CN118103367A - 用于治疗癌症的酸不稳定性化疗紫杉醇类化合物 - Google Patents
用于治疗癌症的酸不稳定性化疗紫杉醇类化合物 Download PDFInfo
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Abstract
本申请公开了一种癌症化疗剂的酸不稳定性亲脂性分子缀合物和用于减少或基本消除与向有此需要的患者给予癌症化疗剂相关的化疗的副作用的方法。
Description
相关申请
本申请要求享有2021年6月16日提交的第63/211253号申请的35USC 119(e)下的权益,该申请的全部内容通过引证结合于本申请中。
技术领域
本发明总体涉及用于治疗患者的化合物和方法。更具体地,本发明涉及用于癌症治疗的分子缀合物,具体为酸不稳定性亲脂性缀合物、用于其形成的方法和中间体,以及用于治疗患者的方法。
背景技术
目前市场上有许多抗癌药物用于各种癌症的治疗。例如,紫杉醇和多烯紫杉醇(docetaxel)是两种有前景的抗癌药物,用于治疗乳腺癌和卵巢癌,并有望治疗各种其他癌症,如皮肤癌、肺癌、头颈癌。其他有前景的化疗剂正在开发或测试用于治疗这些癌症和其他癌症。诸如紫杉醇、多西他赛和其他紫杉烷的化合物引起了极大兴趣。特别感兴趣的是在体外和体内都证实具有抗癌活性的天然产物药物及其合成类似物。
然而,许多已鉴定的抗癌化合物在化疗方案中的应用存在许多困难,包括难以靶向癌症组织而不对正常健康组织产生不利影响。例如,紫杉醇通过中断在癌症细胞中发生频率高于正常细胞的有丝分裂和细胞分裂过程而发挥其抗肿瘤活性。尽管如此,接受化疗治疗的患者可能会经历与正常健康细胞有丝分裂中断相关的各种不良反应。
靶向癌症疗法能够选择性杀死癌症细胞,而不会伤害身体中的其他细胞,将代表癌症临床治疗的重大改进。通过与抗体缀合而成功选择性递送至癌症细胞的靶向药物很有限,这是因为抗体的尺寸大(MW=125-150千道尔顿),因此它们相对不能穿透实体瘤。
因此,开发用于癌症治疗方案中与化疗剂一起直接靶向癌症细胞的新化合物和方法是高度期望的。
这能够导致毒性副作用减少或消除,更有效地将该药物递送到靶位点,并降低给予药物的剂量,从而导致对健康细胞的毒性和化疗方案的成本得以降低。
一种具体的方法是与肿瘤分子缀合的抗癌药物的使用。例如,Safavy的US 6,191,290公开了与能够结合肿瘤细胞表面受体的受体配体肽缀合的紫杉烷部分的用途。Safavy表明,这种受体配体肽可以是蛙皮素(bombesin)/胃泌素(gastrin)释放肽(BBN/GRP)受体识别肽(BBN[7-13])、生长抑素(somatostatin)受体识别肽、表皮生长因子受体识别肽、单克隆抗体或受体识别碳水化合物。
这些药物分子缀合物将这两个单元与一个或多个连接子连接,该连接子会提供具有期望特性和生物活性的缀合物,具体地是系统循环中稳定但一旦内化于癌症细胞中或集中于局部酸性肿瘤环境中就会释放细胞毒性剂的缀合物,这将会预期对正常组织表现出较低的毒性。所得缀合物也应该直到到达靶组织都足够稳定,最大限度地发挥靶向作用,同时降低对正常健康组织的毒性。
血脑屏障(BBB)是一种特殊化的物理和酶屏障,将大脑与系统循环隔离开。BBB的物理部分由排列于紧密连接的会抑制任何显著的细胞旁转运的复杂系统中的内皮细胞组成。BBB会基于脂质溶解度、分子大小和电荷,发挥选择性区分物质细胞转运的扩散抑制功能,由此会对药物递送到大脑带来问题。由于存在高浓度药物外排转运子(例如,P-糖蛋白、多药抗性蛋白、乳腺癌抗性蛋白),跨BBB的药物递送会进一步问题重重。这些转运子甚至在药物分子进入大脑之前就主动将其从内皮细胞质中移除。目前用于治疗脑恶性肿瘤的药物递送的方法通常是非特异性而低效的。
细胞增殖和生长的增加是癌症的标志。细胞增殖的增加与细胞胆固醇的高周转(turnover)有关。需要胆固醇进行膜合成和生长的细胞可以通过受体介导的血浆低密度脂蛋白(LDL)(血液中胆固醇的主要转运蛋白)内吞作用或通过从头合成而获得胆固醇。LDL被称为LDL受体(LDLR)的受体摄取到细胞中;LDL与受体一起被内吞并转运到内体中的细胞中。内体被酸化,从而从LDL中释放LDL受体;LDL受体再循环到表面,在那里它可以参与LDL颗粒的额外摄取。有证据表明,各种组织中的肿瘤对低密度脂蛋白的需求很高,以至于血浆LDL被耗尽。LDL向癌细胞中的输入增加可能是由于这些肿瘤中LDL受体(LDLR)升高。一些已知表达大量LDLR的肿瘤包括某些形式的白血病、肺肿瘤、结直肠癌和卵巢癌症。
对正常和恶性脑组织的比较研究表明,LDLR与恶性和/或快速生长的脑细胞和组织有很高的相关性。一些研究表明,快速生长的脑细胞,如早期发育和恶性生长的脑肿瘤中所见的细胞,由于其对胆固醇的需求增加,表现出LDLR表达增加。
在有问题且治疗无效的脑癌中,有多形性胶质母细胞瘤(GBM)。这种毁灭性的脑瘤100%致命。此外,超过85%的原发性脑癌相关死亡是由GBM引起。目前的治疗依赖于多模式方法,包括神经外科、放射疗法和化疗疗法。即使尽了最大努力使用这些方法,也只能使患有这种肿瘤的患者的生存时间适度增加。培养的GBM细胞具有大量的低密度脂蛋白受体(LDLR)。由于这种受体在神经元细胞和正常神经胶质细胞中几乎不存在,其是递送治疗药物如细胞毒素或放射性药物的理想靶点。改进现有疗法或开发新疗法的努力都没有成功,恶性胶质瘤的治疗结果也仅有微效,中位生存时间为约10个月。
与很少有LDL受体的正常脑细胞不同,培养的GBM细胞表面有大量的LDL受体。由于癌组织的高度增殖性和对胆固醇周转的需要,其他癌症也可能具有高的LDLR表达。这表明,LDL受体是GBM和其他恶性肿瘤中通过LDL颗粒递送抗肿瘤药物的潜在独特分子靶点。
及其同事已经证实,一种称为LDE的富胆固醇微乳液或纳米颗粒制剂在注射到血液中后会浓缩于癌症组织中(R.C./>et al.Improvement ofpaclitaxel therapeutic index by derivatization and association to acholesterol-rich microemulsion:in vitro and in vivo studies.CancerChemotherapy and Pharmacology 55:565-576(2005))。与LDE结合的紫杉醇亲脂性衍生物的细胞毒性、药代动力学、对动物的毒性和治疗作用与商业紫杉醇进行比较。结果表明,LDE-紫杉醇油酸酯是稳定的。/>及其同事证实,LDE-紫杉醇油酸酯是一种稳定的复合物,并且与紫杉醇相比,毒性显著降低,活性增强,这可能会导致临床使用的治疗指数改善。
抓住将化疗化合物经由其LDL受体的过度表达和由此从系统循环中高摄取LDL颗粒而选择性并特异性递送至癌症组织的潜力,要求癌症化疗剂具有高亲脂性,使之保持包埋于LDL颗粒的脂质芯中并且不扩散到血浆中而导致正常组织暴露于该药物的毒副作用。一旦具有化疗有效载荷的LDL颗粒经由LDL受体介导的摄取而进入癌症细胞中并进入内体/溶酶体级联的酸性环境中,LDL受体与LDL离子解离并再循环到细胞表面,并且LDL颗粒会向酶释放其脂质内容物和其亲脂性化疗剂。很少有癌症化疗剂固有地足够亲脂而充分保留于LDL颗粒的脂质核芯内。这产生对癌症化疗剂的合适亲脂性衍生物的需要,这种合适亲脂性衍生物在正常的全身循环中具有高稳定性并且在LDL颗粒的脂质核芯中具有高保留性,但是在内体/溶酶体的酸性环境中容易释放活性化疗剂。本发明的化合物解决了这一需求。
定义:
术语“非对映异构体”是指在含有两个或多个不对称碳原子的化合物中出现的任何一组四种或多种异构体。相互为立体异构体但不是对映体的化合物称为非对映异构体。
从句“非对映异构体纯”是指具有至少约95%、96%、97%、98%、99%、99.5%、99.7%、99.8%或至少99.9%纯的单种非对映异构体或不存在该化合物的任何其他可能的非对映异构体的化合物或非对映异构体。
本文所用的“药用赋形剂”或“药用盐”是指本文公开的化合物的一种或多种赋形剂或盐,其是药用的并提供所需的药理学活性。这些赋形剂和盐包括与无机酸如盐酸、氢溴酸、磷酸等形成的酸加成盐。该盐也可以与有机酸如乙酸、丙酸、己酸、乙醇酸、乳酸、琥珀酸、苹果酸、柠檬酸、苯甲酸等形成。
“治疗有效量”是指引起本说明书中列出的任何生物学效应的药物量。
发明内容
在一个实施方式中,提供了带有羟基的癌症化疗剂(HBCCA)的分子缀合物的新的且有用的组合物。在另一个实施方式中,提供了用于治疗癌症的癌症的癌症化疗剂的酸不稳定性亲脂分子缀合物的组合物。在另一个实施方式中,提供了用于形成用于癌症治疗的分子缀合物的中间体化合物,如酸不稳定性亲脂性前药缀合物。在另一个实施方式中,提供了用于制备酸不稳定性亲脂性药物缀合物的有效方法。在另一个实施方式中,提供了用于向患者给予减少或基本上消除癌症患者常规经历的副作用的化疗剂的方法。在另一个实施方式中,提供了在患者癌症细胞中浓缩化疗剂的方法。
在本申请的一个实施方式中,提供了下式的酸不稳定性亲脂分子缀合物(ALLMC):
及其分离的非对映异构体或其混合物;或其药用盐。
在一个方面中,酸不稳定性亲脂性分子缀合物是(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-((((2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-126)。在另一个方面中,该酸不稳定性亲脂性分子缀合物是(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((S)-2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-131)。在另一个方面中,该酸不稳定性亲脂性分子缀合物是(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((R)-2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-132)。在另一个方面中,在该酸不稳定性亲脂性分子缀合物中,带有羟基的癌症化疗剂是紫杉醇或卡巴他赛。如本文所用,“带有羟基的癌症化疗剂”是具有与碳酸酯基团(-OC(O)O-)缀合的2′-羟基基团的紫杉醇或卡巴他赛。在另一个实施方式中,提供了一种药物组合物,其包含:a)治疗有效量的单一非对映异构体形式的任何上述化合物;和b)药用赋形剂。
在另一个实施方式中,提供了一种治疗患者癌症的方法,该方法包括向需要此治疗的患者给予治疗有效量的任何上述化合物或组合物。在该方法的另一个方面中,癌症选自由白血病、神经母细胞瘤、胶质母细胞瘤、宫颈癌、结肠直肠癌、胰腺癌、肾癌和黑色素瘤组成的组。在另一方面中,该癌症选自由肺癌、乳腺癌、前列腺癌、卵巢癌和头颈癌组成的组。在另一个方面中,与紫杉醇或卡巴他赛的非缀合的带有羟基的癌症化疗剂相比,该方法会提供至少10%-50%的癌细胞表达的抗性的降低程度。
在另一个实施方式中,提供了一种减少或基本消除与向患者给予紫杉醇或卡巴他赛相关的化疗副作用的方法,该方法包括向患者给予治疗有效量的上述任何一种化合物的酸不稳定性亲脂分子缀合物(ALLMC)。在另一个方面中,该方法在患者的癌症细胞中提供更高浓度的紫杉醇或卡巴他赛。在另一个方面中,与向患者给予紫杉醇或卡巴他赛的非缀合癌症化疗剂相比,该方法在癌症细胞中递送浓度高至少5%、10%、20%或至少50%的紫杉醇或卡巴他赛。
在另一个实施方式中,提供了一种稳定的合成低密度脂蛋白(LDL)固体纳米颗粒,其包含:a)式NCP-121、NCP-122、NCP-123、NCP-124、NCP-125、NCP-127、NCP-128、NCP-129、NCP-130、NCP-126、NCP-131和NCP-132的酸不稳定性亲脂性分子缀合物(ALLMC)及其分离的非对映异构体或其混合物;或其药用盐;b)磷脂(PL),其中所述磷脂选自由磷脂酰胆碱、磷脂酰乙醇胺、对称或不对称1,2-二酰基-sn-甘油-3-磷酰胆碱、1,2-二肉豆蔻酰基-sn-甘油-3-磷酰基胆碱、1,22-二肉豆蔻酰基-sn-甘油-3-磷酰乙醇胺、蛋磷脂、蛋磷脂酰甘油、二棕榈酰磷脂酰甘油、蛋卵磷脂、大豆卵磷脂、卵磷脂(NOS)及其混合物组成的组;和c)甘油三酯(TG),其选自由MIGLYOL 812N、三乙酸甘油酯、三丙酸甘油酯、三丁酸甘油酯、三异戊酸甘油酯、三异戊酸甘油酯、三己酸甘油酯、三庚酸甘油酯、三辛酸甘油酯、三壬酸甘油酯、三癸酸甘油酯和三(十一酸)甘油酯组成的组;其中LDL固体纳米颗粒具有40-80nm的平均粒径。在一个变体中,使用的甘油三酯可以是Miglyol 812N(C8/C10甘油三酯(MCT油)),或可以是本文公开的另一种甘油三酯酯或其他中链甘油三酯。
在上述稳定的合成低密度脂蛋白(LDL)固体纳米颗粒的另一个方面中,该酸不稳定性亲脂性分子缀合物是(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-((((2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-126)。在上述稳定的合成低密度脂蛋白(LDL)固体纳米颗粒的另一个方面中,该酸不稳定性亲脂性分子缀合物是(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((S)-2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-131)。在上述稳定的合成低密度脂蛋白(LDL)固体纳米颗粒的另一个方面中,该酸不稳定性亲脂性分子缀合物是(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((R)-2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-132)。在上述稳定的合成低密度脂蛋白(LDL)固体纳米颗粒的一个方面中,该纳米颗粒具有60nm的平均尺寸分布。
在另一个实施方式中,提供了一种药物组合物,其包含:a)治疗有效量的单一非对映异构体形式的上述化合物;和b)药用赋形剂。在另一个方面中,该药物组合物适于口服给予;或作为适于胃肠外给予的液体制剂。在另一个方面中,该组合物适于通过选自由口服、非肠道、腹膜内、静脉内、动脉内、经皮、肌内、直肠、鼻内、脂质体(liposomally)、皮下和鞘内给予组成的组的途径进行给予。在另一个实施方式中,提供了一种用于治疗患者癌症的方法,包括向需要此治疗的患者给予治疗有效量的任何上述化合物或组合物中的任何化合物或组合物。在所述方法的一个方面中,该癌症选自由白血病、神经母细胞瘤、成胶质细胞瘤、宫颈癌、结直肠癌、胰腺癌、肾癌和黑色素瘤组成的组。在该方法的另一个方面中,该癌症选自由肺癌、乳腺癌、前列腺癌、卵巢癌和头颈癌组成的组。在该方法的另一个方面中,与非缀合的带有羟基的癌症化疗剂相比,该方法会提供至少10%、20%、30%、40%或至少50%的癌症细胞表达的抗性的降低程度。
在另一个实施方式中,提供了一种用于减少或基本消除与向患者给予癌症化疗剂相关的化疗副作用的方法,该方法包括向患者给予治疗有效量的本文公开的各式的酸不稳定性亲脂性分子缀合物。
