物的孔中以及添加到对照孔中。板在冰上培养3小时。在培养期后,洗涤板中的细胞,加入与人源性IgG,如抗-B4结合的荧光素标记的二抗,板在冰上培养1小时。在培养期后再洗涤板,用1%甲醛/PBS溶液固定细胞。使用Becton Dickinson FACSCalibur荧光分析器读出板的各个孔中的荧光。数据作为在最高抗体或缀合物浓度下获得的最大荧光的百分数绘制。
实施例23:茅屋霉素衍生物或茅屋霉素衍生物缀合物的体外效力和特异性(存活力试验)
所用一般程序
将茅屋霉素衍生物或茅屋霉素衍生物缀合物的样品加入96孔平底组织培养板中,用1×10-12M至3×10-7M的系列稀释液滴定。将M.抗原阳性肿瘤细胞和抗原阴性肿瘤细胞加入孔中以便对于各细胞系,在各药物浓度下存在三个重复样品。板在5%CO2气氛中在37℃下培养4天。
在培养期结束时,向各个孔中加入20微升四唑鎓试剂WST-8(2-(2-甲氧基-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二硫代苯基)-2-四唑鎓单钠盐),将板放回培养器中2小时。随后使用Molecular Devices板阅读器在450nm测量板的各个孔中的吸光率。绘制在各个茅屋霉素衍生物或缀合物浓度下的细胞存活分数。
测试本发明的化合物和缀合物对MOLT-4、BJAB、HL60/QC、HL60/ATCC和Ramos细胞系的细胞毒性和它们的特异性。结果显示在图1、2、3、6和8中。
实施例24:克隆试验
所用一般程序
MDA-MB-231细胞以每孔3000个细胞接种在两个分开的6孔板中;PC-3和SK-MEL-28细胞以每孔2000个细胞接种在两个分开的6孔板中。向各个板中添加试验制品以获得每孔0、5×10-13、5×10-12、5×10-11、5×10-10和5×10-9M的最终浓度(或类似剂量范围)。例如,当细胞以1毫升接种时,将1毫升2x浓度的试验化合物或缀合物添加到适当的孔中以获得在2毫升中的最终所需浓度。在与细胞系相同的培养基中制造试验制品的最终溶液;因此,对于各个不同的细胞系,必须制造缀合物的不同稀释液。将板置于在37℃,5%CO2中的培养器中。监测细胞生长,当“0”(对照)孔中的细胞已形成群落但没有汇合时(对这些细胞系而言通常为7天),通过抽吸除去上清液。细胞用PBS(磷酸盐缓冲液)洗涤一次,抽吸上清液。向各个孔中加入每孔0.5毫升的0.1%结晶紫/10%***/PBS。板在室温下培养10-15分钟。抽吸上清液,孔用蒸馏水洗涤3次,然后风干。计数各个孔中的群落数,并将各个给药孔中的群落数除以“0”孔中的群落数以获得存活分数。随后由该数据计算IC50值。
实施例中公开的化合物和缀合物分子表现出<1至10000pM的IC50(关于各种细胞系的特定值,参见附图和表I)。
Claims (26)
1.式(I)的化合物:
其中:
U和U’不存在,W和W’代表H;
·R1和R2以及R1’和R2’一起形成分别含有基团=B和=B’的双键;
·B和B’相同或不同且独立地选自链烯基;
·A、A’相同或不同且独立地选自烷基;
·Y、Y’相同或不同且独立地选自OR;
·T是4至10元芳基或杂芳基,各自被一个或更多个不可裂解的连接物取代;
·n、n’相同或不同,是0或1;
·R选自烷基,
其中所述连接物
○具有式-G-D-(Z)p-C(=O)-Z’R”,其中
·G是单键、三键或-O-;
·D是单键或-E-、-E-O-、-E-NR-CO-;
·E独立地选自直链或支链-(OCH2CH2)j-、-烷基-(OCH2CH2)i-;
·i和j相同或不同,是整数且独立地选自0、1至2000;
·Z是直链或支链烷基;
·p是0或1;
○选自:
-(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ’R”、
-(CR13R14)t(OCH2CH2)yO(CR15R16)uCOZ’R”、
-(C≡C)-(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ'R”、
-O(CR13R14)t(CR15R16)u(OCH2CH2)yCOZ'R”、
-O(CR13R14)t(NR19CO)(CR15R16)u(OCH2CH2)yCOZ'R”,
其中:
·R19是具有1至10个碳原子的直链烷基、支链烷基或环烷基;
·R13、R14、R15和R16相同或不同并且是H或具有1至4个碳原子的直链或支链烷基;
·u是1至10的整数并且也可以是0;
·t是1至10的整数并且也可以是0;
·y是1至20的整数并且也可以是0;
-C(=O、)-Z’R”是含羰基的官能团,其中Z’代表单键或-O-且R”代表H、烷基或杂环基;
其中所述烷基为具有1至12个碳原子的直链或支链烷基,所述链烯基为具有2至15个碳原子的直链或支链烯基,所述杂芳基为5至14元单环、二环或多环芳族杂环,所述环烷基为具有3至10个碳原子的环状烷基,且所述杂环基为3至14元单环、二环或多环;
或所述化合物的可药用盐或旋光异构体、外消旋体、非对映体或对映体。
2.根据权利要求1的化合物,其具有下式:
3.根据权利要求1的化合物,其中A=A’。
4.根据权利要求1的化合物,其中A=A’=直链未取代烷基。
5.根据权利要求1的化合物,其中Y=Y’=OMe。
6.根据权利要求1的化合物,其中n=n’=1。
7.根据权利要求1和3-6中任一项的化合物,其中B=B’==CH2或=CH-CH3。
8.根据权利要求1的化合物,其中T是苯基或吡啶基。
9.根据权利要求1的化合物,其中G是单键或-O-。
10.根据权利要求1的化合物,其中D是单键或-E-或-E-O-。
11.根据权利要求9的化合物,其中D是-E-。
12.根据权利要求1的化合物,其中E是直链或支链-烷基-或-烷基(OCH2CH2)i-,其中i是整数且选自1至2000。
13.根据权利要求1的化合物,其中p是0。
16.根据权利要求1的化合物,其中所述连接物选自:
·-O(CR13R14)tCOZ’R”;
·-(OCH2CH2)yCOZ’R”;
·-(C≡C)-(CR13R14)tCOZ’R”;
·-O(CR13R14)t(NR19CO)(CR15R16)uCOZ’R”;
·-(CR13R14)t(OCH2CH2)yCOZ’R”。
18.化合物,选自:
·3-(2-{2-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸;
·3-(2-{2-[2-(2,6-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-吡啶-4-氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸;
·N-[2-(3,5-双-[(S)-2-亚乙-(E)-基-7-甲氧基-1,2,3,11a-四氢-吡咯并[2,1c][1,4]苯并二氮杂-5-酮-8-基氧甲基]-苯氧基)-乙基]-N-甲基-琥珀酰胺酸;
·(2-{2-[2-(2-{3-[3,5-双-(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-基氧甲基)-苯基]-丙氧基}-乙氧基)乙氧基]-乙氧基}-乙氧基)-乙酸;
