CN113260382A - 含整合素配体的细胞抑制性缀合物 - Google Patents
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- Medicinal Preparation (AREA)
Abstract
本发明涉及新型药物化合物,其包含:αvβ3整合素拮抗剂、包含可被弹性蛋白酶切割的L‑Val‑L‑Pro‑L‑Asp的连接单元、聚乙二醇(PEG)间隔物和细胞毒性元件,涉及其制备方法,涉及其在治疗、预防或管理疾病和病症中的用途,所述疾病和病症包括人和其他哺乳动物中的过度增殖性障碍,例如癌症。
Description
本发明涉及新型药物化合物,其包含:αvβ3整合素拮抗剂、包含可被弹性蛋白酶切割的L-Val-L-Pro-L-Asp的连接单元、聚乙二醇(PEG)间隔物和细胞毒性元件,涉及其制备方法,涉及其在治疗、预防或管理人和其他哺乳动物中的疾病和病症(包括过度增殖性障碍,例如癌症)中的用途。
癌症化疗通常伴随着严重的副作用,这是由于化疗药物对肿瘤组织以外的其他组织的增殖细胞的毒性作用所致。多年来,科学家们一直致力于提高所用活性化合物的选择性。经常采用的方法是合成前药,所述前药在靶组织中或多或少选择性地释放,例如通过改变pH(DE-A 42 29 903)、通过酶(例如葡萄糖醛酸酶;EP-A 511 917和595 133)或通过抗体-酶缀合物(WO 88/07378;US 4 975 278;EP-A 595 133)。这些方法中的显著问题是缀合物在其他组织和器官中缺乏稳定性,特别是活性化合物在肿瘤组织中的胞外释放之后的普遍活性化合物分布。
20(S)-喜树碱是五环生物碱,由Wall等人于1966年分离得到(J.Am.Chem.Soc.88,3888(1966))。在众多的体内外试验中,它具有高活性的抗肿瘤潜力。然而不幸的是,由于毒性和溶解度问题,在临床研究阶段未能实现该有希望的潜力。
通过E环内酯的打开和钠盐的形成,得到了水溶性化合物,所述化合物与闭环形式处于pH依赖性的平衡状态。在这方面,临床研究也尚未取得成功。
约20年后,人们发现该生物活性是由拓扑异构酶I的酶抑制作用引起的。此后,为了寻找一种更易溶、更易耐受、在体内有活性的喜树碱衍生物,研究活动又一次增加。
为了提高水溶性,已经描述了A-环和B-环修饰的喜树碱衍生物的盐和具有可电离基团的20-O-酰基衍生物的盐(US 4 943 579)。后一种前药概念后来也被转移到经修饰的喜树碱衍生物中(WO 96/02546)。然而,所述的20-O-酰基前药在体内具有非常短的半衰期,并且非常迅速地裂解得到母体结构。
整合素是存在于细胞表面的异二聚体跨膜蛋白,在细胞与细胞外基质的粘附中起重要作用。它们通过RGD序列(RGD是氨基酸序列精氨酸-甘氨酸-天冬氨酸的单字母编码)识别细胞外糖蛋白,例如细胞外基质上的纤连蛋白或玻连蛋白。
一般而言,整合素,例如,玻连蛋白受体,也称为αvβ3受体,或者可替代地αvβ5受体或GpIIb/IIIa受体,在细胞迁移、血管生成、细胞与基质粘附等生物学过程中起着重要作用,从而在这些过程起着至关重要的疾病中有重要作用。癌症、骨质疏松症、动脉硬化、再狭窄和眼炎可作为示例提及。
αvβ3受体大量存在于例如生长中的内皮细胞上,使其与细胞外基质的粘附成为可能。因此,αvβ3受体在血管生成即新生血管形成中起着重要的作用,而这是肿瘤生长和转移的重要前提。
有可能表明上述受体的阻断是治疗这类障碍的一个重要起点。如果生长中的内皮细胞与细胞外基质的粘附通过阻断其相应的整合素受体而被抑制,例如通过环肽或单克隆抗体,则不会发生血管生成,这导致肿瘤生长的停止或消退(参见,例如,Brooks等人,Cell79,1157-1164(1994))。
WO 98/10795描述了其中靶向肿瘤的分子与功能单元连接的缀合物,所述功能单元例如是细胞抑制剂或可检测标记物例如放射性核素。除其他外,整合素拮抗剂,例如具有上述RGD序列的肽,被描述为靶向肿瘤或肿瘤基质的分子。阿霉素被描述为与针对肿瘤的这种类型的分子连接的细胞抑制剂的一个示例。
在WO 98/10795的化合物的情况下,进行连接,使得针对肿瘤的分子和功能单元直接彼此键合,并保持它们各自的性质(例如,参见第56页,l.17至第58页,l.10和实施例6)。其结果是,这些化合物确实通过结合针对肿瘤的实体而选择性地聚集在紧邻肿瘤细胞处(在通过与特别在通过血管生成作用新形成的内皮细胞上表达的αvβ3整合素受体结合而具有αvβ3整合素拮抗作用的自由基的情况下),但是由于直接组合,功能单元例如细胞抑制剂不能释放到肿瘤组织的细胞内空间中。
从根本上说,对于在一方面通过缀合物中拥有的对αvβ3或αvβ5整合素受体寻址的部分的作用而选择性地聚集在肿瘤组织中,在另一方面包含可从缀合物释放的细胞抑制剂的缀合物,由于与WO 98/10795中描述的缀合物相比,细胞抑制剂可能对肿瘤细胞更直接作用,因此应该对肿瘤组织具有增加的毒性作用。特别地,如果细胞抑制剂的释放发生在紧邻肿瘤组织处或甚至在肿瘤细胞中,这种毒性作用和肿瘤选择性甚至应该更高。
在WO 00/69472中公开了酶激活的抗肿瘤前药化合物,其可被胶原酶(IV)和弹性蛋白酶特异性切割。关于可被弹性蛋白酶切割的连接单元,该申请描述了特异性四肽序列Ala-Ala-Pro-Val和Ala-Ala-Pro-Nva因此是合适的。此外,在该参考文献中,没有提及包含针对αvβ3整合素受体寻址的部分与细胞抑制剂的缀合物。
Y.Liu等人(Mol.Pharmaceutics 2012,9,168)描述了瑞奥西汀通过豆荚蛋白可切割接头连接到αvβ3整合素靶向部分的缀合物。
在EP 1 238 678中公开了与细胞毒性试剂的缀合物,其靶向αvβ3整合素并且具有可以被弹性蛋白酶特异性切割的肽接头。关于可被弹性蛋白酶切割的连接单元,该申请描述了包含因此合适的Pro-Val和Pro-Leu的肽序列。作为毒性基团部分,列举了喜树碱和喹诺酮羧酸。
这些缀合物的特殊挑战包括
·充分的溶解度,使其能够在适当的媒介物中静脉内施用,
·完整缀合物的高肿瘤渗透率,
·在血浆中的高稳定性以避免全身性解离,
·有效结合肿瘤微环境中的靶向受体,
·被肿瘤微环境中存在的酶高效切割,
·切割的毒性基团部分的高稳定性和细胞透性,以相对于再分布增强肿瘤细胞摄取。
因此,本发明的一个目的是开发缀合物,所述缀合物包含针对αvβ3整合素受体寻址的部分和可优先在肿瘤微环境中从缀合物释放的细胞抑制剂,在肿瘤微环境中缀合物中的针对αvβ3整合素受体寻址的部分保持与αvβ3整合素受体结合的能力,因此向这类化合物提供组织选择性。此外,缀合物的可切割性和药物释放应由肿瘤环境中存在切有活性的酶如中性粒细胞弹性蛋白酶介导。最后,毒性基团的谱应与细胞外切割和释放机制以一种方式相匹配,即它应高度可透入肿瘤细胞和组织,而不是药物转运体的底物。
本发明涉及药物化合物,所述药物化合物为缀合物,所述缀合物包含αvβ3整合素拮抗剂,可被弹性蛋白酶选择性切割的连接单元、聚乙二醇(PEG)间隔物和细胞毒性元件(毒性基团)。所述缀合物具有肿瘤特异性作用,这是与αvβ3整合素拮抗剂通过优选的连接单元连接的结果,这些连接单元可以被弹性蛋白酶选择性地切割,即被特别可以在肿瘤间质中找到的酶切割。优选的连接单元在生物介质例如培养基或血清中提供细胞抑制剂与αvβ3整合素拮抗剂的缀合物的足够稳定性,同时,提供肿瘤组织内所需的细胞内作用,这是由于其特异性的酶促或水解可切割性以及释放细胞抑制剂的结果。