在一个方面中,该方法在患者的癌症细胞中会提供更高浓度的癌症化疗剂。在另一个方面中,与向患者给予非缀合癌症化疗剂相比,该方法在癌症细胞中会递送浓度高至少5%、10%、20%、30%、40%或至少50%的癌症化疗剂。
在另一个实施方式中,提供了一种在类似于LDL颗粒或“假LDL颗粒”的纳米颗粒脂质乳液中使用本申请的酸不稳定性亲脂性分子缀合物而在患者的选定靶细胞中浓缩癌症化疗剂的方法。在另一个实施方式中,该方法包括向患者给予所选剂量的治疗有效量的溶解于假LDL颗粒的脂质核芯中的癌症化疗剂的酸不稳定性亲脂性分子缀合物。
在上述实施方式、方面和变体中还包括氨基酸的盐(如精氨酸盐等)、葡萄糖酸盐和半乳糖醛酸盐。本发明的某些化合物可以以非溶剂化形式以及溶剂化形式,包括水合形式存在,并且旨在都处于本发明的范围内。本文还提供了药物组合物,其包含药用赋形剂和治疗有效量的至少一种本发明的化合物。
本发明化合物或其衍生物的药物组合物可以配制成溶液或冻干粉,用于胃肠外给予。粉末可以在使用前通过添加合适的稀释剂或其他药用载体进行重构。液体制剂通常是缓冲的等渗水溶液。合适的稀释剂的实例是标准等渗盐水溶液、5%葡萄糖在水中或缓冲的乙酸钠或乙酸铵溶液。这种制剂特别适合于胃肠外给予,但也可以用于口服给予。也可以加入赋形剂,如聚乙烯吡咯烷酮、明胶、羟基纤维素、阿拉伯胶、聚乙二醇、甘露醇、氯化钠或柠檬酸钠。可选地,这些化合物可以进行封装、压片或制备于乳液或糖浆中,用于口服给予。药用固体或液体载体可以加入而增强或稳定该组合物,或方便该组合物的制备。液体载体包括糖浆、花生油、橄榄油、甘油、盐水、醇或水。固体载体包括淀粉、乳糖、硫酸钙、二水合物、白土、硬脂酸镁或硬脂酸、滑石、果胶、阿拉伯树胶、琼脂或明胶。该载体还可以包括单独的或与蜡一起的缓释材料,如单硬脂酸甘油酯或二硬脂酸甘油酯。固体载体的量各不相同,但优选每剂量单位约20mg-约1g。药物制剂按照传统的药学技术制备,包括研磨、混合、造粒和必要时压制成片剂形式;或研磨、混合和填充硬明胶胶囊形式。当使用液体载体时,制剂将是糖浆、酏剂、乳液或水性或非水性悬浮液的形式。这种液体制剂可以直接口服给予或填充到软明胶胶囊中。用于每种这些给予方法的合适制剂可以参考例如Remington:TheScience and Practice of Pharmacy,A.Gennaro,ed.,20th edition,Lippincott,Williams&Wilkins,Philadelphia,Pa。
当与所附图画和图形一起考虑本发明的示例性实施方式的以下详细描述时,本发明的这些和其他目的将变得更容易参详和理解。整个本申请内引用的所有文件的全部公开内容通过引用结合于本文中。
具体实施方式
以下方案可以用于制备本发明的化合物。用于制备这些化合物的起始原料和试剂可以从商业供应商如Aldrich Chemical Company(Milwaukee,Wis.)、Bachem(Torrance,CA)、Sigma(St.Louis,Mo)获得,或通过本领域普通技术人员公知的方法,按照以下文献中描述方案进行制备:Fieser and Fieser's Reagents for Organic Synthesis,vols.1-17,John Wiley and Sons,New York,N.Y.,1991;Rodd's Chemistry of CarbonCompounds,vols.1-5and supps.,Elsevier Science Publishers,1989;OrganicReactions,vols.1-40,John Wiley and Sons,New York,N.Y.,1991;March J.:AdvancedOrganic Chemistry,4th ed.,John Wiley and Sons,New York,N.Y.;和Larock:Comprehensive Organic Transformations,VCH Publishers,New York,1989。
在某些情况下,可能会引入保护基团并最终移除。用于氨基、羟基和羧基的保护基团描述于Greene et al.,Protective Groups in Organic Synthesis,Second Edition,John Wiley and Sons,New York,1991。标准的有机化学反应能够通过使用多种不同试剂实现,例如,Larock:Comprehensive Organic Transformations,VCH Publishers,NewYork,1989。
实验
通用方案
化学品和试剂购自Sigma-Aldrich(MO,USA)。紫杉醇(>99%)购自LCLaboratories(Woburn,MA)。所有的IR光谱都记录于Agilent 630FTIR(AgilentTechnologies,CA,USA)。1H和13C NMR光谱记录于Bruker(400和500MHz;Bruker Biospin,MA,USA)光谱仪上,且化学位移以ppm表示,以四甲基硅烷作为内标。质谱记录于Agilent1290UHPLC和6120MS(Agilent Technologies)上,且柱色谱在(Merck,MA,USA)硅胶上进行。除非另有说明,所有反应均在氩气氛下进行。薄层色谱(TLC)在预涂硅胶G和GP Uniplates上进行。薄层板用254nm UV光、碘室或用磷钼酸(PMA)碳化进行可视化。
癌症化疗剂的酸不稳定性亲脂性分子缀合物的通用合成方案
酸不稳定性亲脂性缀合物的形成:
酸不稳定性亲脂性缀合物通过HPLC和高分辨率质谱的联用进行表征。每种化合物都有具体说明。
ART 207按照方法A中概述的方案进行制备。HPLC保留时间6.06,方法;紫杉烷缀合物_MKG17(Synergy柱,ACN/H2O 60/40至100%ACN10min,2min 100% ACN,230nm,1.5mL/min,30℃,15min)。+TOF MS:m/z 1220.6156[m+1]和m/z 1237.6382[m+18](M+NH4 +)。
该化合物的HPLC分析采用各种优化的HPLC条件显示出尖单峰,这些条件包括:
1)C18柱,ACN/H2O 50/50至100% ACN 10min,2min 100% ACNH,230nm,1.5mL/min,30℃,16min;
2)Synergy柱,MeOH/H2O 75/25至100% MeOH 10min,2min 100%MeOH,230nm,1.5mL/min,30℃,15min;
3)Synergy柱,ACN/H2O 50/503min,80%-100% ACN/H2O 10min,2min 100% ACN,230nm,1.5ml/min,30℃,15min;
4)Synergy柱,70%-100% ACN/H2O 10min,100% ACN 2min,230nm,1.5mL/min,30℃,15min;
5)C18柱,MeOH/H2O 95/5至100% MeOH 10min,2min 100% MeOH,230nm,1.5mL/min,30℃,16min;和
6)Synergy柱,ACN/H2O 80/20 10min,100% ACN 2min,230nm,1.5mL/min,30℃,15min。
本申请的化合物,包括亲脂性前药(ART-207和NCP-121至NCP-132)设计和制备为比较其与蛋白质结合的紫杉醇的生物相似性。使用DIBAL(-78℃)特意将市售油酸甲酯1过度还原成相应的油醇2,并用氯铬酸吡啶鎓在50℃下将所得伯醇氧化为无色油状的油醛3,产率为76%。如方案1中所述,连接子外消旋丙酮缩甘油碳酸酯(±)-5通过在吡啶和DMAP的存在下使外消旋丙酮缩甘油(solketal)(4)与氯甲酸4-硝基苯基酯反应进行制备,产率为70%。使用相同的化学转化也分别从相应的对映体纯R(-)-丙酮缩甘油[(-)-4]和S(+)-丙酮缩甘油[(+)-4]开始合成对映体纯丙酮缩甘油碳酸酯(-)-5和(+)-5(方案1)。Amberlyst-15催化的油醛3和丙酮缩甘油碳酸酯5之间的缩醛交换导致形成1,3-二氧戊环中间体6,反式异构体具有2:1的优选。先进行缩醛化,然后用氯甲酸4-硝基苯酯进行羰基化是无效的,因为最初的缩醛交换导致5-元和6-元1,3-二氧戊环以5.6:2.9:1.1:1的比率产生不可分离的反式异构体和顺式异构体。由硬脂酸甲酯制备的饱和同系物硬脂醛也通过以下羰基化和缩醛交换过程以65%的总产率转化成相应的外消旋和非对映体纯碳酸酯8。
方案1.试剂和条件:a)DIBAL(2当量,1M己烷溶液),THF,-78℃,2小时;b)氯铬酸吡啶鎓,DCM,50℃,2小时;c)氯甲酸4-硝基苯酯,DMAP,吡啶,DCM,室温,20小时;d)油醛或硬脂醛,5,Amberlyst-15,DCM,室温,48小时。
在单独尝试将1,3-二氧戊环碳酸酯的反式异构体和顺式异构体(-)-6和(+)-6进一步拆分成两组对映体纯的单一异构体中,利用了使用Phenomenex Prep HPLC柱的循环制备高压液相色谱。发现由己烷和THF以94:6(v/v)组成的流动相是理想的等渗溶剂体系,在用洗脱液循环四轮后产生对映体纯的单一异构体[(-)-6至(-)-6a和(-)-6-s;(+)-6至(+)-6a和(+)-6s;a代表反式异构体,而s代表顺式异构体]。采用完整的表征和色谱光谱数据确定了这些单一对映体的纯度。以克级量制备了总共10种用于与细胞毒素缀合的不同易反应性脂质附着丙酮缩甘油硝基苯基碳酸酯(5、6和8)。
方案2.对映体纯1,3-二氧戊环-硝基苯基碳酸酯的制备:a)4-硝基苯基氯甲酸酯,DMAP,吡啶,DCM,室温,20小时;b)油醛,Amberlyst-15,DCM,室温,48小时;c)循环HPLC半制备型(Waters 5010),配备Phenomenex Prep HPLC柱(尺寸250×21.2mm,Luna 5μm氧化硅(2)),在四轮循环后使用己烷:THF(94:6,v/v)作为流动相。
紫杉醇与1,3-二氧戊环硝基苯基碳酸酯(5、6和8)在C2′-位的选择性缀合采用DMAP作为碱以几乎定量的产率实现。通过切换合适的脂质碳酸酯连接子,合成了许多缀合物,包括对映体富集缀合物,如表1所示。例如,DMAP-介导的紫杉醇与1,3-二氧戊环中间体(±)-6之间的等摩尔量反应导致生成86%的白色固体ART-207。类似物NCP-124和NCP-125分别由中间体(-)-6和(+)-6合成。所有其他紫杉醇缀合物都是通过简单地改变1,3-二氧戊环-硝基苯基碳酸酯连接子进行制备,而获得13种独特的亲脂性酸不稳定性前药。
方案3.试剂和条件:a)紫杉醇(1.0当量),1,3-二氧戊环-硝基苯基碳酸酯(5、6或8)(1.0当量,DMAP(0.5当量),DCM,16小时。
表1.紫杉醇的各种异构纯后期不同缀合物的合成
*基于目标化合物将1,3-二氧戊环碳酸酯制成表格。
(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((4R)-2-十七烷基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-121)。
IR:(cm-1;纯净):2927,2853,1718,1654,1235。 1HNMR(400MHz,CDCl3,两种异构体的混合物*)δ8.15-8.13(m,2H),7.75-7.73(m,2H),7.63-7.59(m,1H),7.53-7.49(m,3H),7.45-7.34(m,7H),6.92(dd,J=9.4,2.4Hz,1H),6.29(s,2H),6.00(dd,J=9.4,2.5Hz,1H),5.69(d,J=7.0Hz,1H),5.43-5.42(m,1H),4.99-4.96(m,2H),4.88(t,J=6.6,1H),4.47-4.42(m,1H),4.34-4.30(m,1H),4.29-4.23(m,1H),4.23-4.17(m,2H),4.16-4.08(m,2H),3.92-3.88(m,0.60H),3.82(d,J=7.4Hz,1H),3.59-3.55(m,0.50H),2.60-2.53(m,1H),2.50(d,J=4.1Hz,1H),2.46(s,3H),2.43-2.37(m,1H),2.23(s,3H),2.04(s,1H),1.95-1.92(m,3H),1.90-1.85(m,1H),1.83(s,1H),1.72(s,2H),1.68(s,3H),1.65-1.62(m,1H),1.42-1.38(m,2H),1.27 -1.25m,29H),1.14(s,3H),0.88(t,J=6.7Hz,3H)。13C NMR(101MHz,CDCl3)δ203.77,171.22,171.18,169.85,167.77,167.16,167.00,154.12,154.04,142.56,136.66,133.66,133.49,132.91,132.06,130.24,129.20,129.14,128.75,128.71,128.55,127.17,126.56,105.72,105.03,84.45,81.09,79.12,75.59,75.12,73.02,72.96,72.14,69.12,68.45,66.92,66.78,60.41,58.52,52.65,45.60,43.21,35.58,33.87,33.84,31.93,29.71,29.66,29.57,29.54,29.51,29.37,26.84,23.95,23.87,22.73,22.70,22.17,21.05,20.83,14.81,14.21,14.14,9.62。HRMS(ESI):C69H91NO18Na的m/z(M+Na)+理论值,1244.6133;实测值,1244.6120。
(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((4S)-2-十七烷基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-122)。