·(3-{2-[2-(2-{3-[3,5-双-(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-基氧甲基)-苯基]-丙氧基}-乙氧基)乙氧基]-乙氧基}-乙氧基)-丙酸;
以及相应的N-羟基琥珀酰亚胺基酯,
或它们的可药用盐或它们的旋光异构体、外消旋体、非对映体或对映体。
19.缀合物分子,其包含经由连接物化学连接到任选改性的细胞结合剂上的一种或更多种根据权利要求1至18任一项的化合物,其中所述细胞结合剂选自单克隆抗体。
20.缀合物分子,其包含一种或更多种根据权利要求1至18任一项的化合物,所述化合物通过该化合物的连接物的连接基共价连接到细胞结合剂上,其中所述细胞结合剂选自单克隆抗体。
21.根据权利要求19至20任一项的缀合物分子,其中所述单克隆抗体和所述化合物经由酰胺基团连接。
22.制备缀合物分子的方法,包括下列步骤:使如权利要求1至18任一项所述的化合物或其前体与单克隆抗体反应以使所述化合物和所述单克隆抗体经由酰胺键连接在一起,其中连接物包含末端羧基,所述羧基任选以酰胺基团形式被活化。
23.权利要求22的方法,其中所述缀合物通过尺寸排阻色谱法、吸附色谱法、离子交换色谱法、疏水相互作用色谱法、亲合色谱法、HPLC、在陶瓷羟磷灰石上进行的色谱法、透析或渗滤来提纯。
24.药物组合物,其包含如权利要求19至21任一项所述的缀合物分子或如权利要求1至18任一项所述的化合物以及可药用载体。
25.权利要求1至18任一项所述的化合物,其用在治疗癌症的方法中。
26.权利要求19至21任一项所述的缀合物,其用在治疗癌症的方法中。
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Families Citing this family (132)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7811572B2 (en) | 2005-08-24 | 2010-10-12 | Immunogen, Inc. | Process for preparing purified drug conjugates |
US7638541B2 (en) | 2006-12-28 | 2009-12-29 | Metabolex Inc. | 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine |
EP2185544B1 (en) | 2007-07-19 | 2014-11-26 | Cymabay Therapeutics, Inc. | N-azacyclic substituted pyrrole, pyrazole, imidazole, triazole and tetrazole derivatives as agonists of the rup3 or gpr119 for the treatment of diabetes and metabolic disorders |
DE102008056086A1 (de) * | 2008-11-06 | 2010-05-12 | Gp Solar Gmbh | Additiv für alkalische Ätzlösungen, insbesondere für Texturätzlösungen sowie Verfahren zu dessen Herstellung |
IL295601B1 (en) | 2009-02-05 | 2024-07-01 | Immunogen Inc | History of benzodiazepines and processes for their preparation |
AU2015224492B2 (en) * | 2009-02-05 | 2017-04-20 | Immunogen, Inc. | Novel benzodiazepine derivatives |
MX349210B (es) | 2009-06-03 | 2017-07-18 | Immunogen Inc | Métodos de conjugación. |
FR2947269B1 (fr) | 2009-06-29 | 2013-01-18 | Sanofi Aventis | Nouveaux composes anticancereux |
FR2949469A1 (fr) * | 2009-08-25 | 2011-03-04 | Sanofi Aventis | Derives anticancereux, leur preparation et leur application en therapeutique |
CN102666553B (zh) | 2009-10-01 | 2015-05-06 | 赛马拜制药公司 | 取代的四唑-1-基-苯氧基甲基-噻唑-2-基-哌啶基-嘧啶盐 |
CN105001334A (zh) | 2010-02-10 | 2015-10-28 | 伊缪诺金公司 | Cd20抗体及其用途 |
US20110256157A1 (en) * | 2010-04-15 | 2011-10-20 | Spirogen Limited | Pyrrolobenzodiazepines and conjugates thereof |
CN107019804A (zh) | 2010-04-15 | 2017-08-08 | 西雅图基因公司 | 靶向吡咯并苯并二氮杂卓结合物 |
CN102971329B (zh) | 2010-04-15 | 2016-06-29 | 麦迪穆有限责任公司 | 用于治疗增殖性疾病的吡咯并苯并二氮杂卓 |
CN103037843A (zh) | 2010-06-23 | 2013-04-10 | 麦它波莱克斯股份有限公司 | 5-乙基-2-{4-[4-(4-四唑-1-基-苯氧甲基)-噻唑-2-基]-哌啶-1-基}-嘧啶的组合物 |
FR2963007B1 (fr) | 2010-07-26 | 2013-04-05 | Sanofi Aventis | Derives anticancereux, leur preparation et leur application therapeutique |
BR112013020540B1 (pt) | 2011-02-15 | 2020-12-29 | Immunogen, Inc | métodos para preparação de conjugados compreendendo agente de ligação à célula conjugado a composto citotóxico com grupo ligante |
AU2012236398B2 (en) | 2011-03-29 | 2016-02-11 | Immunogen, Inc. | Preparation of maytansinoid antibody conjugates by a one-step process |