特别地,本发明的化合物显示出有利的特征:
·脲键取代硫代脲后缀合物稳定性的提高
·利用7-乙基喜树碱作为特别合适的毒性基团部分
ο例如对内酯环稳定性的有益影响(Drugs Fut 2002,27(9),869)
ο高细胞透性和低外排(例如与SN38相比)
·对溶解度、整合素结合亲和力、弹性蛋白酶可切割性有有益影响的经修饰的间隔物
·与直接施用相比,缀合物施用后毒性基团的肿瘤积累。
·在各种肿瘤模型中有极好的治疗效果。
为此,特别优选7-乙基喜树碱作为上述缀合物中的毒性基团部分。
本发明提供式(I)的化合物
CT-LI-SP-IA (I)
其中
CT是来自下组的一价自由基:各自可另外携带羟基、羧基或氨基基团的细胞毒性自由基、细胞抑制剂自由基和细胞抑制剂衍生物自由基
LI是下式的二价肽自由基:-L-Val-L-Pro-L-Asp-
SP是下式的基团:-C=O-(CH2)x-O-(CH2-CH2-O)y-CH2-CH2-NH-C=O-,其中x=1-5并且y=0-15
IA是一价自由基,用于针对αvβ3整合素受体寻址
及其盐、溶剂化物和盐的溶剂化物。
二价肽自由基LI可通过其N末端或C末端位置与CT或SP结合。优选地,LI通过其C末端位置与CT结合,并通过其N末端位置与SP结合。
本发明还提供通式(Ia)的化合物
其中x是1-5,并且y是0-15,
及其盐、溶剂化物和盐的溶剂化物。
优选其中x是1-4的式(I)或(Ia)的化合物,更优选其中x是1-2的式(Ia)的化合物,最优选其中x是2的式(Ia)的化合物。
优选其中y是0-10的式(I)或(Ia)的化合物,更优选其中y是0-5的式(Ia)的化合物,最优选其中y是2的式(Ia)的化合物。
优选式II化合物:
及其盐、溶剂化物和盐的溶剂化物。
在本发明的上下文中,优选的盐是本发明化合物的生理上可接受的盐。还包括本身不适合于药物应用,但可用于例如本发明化合物的分离、纯化或储存的盐。
本发明化合物的生理上可接受的盐特别包括无机酸、羧酸和磺酸的酸加成盐,例如盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、萘二磺酸、甲酸、乙酸、三氟乙酸、丙酸、丁二酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、柠檬酸、葡萄糖酸、苯甲酸和扑酸的盐。
另外,本发明化合物的生理上可接受的盐还包括衍生自常规碱的盐,例如,优选碱金属盐(例如钠和钾盐)、碱土金属盐(例如钙和镁盐)、锌盐和衍生自氨或具有1至20个碳原子的有机胺的铵盐,例如优选乙胺、二乙胺、三乙胺、N,N-乙基二异丙胺、单乙醇胺、二乙醇胺、三乙醇胺、二甲基氨基乙醇、二乙基氨基乙醇、三(羟甲基)氨基甲烷、胆碱、苯扎氯铵、普鲁卡因、二苄胺、二环己胺、N-甲基吗啉、N-甲基哌啶、精氨酸、赖氨酸和1,2-乙二胺。
优选的盐是式(II)的化合物的二钠盐。
溶剂化物在本发明的上下文中描述的是本发明化合物的通过与溶剂分子配位形成固态或液态复合物的那些形式。水合物是溶剂化物的一种特殊形式,其中与水配位。在本发明的上下文中优选的溶剂化物是水合物。
本发明还包括本发明化合物的所有合适的同位素变体。本发明化合物的同位素变体在这里被理解为是指这样的化合物,其中本发明化合物中的至少一个原子已被具有相同原子序数但其原子质量与自然界中通常或主要出现的原子质量不同的另一个原子交换。可掺入本发明化合物的同位素的示例是氢、碳、氮、氧、磷、硫、氟、氯、溴和碘的那些同位素,例如2H(氘)、3H(氚)、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I和131I。本发明化合物的特定同位素变体,特别是其中掺入了一个或多个放射性同位素的那些,对于例如检查作用机制或活性成分在体内的分布可能是有益的;由于相对容易制备和检测,特别是用3H、14C和/或18F同位素标记的化合物适用于此目的。此外,掺入同位素,例如氘,由于化合物的代谢稳定性更高,可产生特别的治疗益处,例如延长在体内的半衰期或减少所需的有效剂量;因此,本发明化合物的这种修饰也可能构成本发明的优选实施方案。本发明化合物的同位素变体可以通过本领域技术人员已知的常用方法制备,例如通过下面描述的方法和工作实施例中描述的程序,通过使用相应试剂和/或起始化合物的相应同位素修饰。
本发明(例如实施例1)的缀合物的合成在下面的方案中概述
方案1:αvβ3整合素配体的合成:
对映体的分离也可以通过色谱使用手性柱在不同的步骤中完成。
方案2:αvβ3整合素与7-乙基喜树碱的缀合物的合成:
治疗方法:
本发明还涉及使用所述化合物及其组合物治疗哺乳动物过度增殖性障碍的方法。该方法包括给包括人在内的有需要的哺乳动物施用一定量的化合物,所述量有效地治疗所述障碍。过度增殖性障碍包括但不限于实体肿瘤,如乳腺、呼吸道、脑、生殖器官、消化道、尿路、眼、肝、皮肤、头颈、甲状腺、甲状旁腺的癌症及其远处转移。这些障碍还包括淋巴瘤、肉瘤和白血病。
乳腺癌的示例包括但不限于浸润性导管癌、浸润性小叶癌、导管原位癌和小叶原位癌。
呼吸道癌症的示例包括但不限于小细胞和非小细胞肺癌,以及支气管腺瘤和胸膜肺母细胞瘤。
脑癌的示例包括但不限于脑干和下丘脑胶质瘤、小脑和脑星形细胞瘤、髓母细胞瘤、室管膜瘤,以及神经外胚层和松果体肿瘤。
男性生殖器官的肿瘤包括但不限于前列腺癌和睾丸癌。女性生殖器官的肿瘤包括但不限于子宫内膜癌、宫颈癌、卵巢癌、阴道癌和外阴癌,以及子宫肉瘤。
消化道肿瘤包括但不限于肛门癌、结肠癌、结直肠癌、食道癌、胆囊癌、胃癌、胰腺癌、直肠癌、小肠癌和唾液腺癌。
尿路肿瘤包括但不限于膀胱癌、阴茎癌、肾癌、肾盂癌、输尿管癌和尿道癌。
眼癌包括但不限于眼内黑色素瘤和视网膜母细胞瘤。
肝癌的示例包括但不限于肝细胞癌(具有或不具有纤维板层变异的肝细胞癌)、胆管癌(肝内胆管癌)和混合性肝细胞胆管癌。
皮肤癌包括但不限于鳞状细胞癌、卡波西肉瘤、恶性黑色素瘤、默克尔细胞皮肤癌和非黑色素瘤皮肤癌。
头颈癌包括但不限于喉癌/下咽癌/鼻咽癌/口咽癌,以及唇癌和口腔癌。
淋巴瘤包括但不限于AIDS相关淋巴瘤、非霍奇金淋巴瘤、皮肤T细胞淋巴瘤、霍奇金病和中枢神经系统淋巴瘤。
肉瘤包括但不限于软组织肉瘤、骨肉瘤、恶性纤维组织细胞瘤、淋巴肉瘤和横纹肌肉瘤。
白血病包括但不限于急性髓系白血病、急性成淋巴细胞白血病、慢性淋巴细胞白血病、慢性髓性白血病和毛细胞白血病。
这些疾病在人类中已经很好地表征,但在其他哺乳动物中也以类似的病因存在,并且可以通过施用本发明的药物组合物来治疗。
基于已知的用于评估用于治疗过度增殖性障碍的化合物的标准实验室技术,通过用于在哺乳动物中确定上述病症的治疗的标准毒性试验和标准药理学分析,并通过将这些结果与用于治疗这些病症的已知药物的结果进行比较,可以容易地确定本发明化合物用于治疗每个期望适应症的有效剂量。在治疗这些病症之一时施用的活性成分的量可根据诸如所使用的特定化合物和剂量单位、施用方式、治疗周期、所治疗患者的年龄和性别以及所治疗病症的性质和程度等考虑而广泛变化。