IR:(cm-1;纯净):2924,2851,1718,1664,1369,1235。 1H NMR(400MHz,CDCl3)δ8.15-8.13(m,2H),7.73-7.75(m,2H),7.60(t,J=7.4Hz,1H),7.53-7.48(m,3H),7.45-7.34(m,7H),6.95(dd,J=9.4,5.0Hz,1H),6.29(s,2H),6.00(dd,J=9.4,2.5Hz,1H),5.69(d,J=7.1Hz,1H),5.42(d,J=2.6Hz,1H),4.98(dd,J=9.8,2.2Hz,1H),4.93(d,J=4.8Hz,0.37H),4.87(t,J=4.8Hz,0.47H),4.45-4.41(m,1H),4.32(d,J=8.6Hz,1H),4.29-4.23(m,1H),4.21(dd,J=6.4,2.0Hz,2H),4.16-4.13(m,2H),3.90(dd,J=8.5,7.0Hz,0.50H),3.82-3.79(m,1H),3.61(dd,J=8.5,6.8Hz,0.50H),2.53(dd,J=6.2,3.7Hz,2H),2.46(d,J=1.8Hz,3H),2.43-2.37(m,1H),2.22(s,3H),2.03(s,1H)1.93(s,3H),1.89(s,2H),1.81(s,2H),1.68(s,3H),1.63-1.60(m,1H),1.43-1.33(m,2H),1.25(m,30H),1.14(s,3H),0.88(t,J=6.8Hz,3H)。13C NMR(101MHz,CDCl3)δ203.78,171.23,171.19,169.85,167.78,167.74,167.23,166.99,154.09,154.03,142.56,142.53,136.66,133.66,133.47,132.92,132.07,130.23,129.21,129.13,128.74,128.71,128.56,127.18,126.57,105.67,105.09,84.45,81.10,79.10,75.59,75.12,72.88,72.82,72.14,68.96,68.32,66.66,60.41,58.51,52.69,45.59,43.21,35.59,33.88,33.83,31.93,29.70,29.68,29.66,29.57,29.54,29.50,29.36,26.83,23.96,23.84,22.73,22.70,22.17,21.05,14.79,14.20,9.63。HRMS(ESI):C69H91NO18Na的m/z(M+Na)+理论值,1244.6133;实测值,1244.6116。
(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-((((2-十七烷基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-123)。
IR:(cm-1;纯净):2920,2849,1718,1239。 1H NMR(400MHz,CDCl3)δ8.14(dd,J=7.4,1.6Hz,2H),7.75-7.73(m,2H),7.62-7.57(m,1H),7.53-7.48(m,3H),7.45-7.34(m,7H),6.95-6.91(m,1H),6.30(s,2H),6.01-5.98(m,1H),5.69(d,J=7.1Hz,1H),5.44-5.42(m,1H),4.99-4.94(m,1H),4.89-4.86(m,1H),4.44(dd,J=10.9,6.6Hz,1H),4.32(d,J=8.7Hz,1H),4.30-4.23(m,1H),4.20(ddd,J=8.8,4.9,2.1Hz,2H),4.19-4.15(m,1H),4.12(dd,J=6.9,2.2Hz,1H),3.90(dd,J=8.6,6.9Hz,0.63H),3.83-3.78(m,2H),3.63-3.55(m,0.46H),2.58-2.50(m,1H),2.46(s,3H),2.44-2.38(m,1H),2.23(s,4H),2.04(s,1H),1.93(t,J=1.7Hz,3H),1.90-1.85(m,1H),1.68(s,3H),1.66-1.62(m,1H),1.40-1.35(m,2H),1.32-1.22(m,32H),1.14(s,3H),0.88(t,J=6.8Hz,3H)。13C NMR(101MHz,CDCl3)δ203.78,171.24,169.85,167.77,167.17,167.01,154.10,154.04,142.58,136.67,133.67,133.48,132.90,132.07,130.24,129.20,129.14,128.75,128.71,128.56,127.17,126.56,114.98,105.72,105.68,105.10,105.03,84.45,81.10,79.14,75.59,75.12,73.02,72.96,72.88,72.82,72.14,69.12,68.96,68.45,66.92,66.83,66.67,60.41,58.52,52.68,52.64,45.59,43.21,35.60,35.55,33.88,33.84,31.93,29.71,29.66,29.57,29.54,29.51,29.37,26.84,23.96,23.87,23.85,22.73,22.70,22.18,21.05,14.80,14.21,9.62。HRMS(ESI):C69H91NO18Na的m/z(M+Na)+理论值,1244.6133;实测值,1244.6111。
(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-((((2-((Z)-十七碳-8-烯-1-基)-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(ART-207)。
1H NMR(400MHz,CDCl3)δ8.17-8.11(m,2H),7.74(dt,J=8.3,1.2Hz,2H),7.63-7.57(m,1H),7.53-7.49(m,3H),7.45-7.35(m,7H),6.92(dt,J=8.4,4.1Hz,1H),6.33-6.24(m,2H),6.00(dd,J=9.2,2.4Hz,1H),5.69(d,J=7.1Hz,1H),5.44-5.42(m,1H),5.38-5.30(m,2H),5.00-4.92(m,2H),4.47-4.44(m,1H),4.35-4.24(m,2H),4.24-4.18(m,2H),4.16-4.09(m,1H),3.85-3.77(m,2H),2.61-2.51(m,1H),2.49(dd,J=4.1,1.4Hz,1H),2.46(dd,J=2.6,1.3Hz,3H),2.44-2.36(m,1H),2.23(m,4H),2.00(q,J=6.5Hz,4H),1.93(q,J=1.4Hz,3H),1.90-1.84(m,1H),1.81(d,J=1.3Hz,1H),1.71-1.65(m,6H),1.38 -1.41(m,3H),1.33-1.23(m,22H),1.14(s,3H),0.89-0.87(m,3H)。13C NMR(101MHz,CDCl3)δ203.79,171.27,169.86,167.76,167.14,167.04,142.61,136.66,133.69,133.47,132.89,132.08,130.24,129.99,129.78,129.18,129.15,128.76,128.72,128.56,127.17,126.54,105.67,84.45,81.11,79.16,76.47,75.59,75.11,72.96,72.14,66.85,58.54,52.65,45.57,43.22,35.58,33.83,31.91,29.77,29.75,29.53,29.48,29.45,29.33,29.21,27.23,27.20,26.85,23.96,23.84,22.73,22.69,22.18,14.81,9.62。HRMS(ESI):C69H89NO18Na的m/z(M+Na)+的理论值,1242.5977;实测值,1242.5965。
(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((4R)-2-((Z)-十七碳-8-烯-1-基)-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-124)
1H NMR(400MHz,CDCl3)δ8.16-8.13(m,2H),7.74(dd,J=8.0,1.6Hz,2H),7.62-7.60(m,1H),7.54-7.48(m,3H),7.45-7.34(m,7H),6.92(dd,J=9.4,2.6Hz,1H),6.31-6.27(m,2H),6.00(dd,J=9.4,2.5Hz,1H),5.69(d,J=7.1Hz,1H),5.45-5.41(m,1H),5.35-5.33(m,2H),4.99-4.96(m,1H),4.88(t,J=4.8Hz,1H),4.47-4.41(m,1H),4.32(d,J=8.8Hz,1H),4.29-4.24(m,1H),4.23-4.18(m,2H),4.15-4.08(m,2H),3.90(dd,J=8.6,6.9Hz,0.72H),3.84-3.76(m,2H),3.57(dd,J=8.6,6.8Hz,0.36H),2.60-2.53(m,1H),2.50(d,J=4.1Hz,1H),2.46(s,3H),2.43-2.38(m,1H),2.23(s,3H),2.04(s,1H),2.03-1.97(m,4H),1.94(d,J=1.6Hz,3H),1.90-1.85(m,1H),1.84(s,1H),1.72(s,2H),1.68(s,2H),1.65-1.63(m,1H),1.41-1.37(m,2H),1.32-1.22(m,22H),1.14(s,3H),0.88(t,J=6.7Hz,3H)。13C NMR(101MHz,CDCl3)δ203.79,171.26,169.86,167.77,167.16,167.03,154.03,142.60,136.64,133.68,133.47,132.89,132.08,130.24,129.98,129.78,129.19,129.15,128.75,128.72,128.56,127.16,126.54,105.71,105.02,84.45,81.11,79.14,75.59,75.11,72.96,72.14,69.12,66.93,60.41,58.54,52.63,45.57,43.22,35.59,33.86,33.83,31.91,29.77,29.75,29.53,29.47,29.44,29.32,29.21,27.23,27.20,26.84,23.96,23.86,22.73,22.69,22.18,21.06,14.82,9.62。HRMS(ESI):C69H89NO18Na的m/z(M+Na)+理论值,1242.5977;实测值,1242.5964。
(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((4S)-2-((Z)-十七碳-8-烯-1-基)-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-125)
1H NMR(400MHz,CDCl3)δ8.16-8.13(m,2H),7.75-7.73(m,2H),7.63-7.58(m,1H),7.54-7.48(m,3H),7.45-7.34(m,7H),6.93(dd,J=9.4,4.9Hz,1H),6.29(s,2H),6.00(dd,J=9.4,2.5Hz,1H),5.69(d,J=7.1Hz,1H),5.42(d,J=2.6Hz,1H),5.36-5.33(m,2H),4.99-4.93(m,1H),4.87(t,J=4.8Hz,1H),4.47-4.41(m,1H),4.32(d,J=8.6Hz,1H),4.30-4.23(m,1H),4.23-4.19(m,2H),4.15(dd,J=5.5,2.1Hz,1H),4.13-4.09(m,1H),3.90(dd,J=8.6,6.9Hz,0.73H),3.84-3.78(m,2H),3.61(dd,J=8.6,6.8Hz,0.36H),2.60-2.52(m,1H),2.50(dd,J=4.2,1.7Hz,1H),2.46(d,J=1.8Hz,3H),2.44-2.38(m,1H),2.23(s,3H),2.04(s,1H),2.00(q,J=6.5Hz,4H),1.93(s,3H),1.90-1.85(m,1H),1.83(s,1H),1.69(s,5H),1.65-1.61(m,1H),1.40-1.33(m,2H),1.28-1.26(m,21H),1.14(s,3H),0.90-0.85(m,3H)。13C NMR(101MHz,CDCl3)δ203.78,171.23,169.85,167.77,167.74,167.20,167.00,154.09,154.03,142.57,136.66,133.66,133.47,132.90,132.07,130.23,129.98,129.78,129.20,129.14,128.75,128.71,128.56,127.18,126.56,105.66,105.08,84.45,81.10,79.12,75.59,75.12,72.88,72.82,72.14,68.96,68.32,66.84,60.41,58.52,52.68,45.58,43.22,35.61,35.55,33.87,33.82,31.91,31.59,29.77,29.75,29.52,29.47,29.44,29.32,29.21,27.23,27.20,26.84,23.96,23.84,22.73,22.69,22.19,21.05,14.79,14.20,9.63。HRMS(ESI):C69H89NO18Na的m/z(M+Na)+理论值,1242.5977;实测值,1242.5964。
(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((2R,4R)-2-((Z)-十七碳-8-烯-1-基)-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-127)。
1H NMR(500MHz,CDCl3)δ8.15-8.13(m,2H),7.75-7.73(m,2H),7.62-7.59(m,1H),7.51(q,J=7.4Hz,3H),7.43-7.36(m,7H),6.92(d,J=9.3Hz,1H),6.29(d,J=2.5Hz,2H),6.00(dd,J=9.4,2.6Hz,1H),5.69(d,J=7.1Hz,1H),5.43(d,J=2.6Hz,1H),5.35-5.32(m,2H),4.98(d,J=3.1Hz,1H),4.96(d,J=4.1Hz,1H),4.46-4.42(m,1H),4.33-4.30(m,2H),4.23-4.17(m,3H),4.15-4.10(m,2H),3.81(d,J=7.0Hz,1H),3.57(dd,J=8.7,6.7Hz,1H),2.60-2.54(m,1H),2.48(d,J=8.3Hz,4H),2.42-2.37(m,1H),2.23(s,3H),2.21-2.18(m,1H),2.04(s,1H),2.01-1.98(m,3H),1.93(d,J=1.4Hz,3H),1.90-1.85(m,1H),1.81(s,1H),1.69(d,J=9.1Hz,4H),1.38(dd,J=10.0,5.0Hz,2H),1.31-1.24(m,23H),1.14(s,3H),0.87(t,J=6.8Hz,3H)。13C NMR(126MHz,CDCl3)δ203.79,177.71,171.28,169.86,167.77,167.13,167.04,154.11,142.62,136.63,133.70,133.47,132.87,132.08,130.24,129.98,129.78,129.17,129.15,128.76,128.72,128.56,127.17,126.55,105.01,84.44,81.09,79.15,75.59,75.09,73.02,72.16,72.12,68.51,68.45,66.81,58.53,52.63,45.56,43.21,35.56,35.53,33.85,31.91,29.77,29.75,29.53,29.51,29.44,29.32,29.21,27.80,27.22,27.20,26.84,23.86,22.73,22.69,22.19,14.82,9.61。HRMS(ESI):C69H89NO18Na的m/z(M+Na)+理论值,1242.5977;实测值,1242.5973。