US9156854B2 (en) | 2011-04-18 | 2015-10-13 | Immunogen, Inc. | Maytansinoid derivatives with sulfoxide linker |
CA2849039C (en) | 2011-09-20 | 2018-09-18 | Spirogen Sarl | Pyrrolobenzodiazepines as unsymmetrical dimeric pbd compounds for inclusion in targeted conjugates |
WO2013053871A1 (en) | 2011-10-14 | 2013-04-18 | Spirogen Sàrl | Pyrrolobenzodiazepines |
US9387259B2 (en) | 2011-10-14 | 2016-07-12 | Seattle Genetics, Inc. | Pyrrolobenzodiazepines and targeted conjugates |
EP2755642B1 (en) | 2011-10-14 | 2018-07-18 | Seattle Genetics, Inc. | Pyrrolobenzodiazepines and targeted conjugates |
JP6170497B2 (ja) | 2011-10-14 | 2017-07-26 | メドイミューン・リミテッドMedImmune Limited | ピロロベンゾジアゼピン |
SG11201403179QA (en) * | 2011-12-13 | 2014-07-30 | Immunogen Inc | Use of n-hydroxysuccinimide to improve conjugate stability |
AR090549A1 (es) | 2012-03-30 | 2014-11-19 | Genentech Inc | Anticuerpos anti-lgr5 e inmunoconjugados |
BR112014027166A2 (pt) | 2012-05-01 | 2017-06-27 | Genentech Inc | anticorpo, ácido nucleico, célula hospedeira, método para produzir um anticorpo, imunoconjugado, formulação farmacêutica, método de tratamento, método de inibir proliferação e métodos de detecção. |
WO2013177481A1 (en) | 2012-05-25 | 2013-11-28 | Immunogen, Inc. | Benzodiazepines and conjugates thereof |
BR112015000441A2 (pt) | 2012-07-09 | 2017-12-19 | Genentech Inc | imunoconjugados, formulação farmacêutica e método de tratamento e método para inbir a proliferação de uma célula positiva para cd22 |
BR112015000437A2 (pt) | 2012-07-09 | 2017-06-27 | Genentech Inc | imunoconjugados, formulação farmacêutica, métodos de tratamento e de inbir a proliferação de uma célula |
MX2015001399A (es) | 2012-08-02 | 2015-09-07 | Genentech Inc | Anticuerpos anti-etbr e inmunoconjugados. |
EP2887965A1 (en) | 2012-08-22 | 2015-07-01 | ImmunoGen, Inc. | Cytotoxic benzodiazepine derivatives |
WO2014055877A1 (en) * | 2012-10-04 | 2014-04-10 | Immunogen, Inc. | Use of a pvdf membrane to purify cell-binding agent cytotoxic agent conjugates |
JP6270859B2 (ja) | 2012-10-12 | 2018-01-31 | エイディーシー・セラピューティクス・エス・アー・エール・エルAdc Therapeutics Sarl | ピロロベンゾジアゼピン−抗体結合体 |
US9745303B2 (en) | 2012-10-12 | 2017-08-29 | Medimmune Limited | Synthesis and intermediates of pyrrolobenzodiazepine derivatives for conjugation |
CN105102068B (zh) | 2012-10-12 | 2018-06-01 | Adc疗法责任有限公司 | 吡咯并苯并二氮杂卓-抗体结合物 |
ES2649990T3 (es) | 2012-10-12 | 2018-01-16 | Medimmune Limited | Conjugados de anticuerpos anti-CD22-pirrolobenzodiazepinas |
KR101645905B1 (ko) | 2012-10-12 | 2016-08-04 | 스피로즌 살 | 피롤로벤조디아제핀 및 그의 컨주게이트 |
AU2013328674B2 (en) | 2012-10-12 | 2017-06-22 | Medimmune Limited | Pyrrolobenzodiazepines and conjugates thereof |
EP2906250B1 (en) | 2012-10-12 | 2018-05-30 | ADC Therapeutics SA | Pyrrolobenzodiazepine-anti-psma antibody conjugates |
WO2014057120A1 (en) | 2012-10-12 | 2014-04-17 | Adc Therapeutics Sàrl | Pyrrolobenzodiazepine-antibody conjugates |
ES2703151T3 (es) | 2012-10-12 | 2019-03-07 | Adc Therapeutics Sa | Conjugados de anticuerpos de pirrolobenzodiazepinas |