要施用的活性成分总量一般为每天约0.001mg/kg体重至约200mg/kg体重,优选为每天约0.01mg/kg体重至约20mg/kg体重。临床上有用的给药时间表将从每天一到三次给药到每四周一次给药。此外,“药物假期”(其中在一段时间内不向患者给药)有可能有利于药理作用和耐受性之间的总体平衡。单位剂量可能含有约0.5mg至约1500mg活性成分,并且可以每天施用一次或多次或少于一天一次。注射施用(包括静脉注射、肌内注射、皮下注射和肠胃外注射)和使用输液技术的平均每日剂量优选是0.01至200mg/kg总体重。平均每日直肠施用方案将优选为0.01至200mg/kg总体重。平均每日阴道施用方案将优选为0.01至200mg/kg总体重。平均每日局部施用方案优选为0.1至200mg,每日一至四次施用。经皮浓度优选为维持0.01至200mg/kg的日剂量所需的浓度。平均每日吸入剂量方案将优选为0.01至100mg/kg总体重。
当然,每个患者的特定初始和持续剂量方案将根据由主治医生确定的病症的性质和严重程度、所用特定化合物的活性、患者的年龄和一般状况、施用时间、施用途径、药物排泄速率、药物组合等而变化。本领域技术人员可使用常规治疗试验确定本发明化合物或其药学上可接受的盐或酯或组合物的所需治疗方式和剂量数。
本发明还提供了本发明化合物在制备用于治疗上述障碍的药物组合物中的用途。
施用
本发明的化合物有可能具有系统和/或局部活性。为此目的,它们可以以合适的方式施用,例如经由口服、肠胃外、肺、鼻、舌下、舌、颊、直肠、阴道、真皮、透皮、结膜、耳途径或作为植入物或支架。
对于这些施用途径,可以以合适的施用形式施用本发明的化合物。
对于口服施用,可以将本发明的化合物配制成本领域已知的剂型,其快速和/或以改进的方式递送本发明的化合物,例如片剂(未包衣或包衣片剂,例如具有延迟溶解或不溶的肠溶或控释包衣)、口腔崩解片剂、薄膜/晶片、薄膜/冻干物、胶囊(例如硬或软明胶胶囊)、糖衣片剂、颗粒、微丸、粉剂、乳剂、悬浮剂、气雾剂或溶液。可以将结晶和/或无定形和/或溶解形式的本发明化合物掺入所述剂型中。
可以通过避免吸收步骤(例如静脉内、动脉内、心内、椎管内或管腔内)或包括吸收(例如肌肉内、皮下、皮内、经皮或腹膜内)来实现胃肠外施用。适用于胃肠外施用的施用形式特别是溶液、悬浮剂、乳剂、冻干物或无菌粉末形式的注射和输注制品。
适用于其他施用途径的示例是用于吸入的药物形式[特别是粉末吸入器、雾化器]、滴鼻剂、鼻腔溶液、鼻腔喷雾剂;舌、舌下或颊施用的片剂/薄膜/晶片/片剂/胶囊;栓剂;滴眼剂、眼药膏、眼浴液、眼用插入物、滴耳液、耳喷雾剂、耳粉、耳冲洗液、耳卫生棉条;阴道胶囊、水性悬浮剂(洗剂、搅拌混合物)、亲脂性悬浮剂、乳剂、软膏、乳膏、透皮治疗系统(例如贴剂)、奶、糊剂、泡沫、尘化粉末、植入物或支架。
本发明的化合物可掺入所述施用形式中。这可以通过与药学上合适的赋形剂混合以本身已知的方式实现。药物上合适的赋形剂特别包括,
·软膏基质(例如石油醚、石蜡、甘油三酯、蜡、羊毛蜡、羊毛蜡醇、羊毛脂、亲水性软膏、聚乙二醇),
·栓剂的基质(如聚乙二醇、可可脂、硬脂肪),
·溶剂(例如水、乙醇、异丙醇、甘油、丙二醇、中等链长的甘油三酯、脂肪油、液体聚乙二醇、石蜡),
·表面活性剂、乳化剂、分散剂或润湿剂(例如十二烷基硫酸钠)、卵磷脂、磷脂、脂肪醇(例如失水山梨醇脂肪酸酯(例如聚氧乙烯失水山梨醇脂肪酸酯(例如聚氧乙烯脂肪酸甘油酯(例如聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、甘油脂肪酸酯、泊洛沙姆(例如
·缓冲剂、酸和碱(例如磷酸盐、碳酸盐、柠檬酸、乙酸、盐酸、氢氧化钠溶液、碳酸铵、氨丁三醇、三乙醇胺),
·等渗剂(例如葡萄糖、氯化钠),
·吸附剂(例如高分散二氧化硅),
·用于快速溶解或以改性方式溶解的薄膜或扩散膜的涂层材料(例如糖、虫胶)和成膜剂(例如聚乙烯吡咯烷酮(例如聚乙烯醇、羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、乙酸纤维素、乙酸纤维素邻苯二甲酸酯、聚丙烯酸酯、聚甲基丙烯酸酯例如
·胶囊材料(例如明胶、羟丙基甲基纤维素),
·增塑剂(例如聚乙二醇、丙二醇、甘油、三乙酰、柠檬酸三乙酰酯、邻苯二甲酸二丁酯),
·渗透促进剂,
·稳定剂(例如抗氧化剂,例如抗坏血酸、抗坏血酸棕榈酸酯、抗坏血酸钠、丁基羟基茴香醚、丁基羟基甲苯、没食子酸丙酯),
·防腐剂(如对羟基苯甲酸酯、山梨酸、硫柳汞、苯扎氯铵、醋酸氯己定、苯甲酸钠),
·着色剂(例如无机颜料,例如氧化铁、二氧化钛),
·调味剂、甜味剂、味道掩蔽剂和/或气味掩蔽剂。
本发明还涉及一种药物组合物,其包含至少一种本发明化合物,通常与一种或多种药物上合适的赋形剂一起,并且涉及其根据本发明的用途。
组合
根据另一方面,本发明涉及药物组合,特别是药物,其包含至少一种本发明的通式(I)或(Ia)的化合物和至少一种或多种另外的活性成分,特别是用于治疗和/或预防过度增生性障碍。
本发明中的术语“组合”如本领域技术人员已知的那样使用,所述组合可以是固定组合、非固定组合或部件套件。
本发明中的“固定组合”如本领域技术人员已知的那样使用,并定义为其中例如第一活性成分(如本发明通式(I)的一种或多种化合物)和另一活性成分以一个单位剂量或单一实体一起存在的组合。“固定组合”的一个示例是这样的药物组合物,其中第一活性成分和另一活性成分以混合物形式存在以供同时施用,例如在制剂中。“固定组合”的另一示例是这样的药物组合,其中第一活性成分和另一活性成分存在于一个单元中,而不是混合物。
本发明中的非固定组合或“部件套件”如本领域技术人员已知的那样使用,并定义为其中第一活性成分和另一活性成分以多于一个单位存在的组合。非固定组合或部件套件的一个示例是其中第一活性成分和另一活性成分分开存在的组合。非固定组合或部件套件的组分可以单独、顺序、同时、并发或按时间顺序交错地施用。
本发明的化合物可以作为唯一的药剂施用或与一种或多种其他药物活性成分组合施用,其中组合不会引起不可接受的不良作用。本发明还涵盖这样的药物组合。例如,本发明的化合物可与已知的用于治疗和/或预防过度增生性障碍的活性成分组合。