(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((2S,4R)-2-((Z)-十七碳-8-烯-1-基)-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-128)。
1H NMR(400MHz,CDCl3)δ8.16-8.11(m,2H),7.76-7.71(m,2H),7.63-7.56(m,1H),7.50(td,J=7.5,4.4Hz,3H),7.45-7.35(m,7H),6.95(d,J=9.3Hz,1H),6.32-6.26(m,2H),6.00(dd,J=9.4,2.5Hz,1H),5.69(d,J=7.1Hz,1H),5.43(d,J=2.6Hz,1H),5.35(td,J=7.0,5.9,4.0Hz,2H),4.97(dd,J=9.7,2.3Hz,1H),4.88(t,J=4.8Hz,1H),4.44(ddd,J=10.6,6.5,3.2Hz,1H),4.31(d,J=8.6Hz,1H),4.26(td,J=6.6,3.1Hz,1H),4.23-4.17(m,2H),4.11(dd,J=11.0,6.3Hz,1H),3.90(dd,J=8.7,6.8Hz,1H),3.84-3.76(m,2H),2.54(dq,J=14.5,6.1,4.7Hz,2H),2.46(s,3H),2.43-2.36(m,1H),2.22(s,4H),2.01(q,J=7.1,6.4Hz,4H),1.93(d,J=1.5Hz,3H),1.89(d,J=6.0Hz,2H),1.68(s,3H),1.66(d,J=4.4Hz,1H),1.35-1.22(m,26H),1.14(s,3H),0.88(t,J=6.7Hz,3H)。13C NMR(101MHz,CDCl3)δ203.78,171.24,169.85,167.78,167.22,167.01,154.04,142.57,136.64,133.67,133.47,132.91,132.08,130.24,129.98,129.78,129.20,129.15,128.75,128.72,128.56,127.17,126.56,115.49,105.71,84.45,81.10,79.13,75.59,75.13,72.97,72.14,69.13,66.93,58.52,52.65,45.59,43.22,35.60,35.55,33.83,31.91,29.77,29.75,29.71,29.53,29.47,29.44,29.33,29.21,27.23,27.20,26.84,23.95,22.73,22.69,22.18,14.82,14.21,9.63。HRMS(ESI):C69H89NO18Na的m/z(M+Na)+理论值,1242.5977;实测值,1242.5972。
(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((2R,4S)-2-((Z)-十七碳-8-烯-1-基)-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-129)。
1H NMR(500MHz,CDCl3)δ8.15(d,J=7.7Hz,2H),7.74(d,J=7.7Hz,2H),7.61(t,J=7.4Hz,1H),7.51(q,J=7.2Hz,3H),7.45-7.35(m,7H),6.91(d,J=9.3Hz,1H),6.31(d,J=10.3Hz,2H),6.00(dd,J=9.2,2.4Hz,1H),5.69(d,J=7.1Hz,1H),5.42(d,J=2.5Hz,1H),5.37-5.30(m,2H),4.98(d,J=9.3Hz,1H),4.94(t,J=4.8Hz,1H),4.46-4.42(m,1H),4.34-4.28(m,2H),4.21(t,J=4.3Hz,3H),4.15-4.11(m,2H),3.82(d,J=6.9Hz,1H),3.61(t,J=7.7Hz,1H),2.59-2.53(m,1H),2.49(d,J=4.0Hz,1H),2.47(s,2H),2.41(dd,J=15.4,9.3Hz,2H),2.23(s,3H),2.04(s,1H),2.03-1.96(m,4H),1.93(s,3H),1.91-1.86(m,1H),1.77(d,J=2.9Hz,1H),1.67(d,J=12.1Hz,5H),1.65-1.62(m,1H),1.33-1.23(m,23H),1.14(s,3H),0.88(t,J=6.7Hz,3H)。13C NMR(126MHz,CDCl3)δ203.79,171.28,169.85,167.73,167.12,167.06,154.09,142.63,136.67,133.70,133.46,132.87,132.09,130.25,129.99,129.78,129.16,129.14,128.77,128.73,128.56,127.17,126.55,105.09,84.45,81.10,79.18,75.59,75.09,72.87,72.16,72.12,68.31,66.69,60.42,58.54,52.66,45.57,43.21,35.58,35.53,33.87,31.91,29.78,29.76,29.53,29.52,29.45,29.33,29.22,27.23,27.21,26.85,23.84,22.75,22.70,22.18,14.82,14.22,9.62。HRMS(ESI):C69H89NO18Na的m/z(M+Na)+理论值,1242.5977;实测值,1242.5978。
(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((2S,4S)-2-((Z)-十七碳-8-烯-1-基)-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-130)。
1H NMR(400MHz,CDCl3)δ8.14(d,J=7.7Hz,2H),7.74(d,J=7.7Hz,2H),7.60(t,J=7.4Hz,1H),7.54-7.46(m,3H),7.44-7.35(m,7H),6.92(d,J=9.3Hz,1H),6.28(d,J=8.1Hz,2H),6.00(dd,J=9.3,2.5Hz,1H),5.69(d,J=7.1Hz,1H),5.42(d,J=2.6Hz,1H),5.35-5.32(m,2H),5.01-4.94(m,1H),4.87(t,J=4.8Hz,1H),4.47-4.42(m,1H),4.32(d,J=8.5Hz,1H),4.29-4.23(m,1H),4.21(d,J=8.3Hz,1H),4.15(dd,J=5.5,2.1Hz,2H),4.11(t,J=7.1Hz,2H),3.90(t,J=7.8Hz,1H),3.83-3.80(m,1H),2.58-2.56(m,1H),2.49(d,J=4.1Hz,1H),2.46(s,3H),2.44-2.36(m,1H),2.23(s,3H),2.04(s,1H),2.00(q,J=6.5Hz,4H),1.93(s,3H),1.90-1.84(m,1H),1.77(s,1H),1.69(d,J=5.5Hz,5H),1.65-1.63(m,1H),1.31-1.22(m,23H),1.14(s,3H),0.87(t,J=6.6Hz,3H)。13C NMR(101MHz,CDCl3)δ203.79,171.26,169.85,167.75,167.11,167.05,154.03,142.64,136.68,133.68,133.48,132.87,132.07,130.24,129.99,129.78,129.18,129.14,128.76,128.71,128.55,127.17,126.56,105.67,84.45,81.10,79.19,75.59,75.12,72.82,72.14,68.96,66.86,60.41,58.54,52.67,45.57,43.21,35.60,35.54,33.84,31.91,29.78,29.75,29.53,29.47,29.45,29.33,29.22,27.23,27.20,26.85,23.97,22.74,22.69,22.19,21.06,14.81,14.21,9.62。HRMS(ESI):C69H89NO18Na的m/z(M+Na)+理论值,1242.5977;实测值,1242.5972。
(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-((((2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-126)。
1H NMR(500MHz,CDCl3)δ8.15-8.13(m,2H),7.74-7.72(m,2H),7.62-7.58(m,1H),7.53-7.48(m,3H),7.44-7.35(m,7H),6.95(d,J=9.3Hz,1H),6.32-6.24(m,2H),6.00(dd,J=9.5,2.6Hz,1H),5.69(d,J=7.1Hz,1H),5.42(d,J=2.6Hz,1H),4.97(dd,J=9.7,2.3Hz,1H),4.46-4.41(m,1H),4.33-4.28(m,2H),4.25-4.19(m,2H),4.17-4.12(m,1H),4.09-4.04(m,1H),3.81(d,J=7.0Hz,1H),3.76(dd,J=8.7,5.8Hz,1H),2.60-2.53(m,1H),2.52(d,J=4.0Hz,1H),2.46(s,3H),2.41(dd,J=15.4,9.4Hz,1H),2.22(s,3H),1.93(d,J=1.4Hz,3H),1.90(s,1H),1.89-1.85(m,1H),1.82(s,1H),1.68(s,3H),1.36(d,J=10.3Hz,6H),1.24(s,3H),1.13(s,3H)。13C NMR(126MHz,CDCl3)δ203.79,171.25,169.85,167.77,167.19,167.01,154.10,142.59,136.66,133.67,133.49,132.89,132.07,130.23,129.21,129.13,128.75,128.71,128.54,127.17,126.54,115.60,110.09,109.99,84.45,81.10,79.12,75.59,75.12,73.08,72.13,68.68,65.91,58.52,52.66,45.58,43.21,35.61,35.55,26.84,26.56,25.32,22.73,22.19,20.83,14.79,9.63。HRMS(ESI):C54H61NO18Na的m/z(M+Na)+理论值,1034.3786;实测值,1034.3776。
(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((S)-2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-131)。
1H NMR(500MHz,CDCl3)δ8.16-8.10(m,2H),7.76-7.70(m,2H),7.62-7.57(m,1H),7.53-7.47(m,3H),7.44-7.35(m,7H),6.95(d,J=9.3Hz,1H),6.32-6.24(m,2H),6.00(dd,J=9.5,2.6Hz,1H),5.69(d,J=7.1Hz,1H),5.42(d,J=2.6Hz,1H),4.97(dd,J=9.7,2.3Hz,1H),4.43(ddd,J=10.9,6.6,4.0Hz,1H),4.33-4.28(m,2H),4.25-4.19(m,2H),4.17-4.12(m,1H),4.09-4.04(m,1H),3.81(d,J=7.0Hz,1H),3.76(dd,J=8.7,5.8Hz,1H),2.60-2.53(m,1H),2.52(d,J=4.0Hz,1H),2.46(s,3H),2.41(dd,J=15.4,9.4Hz,1H),2.22(s,3H),1.93(d,J=1.4Hz,3H),1.90(s,1H),1.89-1.85(m,1H),1.82(s,1H),1.68(s,3H),1.37(s,3H),1.35(s,3H),1.24(s,3H),1.13(s,3H)。13C NMR(126MHz,CDCl3)δ203.79,171.25,169.85,167.77,167.19,167.01,154.10,142.59,136.66,133.67,133.49,132.89,132.07,130.23,129.21,129.13,128.75,128.71,128.54,127.17,126.54,115.60,110.09,109.99,84.45,81.10,79.12,75.59,75.12,73.08,72.13,68.68,65.91,58.52,52.66,45.58,43.21,35.61,35.55,26.84,26.56,25.32,22.73,22.19,20.83,14.79,9.63。HRMS(ESI):C54H61NO18Na的m/z(M+Na)+理论值,1034.3786;实测值,1034.3783。
(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((R)-2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-132)。
