CN1684948A - 含有新型强效紫杉烷的细胞毒性剂及其治疗用途 - Google Patents
含有新型强效紫杉烷的细胞毒性剂及其治疗用途 Download PDFInfo
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- CN1684948A CN1684948A CNA038232480A CN03823248A CN1684948A CN 1684948 A CN1684948 A CN 1684948A CN A038232480 A CNA038232480 A CN A038232480A CN 03823248 A CN03823248 A CN 03823248A CN 1684948 A CN1684948 A CN 1684948A
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- taxane
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- carbamate
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Abstract
本发明的范围包括含有连接基团的强效紫杉烷。本发明的范围还包括细胞毒性剂,该细胞毒性剂含有连接到细胞结合剂上的一种或多种紫杉烷。用于在所选择的细胞群体中诱导细胞死亡的治疗组合物包括:(A)细胞毒性剂量的一种或多种紫杉烷,其通过连接基团以共价键结合到细胞结合剂上;以及还包括(B)药学上可接受的载体、稀释剂或赋形剂。本发明还包括在所选择的细胞群体中诱导细胞死亡的方法,该方法包括:使靶细胞或含有靶细胞的组织与有效量的细胞毒性剂相接触,其中的细胞毒性剂含有连接到细胞结合剂上的一种或多种紫杉烷。
Description
[01]本申请是2002年8月2日提交的美国申请USAN 10/210,112的部分继续申请,将该申请USAN 10/210,112引入本文以作参考。
技术领域
[02]本发明涉及新型的细胞毒性剂(cytotoxic agents)和其治疗用途。更具体地,本发明涉及新型的紫杉烷(taxane)、包括该新型紫杉烷的新型细胞毒性剂,及其它们的治疗用途。这些新型的细胞毒性剂具有治疗用途,原因是通过将紫杉烷化学连接到能靶向所选择的细胞群体(cellpopulation)的细胞结合剂(cell-binding agent)上,以靶向的方式将紫杉烷传递到所选择的细胞群体中。
背景技术
[03]采用由细胞毒性剂与细胞结合剂的连接而实现的靶向传递,可使细胞毒性剂的特异性大大提高。
[04]关于采用单克隆抗体-药物共轭体而尝试对癌细胞的特异性靶向,已有许多报道:Sela等,Immunoconjugates 189-216(C.Vogel,ed.1987);Ghose等,Targeted Drugs 1-22(E.Goldberg,ed.1983);Diener等,Antibodymediated delivery systems 1-23(J.Rodwell,ED.1988);Pietersz等,Antibodymediated delivery systems 25-53(J.Rodwell,ed.1988);Bumol等,Antibodymediated delivery systems 55-79(J.Rodwell,ed.1988)。将本文中所引用的所有参考文献和专利并入以作参考。
[05]细胞毒性药如氨甲蝶呤、红比霉素、阿霉素、长春新碱、长春花碱、苯丙氨酸氮芥、丝裂霉素C,以及苯丁酸氮芥已经与各种鼠单克隆抗体相共轭结合。在一些情况下,药物分子通过中间载体分子连接到克隆抗体上,这样的中间载体分子例如血清白蛋白(Garnett等,Cancer Res.46:-2412(1986);Ohkawa等,Cancer Immuol.Immunother.23:86(1986);Endo等,Cancer Res.47:1076-1080(1980)),右旋糖苷(Hurwitz等,Appl.Biochem.2:25-35(1980);Manabi等,Biochem.Pharmacol.34:289-291(1985);Dillman等,Cancer Res.46:4886-4891(1986);Shoval等,Proc.Natl.Acad.Sci.85:8276-8280(1988)),或聚谷氨酸(Tsukada等,J.Natl.Canc.Inst.73:721-729(1984);Kato等,J.Med.Chem.27:1602-1607(1984);Tsukada等,Br.J.Cancer 52:111-116(1985))。
[06]已经采用了大量的连接物技术(linker technologies)来制备这类免疫共轭物,也研究了可断裂或不可断裂的连接物(linker)。然而在多数情况下,只有药物分子可在靶位置上以未改变的形式从共轭物中释放出来时,才能检测到药物的全部细胞毒性效价。
[07]已经用于制备抗体-药物共轭物的一种可断裂连接物(cleavablelinkers)是基于顺式-丙烯三羧酸的酸不稳定连接物,它利用了不同的细胞内区室(intracellular compartments)的酸性环境,细胞内区室如在受体介导的胞吞作用期间所遇到的内含体以及溶酶体。Shen和Ryser将这种方法引入,用于制备红比霉素和大分子载体的共轭物(Biochem.Biophys.Res.Commun.102:1048-1054(1981))。Yang和Reisfeld采用相同的技术将红比霉素共轭结合到抗黑素瘤抗体上(J.Natl.Canc.Inst.80:1154-1159(1988))。Dillman等也采用酸不稳定性连接物以类似的方式制备红比霉素与抗T细胞的抗体共轭物(Cancer Res.48:6097-6102(1988))。
[08]Trouet等提出的另一种方法,涉及将红比霉素通过肽间隔臂(peptide spacer arm)连接到抗体上(Proc.Natl.Acad.Sci.79:626-629(1982))。这种方法的前提是游离药物(free drug)能通过溶酶体的肽酶作用从这类共轭物中释放出来。然而在体外细胞毒性试验中,已揭示了抗体-药物共轭物几乎达不到与采用游离非共轭药物相同的细胞毒性效价。这表明药物分子从抗体上释放出来的机理的效率很低。
[09]在免疫毒素领域中,与含有其它连接物的共轭物相比,通过单克隆抗体和催化活性的蛋白质毒素之间的二硫桥键而形成的共轭物显示出更高的细胞毒性,参见Lambert等,J.Biol.Chem.260:12035-12041(1985);Lambert等,Immunotoxins 175-209(A.Frankel,ed.1988);Ghetie等,Cancer Res.48:2610-2617(1988)。这归因于谷胱甘肽的细胞内浓度高,使得抗体分子和毒素之间的二硫键发生高效断裂。虽然如此,但关于采用二硫桥键制备药物和大分子之间的共轭物,仅报道了几个例子。在Shen等,J.Biol.Chem.260:10905-10908(1985)中,描述了氨甲蝶呤转化为氢硫基乙酰胺(mercaptoethylamide)衍生物,然后通过二硫键与聚-D-赖氨酸共轭连接。另一个报道中描述了含有毒素药物刺孢霉素(calicheamycin)的三硫化物与抗体形成共轭物的制备方法(Hinman等,Cancer Res.53:3336-3342(1993))。
[10]缺乏由二硫化物连接的抗体-药物共轭物的一个原因是:具有易于使药物通过二硫桥键与抗体相连接的含硫原子部分的细胞毒素药物难以获得。另外,在不降低细胞毒性效力的条件下对已有药物进行化学修饰是困难的。
[11]现有的抗体-药物共轭物的另一个主要缺点是它们不能将足够浓度的药物传递到靶位置,原因是靶抗原的数目有限,以及抗癌药物(cancerostatic)例如氨甲蝶呤、红比霉素和长春新碱的细胞毒性相对温和。为了获得显著的细胞毒性,有必要使大量药物分子直接地或通过聚合载体分子与抗体进行连接。然而,这种重大修饰的抗体往往表现出与靶抗原的结合被消弱,加快了在体内从血流中被清除出来。
[12]尽管存在上述的困难,已报道了包含细胞结合部分的有用细胞毒性剂和一组细胞毒性药物(已知为美登木素生物碱(maytansinoid))(USP5,208,020,USP 5,416,064,以及R.V.J.Chari,Advanced Drug DeliveryReviews 31:89-104(1998))。相似地,含有细胞结合部分的有用细胞毒性剂,以及强效抗癌抗生素CC-1065的类似物和衍生物也已见报道(USP5,475,092和USP 5,585,499)。
[13]也已经表明采用可断裂的连接如二硫键达成的具有高度细胞毒性的药物与抗体之间的连接确保了全部活性药物在细胞内部释放出来,这些共轭物的细胞毒性为抗原特异性方式(R.V.J.Chari等,Cancer Res.52:127-131(1992);USP 5,475,092;以及USP 5,416,064)。
[14]紫杉烷(Taxanes)是一族化合物,包括紫杉醇(paclitaxel)(红豆杉醇(Taxol)),为细胞毒性的天然产物;和多西紫杉醇(docetaxel)((泰素替尔)(Taxotere)),为一种半合成的衍生物(参见图1和图4),这两种化合物广泛地应用在癌症治疗中,见E.Baloglu和D.G.I.Kingston,J.Nat.Prod.62:1448-1472(1999)。紫杉烷是有丝分裂的纺锤体毒素,抑制微管蛋白的解聚合作用,导致细胞死亡。尽管多西紫杉醇和紫杉醇是治疗癌症的有用试剂,但由于对正常细胞具有非特异性毒性,使它们的抗癌活性受到了限制。另外,类似于紫杉醇和多西紫杉醇的化合物本身的效价不足以用于与细胞结合剂结合的共轭物中。
[15]近来,已经描述了一些效价大于多西紫杉醇或紫杉醇的多西紫杉醇类似物(I.Ojima等,J.Med.Chem.,39:3889-3896(1996))。然而,这些化合物缺乏允许通过可断裂的键与细胞结合剂进行连接的合适官能度(图1)。
[16]近期已描述了保持高细胞毒性并能有效地与细胞结合剂相连接的新型紫杉烷的合成(USP 6,340,701;USP 6,372,738和USP 6,436,931,以及图2和4)。在这些公开中,采用能与适合的细胞结合剂相连接的化学部分,尤其是含有硫醇基或二硫基的一些化学部分修饰紫杉烷。因此,这些新型的紫杉烷保留了,甚至在一些情况下还提高了已知紫杉烷的细胞毒性效价。
[17]在前述专利所公开的紫杉烷中,在紫杉烷中的C-10,C-7或C-2’位置上引入了连接基团。
[18]在连接基团处于C-7位置上的情况下,C-10位置上不具有游离羟基(free hydroxyl)取代基,但可为酯、醚或氨基甲酸酯取代基。现有技术(I.Ojima等,J.Med Chem.,39:3889-3896(1996))已经表明C-10位置存在酯或氨基甲酸酯取代基产生了具有高效价的紫杉烷。然而,尚未出现对C-10位置具有游离羟基,而C-7位置上具有连接基团的紫杉烷效价的研究。
[19]如本文中所述,已发现C-10位置具有游离羟基,C-7位置上具有连接基团的紫杉烷的效价达到或超过C-10位置具有酯、醚、氨基甲酸酯取代基,C-7位置上具有连接基团的紫杉烷的效价。因此,在第一个方面,本发明的第一方面提供了C-10位置具有游离羟基,C-7位置上具有连接基团的新型紫杉烷,其具有强效细胞毒性活性。
[20]进一步地,在上述专利描述的紫杉烷中,连接基团被引入到紫杉烷的C-10,C-7或C-2’位置上。在所有的紫杉烷中,处于C-3’N和C-3’处的取代基分别被命名为-NHCOR4和R3。而且,在C-3’N处的取代基,即-NHCOR4,如在紫杉醇中那样是一个苯甲酰氨基团(R4=苯基);或如在多西紫杉醇中那样为叔-丁氧羰基氨基(tert-butyloxycarbonylamino)部分(-NH-t-BOC,R4=t-BOC)。根据已公布的数据,认为改变这些取代基将导致效价损失。在C-3’位上的取代基(R3)或者是芳基或者具有1-10个碳原子的直链的、支链的或环状的烷基基团。由于在这些公布数据的基础上认为处于C-3’N和C-3’位的取代基不能在不损失药物活性的情况下进行改变,因此总是将连接基团引入到紫杉烷的另外的位置上,即C-7,C-10或C-2’位。此外,不能改变C-3’或C-3’N位上的取代基,这大大地限制了可以合成的含二硫化物的紫杉烷的种类。
[21]第二个方面,本发明也是基于以下意想不到的发现:在C-3’和C-3’N位上的取代基两者都不必受限于已知的紫杉烷中所存在的那些取代基。如本文中所述,在C-3’N位具有多种不同取代基的紫杉烷的效价达到或超过在该位置上具有苯甲酰氨或-NH-t-BOC取代基的紫杉烷的效价。C-3’或C-3’N位的新型取代基也可含有允许连接到细胞结合剂的连接基团。本发明公开了这些在C-3’和C-3’N位上具有多种不同的取代基的新型高效紫杉烷。现在,连接基团可引入在以下5个位置中的任意一个位置上:C-3’,C-3’N,C-10,C-7或C-2’。
发明概述
[22]在本发明的一种实施方式中,公开了具有高细胞毒性能有效地用于治疗许多疾病的新型紫杉烷。
[23]在本发明的第二种实施方式中,公开了在C-10位上具有游离羟基,在C-7位上具有连接基团,且仍然保持高效价的新型紫杉烷。
[24]在本发明的第三种实施方式中,公开了在C-3’N或C-3’位上具有多种不同的取代基,在C-7,C-10,C-2’或C-3’N或C-3’位上具有连接基团,且仍然保持高效价的新型紫杉烷。
[25]在本发明的第四种实施方式中,公开了细胞毒性剂,其包括一种或多种通过连接基团以共价健结合到细胞结合剂上的新型紫杉烷。
[26]在本发明的第五种实施方式中,公开了治疗组合物,包括:
(a)治疗上有效量的一种或多种新型紫杉烷,与细胞结合剂相连接;和
(b)药学上可接受的载体、稀释剂或赋形剂。
[27]在本发明的第六种实施方式中,公开了在所选择的细胞群体中诱导细胞死亡的方法,包括使靶细胞或含有靶细胞的组织与有效量的细胞毒性剂相接触,其中的细胞毒性剂包括一种或多种与细胞结合剂相连接的新型紫杉烷。
附图说明
[28]图1是一个化学式,代表多种紫杉烷结构,包括前述由Ojima等所描述的更有效力的紫杉烷中的一些。
[29]图2是一个化学式,代表根据本发明的含二硫化物的紫杉烷中的一些,这些含二硫化物的紫杉烷在C-10位上具有游离羟基,而在C-7位上具有连接基团。
[30]图3示出了三种紫杉烷的结构。紫杉烷1在C-10位具有酯基,在C-7位上具有连接基团。紫杉烷2’和紫杉烷3’两者的C-10位上都具有游离羟基,而在C-7位都具有连接基团。
[31]图4是一个化学式,代表多种紫杉烷结构,这些紫杉烷包括USP6,340,701,USP 6,372,738和USP 6,436,931中所描述的一些更有效力的紫杉烷。
[32]图5是一个化学式,代表根据本发明中一些新型紫杉烷结构,这些紫杉烷在R3和/或R4处具有先前未描述过的取代基。
[33]图6是一个代表本发明中一些含二硫化物的新型紫杉烷结构的化学式,这些含二硫键的紫杉烷在R3和/或R4处具有先前未描述过的取代基。
[34]图7示出了10-脱乙酰基浆果赤霉素III(10-deacetylbaccatin III)的结构,该物质是用于制备紫杉烷的起始物质。
[35]图8示出了制备紫杉烷2’的合成步骤。
[36]图9示出了制备紫杉烷3’的合成步骤。
[37]图10示出了紫杉烷1和紫杉烷2’对A431细胞的体外效价比较。
[38]图11示出了紫杉烷3’对A549和MCF-7细胞的体外细胞毒性。
[39]图12示出了抗-EGF受体抗体-紫杉烷共轭物作用在SCID小鼠中的人类鳞状细胞癌(A431)异种移植物上的抗肿瘤效果。
[40]图13示出了实施例8所述的实验中所采用的SCID小鼠的体重变化。
[41]图14示出了抗-EGF受体-紫杉烷共轭物对靶抗原-阳性细胞系A431的细胞毒性测定结果,以及N901-紫杉烷共轭物的细胞毒性测定结果,A431细胞系对N901-紫杉烷共轭物不表达靶抗原。
[42]图15示出了TA1-紫杉烷共轭物的细胞毒性效价和选择性,在靶抗原-阳性细胞系SK-BR-3和非-靶抗原-阴性细胞系A431中。
[43]图16a,16b和16c示出了制备根据本发明第二方面的新型紫杉烷的合成步骤。
[44]图17a和17b示出了制备本发明第二方面新型的含二硫键紫杉烷的合成步骤。
[45]图18示出了本发明第二方面新型紫杉烷的体外细胞毒性。
[46]图19a和19b示出了本发明第二方面新型的含二硫键紫杉烷的体外细胞毒性。
发明详述
[47]本发明描述了保持高细胞毒性并能有效连接到细胞结合剂上的新型紫杉烷。现有技术中已经表明在C-10位具有受保护羟基的紫杉烷是高效价的(USP 6,340,701;USP 6,372,738和USP 6,436,931)。本发明的第一方面是基于以下意想不到的发现:无需对C-10位进行保护,即可获得高效价。只要在C-7位上存在受保护的羟基,如连接基团,则在C-10位具有游离羟基的紫杉烷仍然保持高效力。
[48]本发明还描述了C-10位具有游离羟基,C-7位具有连接基团的紫杉烷的合成和体外评价。
[49]此外,先前已经表明C-3’N位具有苯甲酰氨或叔-丁氧基羰基氨基(-NH-t-BOC)取代基以及其他取代基,如芳基或直链、支链或环状烷基基团的紫杉烷具有高效价。本发明的第二方面是基于以下意想不到的发现:C-3’N位不必具有苯甲酰氨或-NH-t-BOC基团,即可获得高效价。可采用具有烷基、链烯基或杂环侧链的多种不同的酰胺或氨基甲酸酯取代基而并不损失效价。可在侧链的C-3’,C-3’N,或者C-10,C-7或C-2’位上引入连接基团。