用于治疗和/或预防过度增生性障碍的活性成分的示例包括:131I-chTNT、阿巴瑞克、阿贝西利、阿比特龙、阿卡拉布替尼(acalabrutinib)、阿克拉霉素、阿达木单抗、ado曲妥珠单抗-美坦新偶联物(ado-trastuzumab emtansine)、阿法替尼、阿柏西普、阿地白介素、阿来替尼、阿仑单抗、阿仑膦酸(alendronic acid)、阿利维A酸、六甲蜜胺、氨磷汀、氨鲁米特、氨基乙酰丙酸己酯、氨柔比星、安吖啶、阿那曲唑、安塞司亭、茴香脑二硫代乙硫酮(anethole dithiolethione)、雷星-阿奈妥单抗(anetumab ravtansine)、血管紧张素II、抗凝血酶III、阿帕鲁胺(apalutamide)、阿瑞匹坦、阿西莫单抗、阿格拉宾(arglabin)、三氧化二砷、天冬酰胺酶、阿特珠单抗、阿维鲁单抗、阿基仑赛(axicabtagene ciloleucel)、阿昔替尼、阿扎胞苷、巴利昔单抗、贝洛替康、苯达莫司汀、贝索单抗、贝林司他、贝伐珠单抗、贝沙罗汀、比卡鲁胺、比生群、博来霉素、兰妥莫单抗、硼替佐米、博舒替尼、布舍瑞林、维布妥昔单抗、布加替尼、白消安、卡巴他赛、卡波替尼、降钙素(calcitonine)、亚叶酸钙、左亚叶酸钙、卡培他滨、卡罗单抗、卡马西平卡铂、卡波醌、卡非佐米、卡莫氟、卡莫司汀、卡妥索单抗、塞来昔布、西莫白介素、色瑞替尼、西妥昔单抗、苯丁酸氮芥、氯地孕酮、氮芥、西多福韦、西那卡塞、顺铂、克拉屈滨、氯膦酸、氯法拉滨、考比替尼(cobimetinib)、考泮利司(copanlisib)、crisantaspase、克唑替尼、环磷酰胺、环丙孕酮、阿糖胞苷、达卡巴嗪、更生霉素、达妥木单抗、达依泊汀α、达拉菲尼、达沙替尼、柔红霉素、地西他滨、地加瑞克、地尼白介素-2(denileukin diftitox)、地舒单抗、地普奥肽、德舍瑞林、卫康醇、右丙亚胺、二溴螺氯铵、卫康醇、双氯芬酸、地努妥昔单抗(dinutuximab)、多西他赛、多拉司琼、去氧氟尿苷、多柔比星、多柔比星+雌酮、屈大麻酚、度伐鲁单抗、依库珠单抗、依决洛单抗、依利醋铵、依洛妥珠单抗、艾曲波帕、恩西地平、内皮抑素、依诺他滨、恩杂鲁胺、表柔比星、环硫雄醇、依伯汀α(epoetin alfa)、依泊汀β(epoetin beta)、依泊汀ζ(epoetin zeta)、艾铂、艾瑞布林、厄洛替尼、埃索美拉唑、雌二醇、雌莫司汀、炔雌醇、依托泊苷、依维莫司、依西美坦、法倔唑、芬太尼、非格司亭、氟甲睾酮、氟尿苷、氟达拉滨、氟尿嘧啶、氟他胺、亚叶酸、福美司坦、福沙吡坦、福莫司汀、氟维司群、钆布醇、钆特醇、钆特酸葡甲胺(gadoteric acidmeglumine)、钆弗塞胺、钆塞酸、硝酸镓、加尼瑞克、吉非替尼、吉西他滨、吉妥珠单抗、谷卡匹酶、glutoxim、GM-CSF、戈舍瑞林、格拉司琼、粒细胞集落刺激因子、组胺二盐酸盐、组氨瑞林、羟基脲、I-125粒子、兰索拉唑、伊班膦酸、替伊莫单抗、依鲁替尼、伊达比星、异环磷酰胺、伊马替尼、咪喹莫德、英丙舒凡、茚地司琼、英卡膦酸、英吉丁酯(ingenol mebutate)、伊组单抗奥加米星(inotuzumab ozogamicin)、干扰素α、干扰素β、干扰素γ、碘比醇、碘苄胍(123I)、碘美普尔、伊匹木单抗、伊立替康、伊曲康唑、伊沙匹隆、伊沙佐米、兰瑞肽、兰索拉唑、拉帕替尼、Iasocholine、来那度胺、乐伐替尼、来格司亭、香菇多糖、来曲唑、亮丙瑞林、左旋咪唑、左炔诺孕酮、左甲状腺素钠、麦角乙脲、洛铂、罗氮芥、氯尼达明、lutetium Lu177dotatate、马索罗酚、甲羟孕酮、甲地孕酮、美拉胂醇、美法仑、美雄烷、巯基嘌呤、美司钠、美沙酮、甲氨蝶呤、甲氧沙林、甲氨基酮戊酸盐、甲基强的松龙、甲基睾酮、甲酪氨酸、米哚妥林(midostaurin)、米伐木肽(mifamurtide)、米替福新、米铂、二溴甘露醇、米托胍腙、二溴卫矛醇、丝裂霉素、米托坦、米托蒽醌、莫加利珠单抗(mogamulizumab)、莫拉司亭、莫哌达醇(mopidamol)、盐酸吗啡、硫酸吗啡、mvasi、大麻隆、nabiximols、那法瑞林、纳洛酮+戊唑辛、纳曲酮、那托司亭、奈西妥木单抗、奈达铂、奈拉滨、奈雷替尼、奈立膦酸、奈妥吡坦/帕洛诺司琼、纳武单抗、喷曲肽、尼洛替尼、尼鲁米特、尼莫拉唑、尼妥珠单抗、尼莫司汀、尼达尼布、尼雷帕利、二胺硝吖啶(nitracrine)、纳武单抗、奥比妥珠单抗、奥曲肽、奥法木单抗、奥拉帕尼、奥拉妥单抗、高三尖杉酯碱(omacetaxine mepesuccinate)、奥美拉唑、昂丹司琼、奥普瑞白介素、奥古蛋白、奥利莫德(orilotimod)、奥希替尼、奥沙利铂、羟考酮、羟甲烯龙、ozogamicine、p53基因疗法、紫杉醇、帕柏西利、帕利弗明、钯-103粒子、帕洛诺司琼、帕米膦酸、帕尼妥木单抗、帕比司他、泮托拉唑、帕唑帕尼、培门冬酶、PEG-依泊汀β(甲氧基PEG-依泊汀β)、派姆单抗、聚乙二醇非格司亭(pegfilgrastim)、聚乙二醇干扰素α-2b、派姆单抗、培美曲塞、戊唑辛、喷司他丁、培洛霉素、全氟正丁烷、培磷酰胺、珀妥珠单抗、沙培林、匹罗卡品、吡柔比星、匹克生琼、普乐沙福、普卡霉素、聚氨葡糖、磷酸聚雌二醇、聚乙烯吡咯烷酮+透明质酸钠、多糖-K、泊马度胺、帕纳替尼、卟吩姆钠、普拉曲沙、泼尼莫司汀、强的松、丙卡巴肼、丙考达唑、普萘洛尔、喹高利特、雷贝拉唑、雷考妥莫单抗、氯化镭-223、雷多替尼、雷洛昔芬、雷替曲塞、雷莫司琼、雷莫卢单抗、雷莫司汀、拉布立酶、丙亚胺(razoxane)、瑞美替尼(refametinib)、瑞格拉非尼、利波西利、利塞膦酸、依替膦酸铼-186、利妥昔单抗、罗拉吡坦、洛米迪星、洛米司亭、罗莫肽、卢卡帕利、来昔决南钐(153Sm)、沙格司亭、萨玛利珠单抗(sarilumab)、萨妥莫单抗、分泌素、司妥昔单抗、西普鲁塞-T(sipuleucel-T)、西佐喃、索布佐生、甘氨双唑钠(sodium glycididazole)、索尼地吉、索拉非尼、康力龙、链脲佐菌素、舒尼替尼、他拉泊芬、拉他莫基(talimogene laherparepvec)、他米巴罗汀、三苯氧胺、他喷他多、他索纳明、替西白介素、锝(99mTc)巯诺莫单抗、99mTc-HYNIC-[Tyr3]-奥曲肽、替加氟、替加氟+吉美拉西+奥替拉西、替莫泊芬、替莫唑胺、替西罗莫司、替尼泊苷、睾酮、替曲膦、沙利度胺、噻替派、胸腺法新(thymalfasin)、促甲状腺素α、硫鸟嘌呤、tisagenlecleucel、托珠单抗、拓扑替康、托瑞米芬、托西莫单抗、曲贝替定、曲美替尼、曲马多、曲妥珠单抗、曲妥珠单抗-美坦新偶联物(trastuzumab emtansine)、曲奥舒凡、维甲酸、三氟尿苷+替吡拉西(tipiracil)、曲洛司坦、曲普瑞林、曲美替尼、曲磷胺、促血小板生成素、色氨酸、乌苯美司、瓦他拉尼(valatinib)、戊柔比星、万迪他尼(vandetanib)、伐普肽、维拉非尼、长春碱、长春新碱、长春地辛、长春氟宁、长春瑞滨、维莫德吉(vismodegib)、伏立诺他、伏氯唑、钇-90玻璃微球、净司他丁、净司他丁斯酯(zinostatin stimalamer)、唑来膦酸、佐柔比星。
缩写:
下表列出了这里使用的缩写。
Abu -γ-氨基丁酸
ACN -乙腈
Boc -叔丁氧基羰基
Bzl -苄基
DCM -二氯甲烷
DIEA -二异丙基乙胺(Hünig碱)
DMAP -二甲氨基吡啶
DMF -二甲基甲酰胺
DMSO -二甲基亚砜
EDCI -1-乙基-3-(3-二甲基氨基丙基)碳二亚胺
ee -对映体过量
FCS -胎牛血清
Fmoc -芴基-9-甲氧基羰基
HATU -2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐
HPLC -高效液相色谱
MTBE -甲基叔丁基醚
NMP -N-甲基吡咯烷酮
RP -反相
rt -室温
RTV -相对肿瘤体积
TFA -三氟乙酸
THF -四氢呋喃
TLC -薄层色谱法
本申请中描述的本发明的各个方面通过以下实施例来说明,这些实施例并不意味着以任何方式限制本发明。