1H NMR(400MHz,CDCl3)δ8.17-8.10(m,2H),7.77-7.70(m,2H),7.60(t,J=7.4Hz,1H),7.54-7.47(m,3H),7.45-7.34(m,7H),6.93(d,J=9.3Hz,1H),6.30(d,J=4.6Hz,2H),6.00(dd,J=9.3,2.3Hz,1H),5.69(d,J=7.1Hz,1H),5.44(d,J=2.6Hz,1H),4.96(d,J=8.0Hz,1H),4.43(dt,J=10.8,5.3Hz,1H),4.35-4.27(m,2H),4.27-4.18(m,2H),4.16-4.12(m,1H),4.06(dd,J=8.7,6.5Hz,1H),3.81(d,J=7.0Hz,1H),3.73(dd,J=8.7,5.7Hz,1H),2.59-2.49(m,2H),2.45(s,3H),2.42-2.36(m,1H),2.22(s,3H),1.93(s,3H),1.88(s,2H),1.84(s,1H),1.68(s,3H),1.41(s,3H),1.35(s,3H),1.24(s,3H),1.13(s,3H)。13C NMR(101MHz,CDCl3)δ203.77,171.21,169.85,167.75,167.14,167.01,154.09,142.56,136.66,133.65,133.51,132.91,132.05,130.23,129.22,129.14,128.74,128.70,128.54,127.16,126.56,110.14,84.45,81.11,79.14,76.46,75.59,75.14,73.17,72.12,69.07,66.10,58.53,52.65,45.60,43.21,35.56,26.84,26.66,25.28,22.72,22.16,20.82,14.79,9.62。HRMS(ESI):C54H61NO18Na的m/z(M+Na)+理论值,1034.3786;实测值,1034.3791。
NCC-SA-01-(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-乙酰氧基-9-((2R,3S)-3-((叔丁氧基羰基)氨基)-2-((((2,2-二丙基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-11-羟基-4,6-二甲氧基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-12-基苯甲酸酯:1H NMR(500MHz,氯仿-d)δ8.13-8.08(m,2H),7.63-7.57(m,1H),7.49(t,J=7.8Hz,2H),7.44-7.37(m,2H),7.37-7.29(m,3H),6.29(t,J=9.1Hz,1H),5.65(d,J=7.0Hz,1H),5.46(s,1H),5.40(s,1H),5.25(dd,J=8.9,2.6Hz,1H),4.99(dd,J=9.7,2.1Hz,1H),4.83(s,1H),4.34-4.24(m,2H),4.22-4.10(m,3H),4.06(ddd,J=8.4,6.4,3.6Hz,1H),3.90(dd,J=10.7,6.4Hz,1H),3.85(d,J=6.9Hz,1H),3.68(ddd,J=17.8,8.5,6.5Hz,1H),3.44(s,3H),3.30(s,3H),2.70(ddd,J=14.1,9.7,6.4Hz,1H),2.44(s,3H),2.33(s,1H),2.00(s,3H),1.79(ddd,J=13.5,10.6,2.2Hz,1H),1.72(s,3H),2.36-216(m,2H),1.71(s,3H),1.63-1.52(m,4H),1.37-1.26(m,13H),1.22(s,3H),1.20(s,3H),0.91(td,J=7.4,2.3Hz,6H)。13C NMR(126MHz,CDCl3)δ205.10,169.88,168.13,167.19,154.32,135.23,133.74,130.32,129.40,129.11,128.80,128.44,126.58,126.56,113.57,113.52,84.32,82.68,81.77,80.84,80.64,79.03,76.63,74.89,73.34,73.23,72.53,69.10,68.83,66.80,66.59,57.32,57.22,47.51,39.72,39.69,39.34,39.32,35.10,32.19,28.27,26.82,22.97,21.17,17.38,17.04,17.02,14.60,14.50,14.49,10.53。HRMS(ESI):C56H75NO18的m/z[M+Na]+理论值,1072.4984;实测值,1072.4872。
NCC-SA-02-(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-乙酰氧基-9-(((2R,3S)-3-((叔丁氧基羰基)氨基)-2-(((((R)-2,2-二丙基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-11-羟基-4,6-二甲氧基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-12-基苯甲酸酯:1H NMR(500MHz,CDCl3)δ8.14-8.08(m,2H),7.64-7.56(m,1H),7.49(t,J=7.8Hz,2H),7.40(tt,J=7.0,0.9Hz,2H),7.37-7.29(m,3H),6.29(t,J=9.1Hz,1H),5.65(d,J=7.0Hz,1H),5.46(s,1H),5.39(d,J=9.5Hz,1H),5.28-5.22(m,1H),4.99(dd,J=9.7,2.1Hz,1H),4.82(s,1H),4.34-4.24(m,2H),4.22-4.15(m,2H),4.14(dd,J=11.1,5.2Hz,1H),4.06(ddd,J=8.4,6.5,3.6Hz,1H),3.90(dd,J=10.7,6.4Hz,1H),3.85(d,J=6.9Hz,1H),3.70(dd,J=8.4,6.4Hz,1H),3.44(s,1H),3.44(s,2H),3.30(s,3H),2.70(ddd,J=14.1,9.8,6.4Hz,1H),2.44(s,3H),2.36-2.16(m,2H),2.00(s,3H),1.84-1.75(m,1H),1.72(s,3H),1.64-1.51(m,4H),1.41-1.31(m,13H),1.22(s,3H),1.20(s,3H),0.94-0.85(m,6H)。13C NMR(126MHz,CDCl3)δ205.09,169.86,168.13,167.19,154.31,139.55,135.22,133.73,130.31,129.40,129.10,128.79,128.44,126.58,113.57,84.31,82.68,81.77,80.83,80.64,79.03,76.62,74.89,73.23,72.52,68.82,66.59,57.30,57.21,56.98,47.50,39.72,39.69,39.31,35.10,32.18,28.26,26.81,22.97,21.16,17.37,17.02,14.59,14.50,10.52。HRMS(ESI):C56H75NO18的m/z[M+Na]+理论值,1072.4984;实测值,1072.4867。
NCC-SA-03-(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-乙酰氧基-9-(((2R,3S)-3-((叔丁氧基羰基)氨基)-2-(((((S)-2,2-二丙基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-11-羟基-4,6-二甲氧基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-12-基苯甲酸酯:1H NMR(500MHz,氯仿-d)δ8.14-8.08(m,2H),7.63-7.56(m,1H),7.49(t,J=7.8Hz,2H),7.41(dd,J=8.2,6.8Hz,2H),7.37-7.29(m,3H),7.26(s,1H),6.29(t,J=9.2Hz,1H),5.65(d,J=7.0Hz,1H),5.46(s,1H),5.39(d,J=9.9Hz,1H),5.25(dd,J=9.1,2.6Hz,1H),5.02-4.96(m,1H),4.83(s,1H),4.34-4.24(m,2H),4.22-4.10(m,3H),4.06(ddd,J=10.0,6.5,3.6Hz,1H),3.90(dd,J=10.7,6.4Hz,1H),3.85(d,J=6.9Hz,1H),3.68(ddd,J=17.3,8.4,6.5Hz,1H),3.44(s,3H),3.30(s,3H),2.70(ddd,J=13.9,9.8,6.4Hz,1H),2.43(s,3H),2.36-216(m,2H),2.00(s,3H),1.79(ddd,J=13.8,10.9,2.2Hz,1H),1.71(s,3H),1.63-1.52(m,4H),1.42-1.31(m,13H),1.22(s,3H),1.20(s,3H),0.94-0.85(m,6H)。13C NMR(126MHz,CDCl3)δ205.11,169.87,168.13,167.18,154.31,139.54,135.22,133.73,130.31,129.39,129.10,128.79,128.43,126.58,126.56,126.28,113.57,84.31,82.67,81.76,80.83,80.64,79.02,76.62,74.88,73.33,72.52,69.09,66.79,57.30,57.21,56.97,47.50,43.51,39.71,39.33,39.31,35.09,32.17,28.26,26.81,22.96,21.16,17.37,17.03,17.01,14.59,14.48,10.52。HRMS(ESI):C56H75NO18的m/z[M+Na]+理论值,1072.4984;实测值,1072.4857。
NCC-SA-04-(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-乙酰氧基-9-(((2R,3S)-3-((叔丁氧基羰基)氨基)-2-((((2,2-二丁基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-11-羟基-4,6-二甲氧基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-12-基苯甲酸酯:1H NMR(500MHz,CDCl3)δ8.14-8.08(m,2H),7.64-7.56(m,1H),7.49(t,J=7.7Hz,2H),7.41(ddd,J=7.7,6.5,1.6Hz,2H),7.37-7.29(m,3H),6.29(t,J=9.1Hz,1H),5.65(d,J=7.0Hz,1H),5.46(s,1H),5.40(s,1H),5.25(dd,J=7.6,2.6Hz,1H),4.99(dd,J=9.8,2.1Hz,1H),4.82(s,1H),4.34-4.25(m,2H),4.23-4.15(m,2H),4.13(ddd,J=11.2,5.6,2.7Hz,1H),4.06(ddd,J=8.4,6.5,3.5Hz,1H),3.90(dd,J=10.8,6.4Hz,1H),3.85(d,J=6.9Hz,1H),3.68(ddd,J=15.8,8.4,6.5Hz,1H),3.44(d,J=1.0Hz,3H),3.30(s,3H),2.70(ddd,J=14.2,9.8,6.4Hz,1H),2.44(s,3H),2.37-2.17(m,2H),2.00(d,J=1.5Hz,3H),1.79(ddd,J=14.3,10.8,2.3Hz,1H),1.72(s,3H),1.63-1.53(m,4H),1.35(s,9H),1.34-1.24(m,8H),1.21(d,J=8.8Hz,6H),0.90(dtt,J=7.2,5.3,2.8Hz,6H)。13C NMR(126MHz,CDCl3)δ205.10,169.88,168.14,168.12,167.18,154.33,139.53,135.23,133.73,130.31,129.40,129.10,128.80,128.43,126.57,126.56,113.74,113.69,84.32,82.67,81.77,80.83,80.64,79.02,76.63,74.89,73.33,73.22,72.53,69.13,68.89,66.80,66.61,57.31,57.29,57.21,56.98,47.50,43.51,37.20,37.18,36.75,36.72,35.10,32.18,28.26,26.81,26.22,25.89,23.10,23.05,22.97,22.52,21.16,14.59,14.20,10.52。HRMS(ESI):C58H79NO18的m/z[M+H]+理论值,1078.5297;实测值,1078.5378。
NCC-SA-05-(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-乙酰氧基-9-(((2R,3S)-3-((叔丁氧基羰基)氨基)-2-(((((R)-2,2-二丁基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-11-羟基-4,6-二甲氧基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-12-基苯甲酸酯:1H NMR(500MHz,CDCl3)δ8.11(dd,J=8.3,1.3Hz,2H),7.63-7.56(m,1H),7.49(t,J=7.7Hz,2H),7.44-7.37(m,2H),7.36-7.29(m,3H),6.29(t,J=9.1Hz,1H),5.65(d,J=7.0Hz,1H),5.46(s,1H),5.40(d,J=9.3Hz,1H),5.28-5.22(m,1H),4.99(dd,J=9.7,2.1Hz,1H),4.82(s,1H),4.34-4.24(m,2H),4.23-4.13(m,2H),4.16-4.10(m,1H),4.06(ddd,J=8.4,6.4,3.5Hz,1H),3.90(dd,J=10.7,6.4Hz,1H),3.85(d,J=6.9Hz,1H),3.69(dd,J=8.4,6.5Hz,1H),3.44(d,J=1.0Hz,3H),3.30(s,3H),2.70(ddd,J=14.1,9.8,6.4Hz,1H),2.44(s,3H),2.37-2.20(m,2H),2.00(d,J=1.4Hz,3H),1.79(ddd,J=14.0,11.0,2.2Hz,1H),1.64-1.53(m,4H),1.35(s,9H),1.34-1.24(m,8H),1.22(s,3H),1.20(s,3H),0.89(qt,J=5.0,2.8Hz,6H)。13C NMR(126MHz,CDCl3)δ205.10,169.87,168.12,167.17,154.32,139.55,135.21,133.73,130.31,129.40,129.09,128.79,128.43,126.57,113.69,84.31,82.67,81.76,80.83,80.64,79.01,76.62,74.88,73.32,73.22,72.52,68.88,66.61,57.28,57.20,56.97,47.50,43.50,37.17,36.71,35.10,32.18,28.26,26.80,26.21,25.88,23.10,23.04,22.96,21.16,14.58,14.20,10.52。HRMS(ESI):C58H79NO18的m/z[M+Na]+理论值,1100.5297;实测值,1100.5176。