JP6133431B2 (ja) | 2012-11-24 | 2017-05-24 | ハンジョウ ディーエーシー バイオテック シーオー.,エルティディ.Hangzhou Dac Biotech Co.,Ltd. | 親水性連結体及び薬物分子と細胞結合分子との共役反応における親水性連結体の使用 |
WO2014140862A2 (en) | 2013-03-13 | 2014-09-18 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
EP2968494B1 (en) | 2013-03-13 | 2018-11-14 | Seattle Genetics, Inc. | Activated carbon filtration for purification of benzodiazepine adcs |
BR112015023070B1 (pt) * | 2013-03-13 | 2022-06-07 | Genentech, Inc. | Conjugados e compostos de pirrolobenzodiazepinas, composição farmacêutica que compreende os mesmo, bem como seus usos para o tratamento de uma doença proliferativa |
US9562099B2 (en) | 2013-03-14 | 2017-02-07 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
EP2970474B1 (en) | 2013-03-14 | 2017-12-20 | Genentech, Inc. | Anti-b7-h4 antibodies and immunoconjugates |
TWI636792B (zh) | 2013-08-12 | 2018-10-01 | 建南德克公司 | 1-(氯甲基)-2,3-二氫-1h-苯并[e]吲哚二聚體抗體-藥物結合物化合物及使用與治療方法 |
AR097685A1 (es) | 2013-09-17 | 2016-04-06 | Genentech Inc | Métodos de uso de anticuerpos anti-lgr5 |
WO2015052534A1 (en) | 2013-10-11 | 2015-04-16 | Spirogen Sàrl | Pyrrolobenzodiazepine-antibody conjugates |
GB201317981D0 (en) | 2013-10-11 | 2013-11-27 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
US10010624B2 (en) | 2013-10-11 | 2018-07-03 | Medimmune Limited | Pyrrolobenzodiazepine-antibody conjugates |
GB201317982D0 (en) | 2013-10-11 | 2013-11-27 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
US9956299B2 (en) | 2013-10-11 | 2018-05-01 | Medimmune Limited | Pyrrolobenzodiazepine—antibody conjugates |
CA2931340A1 (en) | 2013-12-13 | 2015-06-18 | Genentech, Inc. | Anti-cd33 antibodies and immunoconjugates |
MX2016007578A (es) | 2013-12-16 | 2016-10-03 | Genentech Inc | Compuestos de conjugado anticuerpo-farmaco dimerico de 1-(clorometil)-2,3-dihidro-1h-benzo [e] indol, y metodos de uso y tratamiento. |
JP6417421B2 (ja) | 2014-02-28 | 2018-11-07 | ハンジョウ ディーエーシー バイオテック シーオー.,エルティディ.Hangzhou Dac Biotech Co.,Ltd. | 荷電連結体及び共役体のためのその使用 |
JP2017522861A (ja) | 2014-05-22 | 2017-08-17 | ジェネンテック, インコーポレイテッド | 抗gpc3抗体及びイムノコンジュゲート |
MX2017002605A (es) | 2014-08-28 | 2017-05-19 | Bioatla Llc | Receptores de antigeno quimerico condicionalmente activos para celulas t modificadas. |
TW201613930A (en) | 2014-09-03 | 2016-04-16 | Immunogen Inc | Cytotoxic benzodiazepine derivatives |
DK3189056T3 (da) | 2014-09-03 | 2020-09-14 | Immunogen Inc | Cytotoksiske benzodiazepinderivater |
PE20170670A1 (es) | 2014-09-12 | 2017-06-06 | Genentech Inc | Anticuerpos anti-cll-1 e inmunoconjugados |
KR102508173B1 (ko) | 2014-09-12 | 2023-03-10 | 제넨테크, 인크. | 항-her2 항체 및 면역콘주게이트 |
CN113698485A (zh) | 2014-09-12 | 2021-11-26 | 基因泰克公司 | 抗-b7-h4抗体及免疫缀合物 |
TW201625688A (zh) | 2014-09-12 | 2016-07-16 | 建南德克公司 | 經半胱胺酸改造之抗體及接合物 |
GB201416112D0 (en) | 2014-09-12 | 2014-10-29 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
CA2957148A1 (en) | 2014-09-17 | 2016-03-24 | Genentech, Inc. | Immunoconjugates comprising anti-her2 antibodies and pyrrolobenzodiazepines |