[50]合成紫杉烷的前体是天然存在的化合物10-脱乙酰基浆果赤霉素III(10-DAB)(图7)。可制备出各种各样带有连接基团的紫杉烷。进一步地,这一化合物在C-10位上具有游离羟基。因此,可减少制备根据本发明第一方面的细胞毒性紫杉烷所需的合成步骤数目,原因是羟基基团不必转化为酯、醚或氨基甲酸酯。也增加了带有连接基团的紫杉烷的产量。
[51]本发明进一步描述了在C-3’或C-3’N位具有新取代基;在C-7,C-10,C-2’或者C-3’,C-3’N位具有或不具有连接基团的代表性紫杉烷的合成和体外评价。
[52]技术领域表明对现有药物进行修饰而不降低其细胞毒性效价是特别困难的。本公开的发明采用能连接上合适的细胞结合剂的化学部分,包括一些含有硫醇基或二硫化物基团的化学部分修饰已公开的紫杉烷,从而克服了这一问题。因此,所公开的新型紫杉烷保留了,在一些情况下甚至提高了已知紫杉烷的细胞毒性效价。细胞结合剂-紫杉烷复合物允许全面衡量紫杉烷的细胞毒性作用,这些紫杉烷以靶向方式仅作用于不需要的细胞,从而避免了由于损伤非靶向的健康细胞而造成的副作用。本发明使得紫杉烷是导向靶位点的,这在以前是不可能的。因此,本发明提供了有用的试剂,用于除去将要被杀死或裂解的疾病状态的或异常的细胞,如癌细胞(特别是实体癌细胞)、病毒感染细胞、微生物感染细胞、寄生虫感染细胞、自身免疫细胞(产生自身抗体的细胞或调节自身抗体产生的细胞)、活化细胞(移植排斥或移植物抗宿主病中所涉及的活化细胞)、或任何其它类型的疾病状态的或异常的细胞,同时表现出最小的副作用。
[53]根据本发明的细胞毒性剂包括一种或多种通过连接基团与细胞结合剂相结合的紫杉烷。连接基团是通过传统方法以共价键结合到紫杉烷上的结构。在一种优选实施方式中,细胞结合剂可通过二硫键或硫醚键以共价键结合到紫杉烷上。
[54]在以下针对实施方式(1)到(9)的描述中,适用下列各项:
[55]在未另外指明的情况下,术语“烷基”是指直链、支链或环状的烷基。
[56]直链烷基的例子包括甲基、乙基、丙基、丁基、戊基和己基。
[57]支链烷基的例子包括异丙基、异丁基、仲-丁基、叔-丁基、异戊基和2-乙基-丙基。
[58]环烷基的例子包括环丙烷、环丁烷、环戊烷和环己烷。
[59]链烯基和环烯基的例子包括二甲基丙烯酰基(dimethylacryloyl)、异丁烯基、己烯基、环戊烯基和环己烯基。
[60]单纯芳基(simple aryl)的例子包括苯基和萘基。
[61]取代芳基的例子包括上述那些芳基被烷基,卤素如Cl、Br、F,硝基,氨基,磺酸基,羰基,羟基和烷氧基所取代的芳基。
[62]杂环化合物是其中杂原子选自于O,N和S的化合物,包括吗啉代(morpholino)、哌啶子基(piperidino)、哌嗪基(piperazino)、N-甲基哌嗪基(N-methylpiperazino)、吡咯基(pyrrollyl)、吡啶基、呋喃基、咪唑基、噁唑基、噻唑基和噻吩基、吲哚基、苯并呋喃基(benzofuranyl)、苯并噻吩基(benzothiopheneyl)。
[63]氨基甲酸酯的例子为由烷基、链烯基、环烷基、环烯基、或芳基部分,例如甲基、乙基、丁烯基、环己基、环己烯基、苯基形成的,或由含氮杂环,如吗啉代、哌啶子基、哌嗪基、N-甲基哌嗪基形成的那些氨基甲酸酯。
[64]芳基酯、醚和氨基甲酸酯的例子包括苯基和萘基酯、醚和氨基甲酸酯。
[65]直链、支链或环状烷基或烯基酯的例子包括甲基、乙基、异丙基、烯丙基、丁烯基、环己基、环己烯基酯。
[66]直链、支链或环状烷基或链烯基醚的例子包括甲基、乙基、异丙基、烯丙基、丁烯基和环己基醚。
[67]用于本发明的紫杉烷具有下列的通式(I):
[68]这些新型的紫杉烷可被分为9种实施方式,指定为(1)到(9)。实施方式(1)到(4)的例子如图2所示。实施方式(5)到(9)的例子如图6所示。
实施方式(1)到(4)
[69]在实施方式(1)-(4)中,R1是H,一个吸电子基团如F、NO2、CN、Cl、CHF2和CF3,或一个供电子基团如-OCH3、-OCH2CH3、-NR7R8、-OR9。R1’和R1”相同或不同,是H,一个吸电子基团如F、NO2、CN、Cl、CHF2和CF3,或一个供电子基团如-OCH3、-OCH2CH3、-NR7R8、-OR9。
[70]R7和R8相同或不同,为具有1-10个碳原子的直链、支链、或环状烷基,或单纯的(simple)或取代的芳基。R7和R8的碳原子数目优选为1到4。此外,还优选R7和R8是相同的。优选的-NR7R8基团的例子包括二甲基氨基(dimethyl amino)、二乙基氨基(diethyl amino)、二异丙基氨基(di-isopropylamino)和二丁基氨基(dibutyl amino),其中的丁基部分可为伯丁基、仲丁基、叔丁基或异丁基中的任何一个。
[71]R9是具有1-10个碳原子的直链、支链或环状的烷基。R1优选为-OCH3、Cl、F、NO2或CF3。
[72]更优选地,R1是-OCH3,并位于间位上,且R1’和R1”其中之一为-OCH3,而另一个为H。
[73]在实施方式(1),(2)和(4)中,R2是H,杂环,或芳基醚、酯或氨基甲酸酯,或具有1-10个碳原子的直链、支链或环状的烷基或链烯基酯或醚;或式COX的氨基甲酸酯,其中的X为含氮杂环,如哌啶子基、吗啉代、哌嗪基、N-甲基-哌嗪基;或式-CONR10R11的氨基甲酸酯,其中R10和R11相同或不同,为H,具有1-10个碳原子的直链、支链、或环状烷基,或简单的或取代的芳基。
[74]芳基醚、酯和氨基甲酸酯的优选例子包括苯基和萘基。
[75]烷基和链烯基酯的优选例子包括-COCH3、-COCH2CH3、丁烯基和二甲基丙烯酰基。烷基和链烯基醚的优选例子包括甲基、乙基、烯丙基、丙基、丁烯基和二甲基丙烯酰基。氨基甲酸酯的优选例子包括-CONHCH2CH3、-CONHCH2CH2CH3、-CO-吗啉代、-CO-哌嗪基、-CO-哌啶子基、或-CO-N-甲基哌嗪基。优选地,R2为H。
[76]在实施方式(3)中,R2为连接基团。
[77]在实施方式(1),(3)和(4)中,R3是具有1-10个碳原子的烷基或链烯基,具有3到10个碳原子的环烷基,环烯基,芳基或杂环。
[78]优选地,R3为丁烯基、二甲基丙烯酰基、异丁烯基、己烯基、环戊烯基、环己烯基、呋喃基、吡咯基、噻吩基、噻唑基、咪唑基、吡啶基、吗啉代、哌啶子基、哌嗪基、噁唑基、吲哚基、苯并呋喃基或苯并噻吩基。
[79]更优选地,R3为t-BOC、异-丁烯基、丁烯基、二甲基丙烯酰基、噻吩基、噻唑基或呋喃基。
[80]在实施方式(2)中,R3是-CH=C(CH3)2。
[81]在实施方式(1)到(4)中,R4是具有1到10个碳原子的烷基或链烯基,具有3到10个碳原子的环烯基、环烷基,芳基,杂环,-OC(CH3)3,或由任何所述的烷基、链烯基、环烷基或环烯基、芳基,或含氮杂环所形成的氨基甲酸酯。
[82]优选地,R4为丁烯基、二甲基丙烯酰基、异丁烯基、己烯基、环戊烯基、环己烯基、呋喃基、吡咯基、噻吩基、噻唑基、咪唑基、吡啶基、吗啉代、哌啶子基、哌嗪基、噁唑基、吲哚基、苯并呋喃基或苯并噻吩基。
[83]更优选地,R4是t-BOC、异-丁烯基、丁烯基、二甲基丙烯酰基、噻吩基、噻唑基或呋喃基。
[84]在实施方式(1)和(2)中,R5是连接基团,而R6的定义与实施方式(1),(2)和(4)中对R2的定义相同。
[85]在实施方式(3)中,R5的定义与实施方式(1),(2)和(4)中对R2的定义相同。
[86]在实施方式(3)中,R6的定义与实施方式(1),(2)和(4)中对R2的定义相同。
[87]在实施方式(4)中,R6是连接基团,而R5的定义与实施方式(1),(2)和(4)中对R2的定义相同。
[88]合适的连接基团是本领域公知的,包括二硫基、硫醚基、酸不稳定基团(acid labile group)、光不稳定基团(photolabile group)、肽酶不稳定基团(peptidase labile group)、以及酯酶不稳定基团(esterase labile group)。优选为二硫基或硫醚基。
[89]当连接基团为含硫醇或含二硫键的基团时,带有硫醇基或二硫基的侧链可为直链或支链的、芳香族的或杂环的。本领域的普通技术人员可容易地确定合适的侧链。
[90]含有硫醇或二硫键的取代基的具体例子包括-(CR13R14)m(CR15R16)n(OCH2CH2)ySZ、-CO(CR13R14)m(CR15R16)n(OCH2CH2)ySZ、-(CR13R14)m(CR17=CR18)(CR15R16)mOCH2CH2)ySZ、-CO-(CR13R14)m(CR17=CR18)(CR15R16)m(OCH2CH2)ySZ、-CONR12(CR13R14)m(CR15R16)n(OCH2CH2)ySZ、呋喃基-XSZ、噁唑基-XSZ、噻唑基-XSZ、噻吩基-XSZ、咪唑基-XSZ、吗啉基-XSZ、-哌嗪基-XSZ、哌啶子基-XSZ、CO-呋喃基-XSZ、CO-噻吩基-XSZ、CO-噻唑基-XSZ和-CO-N-甲基哌嗪基-XSZ、-CO-吗啉代-XSZ、-CO-哌嗪基-XSZ、-CO-哌啶子基-XSZ、或-CO-N-甲基哌嗪基-XSZ,其中:
Z是H或SR,
[91]X是具有1-10个碳原子的直链烷基或支链烷基,或具有2到20个乙烯氧基(ethylene oxy)重复单元的聚乙二醇间隔基;
R和R12相同或不同,为具有1到10个碳原子的直链或支链的烷基或环烷基,或单纯的或取代的芳基或杂环,且R12也可为H;
R13、R14、R15和R16相同或不同,为H或具有1-4个碳原子的直链或支链的烷基;
R17和R18为H或甲基;
n为1到10的整数;
m为从1到10的整数,也可为0;
y为从1到20的整数,也可为0。
[92]本发明第一方面的优选紫杉烷是在C-10(即R2)上具有游离羟基,而在C-7位(即R5)上具有连接基团的那些化合物。本发明的最优选紫杉烷是图3所示的紫杉烷2’和3’。
实施方式(5)到(9)
[93]在实施方式(5)到(9)中,R1为H,吸电子基团如F、NO2、CN、Cl、CHF2和CF3,或供电子基团如-OCH3、-OCH2CH3、-NR7R8、-OR9。R1’和R1”可相同或不同,为H,吸电子基团如F、NO2、CN、Cl、CHF2,和CF3,或供电子基团如-OCH3、-OCH2CH3、-NR7R8,和-OR9。
[94]R7和R8相同或不同,为具有1到10个碳原子的直链、支链或环状烷基,或单纯的或取代的芳基。R7和R8的优选碳原子数目是1到4。此外,优选R7和R8相同。-NR7R8基团的优选例子包括二甲基氨基、二乙基氨基、二丙基氨基、二异丙基氨基和二丁基氨基,其中的丁基部分为伯、仲、叔氨基或异丁基中的任何一个。
[95]R9是具有1到10个碳原子的直链、支链或环状烷基。
[96]优选地,R1是-OCH3、Cl、F、NO2和CF3。
[97]更优选地,R1是-OCH3并位于间位,R1’和R1″其中之一为-OCH3,而另一个为H。
[98]在实施方式(5)、(6)和(7)中,R3和R4相同或不同,为具有1到10个碳原子的烷基或链烯基,具有3到10个碳原子的环烷基、环烯基,芳基或杂环,R4还可为-OC(CH3)3,或由任何所述的烷基、链烯基、环烷基或环烯基、芳基、或含氮杂环形成的氨基甲酸酯。
[99]优选地,R3和R4其中之一或两者都是丁烯基、二甲基丙烯酰基、异丁烯基、己烯基、环戊烯基、环己烯基、呋喃基、吡咯基、噻吩基、噻唑基、咪唑基、吡啶基、吗啉代、哌啶子基、哌嗪基、噁唑基、吲哚基、苯并呋喃基或苯并噻吩基。
[100]更优选地,R3和R4其中之一或两者是t-BOC、异丁烯基、丁烯基、二甲基丙烯酰基、噻吩基、噻唑基或呋喃基。
[101]在实施方式(8)和(9)中,R2、R5和R6相同或不同,为H,杂环,或芳基醚、酯或氨基甲酸酯;或具有1到10个碳原子的直链、支链或环状烷基或链烯基的酯或醚;或式-COX的氨基甲酸酯,其中X是含氮杂环,如哌啶子基、吗啉代、哌嗪基、N-甲基哌嗪基;或式-CONR10R11的氨基甲酸酯,其中R10和R11相同或不同,为H,具有1到10个碳原子的直链、支链或环状烷基,或单纯的或取代的芳基。
[102]芳基醚、酯和氨基甲酸酯的优选例子包括苯基和萘基。
[103]烷基和链烯基酯的优选例子包括-COCH3、-COCH2CH3、丁烯基和二甲基丙烯酰基。烷基和链烯基醚的优选例子包括甲基、乙基、烯丙基、丙基、丁烯基和二甲基丙烯酰基。氨基甲酸酯的优选例子包括-CONHCH2CH3、-CO-吗啉代、-CO-哌嗪基或-CO-N-甲基哌嗪基。
[104]优选地,R6是H,R2和R5中的一个是H。
[105]在实施方式(5)中,R2是连接基团,而R5和R6的定义与实施方式(8)和(9)中的定义相同。
[106]在实施方式(6)中,R5是连接基团,而R2和R6的定义与实施方式(8)和(9)中的定义相同。
[107]在实施方式(7)中,R6是连接基团或H,而R2和R5的定义与实施方式(8)和(9)中的定义相同。
[108]在实施方式(8)中,R3是连接基团,而R4的定义与实施方式(5)、(6)和(7)中的定义相同。
[109]在实施方式(9)中,R4是连接基团,而R3的定义与实施方式(5)、(6)和(7)中的定义相同。
[110]合适的连接基团是本领域公知的,包括二硫基、硫醚基、酸不稳定基团、光不稳定基团、肽酶不稳定基团、以及酯酶不稳定基团。优选为二硫基或硫醚基。当连接基团为含硫醇或含二硫化物的基团时,带有硫醇基或二硫基的侧链可为直链或支链的烷基、链烯基、环烯基、芳香族的或杂环的、或聚乙二醇。本领域的普通技术人员可容易地确定合适的侧链。
[111]含有硫羟或二硫键的取代基具体例子包括:-(CR13R14)m(CR15R16)n(OCH2CH2)ySZ、-CO(CR13R14)m(CR15R16)n(OCH2CH2)ySZ、-(CR13R14)m(CR17=CR18)(CR15R16)mOCH2CH2)ySZ、-CO-(CR13R14)m(CR17=CR18)(CR15R16)m(OCH2CH2)ySZ、-CONR12(CR13R14)m(CR15R16)n(OCH2CH2)ySZ、呋喃基-XSZ、噁唑基-XSZ、噻唑基-XSZ、噻吩基-XSZ、咪唑基-XSZ、吗啉基-XSZ、-哌嗪基-XSZ、哌啶子基-XSZ、CO-呋喃基-XSZ、CO-噻吩基-XSZ、CO-噻唑基-XSZ和-CO-N-甲基哌嗪基-XSZ、-CO-吗啉代-XSZ、-CO-哌嗪基-XSZ、-CO-哌啶子基-XSZ、或-CO-N-甲基哌嗪基-XSZ,其中:
Z是H或SR,
[112]X是具有1-10个碳原子的直链烷基或支链烷基,或具有2到20个乙烯氧基重复单元的聚乙二醇间隔基;
R和R12相同或不同,为具有1到10个碳原子的直链烷基、支链烷基或环烷基,或单纯的或取代的芳基或杂环,且R12也可为H;
R13、R14、R15和R16相同或不同,为H或具有1-4个碳原子的直链或支链的烷基;
R17和R18为H或甲基;
n是一个整数,1到10;
m是一个从1到10的整数,也可为0;
y是一个从1到20的整数,也可为0。
[113]本发明的紫杉烷可按照已知的方法合成。合成的起始物质是商购的10-脱乙酰基浆果赤霉素III,如图7所示。引入各种取代基的化学方法在几个公开文献中有所描述(Ojima等,J.Med.Chem.39:3889-3896(1996),Ojima等,J.Med.Chem.40:267-278(1997);I.Ojima等,Proc.Natl.Acad.Sci.,96:4256-4261(1999);I.Ojima等,USP 5,475,011和USP5,811,452)。制备本发明中代表性紫杉烷的方法在下列的实施例中描述。
[114]可改变苯环上的取代基R1和取代基R1的位置,直至获得具有需要毒性的化合物。进一步地,可改变苯环上的取代程度,以获得需要的毒性。也就是说,苯环可以具有一个或多个取代基(如,苯环上进行单-,二-或三-取代),这为获得需要的毒性提供了另一种手段。高细胞毒性的定义是:当癌细胞暴露于药物达72小时后通过体外测定,表现出IC50值范围1×10-12到3×10-9M的毒性。本领域的技术人员可仅仅通过采用常规的实验即可确定R1的合适化学结构部分和R1的合适位置。
[115]举例来说,与母体紫杉烷相比,希望间位上的供电子基团提高细胞毒性效价,而不希望对位上的取代基提高效价。典型地,在一开始时合成制备取代基处于不同位置(邻、间、对位)的几种代表性紫杉烷,然后评价体外细胞毒性。
[116]图5和16中所示的新型紫杉烷可采用合适的衍生的浆果赤霉素III类似物(7)和β-内酰胺作为起始物质,由β-内酰胺合成纤维方法(Ojima,I.;Habus,I.;Zhao,M.;Zucco,M.;Park,Y.H.;Sun,C.M.;Brigaud,T.Tetrahedron,48:6985(1992);Holton,R.A.;Biediger,R.J.;Boatman,P.D.in Taxol:Science and Applications;Suffness,M.,Ed.;CRC:Boca Raton,1995,p.97)制备得到。β-内酰胺4-6d,19-25和38-44可由前述的方法制备得到(Brieva,R.Crich,J.Z.;Sih,C.J.J.Org.Chem.,58:1068(1993);Palomo,C.;Arrieta,A.;Cossio,F.;Aizpurua,J.M.;Mielgo,A.;Aurrekoetxea,N.Tetrahedron Lett.,1990,31,6429)。浆果赤霉素III类似物(7)可采用商购的10-脱乙酰基浆果赤霉素III(10-DAB)(图7)作为起始物质制备得到。
[117]β-内酰胺6a-d,21-25和40-44可在NaH或LiHMDS的存在条件下与浆果赤霉素III类似物(7)相偶合,得到受保护的紫杉烷8-11,26-30和45-49。在HF-吡啶的存在条件下对甲硅烷基保护基团最后进行去保护,生成所需的紫杉烷12-15,31-35和50-54(图16a、16b和16c)。