这里描述的示例性测试实验用于说明本发明,并且本发明不限于所给出的示例。
实验部分
在实验部分中未描述其合成的所有试剂是市售的,或是已知化合物或者可以由本领域技术人员通过已知方法由已知化合物形成。
根据本发明方法制备的化合物和中间体可能需要纯化。有机化合物的纯化对于本领域技术人员是公知的,并且可以有几种纯化相同化合物的方法。在一些情况下,可能不需要纯化。在一些情况下,化合物可以通过结晶纯化。在一些情况下,可以使用合适的溶剂将杂质搅拌出来。在一些情况下,化合物可以通过色谱法来纯化,特别是快速柱色谱法,使用例如预填充的硅胶盒,例如Biotage SNAP盒或以及Biotage自动纯化系统(或Isolera )和洗脱液,例如己烷/乙酸乙酯或DCM/甲醇梯度。在一些情况下,可以通过制备型HPLC纯化化合物,所述制备型HPLC使用例如配备二极管阵列检测器的Waters自动纯化器和/或在线电喷雾电离质谱仪,并结合合适的预填充反相柱和洗脱液,例如水和乙腈的梯度,所述洗脱液可以包含添加剂如三氟乙酸、甲酸或氨水。
在一些情况下,如上所述的纯化方法可以以盐形式提供具有足够碱性或酸性官能度的本发明化合物,例如,在足够碱性的本发明化合物的情况下,为三氟乙酸盐或甲酸盐,或在足够酸性的本发明化合物的情况下,为铵盐。这种类型的盐可以通过本领域技术人员已知的各种方法分别转化为其游离碱或游离酸形式,或者在随后的生物测定中作为盐使用。应当理解,如本文所述和分离的本发明化合物的特定形式(例如盐、游离碱等)不一定是所述化合物可应用于生物测定以定量特定生物活性的唯一形式。
UPLC-MS标准程序:
分析型UPLC-MS如下所述进行。除非指示负模式(ESI-),质量(m/z)由正模式电喷雾电离报告。在大多数情况下使用方法1。如果不是,则会注明。
HPLC和LC-MS方法:
方法0:
质量测定通过采用电子喷雾电离(ESI)法的高效液相色谱-质谱(HPLC-MS)进行或通过FAB或MALDI质谱法进行。
方法1(LC-MS):
仪器:Waters ACQUITY SQD UPLC系统;柱:Waters Acquity UPLC HSS T3 1.8μ50x1mm;洗脱液A:1l水+0.25mL 99%ige甲酸,洗脱液B:1l乙腈+0.25mL 99%甲酸;梯度:0.0min 90%A→1.2min 5%A→2.0min 5%A烘箱:50℃;流量:0.40mL/min;UV-检测:208-400nm。
实施例:
起始材料和中间体:
中间体1
(3R)-3-(3-氨基苯基)-3-[(叔丁氧基羰基)氨基]丙酸
将151g 3-硝基苯甲醛、94g乙酸铵、127g丙二酸和1L 2-丙醇的混合物加热回流5小时。过滤溶液并用0.7L热的2-丙醇洗涤沉淀物。粗产物真空干燥,悬浮于1.5L水中,用1N盐酸处理,并过滤。浓缩滤液,得到146g。
NMR(400MHz,D4-甲醇):δ=3.09(m,2H),4.88(m,1H),7.74(t,1H),7.90(d,1H),8.33(d,1H),8.43(s,1H)。
将20g(95mmol)该中间体和31.2g二叔丁基二碳酸酯溶于150mL二噁烷/水混合物(1:1)中,并添加33mL DIEA。搅拌混合物约90分钟,直到观察到完全溶解。溶剂蒸发后,将剩余残留物溶于1L DCM中,用500mL 5%柠檬酸萃取3次。浓缩有机相,用DCM/二乙醚/石油醚1:1:1的混合物沉淀产物,并过滤。干燥后,得到23.5g(80%)期望产物。
将5g(16.1mmol)该中间体和3.095g(23mmol)(2R)-2-氨基-2-苯乙醇溶于乙腈中并在0℃下放置3天。将沉淀物过滤,溶解于DCM中,并用5%柠檬酸萃取2次。有机相用硫酸钠干燥并蒸发。将该程序重复两次。得到1.52g(30%)期望产物,ee为95%,且[α]D 25=+34.4°/甲醇。
将1500mg(0.243mmol)该中间体溶解在100mL甲醇中,并在常压下在钯/碳上氢化30分钟。分离出催化剂,浓缩溶液,用二乙醚消化,过滤,并将残留物真空干燥。得到1334mg(98%)的标题化合物。
[DC:(二氯甲烷/甲醇/氨(17%ig)(15:4:0.5);Rf=0.18]。
中间体2
(3R)-3-[(叔丁氧基羰基)氨基]-3-{3-[({3-[(丙基氨基甲酰基)氨基]苯基}磺酰基)氨基]苯基}丙酸
将8300mg(29.6mmol)中间体1和9843mg(44.4mmol)3-硝基苯磺酰氯溶解在400mlDCM/DMF 1:1中,并添加7.2mL吡啶。将混合物在室温下搅拌过夜。然后将混合物用200mLDCM稀释,用50mL 5%柠檬酸萃取3次。将有机相浓缩。干燥后得到剩余残留物13.8g(定量)(3R)-3-[(叔丁氧基羰基)氨基]-3-(3-{[(3-硝基苯基)磺酰基]氨基}苯基)丙酸。
[DC:(二氯甲烷/甲醇/氨(17%ig)(15:4:0.5);Rf=0.2]。
将13800mg(29.65mmol)该中间体溶解在1000mL甲醇中,并在常压下在钯/碳上氢化5小时。分离出催化剂,浓缩溶液,并将残留物用二乙醚洗涤两次,然后真空干燥。得到12240mg(95%)(3R)-3-(3-{[(3-氨基苯基)磺酰基]氨基}苯基)-3-[(叔丁氧基羰基)氨基]丙酸。
将12200mg(28mmol)该中间体溶解在600mL二噁烷中,添加5722mg(67mmol)1-异氰酸基丙烷,将混合物搅拌过夜。将溶液真空浓缩,将剩余残留物用DCM/甲醇/NH4OH(17%)15/4/0.5的洗脱液混合物通过快速色谱法纯化。收集相关级分并真空浓缩。真空干燥残留物后,得到11220mg(67%)的标题化合物。
LC-MS(方法1):Rt=0.9min;MS(ESIpos):m/z=521(M+H)+。
中间体3
(3R)-3-{[(4-氨基苯基)氨基甲酰基]氨基}-3-{3-[({3-[(丙基氨基甲酰基)氨基]苯基}磺酰基)氨基]苯基}丙酸
将400mg(0.768mmol)中间体2溶解在10mL DCM中,并添加2mL三氟乙酸。在室温下搅拌90分钟后,真空浓缩反应混合物。将残留物用5%碳酸二钠溶液处理,随后溶解在DCM/甲醇混合物中。用二乙醚沉淀、过滤和真空干燥后,得到260mg(81%)(3R)-3-氨基-3-{3-[({3-[(丙基氨基甲酰基)氨基]苯基}磺酰基)氨基]苯基}丙酸。
LC-MS(方法0):Rt=4.11min;MS:m/z=421=(M+H)+
将250mg(0.595mmol)该中间体溶解在15mL DMF中,添加117mg(0.713mmol)1-异氰酸基-4-硝基苯,在室温下搅拌该溶液30分钟。再添加30mg 1-异氰酸基-4-硝基苯,继续搅拌30分钟。将溶液真空浓缩,将剩余残留物通过快速色谱法纯化。真空浓缩相关级分后,得到160mg(46%)(3R)-3-{[(4-硝基苯基)氨基甲酰基]氨基}-3-{3-[({3-[(丙基氨基甲酰基)氨基]苯基}磺酰基)氨基]苯基}丙酸。
LC-MS(方法0):Rt=5.61min;MS:m/z=585=(M+H)+
将142mg(0.243mmol)该中间体溶解在20mL甲醇/DCM 10:1中,并在常压下在钯/碳上氢化30分钟。分离出催化剂,浓缩溶液,用二乙醚消化,过滤,并将残留物真空干燥。得到103mg(76%)的标题化合物。