EP3223854A1 (en) | 2014-11-25 | 2017-10-04 | ADC Therapeutics SA | Pyrrolobenzodiazepine-antibody conjugates |
BR112017014937A2 (pt) | 2015-01-14 | 2018-03-13 | Bristol-Myers Squibb Company | dímeros de benzodiazepina ligados em ponte a heteroarileno, conjugados dos mesmos, e métodos de preparação e uso |
BR112017014599A2 (pt) | 2015-01-14 | 2018-01-16 | Bristol-Myers Squibb Company | dímeros de benzodiazepina, conjugados dos mesmos, e métodos de preparação e uso |
GB201506411D0 (en) | 2015-04-15 | 2015-05-27 | Bergenbio As | Humanized anti-axl antibodies |
GB201506402D0 (en) | 2015-04-15 | 2015-05-27 | Berkel Patricius H C Van And Howard Philip W | Site-specific antibody-drug conjugates |
MX2017015814A (es) | 2015-06-23 | 2018-04-10 | Squibb Bristol Myers Co | Dimeros de benzodiazepina macrociclica, conjugados de los mismos, preparacion y usos. |
CN113350518A (zh) | 2015-07-12 | 2021-09-07 | 杭州多禧生物科技有限公司 | 与细胞结合分子的共轭偶联的桥连接体 |
US9839687B2 (en) | 2015-07-15 | 2017-12-12 | Suzhou M-Conj Biotech Co., Ltd. | Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule |
HUE051541T2 (hu) | 2015-07-21 | 2021-03-01 | Immunogen Inc | Eljárások citotoxikus benzodiazepin származékok elõállítására |
MA43354A (fr) | 2015-10-16 | 2018-08-22 | Genentech Inc | Conjugués médicamenteux à pont disulfure encombré |
CN107405408B (zh) * | 2015-12-21 | 2021-07-02 | 江苏恒瑞医药股份有限公司 | 一种抗体药物偶联物的制备方法 |
GB201601431D0 (en) | 2016-01-26 | 2016-03-09 | Medimmune Ltd | Pyrrolobenzodiazepines |
GB201602356D0 (en) | 2016-02-10 | 2016-03-23 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
GB201602359D0 (en) | 2016-02-10 | 2016-03-23 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
KR102606938B1 (ko) | 2016-04-15 | 2023-11-29 | 바이오아트라, 인코퍼레이티드 | 항 Axl항체 및 이의 면역접합체와 이것들의 용도 |
GB201607478D0 (en) | 2016-04-29 | 2016-06-15 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
WO2017196847A1 (en) | 2016-05-10 | 2017-11-16 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Variable new antigen receptor (vnar) antibodies and antibody conjugates targeting tumor and viral antigens |
AU2017263568B2 (en) | 2016-05-13 | 2024-01-18 | Bioatla, Llc | Anti-Ror2 antibodies, antibody fragments, their immunoconjugates and uses thereof |
JP7022080B2 (ja) | 2016-05-27 | 2022-02-17 | ジェネンテック, インコーポレイテッド | 部位特異的抗体-薬物複合体の特徴付けのための生化学分析的方法 |
CN107469089B (zh) * | 2016-06-07 | 2022-01-07 | 北京键凯科技股份有限公司 | 一种peg连接子及配基药物偶联物 |
WO2017214182A1 (en) | 2016-06-07 | 2017-12-14 | The United States Of America. As Represented By The Secretary, Department Of Health & Human Services | Fully human antibody targeting pdi for cancer immunotherapy |
AU2017305170A1 (en) | 2016-08-02 | 2019-02-14 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Monoclonal antibodies targeting glypican-2 (GPC2) and use thereof |
AU2017305392A1 (en) | 2016-08-03 | 2019-02-21 | Cymabay Therapeutics, Inc. | Oxymethylene aryl compounds for treating inflammatory gastrointestinal diseases or gastrointestinal conditions |
WO2018031662A1 (en) | 2016-08-11 | 2018-02-15 | Genentech, Inc. | Pyrrolobenzodiazepine prodrugs and antibody conjugates thereof |