[118]本发明含有二硫化物的紫杉烷(图6,17)可从上述的中间体(8-11、26-30、45-49)合成。采用一水合肼(hydrazine monohydrate)可成功得除去C-10乙酸酯。然后在EDC(1-[3-(二甲基氨基)丙基-3-乙基碳化二亚胺盐酸)的存在条件下,采用要求的羧酸的二硫化物衍生物,利用基于碳化二亚胺的偶合机理,可对C-10位进行再酯化。可采用HF-吡啶使偶合的产物去保护,得到所需的含二硫化物的紫杉烷(图17a和17b)。
[119]也可将含有二硫化物或硫醇的取代基引入到已经存在羟基的某个其它位置上。保护各种羟基但使所需的那个羟基进行反应的化学方法在现有技术中已有描述(例如参见前述引用的参考文献,参见上文)。通过简单地将游离的羟基转换为含有二硫化物的醚,含有二硫化物的酯,或含有二硫化物的氨基甲酸酯,可引入取代基。或者,可在二硫化物或硫醇取代基与正在被衍生化的羟基基团之间引入聚乙二醇间隔基(spacer)(如参见2002年5月14日递交的USAN 10/144,042)。按照下述方法完成该转化。按照上述I.Ojima等的文献的方法,在-40℃下采用处于四氢呋喃中的商购试剂六甲基二硅氮烷锂(lithium hexamethyldisilazane)(1.2当量)处理,使所需的羟基进行脱质子化,参见上文。然后将得到的醇盐阴离子与过量的二卤化合物如二溴乙烷反应,得到卤代醚(halo ether)。采用硫醇代替卤素(通过与硫代乙酸钾进行反应和用弱碱或羟基胺进行处理),得到所需的含硫醇的紫杉烷。通过与甲基硫代磺酸甲烷(methylmethane thiolsulfonate)或与二硫代二吡啶(dithiodipyridine)分别反应,可将硫醇基团转化为甲基或吡啶二硫化物(pyridyl disulfide)。该方法在USP 5,416,064中有所描述。
[120]也可通过直接与酰卤,如3-溴基丙酰氯进行反应使所需的羟基酯化,生成溴代酯。通过用硫代乙酸钾处理来替代溴基,然后按照上述的方法进行,将获得含有硫醇或二硫化物的紫杉烷。为制备含有二硫化物的氨基甲酸酯,可使羟基和商购的氯甲酸酯,如对-硝基苯基氯甲酸酯(para-nitrophenyl chloroformate)进行反应,然后与氨基烷基二硫化物(amino alkyl disulfide)(如甲基二硫代半胱胺)进行反应。
[121]或者,可将硫醇或二硫化物取代基并入β-内酰胺亚单元中,然后与合适的受保护的10-脱乙酰基浆果赤霉素III反应,得到在C-3’位上具有硫醇或二硫化物连接基团的所需紫杉烷。
[122]可评价本发明的新型紫杉烷和含有二硫化物的紫杉烷药物在体外抑制人癌细胞系的增殖的能力。采用人类癌细胞系A-549(人类肺癌)和MCF-7(人类乳腺肿瘤)以评价这些化合物的细胞毒性。将细胞暴露于化合物中达72小时,按照前述的直接植板率试验(direct plating efficiencyassays)(Goldmacher等,J.Cell.Biol.102:1312-1319(1986))测定细胞的存活分数(surviving fraction),然后从这些数据计算出IC50值。
[123]本发明第二方面中紫杉烷和含二硫化物的紫杉烷的体外细胞毒性测定结果如图18和19所示。图18示出了本发明12种新型紫杉烷的细胞毒性测定结果。除了在R4处具有苯基取代基的紫杉烷52之外,所有其它的新型紫杉烷对A-549和MCF-7细胞系都特别有效力,IC50值的范围为10-10到10-11M。紫杉烷52的毒性较小,对所测试的两种细胞系的IC50值都为3×10-9M。类似地,本发明中含二硫化物的紫杉烷对A-549和MCF-7细胞也特别有效力,表现出陡峭的杀死曲线(图19)。
[124]本发明化合物作为治疗剂的效能取决于对合适的细胞结合剂的仔细选择。细胞结合剂可为现在已知的或即将变为已知的任何种类,包括肽类和非肽类。一般地,细胞结合剂可为抗体或抗体片段(尤其是单克隆抗体)、淋巴因子、激素、生长因子、维生素、营养转运分子(如转铁蛋白),或任何其它的细胞结合分子或物质。
[125]可采用的细胞结合剂的更多具体例子包括:
-抗体片段,如sFv、Fab、Fab’和F(ab’)2(Parham,J.Immunol.131:2895-2902(1983);Spring等,J.Immunol.113:470-478(1974);Nisonoff等,Arch.Biochem.Biophys.89:230-244(1960));
-干扰素(如α、β、γ);
-淋巴因子,如IL-2、IL-3、IL-4、IL-6;
-激素,如胰岛素、TRH(促甲状腺素释放激素)、MSH(促黑素细胞激素),甾类激素,例如雄激素和雌激素;
-维生素,如叶酸;
-生长因子和集落刺激因子,如EGF、TGF-α、G-CSF、M-CSF和GM-CSF(Burgess,Immunology Today 5:155-158(1984));以及
-转铁蛋白(O′Keefe等,J.Biol.Chem.260:932-937(1985))。
[126]单克隆抗体技术允许以特异性单克隆抗体或其片段的形式制备特异性很高的细胞结合剂。本领域中尤其公知的是通过采用感兴趣的抗原如完整的靶细胞、从靶细胞分离出的抗原、全病毒、减毒的全病毒、以及病毒蛋白如病毒外壳蛋白来免疫小鼠、大鼠、仓鼠或任何其它哺乳动物,从而生成单克隆抗体或其片段的技术。致敏人细胞也可使用。生成单克隆抗体或其片段的其它方法是采用sFv(单链可变区),尤其是人类sFv的噬菌体库(如参见Griffiths等,USP 5,885,793;McCafferty等,WO92/01047;Liming等,WO 99/06587)。
[127]选择合适的细胞结合剂是取决于将被靶向的特定细胞群的一种选择,但是,如果可以得到,则一般来说优选单克隆抗体。
[128]例如,单克隆抗体MY9是特异性结合到CD33抗原的鼠IgG1抗体(J.D.Griffin等,Leukemia Res.,8:521(1984)),其可在靶细胞表达CD33的情况下,如在急性骨髓性白血病(AML)的情况下使用。类似地,单克隆抗体抗-B4是结合到B细胞上CD19抗原的鼠IgG1(Nadler等,J.Immunol.131:244-250(1983)),其可在靶细胞是B细胞或表达该抗原的疾病状态细胞的情况下,例如在非-何杰金氏淋巴瘤或淋巴性白血病的情况下使用。类似地,抗体N901是结合到在小细胞肺癌细胞或神经内分泌源的其他肿瘤细胞上发现的CD56上的鼠单克隆IgG1抗体(Roy等,J.Nat.Cancer Inst.88:1136-1145(1996))。
[129]靶向实体肿瘤的抗体也是有用的,例如结合到在存在于胰腺和结肠肿瘤上的MUC1上发现的糖类抗原上的C242抗体(USP 5,552,293);结合到在前列腺癌细胞和在肿瘤中脉管系统的内皮细胞上表达的PSMA(前列腺特异性膜抗原)上抗体J591(USP 6,107,090,He Liu等,Cancer Res.57:3629-3634(1997);以及在某些乳腺肿瘤上过度表达的对HER-2的抗体。抗-HER-2抗体的例子有TA1抗体(L.A.Maier等,Cancer Res.51:5361-5369(1991))和4D5抗体(USP 6,387,371和6,399,063)。
[130]此外,结合到骨髓细胞的GM-CSF可用作急性骨髓性白血病的疾病状态细胞的细胞结合剂。结合到活性T-细胞的IL-2可用于防止移植排斥,治疗和防止移植物抗宿主病(graft-versus-host disease),以及治疗急性T细胞白血病。与黑色素细胞相结合的MSH可用于治疗黑素瘤。靶向在卵巢癌或其它癌上表达的叶酸受体的叶酸,也是一种合适的细胞结合剂。
[131]可分别采用雌激素(或雌激素类似物)或雄激素(或雄激素类似物)作为细胞结合剂成功地靶向乳腺癌或睾丸癌。
[132]采用现在已知的或以后开发的任何技术,可形成本发明的紫杉烷与细胞结合剂的共轭物。USP 5,416,064和USP 5,475,092中教导了共轭作用的多种方法。可对紫杉烷的酯进行修饰而产生游离的氨基,然后通过对酸不稳定的连接物或对光不稳定的连接物将其连接到抗体或其它的细胞结合剂上。紫杉烷的酯可与肽进行缩合,随后连接到细胞结合剂上,产生对肽酶不稳定的连接物。紫杉烷的酯上的羟基可琥珀酰化并连接到细胞结合剂上而得到共轭物,该共轭物可被细胞内酯酶分裂而释放出游离药物。最优选地,对紫杉烷的醚、酯或氨基甲酸酯进行处理,以生成游离的或受保护的硫醇基团,然后将含有二硫化物或硫醇的紫杉烷通过二硫键连接到细胞结合剂上。
[133]本发明代表性的共轭物有抗体-紫杉烷、抗体片段-紫杉烷、表皮生长因子(EGF)-紫杉烷、促黑素细胞激素(MSH)-紫杉烷、促甲状腺激素(TSH)-紫杉烷、雌激素-紫杉烷、雌激素类似物-紫杉烷、雄激素-紫杉烷,雄激素类似物-紫杉烷,以及叶酸-紫杉烷。
[134]采用已知的方法以相同的方式制备紫杉烷与抗体、抗体片段、蛋白或肽激素、蛋白或肽生长因子以及其它蛋白质的共轭物。例如,可采用交联剂如N-琥珀酰亚胺基3-(2-吡啶二硫代)丙酸酯、N-琥珀酰亚胺基4-(2-吡啶二硫代)戊酸酯(SPP)、4-琥珀酰亚胺基-氧化羰基-α-甲基-α-(2-吡啶二硫代)-甲苯(SMPT)、N-琥珀酰亚胺基-3-(2-吡啶二硫代)丁酸酯(SDPB)、2-亚氨基硫醇(iminothiolane)或S-乙酰基琥珀酸酐通过已知的方法对肽和抗体进行修饰,参见Carlsson等,Biochem.J.173:723-737(1978);Blattler等,Biochem.24:1517-1524(1985);Lambert等,Biochem.22:3913-3920(1983);Klotz等,Arch.Biochem.Biophys.96:605(1962);以及Liu等,Biochem.18:690(1979),Blakey和Thorpe,Antibody,Immunoconjugates & Radiopharmaceuticals,1:1-16(1988);Worrell等,Anti-Cancer Drug Design 1:179-184(1986)。由此产生的含有游离的或受保护的硫醇的细胞结合剂然后与含二硫化物或硫醇的紫杉烷反应得到共轭物。可通过HPLC或凝胶过滤法纯化该共轭物。
[135]类似地,例如,可采用二环己基碳二亚胺作为缩合剂,使雌性激素和雄性激素细胞结合剂如雌二醇或雄烷二醇在C-17羟基基团处与合适的含二硫键的羧酸进行酯化。可利用的这类羧酸的例子有3-(2-吡啶二硫代)丙酸、3-甲基二硫代丙酸、4-(2-吡啶二硫代)戊酸,以及3-苯基二硫代丙酸。通过与含有受到适当保护的含硫醇基团的羧酸酰氯,如3-S-乙酰丙酰氯相反应,也可使C-17处的羟基进行酯化。也可利用文献(Haslam,Tetrahedron 36:2409-2433(1980))中公开的其他酯化方法。含有游离的或受保护的硫醇的雌激素或雄激素然后可与含二硫化物或硫醇的紫杉烷反应生成共轭物。可通过采用了硅胶的柱色谱法或HPLC法纯化共轭物。叶酸可与合适的酰肼,如4-(2-吡啶二硫代)戊酸酰肼在缩合剂如二环己基碳二亚胺存在的条件下缩合,得到含有活性二硫化物的腙。含有二硫化物的叶酸然后可与含有硫醇的紫杉烷反应生成共轭物,该共轭物可通过采用了硅胶的柱色谱或通过HPLC进行纯化。
[136]优选地,单克隆抗体-或细胞结合剂-紫杉烷共轭物是通过如上所述的能传递紫杉烷分子的二硫键进行连接的共轭物。这类细胞结合剂共轭物通过已知的方法制备,如采用琥珀酰亚胺吡啶-二硫代丙酸酯(SPDP)进行修饰(Carlsson等,Biochem.J.173:723-737(1978))。然后用含有硫醇的紫杉烷处理而替代得到的硫代吡啶基团,得到二硫化物连接的共轭物。或者,在芳基二硫代(aryldithio)-紫杉烷的情况下,通过预先引入到抗体分子中的硫氢基直接替代紫杉烷的芳基-硫醇,从而实现细胞结合剂共轭物的形成。易于通过任何一种方法制备得到含有1到10个通过二硫桥键连接的紫杉烷药物的共轭物。
[137]更具体地,用含有硫醇的紫杉烷(1.25摩尔当量/二硫代吡啶基)处理溶于pH为6.5,含有1mM EDTA的0.1M磷酸钾缓冲液中浓度为1mg/ml的二硫吡啶基(dithiopyridyl)修饰的抗体溶液。在343nm下用分光光度法监测硫代吡啶从修饰的抗体上释放出来,该释放过程在约20小时内完成。采用SephadexG-25或Sephacryl S300柱进行凝胶过滤,从而纯化抗体-紫杉烷共轭物,除去未反应的药物和其它低分子量的物质。通过测定在230nm和275nm处的吸光度比率,可确定每抗体分子上结合的紫杉烷部分的数目。采用这种方法可通过二硫键连接平均数目为1到10个的紫杉烷分子/抗体分子。
[138]也可制备具有不可断裂的连接的抗体-紫杉烷共轭物。可采用交联剂如N-琥珀酰亚胺基4-(马来酰亚胺甲基)环己烷-1-羧酸酯(SMCC)、磺基-SMCC、N-琥珀酰亚胺基4-马来酰亚胺丁酸酯(SMB)、磺酸基-SMB、N-琥珀酰亚胺基6-马来酰亚胺己酸酯(SMC)、磺基-SMC、间-马来酰亚胺基苯甲酰基-N-羟基琥珀酰亚胺基酯(MBS)、磺基-MBS或琥珀酰亚胺基-碘代乙酸酯按照文献中所述的方法引入1-10个活性基团,从而对抗体进行修饰。参见Yoshitake等,Eur.J.Biochem.101:395-399(1979);Hashida等,J.Applied Biochem.6:56-63(1984);以及Liu等,Biochem.18:690-697(1979)。修饰的抗体然后与含有硫醇的紫杉烷衍生物进行反应,生成共轭物。采用Sephadex G-25柱进行凝胶过滤,从而纯化共轭物。
[139]用含硫醇的紫杉烷(1.25摩尔当量/马来酰亚胺基团)处理修饰的抗体或其片段。混合物在约4℃下温育过夜。采用Sephadex G-25柱进行凝胶过滤,从而纯化抗体-紫杉烷共轭物。通常,平均每个抗体上连接1到10个紫杉烷。
[140]优选的方法是采用琥珀酰亚胺-4-(马来酰亚胺基甲基)-环己烷-1-羧酸酯(SMCC)引入马来酰亚胺基团而修饰抗体或其片段,然后使修饰的抗体或片段与含硫醇的紫杉烷进行反应,得到硫醚连接的共轭物。结果也是获得了每个抗体分子具有1到10个药物分子的共轭物。
[141]可采用如Goldmacher等,J.Immunol.135:3648-3651(1985)中所述的细胞增殖曲线的反向外推法(back-extrapolation),可测定这些紫杉烷的抗体共轭物对非粘附细胞系如Namalwa和HL-60的细胞毒性。这些化合物对粘附细胞系如SKBR3和A431的细胞毒性可采用如Goldmacher等,J.Cell Biol.102:1312-1319(1986)中所述的克隆源性分析试验(clonogenic assay)进行测定。
[142]本发明还提供了治疗组合物,包括:
(a)有效量的一种或多种连接到细胞结合剂的紫杉烷,以及
(b)药学上可接受的载体、稀释剂或赋形剂。
[143]类似地,本发明提供了在所选择的细胞群中诱导细胞死亡的方法,包括使靶细胞或含有靶细胞的组织与有效量的细胞毒性剂相接触,其中的细胞毒性剂含有一种或多种连接到细胞结合剂的紫杉烷。
[144]细胞毒性剂的制备如上所述。
[145]合适的药学上可接受的载体、稀释剂和赋形剂是公知的,可由本领域的技术人员以临床情况为据而确定。
[146]合适的载体、稀释剂和/或赋形剂的例子包括:(1)Dulbecco’s磷酸盐缓冲盐水,pH约为7.4,含有或不含约1mg/ml至25mg/ml的人类血清白蛋白;(2)0.9%盐水(0.9%w/v NaCl),以及(3)5%(w/v)右旋糖;还可含有抗氧化剂如色胺和稳定剂如吐温20。
[147]诱导所选择的细胞群中的细胞死亡的方法可在体外、体内、或离体进行。
[148]体外应用的例子包括在移植到同一病人的体内之前,对自体骨髓进行处理以杀死疾病状态的或恶性细胞:移植之前处理骨髓,以杀死感受态的T细胞,并防止移植物抗宿主疾(GVHD);处理细胞培养物以杀死除未表达靶抗原的所需变体之外的所有细胞;或杀死表达不希望的抗原的变体。
[149]本领域的普通技术人员容易确定体外应用的非临床条件。
[150]临床离体应用的例子是在癌症治疗或自免疫疾病治疗中,进行自体移植之前将癌细胞或淋巴样细胞从骨髓中去除,或在进行移植之前从自体的或异体(allogenic)的骨髓中去除T细胞或其它淋巴样细胞,以防止GVHD。治疗按如下进行。从病人或其它个体收集骨髓,然后在约37℃下于加入了浓度为10μM到1pM的本发明细胞毒性剂的含血清介质中温育约30分钟。本领域的普通技术人员易于确定温育的浓度和时间,即剂量的确切条件。在温育之后,用含有血清的介质洗涤骨髓细胞,采用已知的方法使骨髓细胞由静脉内返回到病人体内。在病人接受其它治疗,如在收集骨髓和重新灌注处理过的细胞之间的期间内接受烧蚀化疗(ablative chemotherapy)或全身放疗(total-body irradiation)的情况下,采用标准的医疗器械在液氮中储存处理过的骨髓细胞。
[151]对于临床体内应用,本发明的细胞毒性剂以作为测定无菌度和内毒素水平的溶液或冻干粉末而提供。共轭物给药的合适方法的例子如下。共轭物作为静脉推注剂给药,每周一次,为期4周。给药的推注剂量为,在50到100ml标准盐水中可加入5到10ml人类血清白蛋白。每次静脉内给药的剂量将为10μg到2000mg(每天给药的剂量范围为100ng到20mg/kg)。治疗4周之后,病人可继续接受每周一次的治疗。本领域的普通技术人员以临床情况为据,可确定关于给药路线、赋形剂、稀释剂、剂量、时间等的具体临床方案。
[152]根据在所选择的细胞集落中诱导细胞死亡的体内或离体方法可治疗的医学病症的例子包括任何种类的恶性情况,包括如肺癌、乳腺癌、结肠癌、前列腺癌、肾癌、胰腺癌、卵巢癌和淋巴器官癌;自免疫性疾病,如系统性狼疮、风湿性关节炎和多发性硬化;移植排斥,如肾移植排斥、肝移植排斥、肺移植排斥、心脏移植排斥和骨髓移植排斥;移植物抗宿主病;病毒感染,如CMV感染、HIV感染、AIDS等;以及寄生虫感染,如贾第鞭毛虫病、阿米巴病、血吸虫病,以及其它本领域普通技术人员可确定的疾病。