LC-MS(方法0):Rt=4.31min;MS:m/z=555=(M+H)+
1H-NMR(500MHz,D4-甲醇):δ=0.93(t,3H),1.5(m,2H),2.74(d,2H),3.1(dt,2H),5.15(t,1H),6.68(d,2H),6.85(d,1H),7.05(d,1H),7.1(d,1H),7.13(t,1H),7.28-7.4(m,3H),7.6(s,1H),7.66(d,1H)。
中间体4
(4S)-4,11-二乙基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3',4':6,7]吲哚嗪并[1,2-b]喹啉-4-基L-缬氨酸三氟乙酸酯(1:1)
将2.59g(10.6mmol)N-(叔丁氧基羰基)-缬氨酸-N-羧基环内酸酐和0.5g 4-(N,N-二甲基氨基)-吡啶添加到2g(5.3mmol)(4S)-4,11-二乙基-4-羟基-1H-吡喃并[3',4':6,7]吲哚嗪并[1,2-b]喹啉-3,14(4H,12H)-二酮(7乙基喜树碱,如S.Sawada等人在Chem.Phar.Bull 1991-39(6)-1445中描述地合成)在150ml无水二氯甲烷中的搅拌悬浮液中。将混合物在室温下搅拌20小时,随后真空浓缩。向残留物中添加8ml ACN,随后添加5mL二乙醚。过滤混合物,将剩余残留物真空干燥。得到2964mg(92%)的受保护中间体。
LC-MS(方法1):Rt=1.19min;MS(ESIpos):m/z=576(M+H)+。
将2964mg(5.15mmol)该受BoC保护的中间体化合物在6ml二氯甲烷和60ml无水三氟乙酸中在室温搅拌30分钟,然后超声处理1小时。真空浓缩后,从乙腈/水的混合物中冻干产物。得到3.622g(定量)标题化合物。
LC-MS(方法1):Rt=0.68min;MS(ESIpos):m/z=476(M+H)+。
中间体5
(2S)-1-[(19S)-19-(2-叔丁氧基-2-氧代乙基)-2,2-二甲基-4,17,20-三氧代-3,8,11,14-四氧杂-5,18-二氮杂二十烷-20-基]吡咯烷-2-甲酸
该中间体5按照肽化学中已知的经典方法合成,首先是在DIEA存在下,在DMF中将1-(2,5-二氧代吡咯烷-1-基)N-(叔丁氧基羰基)-L-天冬氨酸4-叔丁酯与L-脯氨酸苄酯盐酸盐(1:1)偶联,然后在钯/碳上通过氢化来裂解苄酯。随后,通过将(2S)-1-{(2S)-4-叔丁氧基-2-[(叔丁氧基羰基)氨基]-4-氧代丁酰基}吡咯烷-2-甲酸在15mL TFA和100mL DCM的混合物中的溶液搅拌15分钟,然后用DCM/甲醇3:1作为洗脱液通过快速色谱法纯化,除去叔丁氧基羰基保护基团。将该中间体溶解于DMF中,并在DIEA存在下与{2-[2-(2-{3-[(2,5-二氧代吡咯烷-1-基)氧基]-3-氧代丙氧基}乙氧基)乙氧基]乙基}氨基甲酸叔丁酯(先前通过用1-羟基吡咯烷-2,5-二酮和EDCI将2,2-二甲基-4-氧代-3,8,11,14-四氧杂-5-氮杂十七烷-17-酸在DMF中转化成活化酯而得到)偶联。
LC-MS(方法1):Rt=0.86min;MS(ESIpos):m/z=590(M+H)+。
中间体6
(3R)-3-{[(4-{[(4-硝基苯氧基)羰基]氨基}苯基)氨基甲酰基]氨基}-3-{3-[({3-[(丙基氨基甲酰基)氨基]苯基}磺酰基)氨基]苯基}丙酸
8.99g(43.3mmol)4-硝基苯基氯甲酸酯溶解在1300mL THF中,并添加12g(21.64mmol)(3R)-3-{[(4-氨基苯基)氨基甲酰基]氨基}-3-{3-[({3-[(丙基氨基甲酰基)氨基]苯基}磺酰基)氨基]苯基}丙酸。将混合物加热并在回流下搅拌45分钟,随后冷却至室温并过滤。在减压下将滤液浓缩至100mL的体积。将该溶液倒入二乙醚中,过滤沉淀物。真空干燥过夜后,得到11.6g标题化合物。
LC-MS(方法1):Rt=0.97min;MS(ESIpos):m/z=720(M+H)+。
中间体7:整合素配体的参比化合物(中间体3的S-差向异构体):
(3S)-3-{[(4-氨基苯基)氨基甲酰基]氨基}-3-{3-[({3-[(丙基氨基甲酰基)氨基]苯基}磺酰基)氨基]苯基}丙酸
利用在光学拆分步骤中在母液中发现的中间体1的差向异构体,与上述中间体3类似地合成了该化合物。
实施例1:αvβ3整合素缀合物
(4S)-4,11-二乙基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3',4':6,7]吲哚嗪并[1,2-b]喹啉-4-基1-{(2S)-2-(羧基甲基)-17-[4-({[(1R)-2-羧基-1-{3-[({3-[(丙基-氨基甲酰基)氨基]苯基}磺酰基)氨基]苯基}乙基]氨基甲酰基}氨基)苯胺基]-4,17-二氧代-7,10,13-三氧杂-3,16-二氮杂十七烷-1-酰基}-L-脯氨酰基-L-缬氨酸二钠
40mg(68μmol)中间体4和48mg(81μmol)中间体5溶解在6.4mL DMF中,并添加33.5mg(88μmol)HATU和35μL DIEA。将混合物在室温下搅拌30分钟。将混合物蒸发,剩余残留物用HPLC纯化。得到28mg(39%)的受保护中间体。
LC-MS(方法1):Rt=1.15min;MS(ESIpos):m/z=1047(M+H)+。
将28mg该中间体溶于2ml二氯甲烷中。添加2ml无水三氟乙酸,将混合物在室温下搅拌30分钟,随后超声处理1小时。真空浓缩后,从乙腈/水的混合物中将产物冻干。得到呈橙色固体的30mg(定量)脱保护中间体。
LC-MS(方法1):Rt=0.72min;MS(ESIpos):m/z=891(M+H)+。
将1900mg(1.89mmol)该中间体溶解在60mL DMF中,添加1361mg(1.89mmol)中间体6,并在室温下搅拌混合物2小时。将溶液真空浓缩,将剩余残留物用水和5%柠檬酸处理并过滤。将剩余残留物溶于DCM/甲醇,并添加二乙醚。将沉淀物过滤,并通过使用DCM/甲醇/NH4OH(17%)15/2/0.2->15/4/0.4的洗脱液混合物的快速色谱法纯化。收集相关级分并真空浓缩。真空干燥残留物后,得到942mg(34%)的标题化合物。
LC-MS(方法1):Rt=0.97min;MS(ESIpos):m/z=1471(M+H)+。
将20mg(14μmol)该中间体溶解在4mL二噁烷/水1:1中,并添加30μL(30μmol)氢氧化钠1n水溶液,将混合物在室温下超声处理5分钟并冻干。得到21mg(定量)的标题化合物。
LC-MS(方法1):Rt=0.97min;MS(ESIpos):m/z=1471(M-2Na++2H++H)+。
实施例2:实施例1的参比化合物(S-差向异构体):
(4S)-4,11-二乙基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3',4':6,7]吲哚嗪并[1,2-b]喹啉-4-基1-{(2S)-2-(羧基甲基)-17-[4-({[(1S)-2-羧基-1-{3-[({3-[(丙基-氨基甲酰基)氨基]苯基}磺酰基)氨基]苯基}乙基]氨基甲酰基}氨基)苯胺基]-4,17-二氧代-7,10,13-三氧杂-3,16-二氮杂十七烷-1-酰基}-L-脯氨酰基-L-缬氨酸二钠