GB201617466D0 (en) | 2016-10-14 | 2016-11-30 | Medimmune Ltd | Pyrrolobenzodiazepine conjugates |
EP3538080A4 (en) | 2016-11-14 | 2020-07-08 | Hangzhou Dac Biotech Co., Ltd. | CONJUGATION LINERS, MEDICAMENT-MOLECULE CONJUGATES TO A CELL CONTAINING THE SAME, METHODS OF PREPARING AND USING SUCH CONJUGATES WITH THE BINDERS |
AU2017361887B2 (en) | 2016-11-21 | 2019-08-15 | Cureab Gmbh | Anti-GP73 antibodies and immunoconjugates |
CA3044391A1 (en) | 2016-11-23 | 2018-05-31 | Immunogen, Inc. | Selective sulfonation of benzodiazepine derivatives |
US11236171B2 (en) | 2016-12-21 | 2022-02-01 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human monoclonal antibodies specific for FLT3 and uses thereof |
US20210388102A1 (en) | 2016-12-23 | 2021-12-16 | Immunogen, Inc. | Immunoconjugates targeting adam9 and methods of use thereof |
TW201825515A (zh) | 2017-01-04 | 2018-07-16 | 美商伊繆諾金公司 | Met抗體以及其免疫結合物及用途 |
ES2871001T3 (es) | 2017-02-08 | 2021-10-28 | Adc Therapeutics Sa | Conjugados de pirrolobenzodiazepinas y anticuerpos |
GB201702031D0 (en) | 2017-02-08 | 2017-03-22 | Medlmmune Ltd | Pyrrolobenzodiazepine-antibody conjugates |
RS63502B1 (sr) | 2017-04-18 | 2022-09-30 | Medimmune Ltd | Konjugati pirolobenzodiazepina |
US20200129637A1 (en) | 2017-04-20 | 2020-04-30 | Adc Therapeutics Sa | Combination therapy with an anti-axl antibody-drug conjugate |
US20180346488A1 (en) | 2017-04-20 | 2018-12-06 | Immunogen, Inc. | Cytotoxic benzodiazepine derivatives and conjugates thereof |
AU2018268970A1 (en) | 2017-05-19 | 2019-10-24 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human monoclonal antibody targeting tnfr2 for cancer immunotherapy |
US11318211B2 (en) | 2017-06-14 | 2022-05-03 | Adc Therapeutics Sa | Dosage regimes for the administration of an anti-CD19 ADC |
WO2019005208A1 (en) | 2017-06-30 | 2019-01-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | ANTIBODIES TO HUMAN MESOTHELIN AND USES IN ANTICANCER THERAPY |
CA3066953A1 (en) | 2017-06-30 | 2019-01-03 | Lentigen Technology, Inc. | Human monoclonal antibodies specific for cd33 and methods of their use |
DK3668874T3 (da) | 2017-08-18 | 2022-02-14 | Medimmune Ltd | Pyrrolobenzodiazepin-konjugater |
IL301637B1 (en) | 2017-09-29 | 2024-06-01 | Daiichi Sankyo Co Ltd | Conjugation of an antibody with a pyrrolobenzodiazepine derivative |
US11793885B2 (en) | 2017-12-28 | 2023-10-24 | Immunogen, Inc. | Substituted benzo[5,6][1,4]diazepino[1,2-a]indoles for the treatment of proliferative disorders |
GB201803342D0 (en) | 2018-03-01 | 2018-04-18 | Medimmune Ltd | Methods |
GB201806022D0 (en) | 2018-04-12 | 2018-05-30 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
AU2019301675A1 (en) | 2018-07-12 | 2021-01-28 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Affinity matured CD22-specific monoclonal antibody and uses thereof |
WO2020033430A1 (en) | 2018-08-08 | 2020-02-13 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | High affinity monoclonal antibodies targeting glypican-2 and uses thereof |
TW202029980A (zh) | 2018-10-26 | 2020-08-16 | 美商免疫遺傳股份有限公司 | E p C A M 抗體、可活化抗體及免疫偶聯物以及其用途 |