实施例
[153]现在通过参照非限制性的实施例对本发明进行举例说明。在未另外指出的情况下,所有的百分比、比率、份数等都以重量表示。
实施例1
紫杉烷2’的制备
[154]按照图8所示的方案,由商购的10-脱乙酰基浆果赤霉素(图7)制备紫杉烷2’(3’-脱苯基(dephenyl)-3’-(异丁烯基)-7-(甲基二磺酰基-丙酰基)-多西紫杉醇)。
[155]按照Greene等在J.Am.Chem.Soc.110:5917-5919(1988)和Ojima等,J.Med.Chem.39:3889-3896(1996)以及本文中引用的参考文献中所述的方法制备化合物4-6’
[156]在室温下,通过向溶于乙醇(2ml)的化合物6’(65mg,0.059mmol)的溶液中加入一水合肼(1mL),制备化合物7’(7-(三乙基甲硅烷基(triethylsilyl)))-2’-(三异丙基甲硅烷氧基(triisopropylsilyloxy))-3’-脱苯基-3’-(异丁烯基)-多西紫杉醇)。在室温下搅拌反应,通过采用40%溶于己烷的乙酸乙酯的薄层色谱法进行监测。1小时后薄层色谱监测到反应完成,用氯化铵饱和水溶液(10ml)淬灭反应。用乙酸乙酯(10ml×3)萃取水层。用无水硫酸镁干燥合并的萃取物,并在真空下浓缩。在采用40%溶于己烷的乙酸乙酯作为洗脱剂的硅胶柱上纯化残留物,得到白色固体产物7’(42mg,69%):1H NMR(CDCl3)δ0.53(m,6H),0.92(t,J=8.0Hz,9H),1.11(m,24H),1.20(s,3H),1.23(s,3H),1.32(s,9H),1.71(s,3H),1.72(m,3H),1.78(s,3H),1.92(m,4H),2.35(m,5H),3.89(d,J=6.8Hz,1H),4.18(d,J=8.4Hz,1H),4.23(d,J=2.0Hz,1H),4.28(d,J=8.4Hz,1H),4.37(dd,J=6.4,10.4Hz,1H),4.41(d,J=3.2Hz,1H),4.80(m,2H),4.91(d,J=8.0Hz,1H),5.10(d,J=2.0Hz,1H),5.31(d,J=8.8Hz,1H),5.63(d,J=7.2Hz,1H),6.13(t,J=9.0Hz,1H),7.43(t,J=8.0Hz,2H),7.57(t,J=8.0Hz,1H),8.07(d,J=8.0Hz 2H)。对C56H89NO14Si2Na+的m/z LC/MS分析结果是:计算值为1078.58;实测值为1078.40。
[157]按照以下的步骤制备化合物8’(2’-(三异丙基甲硅氧基)-3’-脱苯基-3’-(异丁基)-多西紫杉醇)。在0℃下加入溶于乙醇(5ml)的0.1N HCl溶液,制备化合物7’(35mg,0.029mmol)的溶液。对溶液进行搅拌,同时逐渐升温到室温,允许搅拌16小时。用碳酸氢钠的饱和水溶液(10ml)淬灭反应,并以乙酸乙酯(15ml×3)萃取水层。用无水硫酸镁干燥合并的萃取物,并在真空下浓缩。在采用了溶于己烷的50%乙酸乙酯作为洗脱剂的硅胶柱上纯化残留物,得到产物8’,其为白色固体(20mg,64%):δ1.11(m,24H),1.23(s,3H),1.26(s,3H),1.30(s,9H),1.74(s,6H),1.79(s,3H),1.84(m,1H),1.92(s,3H),2.36(s,3H),2.38(m,1H),2.57(m,1H),3.92(d,J=6.8Hz,1H),4.17(d,J=1.2Hz,1H),4.22(d,J=8.0Hz,1H),4.23(m,1H),4.31(d,J=8.0Hz,1H),4.42(d,J=2.8Hz,1H),4.75(m,1H),4.85(m,1H),4.95(d,J=7.6Hz,1H),5.20(s,1H),5.33(d,J=8.8Hz,1H),5.68(d,J=7.2Hz,1H),6.14(t,J=8.8Hz,1H),7.46(t,J=8.0Hz,2H),7.60(t,J=8.0Hz,1H),8.10(d,J=8.0Hz 1H)。
[158]按照下列步骤制备化合物9’(2’-(三异丙基甲硅氧基)-3’-脱苯基-3’-(异丁烯基)-7-(甲基二氨磺酰基-丙酰基)-多西紫杉醇)。向溶于二氯甲烷(3mL)的化合物8’(20mg,0.020mmol)的溶液中加入DMAP(3mg,0.02mmol)、二硫代羧酸(3mg,0.018mmol)和EDC(8mg,0.042mmol)。搅拌得到的混合物过夜。采用了溶于己烷的25%乙酸乙酯的薄层色谱法分析实际上表明所有的原料都已消耗完毕,出现了一个新的色谱斑。用氯化铵的饱和水溶液(10ml)淬灭反应,在二氯甲烷中进行萃取(10ml×3)。用无水硫酸镁干燥合并的萃取相,并在真空下浓缩。在采用了溶于己烷的25%乙酸乙酯作为洗脱剂的硅胶柱上纯化残留物,得到化合物9’,其为白色固体(9mg,41%):1H NMR(CDCl3)δ1.11(m,24H),1.22(s,3H),1.34(s,9H),1.76(s,3H),1.80(s,3H),1.85(s,3H),1.95(m,4H),2.36(s,3H),2.41(m,1H),2.42(s,3H),2.54(m,1H),2.70(t,J=7.2Hz,2H),2.88(m,2H),3.93(br s,1H),4.04(d,J=7.2Hz,1H),4.24(d,J=8.8Hz,1H),4.33(d,J=8.8Hz,1H),4.43(d,J=2.8Hz,1H),4.77(m,1H),4.86(m,1H),4.94(d,J=8.0Hz,1H),5.32(m,2H),5.54(dd,J=6.8,10.4Hz,1H),5.69(d,J=7.2Hz,1H),6.13(t,J=8.8Hz,1H),7.47(t,J=8.0Hz,2H),7.61(t,J=8.0Hz,1H),8.10(d,J=8.0Hz 1H)。对C54H81NO15S2SiNa+的m/z LC/MS分析结果是:计算值为1098.48,实测值为1098.28。
[159]按照下列步骤制备紫杉烷2’(3’-脱苯基-3’-(异丁烯基)-7-(甲基二磺酰基-丙烷基)-多西紫杉醇)。在0℃下向溶于吡啶-乙腈(1/1,2mL)的化合物9’(9mg,0.008mmol)的溶液中加入HF/吡啶(70∶30,0.1mL),搅拌混合物24小时,同时逐步升温到室温。用碳酸氢钠饱和水溶液淬灭反应。然后用乙酸乙酯(5mL×2)稀释反应混合物,用水(5mL)洗涤合并的有机层,用无水硫酸钠干燥,并在真空下浓缩。在采用溶于己烷的60%乙酸乙酯作为洗脱剂的硅胶柱上纯化残留物,得到最终的产物2’,其为白色固体(5mg,64%):1H NMR(CDCl3)δ1.10(s,3H),1.21(s,3H),1.36(s,9H),1.56(s,3H),1.77(s,6H),1.86(s,3H),1.94(m,1H),1.97(s,3H),2.35(m,1H),2.37(s,3H),2.42(s,3H),2.56(m,1H),2.70(t,J=7.2Hz,2H),2.88(dd,J=2.4,6.8Hz,2H),3.36(br d,J=4.8Hz,1H),3.95(d,J=3.2Hz,1H),4.01(d,J=6.8Hz,1H),4.23(m,2H),4.33(d,J=8.4Hz,1H),4.77(m,2H),4.94(d,J=7.6Hz,1H),5.31(m,1H),5.32(d,J=1.6Hz,1H),5.51(dd,J=7.2,10.8Hz,1H),5.68(d,J=7.2Hz,1H),6.16(t,J=9.0Hz,1H),7.48(t,J=8.0Hz,2H),7.62(t,J=8.0Hz,1H),8.11(d,J=8.0Hz 1H)。对C45H61NO15S2Na+的m/z LC/MS分析结果是:计算值为942.35,实测值为942.47。
实施例2
制备紫杉烷3’
[160]按照图9所示的路线,从化合物10’出发制备紫杉烷3’(3’-脱苯基-3’-(异丁烯基)-2-脱苯甲酰基-2-(2,5-二甲氧基苯甲酰基)-7-(甲基二磺酰基-丙烷基)-多西紫杉醇)。
[161]由下列步骤制备化合物10’(7-(三乙基甲硅烷基)-2’-(三异丙基甲硅氧基)-3’-脱苯基-3’-(异丁烯基)-2-脱苯甲酰基-2-(2,5-二甲氧基苯甲酰基)-多西紫杉醇)。在室温下向溶于乙醇(1.5mL)的化合物9’(36mg,0.031mmol)的溶液中加入一水合肼(1mL)。在室温下搅拌反应,由采用了溶于己烷的40%乙酸乙酯的薄层色谱法监测反应(展开两次)。1小时后薄层色谱监测到反应完成,用氯化铵饱和水溶液(10mL)淬灭反应。用乙酸乙酯(10ml×3)萃取水层。用无水硫酸镁干燥合并的有机层,并在真空下浓缩。在采用了溶于己烷的35%乙酸乙酯作为洗脱剂的硅胶柱上纯化残留物,得到脱乙酰化的产物10’,其为白色固体(19mg,57%):1H NMR(CDCl3)δ0.56(m,6H),0.92(t,J=8.0Hz,9H),1.11(m,27H),1.22(s,3H),1.23(s,3H),1.38(m,10H),1.69(s,3H),1.72(m,3H),1.78(s,3H),1.89(s,3H),1.93(m,1H),2.18(s,3H),2.32(m,1H),2.44(m,2H),3.81(s,3H),3.82(d,J=6.8Hz,1H),3.96(s,3H),4.25(d,J=2.0Hz,1H),4.29(d,J=8.0Hz,1H),4.34(dd,J=6.4,10.4Hz,1H),4.39(d,J=2.0Hz,1H),4.42(d,J=8.0Hz,1H),4.76(t,J=9.2Hz,1H),4.89(m,2H),5.11(d,J=2.0Hz,1H),5.34(d,J=8.8Hz,1H),5.64(d,J=6.4Hz,1H),6.13(t,J=9.0Hz,1H),6.94(d,J=9.2Hz,1H),7.06(dd,J=9.2,3.2Hz,1H),7.29(d,J=2.8Hz 1H)。对C58H93NO16Si2Na+的m/z LC/MS结果是:计算值为1138.60,实测值为1138.43。
[162]按照下列步骤制备化合物11’(2’-(三异丙基甲硅氧基)-3’-脱苯基-3’-(异丁烯基)-2-脱苯甲酰基-2-(2,5-二甲氧基苯甲酰基)-多西紫杉醇)。在0℃下向化合物10’(86.4mg,0.0774mmol)中加入溶于乙醇(9.0mL)的5%盐酸溶液。在N2气氛下搅拌混合物,升温至室温。5小时后用碳酸氢钠饱和水溶液淬灭反应,在乙酸乙酯(25mL×2)中进行萃取。然后用水(25mL×2)洗涤合并的乙酸乙酯层,用无水硫酸镁干燥,并在真空中浓缩。在采用溶于己烷中的50%乙酸乙酯作为洗脱剂的硅胶柱上纯化粗的残留物。分离出产物11’,其为白色固体(61.5mg,79%):1H NMR(CDCl3)δ1.08(s,27H),1.23(s,3H),1.36(s,9H),1.58(m,1H),1.67(s,3H),1.70(s,3H),1.76(s,3H),1.82(m,2H),1.88(s,3H),2.16(s,3H),2.31(m,1H),2.50(m,2H),3.17(br s,1H),3.79(s,3H),3.85(d,J=6.4Hz,1H),3.95(s,1H),4.18(m,2H),4.29(d,J=8.4Hz,1H),4.37(d,J=2Hz,1H),4.41(d,J=8.4Hz,1H),4.74(t,J=9Hz,1H),4.90(t,J=9.8Hz,2H),5.17(d,J=1.6Hz,1H),5.32(d,J=9.2Hz,1H),5.65(d,J=6.8Hz,1H),6.10(t,J=8.8Hz,1H),6.93(d,J=9.2Hz,1H),7.05(dd,J=9.2,3.0Hz,1H),7.28(d,J=3.0Hz,1H)。对C52H79NO16SiNa+的m/z LC/MS分析结果是:计算值为1024.52,实测值为1024.31。
[163]按照下列步骤制备化合物12’(2’-(三异丙基甲硅氧基)-3’-脱苯基-3’-(异丁烯基)-2-脱苯甲酰基(debenzoyl)-2-(2,5-二甲氧基苯甲酰基((dimethoxybenzoyl))-7-(甲基二磺酰基-丙酰基)-多西紫杉醇)。向溶于二氯甲烷(0.8mL)的化合物11’(25mg,0.025mmol)、EDC(10mg,0.05mmol)和DMAP(3mg,0.025mmol)的溶液中加入溶于二氯甲烷(4.0mL)的甲基二硫代丙酸(3.6mg,0.024mmol)溶液。在室温下于N2气氛中搅拌反应5小时。用氯化铵饱和水溶液淬灭反应,在二氯甲烷(25mL×2)中进行萃取。用水(15mL×1)洗涤合并的有机层,通过无水硫酸镁进行干燥,并在真空下浓缩。在采用了溶于己烷的30%乙酸乙酯作为洗脱剂的硅胶柱上纯化残留物,得到产物12’(21.3mg,75%):1H NMR(CDCl3)δ1.12(s,27H),1.23(s,6H),1.37(s,9H),1.68(s,3H),1.72(s,3H),1.88(s,3H),1.93(s,3H),2.17(s,3H),2.41(s,3H),2.69(t,J=6.8Hz,2H),2.86(m,2H)3.22(br s,1H),3.80(s,3H),3.95(m,4H),4.31(d,J=8.0Hz,1H),4.38(d,J=2.4Hz,1H),4.45(d,J=8.4Hz,1H),4.76(t,J=9.8Hz,1H),4.90(m,2H),5.29(s,1H),5.34(d,J=9.2Hz,1H),5.48(dd,J=7.2,10.8Hz,1H),5.66(d,J=6.4Hz,1H),6.11(t,J=8.8Hz,1H),6.95(d,J=9.2Hz,1H),7.06(dd,J=3.2,9.2Hz,1H),7.28(d,J=3.2Hz,1H)。对C56H85NO17S2SiNa+的m/z LC/MS分析结果是:计算值为1158.50,实测值为1158.33。
[164]按照下列的步骤制备紫杉烷3’(3’-脱苯基-3’-(异丁烯基)-2-脱苯甲酰基-2-(2,5-二甲氧基苯甲酰基)-7-(甲基二磺酰基-丙酰基)-多西紫杉醇)。在N2气氛下,将化合物12’(27.6mg,0.0243mmol)溶解于吡啶-乙腈(1/1,2.0mL)中。在0oC℃下加入HF/吡啶(70∶30,0.28mL),搅拌反应24小时,同时升温至室温。用碳酸氢钠饱和水溶液淬灭反应,然后在乙酸乙酯(30mL×3)中进行萃取。依次用另外的碳酸氢钠饱和水溶液(25mL×1)和硫酸铜饱和水溶液(25mL×3)洗涤合并的有机层。用水(25mL×1)洗涤合并的有机层,用无水硫酸镁干燥,然后在真空下浓缩。在采用溶于己烷的50%乙酸乙酯作为洗脱剂的硅胶柱上纯化粗的残留物,得到化合物3’(19.7mg,82.8%):1H NMR(CDCl3)δ1.25(s,6H),1.38(s,9H),1.69,(s,3H),1.74(s,3H),1.87(s,3H),1.94(s,3H),2.18δ(s,3H),2.41(s,3H),2.68(t,J=6.8Hz,2H),2.86(m,2H),3.12(br s,1H),3.29(d,J=6.4Hz,1H),3.80(s,3H),3.92(m,4H),4.16(d,J=2.0,6.4Hz,1H),4.30(d,J=8.0Hz,1H),4.43(d,J=8.4Hz,1H),4.75(m,2H),4.90(d,J=8.0Hz,1H),5.29(s,1H),5.33(d,J=8.0Hz,1H),5.46(dd,J=7.2,10.8Hz,1H),5.65(d,J=6.4Hz,1H),6.14(t,J=8.8Hz 1H),6.95(t,J=9.2Hz,1H),7.06(dd,J=3.2,9.2Hz,1H),7.28(d,J=3.2Hz,1H)。对C47H65NO17S2Na+的m/z LC/MS分析结果是:计算值为1002.37,实测值为1001.99。
实施例3
体外细胞毒性分析试验
[165]可评价本发明含硫化物、二硫化物和氢硫基的紫杉烷体外抑制各种人类癌细胞系增生的能力。采用四种粘附细胞系A431(人类表皮样癌)、SKBR3(人类乳腺肿瘤)、A549(人类肺癌)和MCF-7(人类乳腺肿瘤),以及非粘附细胞系Namalwa(Burkitt’s淋巴瘤)评价这些化合物的细胞毒性。将细胞暴露到化合物中达72小时,采用直接测定法测定细胞的存活分数。测定A431、SKBR3、A549和MCF-7的植板率(Goldmacher等,J.Cell.Biol.102:1312-1319(1986)),用生长反向外推法(growth backextrapolation)测定Namalwa(Goldmacher等,J.Immunol.135:3648-3651(1985))。然后由这些数据计算出IC50值。
[166]对紫杉烷2‘和3’的细胞毒性值的测定如下。
[167]以不同的密度将A431、A549和MCF-7细胞平板接种到处于补充了10%胎牛血清的DMEM介质的6-孔组织培养皿中。加入浓度不同的紫杉烷2’,使细胞在37℃下保持在潮湿的空气和6%的CO2中,直到形成约20个细胞或20个细胞以上的集落(6到10天)。对照的培养皿中不含紫杉烷。然后用甲醛固定化细胞,用结晶紫染色并在低放大倍率的显微镜下计数。由集落的数目确定植板率,计算细胞的存活分数,存活分数为被处理样品的植板率和对照组的植板率的比值。
[168]图10示出了细胞毒性的测定结果。在C-10上具有游离羟基而在C-7上具有连接基团的紫杉烷2’对A431细胞具有高效价,IC50值为8×10-10M。相反,在C-10上具有酯基的紫杉烷1’(图3)甚至在3×10-9M浓度下对这些细胞也无毒性。这些结果表明紫杉烷的C-10位上无需受到保护也能保持高效价。