该化合物是利用中间体7的αvβ3配体的差向异构体以类似于实施例1的方式合成的。
优选的毒性基团7-乙基喜树碱和实施例1的缀合物的生物学评估
测定细胞透性的体外试验
Caco-2:
物质的细胞透性可以通过使用Caco-2细胞进行通量测定的体外测试来研究[M.D.Troutman和D.R.Thakker,Pharm.Res.20(8),1210-1224(2003)]。为此,将细胞在24孔滤板上培养15-16天。为了测定透性,在HEPES缓冲液中将相应的测试物质施加到细胞顶部(A)或基部(B),并孵育2小时。0小时后和2小时后,从顺式室和反式室取样。样品通过HPLC(Agilent 1200,Germany)使用反相柱分离。HPLC系统通过Turbo离子喷雾接口与Triple Quadropol质谱仪API 4000(AB SCIEX Deutschland GmbH,Darmstadt,Germany)耦合。根据使用Schwab等人公布的公式计算的Papp值来评估透性[D.Schwab等人,J.Med.Chem.46,1716-1725(2003)]。当Papp(B-A)与Papp(A-B)的比值(外排比)>2或<0.5时,物质被归类为主动转运。
在该测定中,在实施例1的缀合物中使用的毒性基团(4S)-4,11-二乙基-4-羟基-1H-吡喃并[3',4':6,7]吲哚嗪并[1,2-b]喹啉-3,14(4H,12H)-二酮(7-乙基-喜树碱)显示出Papp A->B=171nm/s的非常好的透性和1的低外排比。这与从伊立替康释放的毒性基团SN38的谱相比较有利,伊立替康的毒性基团显示出Papp A->B=8nm/s的显著较低的透性和36的外排比。SN38的新数据:Papp A->B=20nm/s的透性和9的外排比。
P-糖蛋白(p-GP)测定:
许多肿瘤细胞表达针对药物的转运蛋白,这常常伴随着对细胞抑制剂的耐药性的发展。因此,不是这些转运蛋白底物的物质,例如P-糖蛋白(P-gp)或BCRP,可以表现出改进的活性谱。
物质对于P-gp(ABCB1)的底物性质是通过使用过表达P-gp的LLC-PK1细胞(L-MDR1细胞)的通量测定确定的[A.H.Schinkel等人,J.Clin.Invest.96,1698-1705(1995)]。为此,将LLC-PK1细胞或L-MDR1细胞在96孔滤板上培养3-4天。为了测定透性,在HEPES缓冲液中将相应的测试物质单独或在抑制剂(例如伊佛霉素或异搏定)存在下施加于细胞顶部(A)或基部(B),并孵育2小时。0小时后和2小时后,从顺式室和反式室取样。样品通过HPLC使用反相柱分离。HPLC系统通过Turbo离子喷雾接口与Triple Quadropol质谱仪API 3000(Applied Biosystems Applera,Darmstadt,Germany)耦合。根据使用Schwab等人公布的公式计算的Papp值来评估透性[D.Schwab等人,J.Med.Chem.46,1716-1725(2003)]。当Papp(B-A)与Papp(A-B)的外排比>2时,将物质归类为P-gp底物。
在该测定中,在实施例1的缀合物中使用的毒性基团(4S)-4,11-二乙基-4-羟基-1H-吡喃并[3',4':6,7]吲哚嗪并[1,2-b]喹啉-3,14(4H,12H)-二酮(7-乙基-喜树碱)显示出Papp A->B=196nm/s的非常好的透性和0.6的低外排比。这与从伊立替康释放的毒性基团SN38的谱相比较有利,伊立替康的毒性基团显示出Papp A->B=10nm/s的显著较低的透性和16的外排比。
对NCI-H1975及其转运体突变体的体外细胞毒性
在用药物转运体P-糖蛋白(P-gp)和乳腺癌耐药蛋白(BCRP)转染肿瘤细胞NCI-H1975后,7-乙基喜树碱的细胞毒活性未被负面影响,这与SN38有明显不同。
表1:对NCI-H1975及其转运体突变体的体外细胞毒性
αvβ3结合试验
来自人A375细胞的αvβ3以类似于Wong等人在Molecular Pharmacology 50,529-537(1996)中所描述的程序纯化。每种情况下,将TBS pH 7.6中的10μLαvβ3(5ng),2mMCaCl2,1mM MgCl2,1%正辛基吡喃葡萄糖苷(Sigma);TBS pH 7.6中的10μL试验物质,0.1%DMSO;和TBS pH 7.6中的45μL试验物质,2mM CaCl2,1mM MgCl2,1mM MnCl2在室温下孵育1小时。在每种情况下,随后添加25μL WGA SPA珠(Amersham,4mg/ml)和10μL锯鳞肽(0.1μCi,Amersham,氯胺-T标记的)。在室温下16小时后,在闪烁测量装置(Wallac 1450)中测量样品。测试结果如下表2所示。
表2:与αvβ3受体结合的IC50值
实施例 | IC<sub>50</sub>[nM] |
1 | 29 |
2 | 700 |
弹性蛋白酶可切割性
在弹性蛋白酶存在和不存在的情况下的体外细胞毒性
细胞的培养按照标准程序进行,采用的培养基由提供商推荐。将总体积为100μL的细胞接种在96孔白底板(#3610)中。在37℃和5%CO2条件下孵育24小时后,通过添加90μL新鲜培养基改变培养基。处理开始于将试验化合物添加到10μL培养基中的细胞。选择从10-5M到10-13M的浓度,一式三份,然后在37℃和5%的二氧化碳中孵育。一组样品仅用测试化合物处理,而对另一组同样处理的样品另外移液10nM弹性蛋白酶。72小时后用MTT测定(ATCC)检测细胞增殖。在孵育期结束时,将MTT试剂添加到所有样品中4小时,然后通过添加洗涤剂裂解细胞过夜。在570nm处检测形成的染料。未用测试物质处理但以其他方式相同处理的细胞的增殖定义为100%值。剂量响应曲线允许确定相应的IC50值,其汇总在表3中。(图1和表4)。
表3 总结了在有和没有弹性蛋白酶时的实施例1和2的IC50值
表4 在并排比较中有和没有弹性蛋白酶(使用具有更高酶活性的弹性蛋白酶)的情况下实施例1和EP 1 238 678的实施例1的IC50值
中性粒细胞弹性蛋白酶的存在使该化合物在肾癌细胞系786-O中的细胞毒性显著提高。这些化合物还揭示了使用结肠癌细胞系HT29对弹性蛋白酶的明显依赖性。弹性蛋白酶诱导的切割再次引起化合物的细胞毒性作用的显著增加。
与EP
1
238
678中实施例1的缀合物相比,实施例1中的缀合物的溶解度:
方法:对于每种要测试的媒介物,称取0.5-1.0mg的测试化合物到2ml Eppendorf瓶中。添加2-3个Glas perls(3mm)和1.0ml媒介物。在室温(25℃)下以1400rpm摇动小瓶24小时。经过这段时间后,将上清液(约230μl)转移到离心管中。在42000rpm 30分钟后,将溶质转移到另一小瓶,并用DMSO(1:5和1:50)稀释。用HPLC对这两种稀释液进行分析(读出:面积)
HPLC-方法:
洗脱液A:1ml三氟乙酸/L水
洗脱液B:1ml三氟乙酸/L乙腈