EP3898693A4 (en) | 2018-12-21 | 2022-09-21 | Avidity Biosciences, Inc. | ANTI-TRANSFERRIN RECEPTOR ANTIBODIES AND USES THEREOF |
US20220096641A1 (en) * | 2019-01-03 | 2022-03-31 | Legochem Biosciences, Inc. | Pyrrolobenzodiazepine dimer compound with improved safety and use thereof |
CN113490510A (zh) | 2019-01-08 | 2021-10-08 | 美国政府(由卫生和人类服务部的部长所代表) | 用于治疗实体瘤的靶向间皮素的跨物种单结构域抗体 |
US20220098323A1 (en) | 2019-01-22 | 2022-03-31 | The United States Of America,As Represented By The Secretary,Department Of Health And Human Services | High affinity monoclonal antibodies targeting glypican-1 and methods of use |
WO2020160156A2 (en) | 2019-01-30 | 2020-08-06 | Immutics, Inc. | Anti-gal3 antibodies and uses thereof |
JP2022529583A (ja) | 2019-03-29 | 2022-06-23 | イミュノジェン・インコーポレーテッド | 異常細胞増殖を阻害するまたは増殖性疾患を治療するための細胞毒性ビス-ベンゾジアゼピン誘導体及び細胞結合剤とのその複合体 |
JP2022552875A (ja) | 2019-10-22 | 2022-12-20 | ザ ユナイテッド ステイツ オブ アメリカ, アズ リプレゼンテッド バイ ザ セクレタリー, デパートメント オブ ヘルス アンド ヒューマン サービシーズ | 多様な固形腫瘍を処置するためのb7h3(cd276)を標的とする高親和性ナノボディ |
EP4041769A1 (en) | 2019-12-12 | 2022-08-17 | The United States of America, as represented by the Secretary, Department of Health and Human Services | Antibody-drug conjugates specific for cd276 and uses thereof |
WO2021188390A1 (en) | 2020-03-19 | 2021-09-23 | Avidity Biosciences, Inc. | Compositions and methods of treating facioscapulohumeral muscular dystrophy |
IL296393A (en) | 2020-03-27 | 2022-11-01 | Avidity Biosciences Inc | Preparations and methods for the treatment of muscle atrophy |
US20230391852A1 (en) | 2020-10-26 | 2023-12-07 | The U.S.A., As Represented By The Secretary, Department Of Health And Human Services | Single domain antibodies targeting sars coronavirus spike protein and uses thereof |
WO2022232612A1 (en) | 2021-04-29 | 2022-11-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Lassa virus-specific nanobodies and methods of their use |
CN117500831A (zh) | 2021-06-09 | 2024-02-02 | 美国政府(由卫生和人类服务部的部长所代表) | 用于治疗实体瘤的靶向pd-l1的跨物种单结构域抗体 |
WO2023288252A1 (en) | 2021-07-13 | 2023-01-19 | Truebinding, Inc. | Methods of preventing protein aggregation |
CA3231330A1 (en) | 2021-09-16 | 2023-03-23 | Avidity Biosciences, Inc. | Compositions and methods of treating facioscapulohumeral muscular dystrophy |
TW202406934A (zh) | 2022-05-03 | 2024-02-16 | 美商建南德克公司 | 抗Ly6E抗體、免疫結合物及其用途 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005023814A1 (en) * | 2003-09-11 | 2005-03-17 | Spirogen Limited | Synthesis of protected pyrrolobenzodiazepines |
WO2005085250A1 (en) * | 2004-03-01 | 2005-09-15 | Spirogen Limited | C8, c8' linked 5-oxo-1,2,3,11a-tetrahydro-5h-pyrrolo[2,1-c][1,4]benzodiazepine dimers with 1h-pyrrole-dicarboxylic acid amide linkers and oligomeric analogs therof as well as related compounds for the treatment of proliferative diseases |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1516743A (fr) | 1966-04-01 | 1968-02-05 | Rhone Poulenc Sa | Nouvel antibiotique et son procédé de préparation par culture de streptomyces croceus |