[169]可类似地证实紫杉烷3’的细胞毒性效价。以不同的密度将A549和MCF-7细胞平板接种到处于补充了10%胎牛血清的DMEM介质中的6孔组织培养皿中。加入浓度不同的紫杉烷2’,使细胞在37℃下保持在潮湿的空气和6%的CO2中,直到形成约20个细胞或20个细胞以上的集落(6到10天)。对照的培养皿中不含紫杉烷。然后用甲醛固定化细胞,用结晶紫染色并在低放大倍率的显微镜下计数。由集落的数目确定植板率,计算细胞的存活分数,存活分数为被处理样品的植板率和对照组的植板率的比值。
[170]图11示出了细胞毒性的测定结果。在C-10上具有游离羟基而在C-7上具有连接基团的紫杉烷3’显示出对所测试的两种癌细胞系具有更高的效价,对A549细胞和MCF-7细胞的IC50值分别为1.8×10-10M和6.3×1011M。这些结果表明紫杉烷的C-10位上无需受到保护也能保持高效价。
实施例4
与抗体的共轭结合
含硫醇的紫杉烷通过二硫键与抗体进行共轭结合
[171]采用两个步骤使含硫醇的紫杉烷通过二硫键与抗体或其片段进行共轭结合。在第一步中,采用琥珀酰亚胺基吡啶二硫代戊酸酯(succinimidyl pyridyldithiopentanoate)(SPP)按照Carlsson等提出的方法将二硫吡啶基引入到抗体或抗体片段中。然后通过与含有硫醇的紫杉烷进行反应,从而替代硫吡啶基,得到共轭物。
制备抗体-SS-紫杉烷共轭物
[172]采用SPDP或SPP按照文献中的方法修饰抗-B4抗体、抗-EGF受体抗体和N901抗体或其片段。平均每个抗体分子上引入1到10个二硫吡啶基。
[173]在25℃下,采用含硫醇的紫杉烷(1.25摩尔当量/二硫吡啶基)处理溶于pH6.5,含有1mM EDTA的0.1M磷酸钾缓冲液中的浓度为1mg/ml的二硫吡啶基修饰的抗体溶液。在343nm下用分光光度法监测硫吡啶(thiopyridine)从修饰的抗体或其片段上释放出的过程,发现该过程在约20小时的时间内完成。采用Sephadex G-25柱进行凝胶过滤,纯化抗体-紫杉烷共轭物,除去未反应的药物和其它低分子量的物质。通过测定在230nm处和在275nm处的吸光度比率,确定每个抗体分子所结合的紫杉烷分子的数目。采用这种方法,通过二硫键可平均将1-10个紫杉烷分子连接到每个抗体分子上。
含硫醇的紫杉烷通过不可断裂的硫醚键与抗体进行共轭结合
[174]采用两个步骤进行含硫醇的紫杉烷的共轭结合。首先使抗体或其片段与琥珀酰亚胺基马来酸酰亚胺甲基环己烷羧酸酯(succinimidylmaleimidomethylcyclohexane carboxylate)(SMCC)反应而引入马来酸酰亚胺基(maleimido group)。修饰的抗体然后再与含硫醇的紫杉烷反应形成硫醚键。
制备抗体-紫杉烷共轭物(不可断裂的)
[175]采用SMCC按照文献中的方法修饰抗-B4抗体、抗-EGF抗体和N901抗体或其片段。
[176]用含硫醇的紫杉烷(1.25摩尔当量/马来酸酰亚胺基团)处理修饰的抗体或抗体片段。在4℃下温育混合物过夜。按照前述的方法纯化抗体-紫杉烷共轭物。通常,平均为每个抗体分子上连接有1-10个紫杉烷。
实施例5
抗体-紫杉烷共轭物的特殊制备
[177]开发针对人类EGF受体(EGFR)的鼠单克隆抗体。已知EGF受体在几种人类鳞状细胞癌,如头和颈,以及肺和胸中过度表达。KS-61(IgG2a)、KS-77(IgG1)、KS-78(Ig2a)和KS-62(IgG2a)四种不同的抗体通过二硫键连接到紫杉烷。采用针对在人类乳腺癌和卵巢癌中过度表达的神经致癌基因(neu oncogene)的鼠单克隆抗体TA1制备TA1-紫杉烷共轭物。这些特殊的共轭物的制备方法如下所述。
制备抗-EGFR抗体KS-61-紫杉烷共轭物
[178]首先采用N-琥珀酰亚胺基-4-[2-吡啶二硫]戊酸酯(SPP)修饰抗-EGFR抗体KS-61,以引入二硫吡啶基团。用SPP(11摩尔当量,乙醇中)处理处于pH6.5,含有NaCl(50mM)和EDTA(2mM)的50mM磷酸钾缓冲液中的抗体(2.3mg/mL)。乙醇的最终浓度是1.4%(v/v)。在环境温度下保持90分钟之后,加入赖氨酸(50mM),以帮助除去任何未共价结合的SPP。反应进行2小时,然后在上述缓冲液中采用平衡的Sephadex G25柱进行凝胶过滤,从而进行纯化。收集含有抗体的级份,采用二硫苏糖醇处理样品,测定在343nm处的吸光度变化(释放吡啶-2-硫酮,ε343=8,080M-1 cm-1),从而测定修饰程度。抗体的回收率为约90%,每个抗体分子上连接有5.0个吡啶二硫基团。
[179]用pH6.5,含有NaCl(50mM)和EDTA(2mM)的50mM磷酸钾缓冲液稀释修饰的抗体,直至最终的浓度为1.28mg/mL。然后向修饰的抗体溶液中加入存在于乙醇(在最终的反应混合物中为10%v/v)中的紫杉烷-SH(1.7eq/二硫吡啶基)。反应在氩气氛和环境温度下进行24小时。采用343nm下的分光光度法监测释放吡啶-2-硫酮的反应进程,吡啶-2-硫酮的释放是由紫杉烷-SH和抗体上的二硫代吡啶基之间的二硫化物交换造成的。343nm处吸光率的增加表明紫杉烷已经连接到抗体上。然后将反应混合物装载到以含有20%丙二醇的磷酸盐缓冲盐水(PBS,pH6.5)平衡的Sephadex G25 SF凝胶过滤柱上。主峰包括单体KS-61-紫杉烷。通过测定280nm处的吸光度,从而确定共轭物的浓度。采用吐温80(0.05%)和人类血清白蛋白(HSA,1mg/mL)将共轭物制成制剂。
抗-EGFR抗体KS-77-紫杉烷共轭物的制备
[180]采用N-琥珀酰亚胺基4-[2-吡啶二硫代]戊酸酯(SPP)修饰抗-EGFR抗体KS-77,以引入二硫代吡啶基。用SPP(11摩尔当量,乙醇中)处理处于pH6.5的50mM磷酸钾缓冲液中的抗体(5.0mg/mL)。乙醇的最终浓度是2%(v/v)。在环境温度下保持90分钟之后,加入赖氨酸(50mM),以助于除去任何未共价结合的SPP。温育反应混合物达2小时,然后采用在上述缓冲液中平衡的Sephadex G25柱进行凝胶过滤,从而纯化反应混合物。收集含有抗体的级份,采用二硫苏糖醇处理样品,测定在343nm处的吸光度变化(释放2-巯基吡啶,ε343=8,080M-1 cm-1),从而测定修饰程度。抗体的回收率为约90%,每个抗体分子上连接有4.24个吡啶二硫代基团。
[181]用pH6.5,含有NaCl(50mM)和EDTA(2mM)的50mM磷酸钾缓冲液稀释修饰的抗体,直至最终的浓度为1.4mg/mL。然后向修饰的抗体溶液中加入存在于乙醇(在最终的反应混合物中为10%v/v)中的紫杉烷-SH(1.7eq/二硫代吡啶基)。反应在氩气氛和环境温度下进行24小时。在343nm处观察到吸光度增加,这表明正在释放出吡啶-2-硫酮,且紫杉烷已经连接到抗体上。然后将反应混合物装载到以磷酸盐缓冲盐水(PBS,pH6.5)平衡的Sephacryl S300HR凝胶过滤柱上。主峰包括单体KS-77-紫杉烷。通过测定280nm处的吸光度,从而确定抗体-KS77的浓度。采用吐温80(0.06%)和HAS(1mg/mL)将共轭物制成制剂。
抗-EGFR抗体KS-62-紫杉烷共轭物的制备
[182]以类似于制备上述抗-EGFR抗体KS-77-紫杉烷共轭物的方式制备抗-EGFR抗体-紫杉烷共轭物(KS-62-紫杉烷)。用pH6.5,含有NaCl(50mM)和EDTA(2mM)的50mM磷酸钾缓冲液稀释修饰的抗体,直至最终的浓度为2.5mg/mL。采用SPP修饰抗体以在每个抗体分子上引入5.25个吡啶二硫代基,然后向该修饰的抗体溶液中加入存在于乙醇(在最终的反应混合物中为10%v/v)中的紫杉烷-SH(1.7eq)。反应在氩气氛和环境温度下进行24小时。使共轭物通过以磷酸盐缓冲盐水(PBS,pH6.5)平衡的Sephacryl S300HR凝胶过滤柱而进行纯化。主峰包括单体KS-62-紫杉烷。在含有吐温80(0.01%)和HAS(1mg/mL)的PBS中将共轭物制成制剂。
抗-EGFR抗体KS-78-紫杉烷共轭物的制备
[183]以类似于制备上述抗-EGFR抗体KS-77-紫杉烷共轭物的方式制备抗-EGFR抗体-紫杉烷共轭物,即KS-78-紫杉烷。用pH6.5,含有NaCl(50mM)和EDTA(2mM)的50mM磷酸钾缓冲液稀释修饰的抗体,直至最终的浓度为1.6mg/mL。采用SPP修饰抗体而在每个抗体分子上引入4.0个吡啶二硫代基,然后向修饰的抗体溶液中加入存在于乙醇(在最终的反应混合物中为15%v/v)中的紫杉烷-SH(1.7eq)。反应在氩气氛和环境温度下进行24小时。之后将溶液分为两批,A批和B批,分别进行处理。A批在pH6.5,含有2mM CHAPS(3-[(胆酰胺基丙基)-二甲基铵]-1-丙磺酸盐)和20%(v/v)丙二醇的PBS中进行渗析。最终溶液的pH为6.0。B批在pH6.5,含有20%(v/v)丙二醇的PBS中进行渗析。渗析之后,向两批中都加入HSA(1mg/mL)。用吐温80(0.05%,w/v)进一步处理B批。
TA1-紫杉烷共轭物的制备
[184]在紫杉烷类共轭物的制备中采用与在乳腺和卵巢肿瘤上表达的神经致癌基因相结合的鼠单克隆抗体TA1。用SPP(8摩尔当量,乙醇中)处理存在于pH6.5,含有NaCl(50mM)和EDTA(2mM)的50mM磷酸钾缓冲液中的TA1(3.2mg/mL)。最终的乙醇浓度为5%(v/v)。在环境温度下经历90分钟之后,加入赖氨酸(50mM)以助于除去任何非共价结合的SPP。温育反应混合物2小时,然后凝胶滤过在上述缓冲液中平衡的Sephadex G25柱。收集含有抗体的级份,用二硫苏糖醇处理样品,并测量在343nm处的吸光度变化(释放吡啶-2-硫酮,ε343=8,080M-1cm-1),从而测定修饰的程度。抗体回收率为约90%,每个抗体分子上连接4.9个吡啶二硫代基。
[185]用pH6.5,含有NaCl(50mM)和EDTA(2mM)的50mM磷酸钾缓冲液稀释修饰的抗体,至最终浓度为1.0mg/mL。然后将处于乙醇(乙醇在最终反应混合物中浓度为10%v/v)中的紫杉烷-SH(1.7当量/并入的吡啶二硫代基)加入到修饰的抗体溶液中。反应于环境温度下在氩气氛中进行24小时。吡啶-2-硫酮的释放(在343nm处监测到)表明在紫杉烷-SH和抗体上的吡啶二硫代取代基之间发生了二硫化物交换。然后将反应混合物(4.0mg)的一部分装载到以磷酸缓冲盐水(PBS,pH6.5)平衡的SephacrylS300HR凝胶过滤柱上。主要的峰包括单体TA1-紫杉烷。将其余的共轭物稀释到0.5mg/mL,并在pH6.5,含有NaCl(50mM),EDTA(2mM)和20%丙二醇的50mM磷酸钾缓冲液中进行渗析。测定在280nm处的吸光度,从而确定两种样品中抗体TA1的浓度。共轭物在含有吐温80(0.01%)和HSA(1mg/mL)的PBS中制成制剂。
实施例6
连接紫杉烷的其它方法
对酸不稳定的连接物
[186]可采用N-保护的氨基酸,如N-tboc-L-丙氨酸在二环己基-碳化二亚胺和二甲基氨基吡啶(DMAP)的存在下通过化学文献中所述的标准方法对紫杉烷进行酯化。采用三氟乙酸使t-boc保护基团断裂,将得到含有末端氨基的紫杉烷的酯。该含有氨基基团的紫杉烷通过前述的对酸不稳定的连接物可连接到抗体或其片段,以及其他的细胞结合剂上(Blattler等,Biochemistry,24:1517-1524(1985),;专利号为4,542,225、4,569,789和4,764,368的美国专利)。
对光不稳定的连接物
[187]上述含有氨基基团的紫杉烷可通过前述的对光不稳定的连接物连接到细胞结合剂上(Senter等,Photochemistry and Photobiology,42:231-237(1985),美国专利4,625,014)。
对肽酶不稳定的连接物
[188]上述含有氨基基团的紫杉烷类衍生物也可通过肽间隔基连接物(peptide spacer linker)连接到细胞结合剂上。之前已经表明了药物和大分子蛋白质载体之间短的肽间隔基在血清中是稳定的,但易于被细胞内的溶酶体肽酶水解(Trouet等,Proc.Nat’l Acad.Sci.,79:626-629(1982))。采用缩合剂如1-[3-(二甲基氨基)丙基]-3-乙基碳化二亚胺-HCl,可使含有氨基基团的紫杉烷与肽如Ala-Leu、Leu-Ala-Leu或Ala-Leu的二聚体进行缩合,得到紫杉烷的肽衍生物,该衍生物随后可连接到细胞结合剂上。
对酯酶不稳定的连接物
[189]通过羟基与琥珀酸酐的反应可使紫杉烷酯化,然后连接到细胞结合剂上,得到共轭物,该共轭物可在细胞内酯酶的作用下发生断裂而释放出游离药物。(例如参见:Aboud-Pirak等,Biochem.Pharmacol.,38:641-648(1989);Laguzza等,J.Med.Chem.,32:549-555(1989))。
实施例7
体内抗肿瘤活性
[190]按照下列方法确定抗-EGF受体抗体-紫杉烷共轭物对SCID小鼠体内人类鳞癌(A431)异种移植物的抗肿瘤效果。在SUM小鼠的人类肿瘤异种移植物模型中评价两种不同的抗-人类表皮生长因子受体-紫杉烷共轭物(抗-EGFR-紫杉烷共轭物),即KS-61-紫杉烷和KS-77-紫杉烷的抗肿瘤作用。
[191]采用处于0.1mL不含血清的介质中的A-431人类鳞癌细胞(1.5×106细胞/小鼠)从右肋腹通过皮下接种到5周龄的雌性SCID小鼠体内(25只小鼠)。肿瘤生长11天,直至平均大小为100.0mm3(肿瘤大小的范围为54-145mm3)。然后根据肿瘤的大小将小鼠随机分为四组(3-5只动物/组)。第一组通过静脉内给药而接受KS-61-紫杉烷共轭物(10mg/kg,qd×5)。第二组通过静脉内给药而接受KS-77-紫杉烷共轭物(10mg/kg,qd×5)。第三组接受游离的(非共轭的)紫杉烷(0.24mg/kg,qd×5,静脉内),其剂量与共轭物中存在的剂量相同。第四组是对照组动物,采用与第1-3组的相同处理方案接受PBS。
[192]每周两次测量肿瘤的大小,用下式计算肿瘤的体积:1/2(长×宽×高)。动物的体重也每周测量两次。结果示于图12和13中。在31天内,对照组小鼠的肿瘤大小生长至接近1000mm3。用游离紫杉烷的处理显示无治疗效果,且这组的肿瘤生长速率基本上与接受PBS的对照组动物的肿瘤生长速率相同。
[193]相反,用抗-EGFR-紫杉烷共轭物处理的两个组都表现出明显的抗肿瘤活性,结果是KS-61-紫杉烷共轭物在34天的试验期间完全抑制了所有被处理动物中的肿瘤生长,而KS-77-紫杉烷共轭物则在27天的试验期间完全抑制了所有被处理动物中的肿瘤生长。该数据也表明了采用肿瘤特异性抗体对紫杉烷进行靶向传递对抗肿瘤活性是必要的,原因是等剂量的非共轭紫杉烷在该模型中并未表现出抗肿瘤效果。重要的是,未发生体重损失(参见图13)表明,所采用的抗体-紫杉烷共轭物的剂量对动物是无毒性的。
实施例8
抗体-紫杉烷共轭物的体外细胞毒性
[194]在克隆源性分析试验中采用EGF受体-阳性人类A431细胞系(ATCC CRL 1555)测定抗EGFR-紫杉烷共轭物,KS-78-紫杉烷的细胞毒性。N901-紫杉烷共轭物,一种用针对人类CD56的小鼠单克隆抗体N901制备的类似共轭物,作为特异性对照物进行测定,原因是A431细胞并不表达其靶抗原CD56。测定TA1-紫杉烷共轭物,一种用针对人类神经抗原的小鼠单克隆抗体TA1制备的共轭物,对抗原-阳性人类细胞系SK-BR-3(ATCC HTB 30)和抗原-阴性A431细胞系的细胞毒性。细胞以不同的密度平板接种到6孔组织培养皿中,该培养皿处于补充了10%胎牛血清的DMEM介质中。加入不同浓度的免疫共轭物,使细胞保持在37oC和6%的CO2的湿润空气中直到形成约20个细胞或更多细胞的集落(6-10天)。对照培养皿中不含免疫共轭物。然后用甲醛固定化细胞,用结晶紫染色,然后在低倍率的显微镜下计数。然后由集落数目确定植板率,并计算细胞的存活分数-被处理样品的植板率和对照组的植板率的比值。
[195]图14示出了两批KS-78-紫杉烷共轭物对靶抗原-阳性细胞系A431的细胞毒性测定结果。两批的共轭物都显示出对靶细胞类似的毒性;以10-8M的浓度处理6天所达到的存活分数小于10-2(小于1%的细胞存活)。对于A431细胞表面不存在抗原的对照共轭物N901-紫杉烷,在浓度高达3×10-8M时显示出对细胞无毒性。非共轭的KS-78抗体也显示出非常低的细胞毒性效果。这些结果显示KS-78-紫杉烷共轭物的靶抗原-特异性细胞毒性。
[196]用靶抗原-阳性细胞系SK-BR-3和靶抗原-阴性细胞系A431测试TA1-紫杉烷共轭物的细胞毒性效力和选择性。结果示于图15中。在共轭物浓度为10-9M处,杀死了90%以上的靶SK-BR-3细胞(存活分数小于0.1),同时未观察到对非靶细胞A431细胞的细胞毒性。这些结果表明选择性地杀死了抗原-阳性细胞,而共轭物的细胞毒性效应取决于通过其抗体成分的特异性结合。
实施例9和10
一般方法:
[197]在不另行指出的情况下,从Aldrich Chemical Co.或其它商业渠道获得的化学品无需纯化即可使用。在用烘箱干燥的玻璃器皿中于氩气下进行所有的无水反应。在钠/二苯甲酮的存在下蒸馏四氢呋喃(THF)。以E.Merck分析性薄层色谱(TLC)板监测所有的反应(硅胶60GF,铝背面),以254nm的UV光和/或香兰素/硫酸喷射法和/或磷钼酸/乙醇喷射法分析所有的反应。柱色谱的硅胶购自E.Merck(230-400目)。制备薄层色谱(PTLC)板(硅胶60GF)购自Analtech。在Bruker 400MHz分光计上获得了采用CDCl3的1H和13C NMR谱,通过将这些谱图上化学位移和偶合常数与相关化合物的化学位移和偶合常数进行比较,从而对谱图进行排布。化学位移以δ值表示,而偶合常数以赫兹表示。在Agilent Esquire 3000电喷雾质谱仪上获得质谱。在未另行指出的情况下,短语“以常规方式处理”是指用过量的有机溶剂稀释反应混合物,用水和盐水洗涤,用硫酸钠干燥和在真空下蒸发掉溶剂。按照下列文献中报道的方法制备β-内酰胺4,19和38浆果赤霉素III衍生物7(Brieva,R.Crich,J.Z.;Sih,C.J.J.Org.Chem.,58:1068-1075(1993);Holton,R.A.;Zhang,Z.;Clarke,P.A.;Nadizadeh,H.;Procter,J.D.Tetrahedron Lett.39:2883-2886(1998);Chen,S-H.;Vittorio,F.;Wei,J-M.;Long,B.;Fairchild,C.;Mamber,S.W.;Kadow,J.F.;Vyas,D.;Doyle,T.W.Bioorganic Med.Chem.Lett.,4(3):479-482(1994)。这些化合物的NMR数据与文献中报道的相同。
实施例9
本发明的新型紫杉类药物(Taxoids)12-15,31-35和50-54的合成(图5
和16)如下所述。
[198]浆果赤霉素III衍生物7与β-内酰胺6a-d,21-25和40-44进行偶联的一般方法。
[199]甲硅烷基保护的紫杉类药物8-11,26-30和45-49的合成:向处于THF(2mL)中的浆果赤霉素衍生物7(0.04mmol)的搅拌溶液中加入NaH(2mmol)。反应混合物搅拌15分钟,加入β-内酰胺,如6a-d21-25或40-44(0.08mmol),然后反应混合物继续搅拌4-6小时。用EtOAc稀释反应,用乙酸淬灭反应,然后以常规方式进行处理。最后将粗产物加到PTLC板(30%EtOAc/己烷)上,分离出所需的产物。
除去甲硅烷基保护基团的一般方法;紫杉类药物12-15,31-35和50-54
的合成
[200]在0℃下,向溶于THF(0.5mL)的每10mg受保护的紫杉类药物8-11,26-30或45-49的搅拌溶液中加入0.15mL吡啶。在超过5分钟的时间里,向搅拌的溶液中加入0.15mL HF-吡啶。使反应混合物升温到室温,并继续搅拌24小时。然后用EtOAc稀释反应混合物,用NaHCO3的饱和水溶液洗涤,并以常规方式进行处理。最后将粗产物加到PTLC板(60%EtOAc/己烷)上,分离出所需的产物。
本发明代表性含二硫化物的紫杉类药物的合成(图6,17)
去除C-10醋酸酯基团;合成16
[201]在室温下向溶于乙醇(1.5mL)的紫杉类药物10(~70mg)的搅拌溶液中加入一水合肼(0.6mL)。反应混合物在室温下搅拌1小时,然后用乙酸乙酯进行稀释,用氯化铵饱和水溶液洗涤,然后以常规方式进行处理。最后将粗产物加到PTLC板(10%EtOAc/CH2Cl2)上,分离出所需的产物。
对紫杉类药物上C-10羟基的酯化;合成17和36
[202]在室温下向溶于二氯甲烷的羧酸搅拌溶液(对每30mg酸的用量为2mL)中加入EDC(1-[3-(二甲基氨基)丙基-3-乙基碳化二亚胺盐酸)(1当量),搅拌反应混合物15分钟。然后加入DMAP(4-(二甲基氨基)吡啶)(催化量),再搅拌反应混合物5分钟。然后在室温下加入C-10脱乙酰基紫杉烷16(1/15当量),反应混合物继续搅拌4小时。用乙酸乙酯稀释反应混合物,用水和NaHCO3饱和水溶液洗涤,然后以常规方式进行处理。最后将粗产物加到PTLC板(10%EtOAc/己烷)上,分离出所需的产物。
含二硫化物的紫杉类药物18和37的合成
[203]在0℃下,向溶于THF(0.5mL)的每10mg的受保护紫杉类药物17或36的搅拌溶液中加入0.15mL吡啶。在超过5分钟的时间里,向搅拌的溶液中加入0.15mL HF-吡啶。使反应混合物升温到室温,继续搅拌24小时。然后用EtOAc稀释反应混合物,用NaHCO3的饱和水溶液洗涤,并以常规方式进行处理。最后将粗产物加到PTLC板(60%EtOAc/己烷)上,分离出所需的产物18和37。
化合物6a.
[204]1H NMR(CDCl3)δ7.03(m,1H),5.26(dt,1H),4.96(t,1H),4.94(t,1H),1.82(s,3H),1.76(s,3H),1.63(m,8H),1.06(m,21H)
化合物6b.
[205]1H NMR(CDCl3)δ7.31(m,1H),5.26(dt,1H),4.96(t,1H),4.92(t,1H),2.6(m,6H),1.82(s,3H),1.76(s,3H),1.06(m,21H)
化合物6c.
[206]1H NMR(CDCl3)δ7.1(m,1H),6.74(dd,1H),5.24(dt,1H),5.02(d,J=6Hz,1H),4.85(m,1H),1.91(dd,3H),1.81(s,3H),1.77(s,3H),1.06(m,21H);13C NMR(CDCl3)δ166.93,162.99,145.98,140.20,124.01,117.68,76.89,55.77,26.05,18.33,18.28,17.66,17.50,17.46;对C20H35NO3SiNa(M+Na)+的LRMS m/z分析结果是:计算值为388.23,实测值为388。
化合物6d.
[207]1H NMR(CDCl3)δ6.55(m,1H),5.24(dt,1H),4.98(d,J=5.6Hz,1H),4.85(m,1H),2.17(s,3H),1.94(s,3H),1.81(s,3H),1.77(s,3H)1.06(m,21H);13C NMR(CDCl3)δ166.65,163.29,159.81,139.58,126.15,118.27,117.45,76.59,55.71,27.92,26.07,21.25,18.34,17.50,17.46;LRMSm/z对C21H37NO3SiNa(M+Na)+的计算值为402.24,实测值为402.1。
化合物8.
[208]1H NMR(CDCl3)δ7.32(d,J=3.2Hz,1H),7.07(d,J=3.2Hz,1H),7.04(d,J=3.2Hz,1H),6.95(d,J=9.2Hz,1H),6.58(bs,1H),6.43(s,1H),6.12(d,J=9.2Hz,1H),6.03(t,1H),5.67(d,J=6.4Hz,1H),5.38(d,J=8.8Hz,1H),5.09(t,1H),4.89(d,J=8.4Hz,1H),4.47(s,1H),4.42(m,2H),4.28(d,J=8Hz,1H),3.97(s,3H),3.79(s,3H),3.74(m,1H),2.48(m,1H),2.36(d,1H),2.20(s,3H),2.17(s,6H),2.08(m,2H),1.98(s,3H),1.89(m,2H),1.72(s,9H),1.60(m,5H),1.22(s,3H),1.21(s,3H),1.11(s,21H),0.91(t,9H),0.56(m,6H)。
化合物9.
[209]1H NMR(CDCl3)δ7.32(d,J=3.2Hz,1H),7.07(d,J=2.8Hz,1H),7.04(d,J=3.2Hz,1H),6.95(d,J=8.8Hz,1H),6.47(bs,1H),6.43(s,1H),6.07(d,J=9.2Hz,1H),6.4(t,1H),5.68(d,J=6.8Hz,1H),5.38(d,J=9.2Hz,1H),5.09(t,1H),4.89(d,J=8.4Hz,1H),4.47(s,1H),4.42(m,2H),4.28(d,J=8.4Hz,1H),3.96(s,3H),3.79(s,3H),3.74(d,J=6.4Hz,1H),2.45(m,5H),2.35(d,J=9.2Hz,1H),2.17(s,3H),2.15(s,3H),1.98(s,3H),1.89(m,4H),1.72(s,9H),1.24(s,3H),1.22(s,3H),1.11(s,21H),0.90(t,9H),0.55(m,6H)。
化合物10.
[210]1H NMR(CDCl3)δ7.29(d,J=3.2Hz,1H),7.05(dd,1H),6.94(d,J=9.2Hz,1H),6.71(m,1H),6.43(s,1H),6.05(t,1H),5.74(m,2H),5.67(d,J=6.8Hz,1H),5.37(d,J=8.8Hz,1H),5.10(t,1H),4.88(d,J=9.6Hz,1H),4.25-4.47(m,5H),4.10(m,1H),3.96(s,3H),3.79(s,3H),3.73(m,1H),2.48(m,1H),2.36(bs,1H),2.33(bs,1H),2.17(s,3H),2.15(s,3H),1.97(s,3H),1.79(d,J=6.8Hz,3H),1.71(s,9H),1.21(m,7H),1.10(s,21H),0.90(t,12H),0.55(m,6H);13C NMR(CDCl3)δ201.97,171.67,169.68,169.27,166.77,164.65,153.40,152.83,140.51,139.82,136.79,133.72,124.99,121.57,120.26,119.93,115.91,113.54,84.35,81.00,77.22,76.44,76.24,75.27,74.72,72.19,71.91,58.62,56.78,55.81,50.16,46.54,42.86,37.30,36.47,26.55,25.59,22.54,21.13,20.82,18.47,18.01,17.93,17.63,14.37,12.53,9.98,6.68,5.27;对C59H91NO16Si2Na(M+Na)+的LRMS m/z分析结果是:计算值为1148.58,实测值为1148.5。
化合物11.
[211]1H NMR(CDCl3)δ7.29(d,J=3.2Hz,1H),7.05(dd,1H),6.94(d,J=9.2Hz,1H),6.44(s,1H),6.04(t,1H),5.65(m,2H),5.49(s,1H),5.38(d,J=9.2Hz,1H),5.13(t,1H),4.89(d,J=8.4Hz,1H),4.45(s,1H),4.40(m,2H),4.27(d,J=8Hz,1H),3.98(s,3H),3.79(s,3H),3.74(m,1H),3.14(s,1H),2.48(m,3H),2.17(s,3H),2.15(s,3H),2.04(s,3H),1.98(s,3H),1.71(s,9H),1.21(s,3H),1.10(s,3H),1.10(s,21H),0.90(t,9H),0.55(m,6H);13C NMR(CDCl3)δ203.94,202.03,171.80,169.66,169.28,166.86,165.62,153.42.152.75,151.23,150.56,140.71,136.39,136.17,133.64,132.41,121.83,120.35,119.96,118.46,115.84,113.58,113.49,106.05,84.37,81.03,77.18,76.45,76.40,75.32,74.90,72.20,72.06,60.88,58.64,56.74,55.82,49.78,46.55,45.82,42.84,37.32,36.51,26.96,26.47,25.59,22.55,21.12,20.83,19.68,18.02,17.85,14.40,12.54,9.98,6.69,5.28;对C60H93NO16Si2Na(M+Na)+的LRMS m/z分析结果是:计算值为1162.59,实测值为1162.3。
化合物12.
[212]1H NMR(CDCl3)δ7.32(d,J=3.2Hz,1H),7.07(dd,1H),6.94(d,J=9.2Hz,1H),6.58(s,1H),6.29(s,1H),6.18(t,1H),5.89(d,J=8.4Hz,1H),5.66(d,J=6.8Hz,1H),5.38(d,1H),5.10(t,1H),4.93(d,1H),4.40(d,J=8.4Hz,1H),4.35(m,1H),4.27(d,J=8.4HZ,1H),4.24(m,1H),3.94(s,3H),3.80(s,3H),3.74(d,J=6.8Hz,1H),3.61(d,J=6.4Hz,1H),3.00(s,1H),2.58-2.30(m,4H),2.23(s,3H),2.20(s,3H),2.13(m,4H),1.86(s,3H),1.75(s,3H),1.72(s,3H),1.69(s,3H),1.63(s,6H),1.60(m,2H),1.29(s,3H),1.15(s,3H);对C47H61NO16Na(M+Na)+的LRMS m/z分析结果是:计算值为918.39,实测值为918.3。
化合物13.
[213]1H NMR(CDCl3)δ7.33(d,J=3.2Hz,1H),7.06(dd,1H),6.94(d,J=9.2Hz,1H),6.50(s,1H),6.29(s,1H),6.19(t,1H),5.86(d,J=8.4Hz,1H),5.66(d,J=6.8Hz,1H),5.38(d,J=9.2Hz,1H),5.08(t,1H),4.93(d,J=8.4Hz,1H),4.39(m,2H),4.29(d,J=8.4Hz,1H),4.25(m,1H),3.93(s,3H),3.80(s,3H),3.74(d,J=6.4Hz,1H),3.64(d,J=6.4Hz,1H),3.00(s,1H),2.41-2.56(m,7H),2.32(m,1H),2.23(s,3H),2.22(s,3H),1.98(m,2H),1.86(s,3H),1.75(m,11H),1.29(s,3H),1.15(s,3H);13C NMR(CDCl3)δ203.90,172.88,171.24,170.21,166.63,164.86,153.39,153.03,142.25,139.02,138.93,138.60,133.33,120.24,120.14,119.90,115.93,113.55,84.51,81.04,77.74,76.47,76.10,75.77,73.56,72.23,72.17,58.83,56.69,55.86,49.95,45.56,42.88,36.56,35.74,33.14,31.48,26.90,25.67,23.25,22.42,21.72,20.86,18.55,14.97,9.53;对C46H59NO16Na(M+Na)+的LRMS m/z分析结果是:计算值为904.37,实测值为904.4。
化合物14.
[214]1H NMR(CDCl3)δ7.33(d,J=3.2Hz,1H),7.07(dd,1H),6.95(d,J=9.2Hz,1H),6.78(m,1H),6.29(s,1H),6.19(t,1H),5.74(d,J=15.2Hz,1H),5.67(d,J=6.4Hz,1H),5.62(d,J=8.4Hz,1H),5.39(d,J=8.8Hz,1H),5.09(t,1H),4.93(d,1H),4.40(d,J=8.4Hz,1H),4.37(m,1H),4.30(d,J=8.4Hz,1H),4.24(m,1H),3.94(s,3H),3.80(s,3H),3.74(d,J=6.4Hz,1H),3.59(d,J=6Hz,1H),2.97(s,1H),2.31-2.56(m,5H),2.23(s,3H),2.21(s,3H),1.84(s,3H),1.82(m,3H),1.75(s,3H),1.72(s,3H),1.69(s,3H),1.60(s,3H),1.29(s,3H),1.15(s,3H);对C44H57NO16Na(M+Na)+的LRMS m/z分析结果是:计算值为878.36,实测值为878.3。
化合物15.
[215]1H NMR(CDCl3)δ7.33(d,J=3.2Hz,1H),7.07(dd,1H),6.94(d,J=8.8Hz,1H),6.29(s,1H),6.18(t,1H),5.67(d,J=6.8Hz,1H),5.52(m,2H),5.40(d,J=8.8HZ,1H),5.05(t,1H),4.93(d,1H),4.40(m,2H),4.29(d,J=8.4Hz,1H),4.23(m,1H),3.94(s,3H),3.80(s,3H),3.75(d,J=6.4Hz,1H),3.57(d,J=6.4Hz,1H),2.97(s,1H),2.33-2.58(m,4H),2.23(s,3H),2.21(s,3H),2.07(s,3H),1.87(s,3H),1.81(s,3H),1.75(s,3H),1.72(s,3H),1.68(s,3H),1.40(t,1H),1.29(s,3H),1.15(s,3H);13C NMR(CDCl3)δ203.95,196.43,173.15,171.25,170.08,166.71,166.28,153.41,152.97,152.13,151.25,142.50,138.44,136.19,133.19,120.45,120.19,119.96,117.80,115.85,113.53,106.08,94.84,91.01,84.52,81.01,77.71,76.45,76.24,75.79,73.61,72.50,72.18,58.82,56.64,55.86,49.85,45.84,45.55,42.86,36.63,35.71,27.12,26.80,25.60,22.41,21.75,20.85,19.73,18.48,14.95,9.52;对C45H59NO16Na(M+Na)+的LRMS m/z分析结果是:计算值为892.37,实测值为892.3。
化合物16.