NCC-SA-06-(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-乙酰氧基-9-(((2R,3S)-3-((叔丁氧基羰基)氨基)-2-(((((S)-2,2-二丁基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-11-羟基-4,6-二甲氧基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-12-基苯甲酸酯:1H NMR(500MHz,CDCl3)δ8.14-8.08(m,2H),7.64-7.56(m,1H),7.49(t,J=7.8Hz,2H),7.41(dd,J=8.2,6.8Hz,2H),7.37-7.29(m,3H),6.29(t,J=9.2Hz,1H),5.65(d,J=7.0Hz,1H),5.46(s,1H),5.39(d,J=10.5Hz,1H),5.26(d,J=2.5Hz,1H),4.99(dd,J=9.7,2.1Hz,1H),4.82(s,1H),4.34-4.25(m,2H),4.23-4.09(m,3H),4.12-4.03(m,1H),3.90(dd,J=10.7,6.4Hz,1H),3.85(d,J=6.9Hz,1H),3.66(dd,J=8.5,6.6Hz,1H),3.44(s,3H),3.30(s,3H),2.70(ddd,J=14.2,9.8,6.4Hz,1H),2.43(s,3H),2.37-2.16(m,2H),
(s,1H),2.00(s,3H),1.79(ddd,J=13.4,10.8,2.2Hz,1H),1.71(s,3H),1.63-1.55(m,4H),1.34(s,9H),1.34-1.23(m,8H),1.22(s,3H),1.20(s,3H),0.89(td,J=7.1,2.2Hz,6H)。13C NMR(126MHz,CDCl3)δ205.12,169.89,168.14,167.19,154.33,139.53,135.23,133.74,130.32,129.40,129.11,128.80,128.44,126.56,113.74,84.32,82.68,81.77,80.83,80.65,79.02,76.63,74.89,73.33,72.53,69.13,66.80,57.30,57.21,56.98,47.50,43.51,37.20,36.75,35.10,32.18,28.26,26.81,26.22,25.89,23.11,23.04,22.97,21.16,14.59,14.20,10.53。HRMS(ESI):C58H79NO18的m/z[M+H]+理论值,1078.5297;实测值,1078.5388。
NCC-SA-07-(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-乙酰氧基-9-(((2R,3S)-3-((叔丁氧基羰基)氨基)-2-((((2,2-二丁基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-11-羟基-4,6-二甲氧基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-12-基苯甲酸酯:1H NMR(500MHz,CDCl3)δ8.12-8.09(m,2H),7.65-7.56(m,1H),7.49(t,J=7.8Hz,2H),7.44-7.38(m,2H),7.36-7.30(m,3H),6.29(t,J=9.2Hz,1H),5.65(d,J=7.0Hz,1H),5.46(s,1H),5.42-5.35(m,1H),5.25(dd,J=6.7,2.6Hz,1H),4.99(dd,J=9.8,2.1Hz,1H),4.83(s,1H),4.36-4.25(m,2H),4.23-4.10(m,3H),4.06(ddd,J=8.4,6.5,3.4Hz,1H),3.90(dd,J=10.7,6.4Hz,1H),3.85(d,J=7.0Hz,1H),3.68(ddd,J=17.0,8.4,6.5Hz,1H),3.44(d,J=1.0Hz,3H),3.30(s,3H),2.70(ddd,J=14.1,9.7,6.4Hz,1H),2.44(s,3H),2.36-2.16(m,2H),2.00(s,3H),1.79(ddd,J=13.8,11.0,2.2Hz,1H),1.72(s,3H),1.67-1.53(m,4H),1.34(s,9H),1.34-1.23(m,12H),1.22(s,3H),1.20(s,3H),0.88(td,J=7.1,2.2Hz,6H)。13C NMR(126MHz,CDCl3)δ205.15,169.88,168.14,168.12,167.19,154.32,139.56,135.22,133.74,130.31,129.39,129.11,128.80,128.44,126.57,126.56,126.31,113.76,113.70,84.32,82.67,81.77,80.83,80.66,79.02,76.63,74.88,73.32,73.20,72.52,69.18,68.92,66.82,66.64,57.29,57.21,56.98,47.50,43.51,37.43,37.40,36.96,36.92,35.10,32.21,32.18,32.16,32.15,28.26,26.81,23.74,23.42,23.41,22.96,22.75,22.73,21.16,14.58,14.19,14.17,10.53。HRMS(ESI):C60H84NO18的m/z[M+H]+理论值,1106.5610;实测值,1106.5680。
NCC-SA-08-(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-乙酰氧基-9-(((2R,3S)-3-((叔丁氧基羰基)氨基)-2-(((((R)-2,2-二戊基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-11-羟基-4,6-二甲氧基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-12-基苯甲酸酯:1H NMR(500MHz,CDCl3)δ8.14-8.08(m,2H),7.63-7.56(m,1H),7.49(t,J=7.8Hz,2H),7.44-7.37(m,2H),7.37-7.29(m,3H),6.29(t,J=9.2Hz,1H),5.65(d,J=7.0Hz,1H),5.46(s,1H),5.39(d,J=9.8Hz,1H),5.25(d,J=2.6Hz,1H),4.99(dd,J=9.8,2.1Hz,1H),4.82(s,1H),4.34-4.24(m,2H),4.22-4.03(m,5H),3.90(dd,J=10.8,6.4Hz,1H),3.85(d,J=6.9Hz,1H),3.68(td,J=8.5,6.4Hz,1H),3.44(s,3H),3.30(s,3H),2.70(ddd,J=14.2,9.8,6.4Hz,1H),2.44(s,3H),2.36-2.17(m,2H),2.00(d,J=1.5Hz,3H),1.79(ddd,J=13.4,10.9,2.2Hz,1H),1.72(s,3H),1.64-1.53(m,4H),1.35(s,9H),1.33-1.23(m,12H),1.22(s,3H),1.20(s,3H),0.88(td,J=7.1,1.6Hz,6H)。13C NMR(126MHz,CDCl3)δ205.09,169.86,168.13,168.11,167.18,154.32,139.54,135.23,133.73,130.31,129.40,129.09,128.79,128.43,126.57,113.69,84.31,82.67,81.76,80.83,80.63,79.02,76.62,74.89,73.19,72.52,68.92,66.64,57.30,57.21,56.97,47.50,43.51,37.40,36.92,35.10,32.21,32.18,32.16,32.14,28.26,26.81,23.74,23.42,22.97,22.72,21.16,14.58,14.34,14.17,10.52。HRMS(ESI):C60H84NO18的m/z[M+Na]+理论值,1128.5610;实测值,1128.5492。
NCC-SA-09-(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-乙酰氧基-9-(((2R,3S)-3-((叔丁氧基羰基)氨基)-2-(((((S)-2,2-二戊基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-11-羟基-4,6-二甲氧基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-12-基苯甲酸酯:1H NMR(500MHz,CDCl3)δ8.11(d,J=7.3Hz,2H),7.63-7.56(m,1H),7.49(t,J=7.8Hz,2H),7.41(t,J=7.5Hz,2H),7.37-7.29(m,3H),6.29(t,J=9.3Hz,1H),5.65(d,J=7.0Hz,1H),5.46(brs,1H),5.39(d,J=10.0Hz,1H),5.25(dd,J=6.6,2.5Hz,1H),4.99(dd,J=9.9,2.2Hz,1H),4.82(s,1H),4.34-4.25(m,2H),4.22-4.09(m,3H),4.11-4.03(m,1H),3.90(dd,J=10.7,6.4Hz,1H),3.85(d,J=7.0Hz,1H),3.66(dd,J=8.5,6.5Hz,1H),3.44(s,3H),3.30(s,3H),2.70(ddd,J=14.1,9.8,6.4Hz,1H),2.43(s,3H),2.36-2.17(m,2H),2.00(s,3H),1.79(ddd,J=13.8,10.9,2.3Hz,1H),1.71(s,3H),1.67-1.55(m,4H),1.34(s,9H),1.34-1.23(m,12H),1.22(s,3H),1.20(s,3H),0.88(td,J=7.1,2.2Hz,6H)。13C NMR(126MHz,CDCl3)δ205.10,169.88,168.14,167.18,154.33,139.52,135.24,133.73,130.31,129.40,129.11,128.79,128.43,126.56,113.75,84.32,82.68,81.77,80.83,80.64,79.02,76.63,74.89,73.32,72.53,69.17,66.82,57.31,57.21,56.98,47.50,43.51,37.43,36.96,35.10,32.21,32.15,28.26,26.81,23.74,23.41,22.97,22.72,21.17,14.59,14.19,10.52。HRMS(ESI):C60H84NO18的m/z[M+H]+理论值,1106.5610;实测值,1106.5692。
NCC-SA-10-(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-2-((((1,4-二氧杂螺[4.5]癸烷-2-基)甲氧基)羰基)氧基)-3-((叔丁氧基羰基)氨基)-3-苯基丙酰基)氧基)-12b-乙酰氧基-11-羟基-4,6-二甲氧基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-[7,11]甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-12-基苯甲酸酯:1H NMR(500MHz,氯仿-d)δ8.13-8.08(m,2H),7.63-7.56(m,1H),7.49(t,J=7.8Hz,2H),7.44-7.37(m,2H),7.37-7.29(m,3H),6.28(s,1H),5.65(d,J=7.0Hz,1H),5.47-5.39(m,2H),5.25(dd,J=7.8,2.5Hz,1H),4.99(dd,J=9.1,2.0Hz,1H),4.82(s,1H),4.34-4.25(m,2H),4.21-4.09(m,3H),4.05(ddd,J=8.5,6.4,2.1Hz,1H),3.90(dd,J=10.7,6.4Hz,1H),3.85(d,J=6.9Hz,1H),3.75(ddd,J=16.0,8.6,5.6Hz,1H),3.44(d,J=1.1Hz,3H),3.30(s,3H),2.70(ddd,J=14.1,9.7,6.3Hz,1H),2.44(d,J=3.1Hz,3H),2.00(s,3H),1.79(ddd,J=13.9,11.0,2.2Hz,1H),1.71(s,3H),1.65-1.53(m,9H),1.45-1.39(m,1H),1.34(s,9H),1.22(s,3H),1.20(s,3H)。13C NMR(126MHz,CDCl3)δ205.09,169.88,168.16,168.15,167.18,154.30,135.22,133.73,130.31,129.40,129.10,129.08,128.79,128.42,126.57,110.84,110.74,84.31,82.67,81.75,80.83,80.63,79.02,76.62,74.89,72.84,72.75,72.52,69.19,68.77,66.07,65.86,57.30,57.29,57.21,56.98,47.50,43.50,36.50,36.39,35.10,34.94,34.88,32.18,28.27,26.82,25.17,24.10,24.06,23.88,22.96,22.60,21.17,14.59,14.07,10.52。HRMS(ESI):C55H71NO18的m/z[M+Na]+理论值,1056.4671;实测值,1056.4549。