梯度:
时间[min] A[%] B[%] 流量:[ml/min]
0.0 98 2 1.5
0.2 98 2 1.5
3.3 10 90 1.5
4.0 10 90 1.5
4.1 98 2 2.5
4.7 98 2 2.5
5.0 98 2 1.5
柱:ZORBAX Extend-C18,3.0x50mm,3.5μm
柱温箱温度:30℃
检测:214和254nm
注射体积:20μl
为了定量,通过使用相同的HPLC方法从测试化合物(100μl/ml、20μg/ml和2.5μg/ml)的DMSO溶液获得校准曲线。
表5:实施例1和EP 1 238 678实施例1的溶解度
与EP
1
238
678中实施例1的缀合物相比,实施例1的缀合物在pH为4的柠檬酸缓
冲液中的稳定性:
方法:将0.15mg测试化合物溶解在0.1ml二甲基亚砜和0.4ml乙腈中。为了完全溶解,将装有样品溶液的HPLC小瓶摇动并进行超声处理。然后添加1.0ml各自的缓冲溶液(柠檬酸缓冲液pH 4;柠檬酸/氢氧化钠/氯化钠Fluka 33643)并涡旋样品。在37℃下在24小时内,用HPLC分析样品溶液,以确定特定时间(0、1、2、4、24小时)的测试化合物和多达两种副产物的量。t(0)值由在室温下用缓冲液涡旋后立即取的样品得到。峰面积(百分比)用于定量。
LC和LC/MS纯度分析:通过LC分析起始材料的纯度;另外通过LC/MS(WatersQuattro Micro)对24小时样品进行分析。
表6:实施例1和EP 1238 678实施例1在pH 4的柠檬酸缓冲液中的稳定性
化合物 | 4h | 24小时 |
实施例1 | 100% | 95% |
EP 1 238 678实施例1 | 100% | 74% |
实施例1中缀合物的血浆稳定性
母体化合物在大鼠血浆中的释放的测定;
将1mg实施例1的测试化合物溶解在1.5mL二甲基亚砜和1ml水的混合物中。为了完全溶解,摇动HPLC瓶并用超声处理。在37℃的温度伴随涡旋下将500μL该溶液添加0.5mL大鼠血浆中。在相应时间点取等分试样(各10μL),并通过HPLC分析,以确定测试化合物的量。所有数据都以t0处初始化合物的面积百分比给出。
实施例1的化合物在大鼠血浆中稳定>24小时。
7-乙基喜树碱(实施例1的毒性基团)和喜树碱(EP
1
238
678中实施例1的毒性基
团)在人血浆中的稳定性:
将1mg测试化合物溶于0.5ml乙腈/二甲基亚砜1:1中。为了完全溶解,将HPLC小瓶摇动并进行超声处理。在涡旋过程中,将20μl该溶液添加1ml 37℃温血浆中。在0.17、0.5、1、1.5、2和4小时后,通过在室温下向含有300μl乙腈/缓冲液pH3(80:20)的小瓶中添加100μl复合血浆溶液来停止酶促反应。将混合物以5000rpm离心10分钟。通过HPLC分析上清液,以确定测试化合物和多达两种副产物的量。t(0)值由在室温下与血浆涡旋后立即取的经处理样品得到。峰面积(百分比)用于定量。
在测定条件下,7-乙基喜树碱至少稳定4小时,同时喜树碱降解约50%。
药代动力学
将4mg实施例1的缀合物溶于盐水中,并静脉注射给携带786-O肿瘤的NMRI nu/nu雌性小鼠。在不同时间点采集肿瘤和血浆样品,并测定完整缀合物和从缀合物裂解的毒性基团7-乙基喜树碱的含量。
作为比较,将1mg/kg 7-乙基喜树碱溶于5%葡萄糖/solutol/DMSO 85/10/5水溶液中,并静脉注射给携带786-O肿瘤NMRI nu/nu雌性小鼠。同样在不同时间点采集肿瘤和血浆样品,并测定7-乙基喜树碱的水平。
最后,为了比较,将4mg实施例23的差向异构体参比缀合物(具有较弱的αvβ3结合亲和力)溶解于盐水中,并静脉施用给携带786-O肿瘤的NMRI nu/nu雌性小鼠。在不同时间点采集肿瘤和血浆样品,并测定完整缀合物和从缀合物裂解的毒性基团7-乙基喜树碱的含量。
在表4中,总结了在这些实验的每一个中检测到的7-乙基喜树碱的肿瘤/血浆比率。显示出与直接施用毒性基团和施用弱结合差向异构体对照缀合物相比较,7-乙基喜树碱经由αvβ3整合素缀合物向肿瘤的递送增强。
表4:
体内异种移植研究
在人类癌症的鼠异种移植模型中检测实施例1的抗肿瘤活性。为此目的,向免疫缺陷小鼠皮下植入肿瘤细胞或肿瘤碎片。在肿瘤平均大小为20-40mm2时,将动物随机分为治疗组和对照组(n=8只/组),治疗以仅媒介物或实施例1(配制:磷酸盐缓冲盐水(“PBS”);施加途径:静脉注射到尾静脉(“i.v.”)开始。静脉治疗连续三天,每日一次,随后有四天药物假期不进行治疗。至少每周测量肿瘤大小和体重。用电子卡尺[长(mm)×宽(mm)]检测肿瘤面积。当实验组达到基于德国和欧洲动物福利法规的预先确定的伦理终点时,实验组停止。体内抗肿瘤功效表示为在媒介物对照留在研究中的最后一天,治疗组和对照组测量的平均肿瘤面积的T/C比(治疗/对照;治疗组的平均肿瘤面积/对照组的平均肿瘤面积)。T/C低于0.5的化合物定义为活性(即有效)。使用SigmaStat软件进行统计学分析。进行单因素方差分析,并通过两两比较法(Dunn方法)比较与对照的差异。
结果:
实施例1在不同的人肿瘤异种移植模型中显示出单药治疗后的有效抗肿瘤功效。具体地说,实施例1在缩小乳腺癌、结肠癌、肺癌和肾癌模型中的肿瘤面积方面是有效的。
表5:实施例1在小鼠中的不同人类癌症异种移植物模型中的抗肿瘤活性。
*P<0.05(与媒介物处理的对照相比)
T/C=对照组留在研究中的最后一天,治疗组的平均肿瘤面积与对照组的平均肿瘤面积之比
Claims (12)
1.式(I)的化合物
CT-LI-SP-IA (I)
其中
CT是来自下组的一价自由基:各自可另外携带羟基、羧基或氨基基团的细胞毒性自由基、细胞抑制剂自由基和细胞抑制剂衍生物自由基
LI是下式的二价肽自由基:-L-Val-L-Pro-L-Asp-
SP是下式的基团:
-C=O-(CH2)x-O-(CH2-CH2-O)y-CH2-CH2-(NH)z-C=O-,
其中x=1-5,y=0-15并且z=0-1
IA是一价自由基,用于针对αvβ3整合素受体寻址
及其盐、溶剂化物和盐的溶剂化物。
3.如权利要求1至2中任一项所述的化合物,其中x=1-4,并且y=0-10。
4.如权利要求1至2中任一项所述的化合物,其中x=1-2,并且y=0-5。
6.如权利要求5所述的化合物,其呈其二钠盐形式。
7.如权利要求1至6中任一项所定义的化合物,其用于治疗和/或预防疾病。
8.如权利要求1至6中任一项所定义的化合物,其用于治疗和/或预防过度增生性障碍。
9.如权利要求1至6中任一项所定义的化合物在制备用于治疗和/或预防过度增生性障碍的药物中的用途。
10.药物,其包含如权利要求1至6中任一项所定义的化合物与一种或多种惰性、无毒、药学上合适的赋形剂组合。
11.如权利要求10所述的药物,其用于治疗和/或预防过度增生性障碍。
12.治疗和/或预防人和动物的眼科障碍和癌症或肿瘤的方法,所述方法是通过施用有效量的至少一种如权利要求1至6中任一项所定义的化合物或如权利要求10至11中任一项所定义的药物。
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