[216]1H NMR(CDCl3)δ7.30(t,1H),7.06(dm,1H),6.95(d,J=9.2Hz,1H),6.72(m,1H),6.12(q,1H),5.75(m,2H),5.64(d,J=6.8Hz,1H),5.62(d,J=8.4Hz,1H),5.37(m,1H),5.10(m,2H),4.89(d,1H),4.26-4.47(m,5H),3.97(s,3H),3.80(s,3H),3.79(d,1H),3.10(d,J=15.6Hz,1H),2.31-2.44(m,3H),2.18(d,3H),2.09(t,1H),1.91(s,3H),1.69-1.82(m,12H),1.57(m,1H),1.25(s,3H),1.12(m,25H),0.9(m,12H),0.5(m,6H)。
化合物17.
[217]1H NMR(CDCl3)δ7.30(t,1H),7.06(dm,1H),6.95(d,J=9.2Hz,1H),6.72(m,1H),6.47(s,1H),6.05(t,1H),5.72(m,2H),5.38(m,1H),5.10(m,1H),4.89(d,1H),4.40-4.48(m,3H),4.28(d,J=8Hz,1H),3.98(s,3H),3.80(s,3H),3.74(d,J=6.4Hz,1H),3.13(d,J=12Hz,1H),2.82-3.15(m,4H),2.43(s,3H),2.35-2.51(m,3H),2.18(d,3H),2.09(m,1H),1.99(s,3H),1.79-1.93(m,2H),1.71(m,9H),1.56(s,3H),1.22(s,6H),1.11(s,21H),0.9(m,12H),0.5(m,6H)。
化合物18.
[218]1H NMR(CDCl3)δ7.32(t,1H),7.06(dm,1H),6.95(d,J=8.8Hz,1H),6.72(m,1H),6.33(s,1H),6.05(q,1H),5.67(d,J=6.8Hz,1H),5.60(d,1H),5.39(m,1H),5.07(m,1H),4.93(d,1H),4.20-4.42(m,4H),3.95(s,3H),3.80(s,3H),3.74(d,J=6.4Hz,1H),2.91-3.04(m,5H),2.42(s,3H),2.31-2.53(m,3H),2.18(d,3H),2.10(m,1H),1.87(s,3H),1.79-1.93(m,2H),1.75(s,3H),1.72(s,3H),1.67(d,3H),1.51-1.64(m,3H),1.29(s,3H),1.15(s,3H),0.9(t,2H);对C46H61NO16S2Na(M+Na)+的LRMS m/z分析结果是:计算值为970.33,实测值为970.2。
化合物19.
[219]1H NMR(CDCl3)δ7.41(s,1H),7.30(m,2H),6.80(m,2H),6.38(m,2H),5.24(d,J=4.8Hz,1H),5.20(d,J=5.2Hz,1H),3.75(s,3H),1.03(s,21H);13C NMR(CDCl3)δ165.33,156.24,148.27,142.83,130.91,118.45,114.29,110.64,110.26,77.94,57.06,55.41,17.55,17.49,11.80;对C23H33NO4SiNa(M+Na)+的LRMS m/z分析结果是:计算值为438.21,实测值为438.1。
化合物20.
[220]1H NMR(CDCl3)δ7.39(s,1H),6.54(bs,1H),6.35(m,2H),5.15(m,1H),4.81(d,J=4.4Hz,1H),0.98(s,21H);13C NMR(CDCl3)δ169.81,150.49,142.53,110.48,109.09,80.03,53.52,17.49,17.43,11.73;LRMS m/z对C16H27NO3SiNa(M+Na)+的计算值为332.17,实测值为332.0。
化合物21.
[221]1H NMR(CDCl3)δ7.38(s,1H),7.13(m,1H),6.80(dd,1H),6.35(m,2H),5.25(d,J=5.6Hz,1H),5.19(d,J=5.6Hz,1H),1.93(dd,3H),0.98(m,21H);13C NMR(CDCl3)δ166.40,162.72,147.47,146.94,142.79,123.57,110.43,109.82,77.51,54.96,18.35,17.45,17.38,11.71;对C20H31NO4SiNa(M+Na)+的LRMS m/z分析结果是:计算值为400.19,实测值为400.0。
化合物22.
[222]1H NMR(CDCl3)δ7.38(s,1H),6.61(m,1H),6.34(m,2H),5.23(d,J=5.6Hz,1H),5.15(d,J=6Hz,1H),2.18(s,3H),1.95(s,3H),0.98(m,21H);13C NMR(CDCl3)δ166.08,162.86,160.95,147.82,142.67,120.73,117.02,115.12,110.40,109.62,77.11,54.80,27.96,27.53,21.33,17.44,17.37,11.70;对C21H33NO4SiNa(M+Na)+的LRMS m/z分析结果是:计算值为414.21,实测值为414.0。
化合物23.
[223]1H NMR(CDCl3)δ8.00(m,2H),7.58(tt,1H),7.42-7.48(m,3H),6.45(d,J=3.2Hz,1H),6.38(m,1H),5.47(d,J=6Hz,1H),5.23(d,J=6Hz,1H),0.99(s,21H);13C NMR(CDCl3)δ166.22,164.95,147.77,142.93,133.34,131.96,129.89,128.13,110.47,110.00,76.81,55.17,17.48,17.41,11.73;对C23H31NO4SiNa(M+Na)+的LRMS m/z分析结果是:计算值436.19,实测值为436.0。
化合物24.
[224]1H NMR(CDCl3)δ7.40(s,1H),6.36(m,2H),5.14(d,J=5.6Hz,1H),5.11(d,J=5.6Hz,1H),1.43(s,9H),0.96(m,21H);13C NMR(CDCl3)δ165.76,147.97,147.75,142.73,110.45,109.72,83.46,77.83,56.16,27.87,17.44,17.38,11.69;对C21H35NO5SiNa(M+Na)+的LRMS m/z分析结果是:计算值为432.22,实测值为432.1。
化合物25.
[225]1H NMR(CDCl3)δ8.03(d,1H),7.65(m,1H),7.39(m,1H),6.56(m,1H),6.42(d,J=3.2Hz,1H),6.34(m,1H),5.45(d,J=5.6Hz,1H),5.23(d,J=6Hz,1H),0.99(s,21H);13C NMR(CDCl3)δ164.52,154.39,147.56,147.48,145.45,142.88,120.86,112.10,110.44,110.08,76.56,17.45,17.38,11.71;对C21H29NO5SiNa(M+Na)+的LRMS m/z分析结果是:计算值为426.17,实测值为426.0。
化合物26.
[226]1H NMR(CDCl3)δ7.32(s,1H),7.04(dd,1H),6.93(d,J=9.2Hz,1H),6.78(m,1H),6.45(s,1H),6.31(m,1H),6.16(m,2H),5.86(dd,1H),5.68(d,J=6.8Hz,1H),5.56(d,J=9.2Hz,1H),5.00(s,1H),4.89(d,J=8Hz,1H),4.46(m,1H),4.10(d,J=8Hz,1H),4.28(d,J=8Hz,1H),3.94(s,3H),3.79(s,3H),3.76(m,1H),3.47(m,1H),2.48(m,1H),2.25(s,3H),2.11(s,3H),1.95(s,3H),1.87(m,4H),1.74(s,3H),1.22(s,6H),1.10(s,21H),1.03(t,12H),0.55(m,6H)。
化合物27.
[227]1H NMR(CDCl3)δ7.32(s,1H),7.04(dd,1H),6.93(d,J=9.2Hz,1H),6.45(s,1H),6.31(m,1H),6.16(m,2H),6.05(d,J=9.2Hz,1H),5.57-5.69(m,3H),4.99(s,1H),4.91(d,J=8Hz,1H),4.44(m,2H),4.28(d,J=8Hz,1H),3.94(s,3H),3.79(s,3H),3.76(m,1H),2.31(s,3H),2.11(s,3H),2.09(s,3H),2.04(s,3H),1.87(s,3H),1.74(s,3H),1.22(s,6H),1.10(s,21H),1.03(t,12H),0.55(m,6H);对C60H89NO17Si2Na(M+Na)+的LRMS m/z分析结果是:计算值为1174.56,实测值为1174.3。
化合物28.
[228]1H NMR(CDCl3)δ7.76(d,1H),7.43-7.56(m,3H),7.04(dd,1H),6.93(dd,1H),6.44(s,1H),6.22(m,1H),5.69(m,1H),4.90(m,1H),4.44(m,2H),4.30(d,J=8Hz,1H),3.87(s,3H),3.79(s,3H),3.76(m,1H),2.31(s,1H),2.19(s,3H),2.02(m,2H),1.74(s,3H),0.88-1.13(m,33H),0.58(m,6H);对C62H87NO17Si2Na(M+Na)+的LRMS m/z分析结果是:计算值为1196.54,实测值为1196.3。
化合物29.
[229]1H NMR(CDCl3)δ7.32(s,1H),7.04(dd,1H),6.92(d,J=9.2Hz,1H),6.45(s,1H),6.32(m,1H),6.22(s,1H),6.18(t,1H),5.67(d,J=6.4Hz,1H),5.25(q,2H),4.94(s,1H),4.91(d,J=8Hz,1H),4.44(m,2H),4.29(d,J=8Hz,1H),3.93(s,3H),3.78(s,3H),3.76(m,1H),2.50(m,1H),2.37(m,1H),2.29(s,3H),2.17(s,3H),2.00(s,3H),1.74(s,3H),1.41(s,9H),1.38(m,2H),1.22(s,3H),1.20(s,3H),1.06(m,6H),0.83-0.98(m,30H),0.55(m,6H);对C60H91NO18Si2Na(M+Na)+的LRMS m/z分析结果是:计算值为1192.57,实测值为1192.3。
化合物30.
[230]1H NMR(CDCl3)δ7.48(s,1H),7.35(s,1H),7.27(d,J=3.2Hz,1H),7.14(d,J=9.6Hz),7.06(d,1H),7.04(d,J=3.2Hz,1H),6.94(d,J=9.2Hz,1H),6.51(m,1H),6.45(s,1H),6.33(m,1H),6.24(s,1H),6.20(t,1H),5.69(d,J=6.4Hz,1H),5.64(d,J=9.2Hz),5.06(s,1H),H),4.91(d,1H),4.44(m,2H),4.29(d,J=8Hz,1H),3.95(s,3H),3.81(s,3H),3.79(m,1H),3.18(s.1H),2.50(m,1H),2.37(m,1H),2.33(s,3H),2.16(s,3H),2.01(s,3H),1.92(m,1H),1.74(s,3H),1.25(s,3H),1.23(s,3H),0.88-1.02(m,27H),0.55(m,6H);对C60H85NO18Si2Na(M+Na)+的LRMS m/z分析结果是:计算值为1186.52,实测值为1186.3。
化合物31.
[231]1H NMR(CDCl3)δ7.39(s,1H),7.30(d,J=3.2Hz,1H),7.07(dd,1H),6.95(d,J=9.2Hz,1H),6.84(m,1H),6.35(m,1H),6.32(m,1H),6.29(s,1H),6.23(t,1H),6.05(d,J=9.2Hz,1H),5.83(dd,1H),5.65(m,2H),4.92(d,1H),4.71(s,1H),4.40(m,2H),4.30(d,J=8Hz,1H),3.91(s,3H),3.75(s,3H),3.73(d,1H),3.40(m,1H),3.06(s,1H),2.56(m,1H),2.34(m,3H),2.22(s,3H),2.17(s,3H),1.85(s,6H),1.70(s,3H),1.29(s,3H),1.25(s,1H),1.16(s,3H);对C44H53NO17Na(M+Na)+的LRMS m/z分析结果是:计算值为890.32,实测值为890.2。
化合物32.
[232]1H NMR(CDCl3)δ7.39(s,1H),7.30(d,J=3.2Hz,1H),7.07(dd,1H),6.95(d,J=9.2Hz,1H),6.36(m,1H),6.31(m,2H),6.22(t,1H),5.92(d,J=9.2Hz,1H),5.59-5.67(m,3H),4.92(d,1H),4.71(m,1H),4.40(m,2H),4.30(d,J=8Hz,1H),3.91(s,3H),3.81(s,3H),3.74(d,1H),3.35(d,1H),3.10(s,1H),2.95(s,1H),2.34-2.58(m,4H),2.23(s,3H),2.20(s,3H),2.09(s,3H),1.86(s,3H),1.85(s,3H),1.73(s,3H),1.29(s,3H),1.25(s,1H),1.16(s,3H);对C45H55NO17Na(M+Na)+的LRMS m/z分析结果是:计算值为904.34,实测值为904.2。
化合物33.
[233]1H NMR(CDCl3)δ7.75(d,1H),7.43-7.56(m,4H),7.29(d,J=2.8Hz,1H),7.06(dd,1H),6.95(d,J=9.2Hz,1H),6.38(s,1H),6.29(m,2H),5.83(d,1H),5.66(d,1H),4.91(d,1H),4.79(m,1H),4.41(d,J=8Hz,1H),4.40(m,1H),4.33(d,J=8Hz,1H),3.95(s,3H),3.81(s,3H),3.77(m,1H),3.12(s,1H),2.42(m,1H),2.25(s,3H),2.24(s,3H),1.86(s,3H),1.73(s,3H),1.29(s,3H),1.25(s,3H);对C47H53NO17Na(M+Na)+的LRMSm/z分析结果是:计算值为926.32,实测值为926.2。
化合物34.
[234]1H NMR(CDCl3)δ7.39(s,1H),7.28(d,J=2.8Hz,1H),7.07(dd,1H),6.95(d,J=9.2Hz,1H),6.36(m,1H),6.31(m,2H),6.21(t,1H),5.67(d,J=6.4Hz,1H),5.26(d,1H),5.19(d,1H),4.93(d,1H),4.68(m,1H),4.40(m,2H),4.30(d,J=8Hz,1H),3.93(s,3H),3.80(s,3H),3.74(d,1H),3.17(m,2H),2.38-2.57(m,4H),2.24(s,3H),2.22(s,3H),1.88(s,3H),1.73(s,3H),1.41(s,9H),1.29(s,3H),1.25(s,3H)1.16(s,3H);对C45H57NO18Na(M+Na)+的LRMS m/z分析结果是:计算值为922.35,实测值为922.2。
化合物35.
[235]1H NMR(CDCl3)δ7.47(s,1H),7.42(s,1H),7.30(d,J=3.2Hz,1H),7.05-7.09(m,2H),6.94-6.99(m,2H),6.51(m,1H),6.38(m,2H),6.28(m,2H),5.75 dd,,1H),5.68(d,J=6.4Hz,1H),4.93(d,1H),4.77(m,1H),4.40(m,2H),4.31(d,J=8.4Hz,1H),3.95(s,3H),3.81(s,3H),3.74(d,1H),3.46(d,1H),3.08(s,1H),2.55(m,1H),2.36-2.43(m,3H),2.23(s,6H),1.85(s,3H),1.73(s,3H),1.29(s,3H),1.16(s,3H);13C NMR(CDCl3)δ204.21,172.66,171.62,170.70,167.21,157.98,153.84,153.23,151.08,147.39,144.88,143.11,142.26,134.01,120.59,120.40,116.10,115.69,113.95,112.73,111.16,108.33,84.95,81.51,78.01,76.89,76.61,76.11,73.14,72.58,72.03,59.28,57.11,56.28,49.81,45.99,43.26,36.97,36.15,27.36,22.97,22.10,21.25,15.33,9.94;对C45H51NO18Na(M+Na)+的LRMSm/z分析结果是:计算值为916.30,实测值为916.2。
化合物36.
[236]1H NMR(CDCl3)δ7.30(t,1H),7.05(dm,1H),6.95(dd,1H),6.72(m,1H),6.45(s,1H),6.05(bt,1H),5.76(d,1H),5.67(d,J=6.4Hz,1H),5.38(m,1H),5.09(m,1H),4.88(d,1H),4.39-4.48(m,3H),4.27(d,J=8.4Hz,1H),3.98(s,3H),3.81(s,3H),3.64-3.80(m,22H),3.56(d,1H),2.90(t,2H),2.74(m,2H),2.41(s,3H),2.16(d,3H),2.10(m,1H),2.00(s,3H),1.90(m,1H),1.81(m,1H),1.71(s,6H),1.69(d,3H),1.61(m,2H),1.21-1.31(m,14H),1.21(s,21H),0.92(m,16H),0.58(m,6H)。
化合物37.
[237]1H NMR(CDCl3)δ7.32(t,1H),7.07(dm,1H),6.95(d,J=9.2Hz,1H),6.78(m,1H),6.31(s,1H),6.16(q,1H),5.66(d,1H),5.61(d,1H),5.39(m,1H),5.06(m,1H),4.93(d,1H),4.39(m,2H),4.25(d,1H),4.21(ddd,1H),3.94(s,3H),3.85(d,1H),3.80(s,3H),3.73(t,3H),3.64-3.65(m,13H),2.98(d,1H),2.90(t,2H),2.80(t,2H),2.39(s,3H),2.21(d,3H),2.06(m,1H),1.86(s,3H),1.84(m,2H),1.75(s,3H),1.71(s,3H),1.69(d,3H),1.61(m,2H),1.27(s,3H),1.14(s,3H),0.89(t,2H);13C NMR(CDCl3)δ203.72,173.09,172.89,172.28,171.68,170.16,170.04,166.74,166.69,165.27,153.42,153.01,152.94,142.36,142.32,140.84,138.82,138.63,133.27,124.49,120.38,120.26,120.19,115.88,115.85,113.57,84.52,81.03,77.74,77.63,76.46,75.79,73.49,73.28,72.46,72.24,72.17,70.64,70.62,70.56,70.51,70.40,69.76,66.36,58.82,56.70,56.66,55.86,50.08,49.76,45.58,42.84,38.39,37.59,36.58,35.76,35.01,26.93,26.86,25.64,25.59,23.47,22.43,21.77,19.14,18.51,18.46,17.74,14.97,14.94,13.58,9.54。
化合物38.
[238]1H NMR(CDCl3)δ7.31(m,3H),7.10(d,1H),6.99(dd,1H),6.78(m,2H),5.41(d,J=4.8Hz,1H),5.23(d,J=5.2Hz,1H),3.73(s,3H),1.01(s,21H);13C NMR(CDCl3)δ165.34,156.22,137.45,130.81,127.49,126.64,126.15,118.65,114.26,78.02,59.28,55.37,17.55,17.46,11.79;对C23H33NO3SSiNa(M+Na)+的LRMS m/z分析结果是:计算值为454.18,实测值为454.0。
化合物40.