NCC-SA-12-(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-2-(((((R)-1,4-二氧杂螺[4.5]癸烷-2-基)甲氧基)羰基)氧基)-3-((叔丁氧基羰基)氨基)-3-苯基丙酰基)氧基)-12b-乙酰氧基-11-羟基-4,6-二甲氧基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-[7,11]甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-12-基苯甲酸酯:1H NMR(500MHz,CDCl3)δ8.13-8.08(m,2H),7.63-7.56(m,1H),7.49(t,J=7.8Hz,2H),7.44-7.36(m,2H),7.36-7.29(m,3H),6.29(t,J=9.0Hz,1H),5.65(d,J=7.0Hz,1H),5.44(d,J=12.3Hz,2H),5.25(dd,J=7.8,2.4Hz,1H),5.02-4.96(m,1H),4.82(s,1H),4.29(dt,J=10.8,7.1Hz,2H),4.21-4.10(m,3H),4.05(ddd,J=8.6,6.4,2.1Hz,1H),3.89(dd,J=10.7,6.4Hz,1H),3.85(d,J=7.0Hz,1H),3.74(ddd,J=15.9,8.7,5.6Hz,1H),3.44(d,J=1.1Hz,3H),3.30(s,3H),2.70(ddd,J=14.1,9.8,6.4Hz,1H),2.43(d,J=3.3Hz,3H),2.37-2.16(m,2H),2.00(s,3H),1.79(ddd,J=13.9,11.0,2.2Hz,1H),1.71(s,3H),1.65-1.53(m,9H),1.45-1.39(m,1H),1.34(s,9H),1.22(s,3H),1.20(s,3H)。13C NMR(126MHz,CDCl3)δ205.09,169.87,168.16,168.14,167.17,154.29,139.56,135.20,133.72,130.30,129.40,129.09,128.79,128.42,126.57,110.79,110.74,84.31,82.66,81.75,80.82,80.62,79.01,76.62,74.89,72.75,72.51,68.76,65.85,57.29,57.21,56.97,47.49,43.50,36.39,34.93,34.88,32.17,28.26,26.81,25.17,24.05,23.87,22.95,21.16,14.59,10.52。HRMS(ESI)C55H71NO18:的m/z[M+Na]+理论值,1056.4671;实测值,1056.4555。
NCC-SA-11-(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-2-(((((S)-1,4-二氧杂螺[4.5]癸烷-2-基)甲氧基)羰基)氧基)-3-((叔丁氧基羰基)氨基)-3-苯基丙酰基)氧基)-12b-乙酰氧基-11-羟基-4,6-二甲氧基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-[7,11]甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-12-基苯甲酸酯:1H NMR(500MHz,CDCl3)δ8.13-8.08(m,2H),7.63-7.56(m,1H),7.49(t,J=7.7Hz,2H),7.44-7.37(m,2H),7.36-7.30(m,3H),6.28(t,J=9.0Hz,1H),5.65(d,J=7.0Hz,1H),5.46(s,1H),5.40(d,J=10.3Hz,1H),5.25(dd,J=8.0,2.5Hz,1H),4.99(dd,J=9.7,2.1Hz,1H),4.82(s,1H),4.34-4.26(m,2H),4.21-4.14(m,2H),4.17-4.09(m,1H),4.05(ddd,J=8.5,6.4,2.2Hz,1H),3.89(dd,J=10.7,6.4Hz,1H),3.85(d,J=7.0Hz,1H),3.74(td,J=8.7,8.1,5.6Hz,1H),3.44(s,3H),3.30(s,3H),2.70(ddd,J=14.1,9.8,6.4Hz,1H),2.44(d,J=3.1Hz,3H),2.37-2.16(m,2H),2.00(s,3H),1.79(ddd,J=13.9,11.0,2.2Hz,1H),1.71(s,3H),1.64-1.53(m,9H),1.45-1.39(m,1H),1.34(s,9H),1.22(s,3H),1.20(s,3H)。13C NMR(126MHz,CDCl3)δ205.09,169.88,168.14,167.17,154.30,139.53,135.22,133.73,130.31,129.40,129.09,128.79,128.43,126.57,110.79,84.31,82.67,81.75,80.82,80.63,79.02,76.62,74.88,72.84,72.52,69.19,66.06,57.30,57.21,56.97,47.49,43.50,36.50,35.10,34.88,32.17,28.26,26.81,25.17,24.10,23.87,22.95,21.16,14.59,10.52。HRMS(ESI):C55H71NO18的m/z[M+Na]+理论值,1056.4671;实测值,1056.4548。
手性化合物(非对映异构纯化合物)的色谱分离:
在一种方法中,当在合成中获得非对映异构体化合物的混合物时,也可以使用基于氧化硅的离子交换,如使用化学结合的磺酸基团,与银离子进行纯化或分离单种非对映体。因此,银浸渍柱的制备涉及使用具有合适固定相的标准预填充柱,如NucleosilTM5SA,并通过RheodyneTM注射器引入银离子,同时泵水通过该柱。然后用有机溶剂代替水相。通常,使用这种方法,将约50mg-80mg的银离子结合至固定相。银离子柱也可以从商业来源获得,如Chromospher LipidsTM,Varian Chrompack International,Middelburg,Netherlands。参见Morris,L.J.Separation of lipids by silver ion chromatography.J.Lipid Res.,7,717-732(1966)。
化合物的配制:
下表是使用本文中制备的代表性化合物制成的制剂的代表性组成:
可以选择化合物(API)并将其添加到上表所示的组合物中,而获得配制产品的最终浓度,以提供例如0.500g化合物如ART 207,而配制出约5mg/mL的制剂产品。Miglyol812N(C8/C10甘油三酯(MCT油))可以用本文公开的其它甘油三酯酯或其他中链甘油三酯代替。
以下通用方案用于制备组合物:
将前五(5)种成分称重到各个称量盘中,并将各内容物直接转移到400mL烧杯中。将随后的三(3)种成分称重到各个闪烁瓶中。向闪烁瓶盖中加入约5mL DCM,并通过倒置进行混合。将各内容物从小瓶转移到烧杯中。用约5mL DCM冲洗小瓶2次,并将每次洗涤液都加入烧杯中(DCM总体积~15mL;溶液总体积~18mL)。用表面皿盖住烧杯,并使DCM在45℃的烘箱中回流,直到所有成分都溶解;每隔几分钟旋荡一次。大致时间:15min。
取下表面皿,将烧杯置于60℃水浴中,并将平缓氮气流引导穿过DCM混合物的表面,以产生平缓的湍流。使用平缓搅拌继续蒸发DCM,直到混合物形成粘性膜。
将烧杯放入全真空的45℃真空烘箱中至少一(1)小时;如果混合物溶胀超过200mL,则降低真空度。将烧杯放入60℃水浴中,然后加入~94mL预热(60℃)的10mM乙酸钠pH 5.5缓冲液(参见ELN 2020Dec07_R_D_dle_039),并旋荡而产生均匀的乳白色溶液。
用Oster手动共混器低速进行共混,使用一(1)至两(2)秒脉冲;持续脉冲三(3)分钟(至少两(2)分钟)。测量粒径。
使用十(10)秒脉冲,继续用手动共混器脉冲两(2)分钟。测量粒径。
将所得溶液转移到微射流机(Microfluidizer)入口储液器,并使混合物通过微射流机(60℃,25k psi)至少10次。第二次通过后测量粒径(至少10a至10e)。在监测粒径而评估可过滤性的同时,根据需要继续进行另外的过滤。
使用30mL缓冲液和精确的四(4)次泵冲程从微射流机吸留体积中收集产品,得到约100mL处理的物料。将溶液转移到100mL刻度量筒中,并验证最终体积;为粒径和效力进行取样。所得溶液通过单个Nalgene0.2μm aPES过滤器过滤,直到过滤器堵塞。根据需要使用一个或多个额外的过滤器。测量每种滤液的粒径。测量每种滤液的效力。将100mL IPA加入到微射流机进料料斗中,并丢弃剩余的缓冲液冲洗液和IPA(MF洗涤1)。注:此洗涤液含有IPA和来自混合室内的残余缓冲液。用另一100mL IPA冲洗微射流机(MF洗涤2)。
NCI-60细胞一剂量和五剂量筛选数据:
癌症筛选小组的人肿瘤细胞系在含有5%胎牛血清和2mM L-谷氨酰胺的RPMI1640培养基中生长。对于典型的筛选实验,根据各细胞系的翻倍时间,以5000-40000个细胞/孔范围内的接种密度,将细胞接种于100μL96孔微量滴定板中。细胞接种后,在添加实验药物之前,将微量滴定板在37℃、5% CO2、95%空气和100%相对湿度下培养24小时。
24小时后,每个细胞系的两个板用TCA原位固定,以代表在药物添加(Tz)时每个细胞系的细胞群体的测量值。实验药物以所需最终最大测试浓度的400倍溶解于二甲基亚砜中,并在使用前冷冻储存。在添加药物时,将冷冻浓缩物等分试样解冻,并用含有50μg/mL庆大霉素的完整培养基稀释至所需最终最大测试浓度的两倍。额外进行4倍、10倍或1/2log系列稀释,以提供共5种药物浓度+对照。将100μL这些不同药物稀释液的等分试样加入到已经含有100μL培养基的合适微量滴定器孔中,导致获得所需的最终药物浓度。
在药物添加后,将各板在37℃、5% CO2、95%空气和100%相对湿度下培养另外48小时。对于粘附细胞,测试通过添加冷TCA终止。细胞通过平缓添加50μL冷50%(w/v)TCA(最终浓度,10% TCA)原位固定,并在4℃下培养60min。弃去上清液,用自来水将板洗涤五次并风干。将0.4%(w/v)磺基罗丹明B(SRB)的1%乙酸溶液(100μL)加入每个孔中,并将各板在室温下培养10min。染色后,通过用1%乙酸洗涤五次而去除未结合的染料,并将各板风干。结合的染色剂随后用10mM trizma碱溶解,并在515nm波长下于自动读板器上读取吸光度。对于悬浮细胞,除了通过平缓添加50μL 80% TCA(最终浓度为16% TCA)将沉降的细胞固定于孔底部而终止测定之外,方法相同。使用七次吸光度测量[时间零点(Tz)、对照生长(C)和在五个浓度水平(Ti)下存在药物的测试生长],计算每种药物浓度水平下的生长百分比。生长抑制百分比如下计算:
[(Ti-Tz)/(C-Tz)]×100,对于Ti>/=Tz的浓度
[(Ti-Tz)/Tz]×100,对于Ti<Tz的浓度。
对于每种实验药物,计算三个剂量反应参数。50%的生长抑制(GI50)由[(Ti-Tz)/(C-Tz)]×100=50计算,这是在药物培养期间导致对照细胞中净蛋白增加(通过SRB染色测定)减少50%的药物浓度。导致总生长抑制(TGI)的药物浓度由Ti-Tz计算。表示治疗后细胞净损失的LC50(导致药物治疗结束时测得的蛋白质与治疗开始时相比减少50%的药物浓度)由[(Ti-Tz)/Tz]×100=-50计算。如果达到活性水平,则对于这三个参数中计算出各值;然而,如果未达到或超过该效果,则该参数的值表示为大于或小于所测试的最大或最小浓度。
细胞培养:
从ATCC(Manassas,VA)获得乳腺(MDA-MB-231和MDA-MB-453)、胰腺(MIA-ca-2)、肺(A549和NIH-1975)、前列腺(DU145)和卵巢(SKOV-3)癌症细胞系。癌症细胞系在其各自的培养基(DMEM或RPMI,根据ATCC的建议)中补充10%胎牛血清(Atlanta Biological,GA)和1%青霉素/链霉素(Invitrogen-Gibco,Carlsbad,CA),在37℃、5% CO2加湿室中继续培养。
细胞存活率测试:
癌症细胞以3000个细胞/孔接种于384孔板格式中。24小时后,细胞用生理盐水(0.9% NaCl)、载体和ART-207以结果部分中报告的剂量处理48和72小时。通过添加细胞计数试剂盒-8(CCK8,APExBio,Houton,TX)测定抑制作用。在37℃下培养2小时后,使用SpectraMax M3分光光度计(Molecular Devices,San Jose,CA)在450nm下测量光密度。
肿瘤异种移植物抑制测试:
6-8周龄NOD-SCID.Cg-Prkdcscid Il2rgtm1Wjl/SzJ小鼠获自Jackson Laboratories(Bar Harbor,ME),并在实验前在实验室中驯化6天。小鼠饲养于密西西比医学中心动物部实验室(Laboratory of Animal Facility of the Mississippi Medical Center)(Jackson,MS)中。所有动物都被安置在微型隔离笼中,每个笼子最多5只,采用12h光/暗循环。各动物接受过滤的Jackson市政供水和无菌啮齿动物饮食(Teklad LM-485Mouse/RatDiet7912,ENVIGO)。笼子每周更换两次。每天对动物进行观察,并关注临床性征。所有实验程序都获批于密西西比大学医学中心所内动物护理和使用委员会(Institutional AnimalCare and Use Committee of the University of Mississippi Medical Center)(UMMC)。UMMC动物实验室经AAALAC认证。在50μL PBS中的2×106SKOV-3卵巢癌症细胞与50μL Matrigel(Corning,location)一起皮下注射于小鼠右侧。使用卡尺测量肿瘤大小,并使用公式计算肿瘤体积:肿瘤体积=长度×宽度2/2,其中长度表示最大肿瘤直径,宽度表示垂直肿瘤直径。每天监测小鼠,直到肿瘤达到150-200mm3的大小。在连续5天期间注射第一轮治疗,而在2周后给予第二轮5天治疗。在实验结束时,对小鼠实施安乐死,收集肿瘤并称重。
特定化合物的细胞毒性:
使用SK-N-AS细胞的MTS增殖分析测试:
第1天:将SK-N-AS细胞以5×103/孔按照100μL接种于96孔组织培养板Falcon中的合适生长培养基中,每种待测化合物一个培养板中。第1列为空白;其含有培养基,但没有细胞。将各板在37℃5%CO2中放置过夜,以使之附壁。
第2天:一式四份,将在培养基中稀释的药物以0.005nM-10μM的浓度添加到各细胞中。药物暴露48-72小时后,依照CellTiter AQueous Non-Radioactive CellProliferation Assay(MTS),Promega,根据细胞类型将MTS试剂添加到所有孔中,并培养1-6小时(37℃,5% CO2)。使用Bio-Tek Synergy HT Multi-detection微量滴定板读取器以490nm波长对各板进行处理,数据使用KC4V.3软件进行处理。绘制药物浓度相对于吸光度的数据图,并外推每种测试化合物导致50%抑制作用的浓度(IC50)。
使用配对MDR+和MDR-细胞系的MTT增殖测试:
对酸不稳定性亲脂性分子缀合物的细胞毒性进行了第二次评价。这些实验的目的是比较缀合物在多药物抗性细胞及其亲代易感细胞系中的毒性,以检验这些化合物子组在耐药细胞系中表现出与在亲代易敏感细胞系中观察到的相似毒性水平的假设。
基于MTT的细胞毒性测试使用显示多药物抗性的人癌症细胞系和配对亚系进行。这些品系包括子宫肉瘤品系MES-SA及其耐阿霉素亚系MES-SA/Dx5。参见W.G.Harker etal.Development and characterization of a human sarcoma cell line,MES-SA,sensitive to multipledrugs.Cancer Research 43:4943-4950(1983);W.G.Harker etal.Multidrug(pleiotropic)resistance in doxorubicin-selected variants of thehuman sarcoma cell line MES-SA.Cancer Research 45:4091 4096(1985)。
评价该酸不稳定性亲脂性分子缀合物在血浆中的水解稳定性,以确定其将活性癌症化疗剂释放到全身循环中而由此引起一般性脱靶毒性(“副作用”)的潜力。各缀合物用小鼠、大鼠和人源的血浆进行培养。
HPLC级甲醇来自Fisher(Fair lawn,NJ,USA)。货号:A452-4(074833)。HPLC级水来自Fisher(Fair lawn,NJ,USA)。货号:W5-4(073352)。无药物小鼠、大鼠和人血浆购自Innovative Research Inc.(Southfield,MI,USA)。I.V.Fat Emulsion来自Hospira,Inc.(Lake Forest,Illinois)。
血浆培养的制备:
每种化合物在小鼠、大鼠和人血浆中各自以10μg/mL的浓度一式三份进行制备,并涡旋1min,并将其置于37℃水浴中,摇动速度为75次/min。在0、15、30、45、60、75、90、105、120、135、150、165、180、210、240、300、360和480min的时间点进行取样。
本文中制备的化合物在血浆中分析的分析方法:
化合物的色谱分离在Waters Acquity UPLCTM上使用BEH C18柱(1.7μm,2.1×50mm)进行。流动相由甲醇:0.1%甲酸(80:20)组成。流速为0.3mL/min;样品注射体积为5μL,导致运行时间为3min。
MS仪器由Waters Micromass Quattro MicroTM三重四极杆系统(Manchester,UK)组成。MS系统由4.0版本的MassLynx软件控制。电离在正电喷雾电离模式下进行。MS/MS条件如下:毛细管(capillary)电压3.02kV;锥孔(cone)电压50v;提取器(extractor)电压5V;和RF透镜电压0.5V。源温度和去溶剂化温度分别为100℃和400℃,并且去溶剂化和锥孔气流量分别为400和30L/h。
在所选的离子监测(SIM)中使用的化合物的所选质荷比(m/z)转变如所述。停留时间设置为200毫秒。MS条件通过直接输注制备于甲醇中的标准溶液进行优化,并通过注射泵以20μL/min的流速进行递送。
血浆样品制备:
在0、15、30、45、60、75、90、105、120、135、150、165、180、210、240、300、360和480min的时间点收集100μL样品,并用甲醇终止反应。在一组单独实验中,将酸不稳定性亲脂性分子缀合物溶解于少量乙醇中,并稀释成脂质乳液并在培养前加入小鼠和人血浆中,并类似地测量该缀合物的水解作用。将采集的含有选定化合物的100μL血浆样品放置于分开的Eppendorf微型离心管中进行处理。使用蛋白质沉淀技术,加入甲醇(200μL)提取药物。然后将微型管涡旋混合10min,并以10000rpm的速度离心15min(Eppendorf 5415C离心机)。在分析之前,收集上清液并使用0.45μm过滤器(Waters 13mm GHP 0.45μm)过滤。
对空白小鼠、大鼠和人血浆样品的UPLC/MS/MS分析表明上述化合物的定量没有内源性峰值干扰。
使用加权线性最小二乘(1/x)回归作为数学模型。这些化合物的系数(r)范围为0.9925-0.9999。根据待测定样品中的预期浓度选择校准范围。最终校准范围为10-12500ng/mL,定量下限为10ng/mL。重复性和再现性偏差(%)处于低浓度下的±20%可接受限度内和其他浓度水平下的±15%可接受限度内,而所有评价浓度下的RSD均小于5%。
在受试化合物的三种不同血浆浓度下,该方法的平均回收率处于86.22%-99.83%的范围内。这些结果表明,在不同浓度水平下,提取回收率没有相关性差异。
制备的化合物的培养:
将本文中制备的所选化合物的210.6μg/mL原液中的0.2mL等分试样加入预培养15min(37℃)的3.8mL人血浆中,并在37℃的往复式水浴中培养。在0、0.5、1、2、3、4、6、8、10、12和24小时之时抽取样品。
制备的化合物的分析方法(液相色谱-串联质谱法):
使用由二元泵、自动进样器、脱气器和柱箱组成的ACQUITY UPLC液相色谱仪(Waters Corporation,Milford,MA,USA)进行色谱分离。甲醇-乙腈(50:50,v/v)的流动相以0.4mL/min的流速泵送通过维持于25℃的ACQUITY UPLC BEH C18柱(1.7μm,2.1×50mmi.d.,Waters Corporation)。注入10μL样品,运行时间为3.0min。LC洗脱液直接连接到配备有电喷雾电离(ESI)离子源的ESCi三重四级杆质谱仪。四极杆在正离子模式下工作。多反应监测(MRM)模式用于使用MassLynx 4.1版软件进行定量。对于停留时间为0.5s的所选化合物,优化了所选m/z的质量转换。氮气用作雾化气体(30L/h)和去溶剂化气体(300L/h),而去溶剂化温度为250℃,氩气用作碰撞气体。毛细管电压设置为3.5kV,锥体电压设置为90V;并且源温度设置为100℃。
血浆样品制备:
在不同的时段(0、0.5、1、2、3、4、6、8、10、12和24小时),取200μL等分试样,立即加入到1.3mL冷TBME中,并随后加入20μL内标原液(80.7μg/mL甲醇溶液)。每根管涡旋混合约2min,然后以13000rpm离心10min。将1.0mL所得上清液转移到另一根管中,并在35℃的氮气流下干燥。用200μL甲醇重构每个干燥的剩余物,并涡旋混合0.5min。以13000rpm离心10min后,将上清液转移到HPLC自动进样器小瓶中,并将每个样品的10μL等分试样注射到LC-MS-MS中。
在不同时间收集样品,并测定化合物的酸不稳定性亲脂性分子缀合物的剩余百分比和从该缀合物水解中释放的化疗剂的百分比。
将一组本文公开的亲脂性的酸不稳定性紫杉醇缀合物在国家癌症研究所(National Cancer Institute)NCI-60人肿瘤细胞系筛选程序中进行筛选(NCI-60细胞系筛选的方法描述于https://dtp.cancer.gov/discovery_development/nci-60/)而探测其细胞毒性并比较母体紫杉醇。该组分为九个子组,代表各种组织学:白血病、黑色素瘤、肺、结肠、肾脏、卵巢、乳腺、前列腺和中枢神经系统。筛选是一个两阶段的过程,首先在EtOH中以10μM的单剂量对60个细胞系进行所有化合物的评价。所有样品溶解于乙醇中,而不是标准溶剂DMSO中。参考药物紫杉醇(NSC125793)的结果从公开可获得的来源http:// dtp.nci.nih.gov进行检索。各缀合物单剂量结果的体外效果绘制成雷达图,以综合分析多种类似物对多种测试细胞系的细胞毒性。注意到所有缀合物对卵巢癌症细胞系的显著细胞毒性,包括紫杉醇抗性细胞系SK-OV-3的显著细胞毒性。各缀合物对NCI-60细胞产生了与紫杉醇相似的敏感性和耐药性分布曲线。各缀合物表现出显著的生长抑制作用,并对NCI-60细胞系在五个浓度水平下评价至最终浓度0.1nM(支撑信息,S6),而建立GI50值;鉴于相应的非缀合化合物,其显示出优异的活性。
降低癌症细胞(与所配制的缀合物一起培养的)SK-OV-3细胞存活率的能力通过改变暴露时间和剂量与FDA-批准的紫杉醇制剂进行了比较。即使在暴露72小时后,与假-LDL纳米颗粒制剂的缀合物的EC50也比/>强至少3倍,而与所测试的浓度无关。
当结合附图,通过考虑以下对本发明示例性实施方式的详细描述,将更容易领会和理解本发明的这些和其他目的。整个本申请内引用的所有文件的全部公开内容通过引用结合于本文中。
Claims (21)
1.一种下式的酸不稳定性亲脂性分子缀合物(ALLMC):
和它们的分离的非对映异构体或其混合物;或
其药用盐。
2.一种下式的酸不稳定性亲脂性分子缀合物(ALLMC):
3.根据权利要求1所述的酸不稳定性亲脂性分子缀合物,其为(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-((((2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-126),并且其式为:
4.根据权利要求1所述的酸不稳定性亲脂性分子缀合物,其为(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((S)-2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-131),并且其式为:
5.根据权利要求1所述的酸不稳定性亲脂性分子缀合物,其为(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((R)-2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-132)并且其式为:
6.根据权利要求1所述的酸不稳定性亲脂性分子缀合物,其中,带有羟基的癌症化疗剂为紫杉烷。
7.根据权利要求1-5中任一项所述的酸不稳定性亲脂性分子缀合物,其中,带有羟基的癌症化疗剂是紫杉醇。
8.根据权利要求1-6中任一项所述的酸不稳定性亲脂性分子缀合物,其中,带有羟基的癌症化疗剂是卡巴他赛。
9.一种药物组合物,包含:a)治疗有效量的单一非对映异构体形式的权利要求1-8中任一项所述的化合物;和b)药用赋形剂。
10.一种用于治疗患者的癌症的方法,包括向需要此治疗的患者给予治疗有效量的根据权利要求1-9中任一项所述的化合物或组合物。
11.根据权利要求10所述的方法,其中,所述癌症选自由白血病、神经母细胞瘤、成胶质细胞瘤、宫颈癌、结直肠癌、胰腺癌、肾脏癌和黑色素瘤组成的组。
12.根据权利要求10所述的方法,其中,所述癌症选自由肺、乳腺、前列腺、卵巢和头颈癌组成的组。
13.根据权利要求10所述的方法,其中,与紫杉醇或卡巴他赛的非缀合的带有羟基的癌症化疗剂相比,所述方法提供至少10%-50%的癌症细胞表达的抗性的降低程度。
14.一种用于减少或基本消除与向患者给予紫杉醇或卡巴他塞相关的化疗的副作用的方法,所述方法包括向所述患者给予治疗有效量的权利要求1-9中任一项所述的酸不稳定性亲脂性分子缀合物(ALLMC)。
15.根据权利要求14所述的方法,其中,所述方法在所述患者的癌细胞中提供更高浓度的紫杉醇或卡巴他赛。
16.根据权利要求15所述的方法,其中,当与向所述患者给予非缀合的癌症化疗剂紫杉醇或卡巴他赛相比时,所述方法在癌细胞中递送高至少5%、10%、20%或至少50%的浓度的紫杉醇或卡巴他赛。
17.一种稳定的合成低密度脂蛋白(LDL)固体纳米颗粒,包含:
a)下式的酸不稳定性亲脂性分子缀合物(ALLMC):
和它们的分离的非对映异构体或其混合物;或
其药用盐;
b)磷脂(PL),其中所述磷脂选自由磷脂酰胆碱、磷脂酰乙醇胺、对称或不对称1,2-二酰基-sn-甘油-3-磷酰胆碱、1,2-二肉豆蔻酰基-sn-甘油-3-磷酰基胆碱、1,2-二肉豆蔻酰基-sn-甘油-3-磷酰乙醇胺、蛋磷脂、蛋磷脂酰甘油、二棕榈酰磷脂酰甘油、蛋卵磷脂、大豆卵磷脂、卵磷脂(NOS)及其混合物组成的组;和
c)甘油三酯(TG),选自由MIGLYOL 812N、三乙酸甘油酯、三丙酸甘油酯、三丁酸甘油酯、三异戊酸甘油酯、三异戊酸甘油酯、三己酸甘油酯、三庚酸甘油酯、三辛酸甘油酯、三壬酸甘油酯、三癸酸甘油酯和三(十一酸)甘油酯组成的组;
其中LDL固体纳米颗粒具有40-80nm的平均粒径。
18.根据权利要求17所述的稳定的合成低密度脂蛋白(LDL)固体纳米颗粒,其中所述酸不稳定性亲脂性分子缀合物是(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-((((2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-126),并且其式为:
19.根据权利要求17所述的稳定的合成低密度脂蛋白(LDL)固体纳米颗粒,其中所述酸不稳定性亲脂性分子缀合物为(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((S)-2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-131),并且其式为:
20.根据权利要求17所述的稳定的合成低密度脂蛋白(LDL)固体纳米颗粒,其中所述酸不稳定性亲脂性分子缀合物为(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((((R)-2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲桥环十碳[3,4]苯并[1,2-b]氧杂环丁烷-6,12b(2aH)-二基二乙酸酯(NCP-132),并且其式为:
21.根据权利要求17-20中任一项所述的稳定的合成低密度脂蛋白(LDL)固体纳米颗粒,其中,所述纳米颗粒具有60nm的平均尺寸分布。
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