US4981979A (en) | 1987-09-10 | 1991-01-01 | Neorx Corporation | Immunoconjugates joined by thioether bonds having reduced toxicity and improved selectivity |
US5208020A (en) | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
ES2149768T3 (es) | 1992-03-25 | 2000-11-16 | Immunogen Inc | Conjugados de agentes enlazantes de celulas derivados de cc-1065. |
GB9818731D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Compounds |
EP1193270B1 (en) | 1998-08-27 | 2003-05-14 | Spirogen Limited | Pyrrolobenzodiazepines |
EP1242401B1 (en) | 1999-11-24 | 2006-12-27 | Immunogen, Inc. | Cytotoxic agents comprising taxanes and their therapeutic use |
US6756397B2 (en) | 2002-04-05 | 2004-06-29 | Immunogen, Inc. | Prodrugs of CC-1065 analogs |
US8034904B2 (en) | 2002-06-14 | 2011-10-11 | Immunogen Inc. | Anti-IGF-I receptor antibody |
AU2003285878B2 (en) | 2002-11-07 | 2011-04-28 | Immunogen, Inc. | Anti-CD33 antibodies and method for treatment of acute myeloid leukemia using the same |
DE60324607D1 (de) * | 2003-03-31 | 2008-12-18 | Council Scient Ind Res | Pyrrolo(2,1-c)(1,4)benzodiazepin-dimere als antitumormittel und verfahren dafür |
WO2004091542A2 (en) | 2003-04-15 | 2004-10-28 | Covx Pharmaceuticals, Inc. | Nitrogen containing integrin targeting compounds |
WO2005009369A2 (en) | 2003-07-21 | 2005-02-03 | Immunogen, Inc. | A ca6 antigen-specific cytotoxic conjugate and methods of using the same |
AU2004284075A1 (en) * | 2003-10-22 | 2005-05-06 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto |
GB0404577D0 (en) * | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
US7528126B2 (en) | 2004-03-09 | 2009-05-05 | Spirogen Limited | Pyrrolobenzodiazepines |
GB0410725D0 (en) * | 2004-05-13 | 2004-06-16 | Spirogen Ltd | Pyrrolobenzodiazepine therapeutic agents |
PL1813614T3 (pl) * | 2006-01-25 | 2012-03-30 | Sanofi Sa | Środki cytotoksyczne zawierające nowe pochodne tomaymycyny |
ZA200900545B (en) * | 2006-07-18 | 2010-03-31 | Sanofi Aventis | Antagonist antibody against EPHA2 for the treatment of cancer |
EP1914242A1 (en) | 2006-10-19 | 2008-04-23 | Sanofi-Aventis | Novel anti-CD38 antibodies for the treatment of cancer |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005023814A1 (en) * | 2003-09-11 | 2005-03-17 | Spirogen Limited | Synthesis of protected pyrrolobenzodiazepines |
WO2005085250A1 (en) * | 2004-03-01 | 2005-09-15 | Spirogen Limited | C8, c8' linked 5-oxo-1,2,3,11a-tetrahydro-5h-pyrrolo[2,1-c][1,4]benzodiazepine dimers with 1h-pyrrole-dicarboxylic acid amide linkers and oligomeric analogs therof as well as related compounds for the treatment of proliferative diseases |
Non-Patent Citations (3)
Title |
---|
J. Dean Farmer, et al..Synthesis and DNA crosslinking ability of a dimeric anthramycin analog.《Tetrahedron letters》.1988,第29卷(第40期),5105-5108. * |
Rohtash Kumar,et al..Design, synthesis and in vitro cytotoxic studies of novel bis-pyrrolo[2,1][1,4] benzodiazepine-pyrrole and imidazole polyamide conjugates.《European Journal of Medicinal Chemistry》.2005,第40卷641-654. * |
RohtashKumar et al..Design |
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