[239]1H NMR(CDCl3)δ7.28(dd,1H),7.11(m,2H),6.98(dd,1H),6.78(dd,1H),5.50(d,J=5.6Hz,1H),5.21(d,J=6Hz,1H),1.93(dd,3H),1.01(s,21H);13C NMR(CDCl3)δ166.40,162.70,147.00,136.39,127.61,126.54,125.88,123.61,77.39,57.01,18.35,17.67,17.47,17.37,12.26,11.72;对C20H31NO3SSiNa(M+Na)+的LRMS m/z分析结果是:计算值为416.17,实测值为416.1。
化合物41.
[240]1H NMR(CDCl3)δ7.28(dd,1H),7.11(m,1H),7.00(dd,1H),6.80(s,1H),6.26(dd,1H),5.87(dd,IH),5.50(d,J=6Hz,1H),5.19(d,J=5.6Hz,1H),2.35(s,1H),2.20(dd,6H),0.98(m,21H);13C NMR(CDCl3)δ166.04,164.59,162.83,160.70,148.34,136.96,127.39,126.50,125.65,122.38,120.70,117.18,117.12,115.25,77.14,56.90,17.48,17.39,12.34,11.82;对C21H33NO3SSiNa(M+Na)+的LRMS m/z分析结果是:计算值为430.18,实测值为430.1。
化合物42.
[241]1H NMR(CDCl3)δ7.99(d,2H),7.57(t,1H),7.47(t,2H),7.30(dd,2H),7.18(d,1H),7.01(t,1H),5.73(D,J=6Hz,1H),5.25(d,J=6.4Hz,1H),1.04(m,21H);13C NMR(CDCl3)δ166.13,164.82,136.86,129.89,128.11,127.80,126.58,125.96,76.89,57.11,17.50,17.41,11.83;对C23H31NO3SSiNa(M+Na)+的LRMS m/z分析结果是:计算值为452.17,实测值为452.0。
化合物43.
[242]1H NMR(CDCl3)δ7.30(dd,1H),7.08(dd,1H),6.99(dd,1H),5.34(d,J=5.6Hz,1H),5.15(d,J=5.6Hz,1H),1.42(s,9H)0.95(m,21H);13CNMR(CDCl3)δ165.75,147.74,136.80,127.58,126.48,125.97,122.05,83.53,77.76,58.26,27.88,17.67,17.47,17.37,12.26,11.70;对C21H35NO4SSiNa(M+Na)+的LRMS m/z分析结果是:计算值为448.20,实测值为448.1。
化合物44.
[243]1H NMR(CDCl3)δ7.98(d,1H),7.65(dd,1H),7.29(dd,1H),7.15(dd,1H),6.99(dd,1H),6.56(m,1H),5.71(d,J=6Hz,1H),5.25(d,J=6Hz,1H),0.99(m,21H);13C NMR(CDCl3)δ164.11,147.61,127.96,126.57,126.06,120.95,112.12,76.52,57.17,17.67,17.50,17.39,11.74;对C21H29NO4SSiNa(M+Na)+的LRMS m/z分析结果是:计算值为442.15,实测值是442.0。
化合物45.
[244]1H NMR(CDCl3)δ7.27(d,1H),7.20(d,1H),7.05(dd,1H),6.87-6.95(m,4H),6.76(m,1H),6.45(s,1H),6.27(d,J=9.2Hz,1H),6.17(t,1H),5.85(d,1H),5.75(d,J=9.2Hz,1H),5.68(d,J=6.8Hz,1H),4.92(d,1H),4.83(s,1H),4.40-4.45(m,2H),4.28(d,J=8Hz,1H),3.96(s,3H),3.84(d,1H),3.82(s,3H),3.79(d,1H),3.46(m,1H),3.19(s,1H),2.34-2.49(m,3H),2.30(s,3H),2.17(s,3H),2.00(s,3H),1.85-1.97(m,9H),1.72(s,3H),1.55-1.67(m,5H),1.23(s,6H),1.00(s,21H),0.92(t,9H),0.58(m,6H);对C59H87NO16SSi2Na(M+Na)+的LRMS m/z分析结果是:计算值为1176.52,实测值为1176.4。
化合物46.
[245]1H NMR(CDCl3)δ7.27(d,1H),7.20(d,1H),7.05(dd,1H),6.87-6.95(m,4H),6.45(s,1H),6.15-6.19(m,2H),5.78(d,1H),5.68(d,J=6.8Hz,1H),5.60(s,1H),4.90(d,1H),4.82(s,1H),4.40-4.46(m,2H),4.29(d,J=8Hz,1H),3.96(s,3H),3.84(d,1H),3.82(s,3H),3.76(d,1H),3.46(m,1H),3.23(s,1H),2.49(m,1H),2.34(m,2H),2.31(s,3H),2.17(m,2H),2.14(s,3H),2.07(s,3H),2.01(s,3H),1.85-1.97(m,9H),1.83(s,3H),1.71(s,3H),1.55-1.67(m,3H),1.39(m,1H),1,23(s,6H),1.00(s,21H),0.92(t,9H),0.58(m,6H);对C60H89NO16SSi2Na(M+Na)+的LRMS m/z分析结果是:计算值为1190.53,实测值为1190.5。
化合物47.
[246]1H NMR(CDCl3)δ7.53-7.60(m,3H),7.42-7.46(t,2H),7.20(d,1H),7.13-7.15(m,3H),6.92-7.01(m,3H),6.54(d,J=9.2Hz,1H),6.45(s,1H),6.20(d,1H),5.84(m,1H),5.56(d,J=6.4Hz,1H),4.92(m,1H),4.84(s,1H),4.65(d,1H),4.64(d,1H),4.22(d,J=8Hz,1H),4.08(m,1H),3.79(m,2H),3.74(s,3H),3.30(m,1H),3.25(s,3H),2.67(m,1H),2.46(m,2H),2.18(s,3H),2.17(m,2H),2.07(s,3H),1.69(s,3H),1.21(s,3H),1.18(s,3H),1.17(s,3H),1.13(m,21H),0.92(t,9H),0.58(m,6H);对C62H87NO16SSi2Na(M+Na)+的LRMS m/z分析结果是:计算值为1212.52,实测值为1212.5。
化合物48.
[247]1H NMR(CDCl3)δ7.27(d,1H),7.21(d,1H),7.06(dd,1H),6.90-6.97(m,3H),6.46(s,1H),6.17(t,1H),5.68(d,J=6.8Hz,1H),5.43(d,1H),5.42(d,1H),4.90(d,1H),4.76(s,1H),4.41-4.46(m,2H),4.29(d,J=8Hz,1H),3.94(s,3H),3.79(s,3H),3.77(d,1H),3.24(s,1H),2.52(m,1H),2.41(m,2H),2.30(s,3H),2.01(s,3H),1.88(s,1H),1.73(s,3H),1.40(s,9H),1.23(s,3H),1.22(s,3H),1.00(s,21H),0.92(t,9H),0.58(m,6H);对C60H91NO17SSi2Na(M+Na)+的LRMS m/z分析结果是:计算值为1208.54,实测值为1208.5。
化合物49.
[248]1H NMR(CDCl3)δ7.47(s,1H),7.22-7.29(m,3H),7.06(d,1H),7.05(d,1H),6.94-6.98(m,3H),6.50(m,1H),6.44(s,LH),6.19(t,1H),5.84(d,1H),5.69(d,J=6.8Hz,1H),4.90(d,1H),4.89(s,1H),4.41-4.46(m,2H),4.29(d,J=8.4Hz,1H),3.98(s,3H),3.82(s,3H),3.77(d,1H),3.16(s,1H),2.52(m,1H),2.36(m,1H),2.31(s,3H),2.24(m,1H),2.15(s,3H),2.00(s,3H),1.88(s,1H),1.72(s,3H),1.17(s,6H),1.00(s,21H),0.92(t,9H),0.58(m,6H);对C60H85NO17SSi2Na(M+Na)+的LRMS m/z分析结果是:计算值为1202.50,实测值为1202.4。
化合物50.
[249]1H NMR(CDCl3)δ7.32(d,1H),7.27(dd,1H),7.06-7.10(m,2H),6.95-7.01(m,2H),6.80(m,1H),6.28(s,1H),6.23(t,1H),6.10(d,J=9.2Hz,1H),5.77-5.84(m,2H),5.66(d,J=6.8Hz,1H),4.92(d,1H),4.67(s,1H),4.40(d,J=8.8Hz,1H),4.35(m,1H),4.29(d,J=8Hz,1H),3.96(s,3H),3.82(s,3H),3.73(d,J=6.4Hz,1H),3.54(bs,1H),3.06(bs,1H),2.55(m,1H),2.38(m,3H),2.24(s,3H),2.20(s,3H),1.84(dd,3H),1.82(s,3H),1.29(s,3H),1.16(s,3H);13C NMR(CDCl3)δ203.82,172.30,171.23,170.22,166.79,164.91,153.44,152.91,141.88,141.56,140.94,133.58,127.06,125.82,125.59,124.25,120.32,119.91,115.68,113.59,99.99,84.51,81.15,77.60,76.50,76.12,75.72,73.06,72.76,72.20,58.88,56.74,55.90,50.77,45.58,42.87,36.56,35.75,26.96,22.68,21.67,20.86,17.82,14.98,9.53;对C44H53NO16SNa(M+Na)+的LRMS m/z分析结果是:计算值为906.3,实测值为906.2。
化合物51.
[250]1H NMR(CDCl3)δ7.32(d,1H),7.27(dd,1H),7.06-7.09(m,2H),6.94-6.99(m,2H),6.29(s,1H),6.22(t,1H),6.01(d,J=9.2Hz,1H),5.79(d,1H),5.66(d,J=6.8Hz,1H),5.56(s,1H),4.92(d,1H),4.65(s,1H),4.40(d,J=8Hz,1H),4.35(m,1H),4.30(d,J=8.4Hz,1H),3.95(s,3H),3.82(s,3H),3.74(d,J=6.4Hz,1H),3.52(bs,1H),3.07(bs,1H),2.34-2.57(m,4H),2.24(s,3H),2.21(s,3H),1.84(s,6H),1.72(s,3H),1.29(s,3H),1.15(s,3H);13C NMR(CDCl3)δ203.82,172.51,171.23,170.14,166.79,165.83,153.43,153.19,152.87,142.01,141.21,133.49,127.05,125.64,125.45,120.32,119.90,117.48,115.62,113.55,84.51,81.11,77.56,76.18,75.73,73.17,72.90,72.18,58.85,56.68,55.89,50.57,45.57,42.86,35.73,27.21,26.85,22.67,21.68,20.86,19.84,14.96,9.52;对C45H55NO16SNa(M+Na)+的LRMS m/z分析结果是:计算值为920.31,实测值为920.2。
化合物52.
[251]1H NMR(CDCl3)δ7.66(dd,2H),7.53(tt,1H),7.43(t,2H),7.33(d,1H),7.22(dd,1H),6.97-7.06(m,3H),6.76(d,1H),6.27(s,1H),6.16(d,1H),5.91(d,1H),5.62(d,J=6.4Hz,1H),4.96(bs,1H),4.89(dd,1H),4.74(s,1H),4.52(d,J=7.6Hz,1H),4.16(d,J=7.6Hz,1H),4.00(m,1H),3.80(s,3H),3.63(s,3H),3.34(d,J=6.4Hz,1H),2.87(bs,1H),2.40-2.61(m,4H),2.24(s,3H),1.99(m,1H),1.77(s,3H),1.66(s,3H),1.13(s,3H),1.12(s,3H);对C47H53NO16SNa(M+Na)+的LRMS m/z分析结果是:计算值为942.30,实测值为942.2。
化合物53.
[252]1H NMR(CDCl3)δ7.30(d,1H),7.27(dd,1H),7.06-7.09(m,2H),6.94-7.00(m,2H),6.30(s,1H),6.21(t,1H),5.66(d,J=6.8Hz,1H),5.42(d,1H),5.28(d,1H),4.91(d,1H),4.59(s,1H),4.41(d,J=8Hz,1H),4.38(m,1H),4.30(d,J=8.4Hz,1H),3.94(s,3H),3.81(s,3H),3.74(d,J=6.4Hz,1H),3.48(bs,1H),3.11(bs,1H),2.34-2.57(m,4H),2.22(s,3H),2.19(s,3H),1.89(m,1H),1.85(s,3H),1.72(s,3H),1.39(s,9H),1.29(s,3H),1.15(s,3H);13C NMR(CDCl3)δ203.83,172.63,171.20,170.00,166.81,154.88,153.45,152.74,142.06,141.29,133.46,127.05,125.36,120.23,119.99,115.61,113.47,84.51,81.11,80.36,77.51,76.43,75.72,73.21,73.00,72.15,58.84,56.54,55.85,45.58,42.85,36.47,35.72,28.12,26.73,22.63,20.84,14.95,9.51;对C45H57NO17SNa(M+Na)+的LRMS m/z分析结果是:计算值为938.32,而实测值为938.2。
化合物54.
[253]1H NMR(CDCl3)δ7.46(s,1H),7.32(d,1H),7.28(dd,1H),7.16(d,1H),6.95-7.09(m,4H),6.50(m,1H),6.28(s,1H),6.25(t,1H),5.93(d,1H),5.67(d,J=6.8Hz,1H),4.92(d,1H),4.73(s,1H),4.41(d,J=8.4Hz,1H),4.38(m,1H),4.30(d,J=8.4Hz,1H),3.96(s,3H),3.80(s,3H),3.74(d,J=6.4Hz,1H),3.63(bs,1H),3.09(bs,1H),2.33-2.58(m,4H),2.22(s,3H),2.19(s,3H),1.89(m,1H),1.82(s,3H),1.73(s,3H),1.28(s,3H),1.15(s,3H);对C45H51NO17SNa(M+Na)+的LRMS m/z分析结果是:计算值为932.28,实测值为932.2。
实施例10
体外细胞毒性分析试验
[254]对本发明的新型紫杉类药物和含有二硫化物的紫杉烷药物体外抑制人类肿瘤细胞系增生的能力进行评价。采用人类肿瘤细胞系A-549(人类肺癌)和MCF-7(人类乳腺肿瘤)评价这些化合物的细胞毒性。将细胞暴露于化合物中达72小时,然后用直接测定法(direct assay)测定细胞的存活分数。测定A549和MCF-7的植板率(plating efficiency)(Goldmacher等,J.Cell.Biol.102:1312-1319(1986)),然后从这一数据计算IC50值。
[255]按照以下的方法测定紫杉类药物14、15、31-35、50-54和含有二硫化物的紫杉类药物18和37的细胞毒性。
[256]以不同的密度将A549和MCF-7细胞平板接种到处于补充了10%胎牛血清的DMEM介质中的6孔组织培养皿中。加入不同浓度的紫杉烷,使细胞保持于37℃和6%的二氧化碳的潮湿空气中,直至形成约20个或20个以上细胞的集落(6到10天)。对照板不含紫杉烷。然后采用甲醛固定化细胞,用结晶紫染色,并在低放大倍率的显微镜下计数。然后由集落数目确定植板率,计算细胞的存活分数——被处理样品的植板率和对照组的植板率的比值。
[257]图10示出了本发明12种新型紫杉类药物的细胞毒性测定结果。除了在R4处具有苯基取代基的紫杉烷52之外,其余所有的新型紫杉类药物对A-549和MCF-7细胞系两者都特别有效力,IC50值的范围为10-10到10-11M。紫杉烷52的细胞毒性较小,对所测试的两种细胞系的IC50值为3×10-9M。
[258]图11示出了本发明代表性的含二硫化物的紫杉类药物的细胞毒性曲线。含二硫化物的紫杉类药物18和37两者对A-549和MCF-7细胞都特别有效力,显示出陡峭的杀死率曲线。
Claims (7)
1.式(I)表示的化合物:
其中:
R1是H、吸电子基团、或供电子基团;R1’和R1”相同或不同,为H、吸电子基团或供电子基团;
R2是H;
R3是具有1到10个碳原子的烷基或链烯基、具有3到10个碳原子的环烷基或环烯基、芳基或杂环;
R4是具有1到10个碳原子的烷基或链烯基、具有3到10个碳原子的环烷基或环烯基、芳基、杂环、-OC(CH3)3,或由任意一个的所述的烷基、链烯基、具有3到10个碳原子的环烷基、环烯基、芳基或杂环形成的氨基甲酸酯;
R5是连接基团;以及
R6是H,杂环或芳基醚、酯或氨基甲酸酯;或具有1到10个碳原子的直链、支链或环状烷基或链烯基的酯或醚;或式-COX的氨基甲酸酯,其中X是含氮杂环;或式-CONR10R11的氨基甲酸酯,其中R10和R11相同或不同,为H、具有1到10个原子的直链、支链或环状烷基,或具有1到10个碳原子的单纯的或取代的芳基。
2.权利要求1的化合物,其中R3是-CH=C(CH3)2。
3.式(I)表示的化合物:
其中:
R2是连接基团;
R1是H、吸电子基团或供电子基团;
R1’和R1”相同或不同,为H、吸电子基团或供电子基团;
R3和R4相同或不同,为具有1到10个碳原子的烷基或链烯基、具有3到10个碳原子的环烷基或环烯基、芳基或杂环,R4还可为-OC(CH3)3,或由任意一个的所述的烷基、链烯基、具有3到10个碳原子的环烷基、环烯基、芳基、或杂环形成的氨基甲酸酯;
R5和R6相同或不同,为H;杂环或芳基醚、酯或氨基甲酸酯;或具有1到10个碳原子的直链、支链或环状烷基或链烯基的酯或醚;或式-COX的氨基甲酸酯,其中X是含氮杂环;或式-CONR10R11的氨基甲酸酯,其中R10和R11相同或不同,为H、具有1到10个原子的直链、支链或环状烷基,或具有1到10个碳原子的单纯的或取代的芳基。
4.式(I)表示的化合物
其中:
R5是连接基团;
R1是H、吸电子基团或供电子基团;
R1’和R1”相同或不同,为H、吸电子基团或供电子基团;
R3和R4相同或不同,为具有1到10个碳原子的烷基或链烯基、具有3到10个碳原子的环烷基或环烯基、芳基或杂环;R4还可为-OC(CH3)3或由任意一个的所述的烷基、链烯基、具有3到10个碳原子的环烷基、环烯基、芳基、或杂环形成的氨基甲酸酯;
R2和R6相同或不同,是H;杂环或芳基醚、酯或氨基甲酸酯;或具有1到10个碳原子的直链、支链或环状烷基或链烯基的酯或醚;或式-COX的氨基甲酸酯,其中X是含氮杂环;或式-CONR10R11的氨基甲酸酯,其中R10和R11相同或不同,为H,具有1到10个原子的直链、支链或环状烷基,或具有1到10个碳原子的单纯的或取代的芳基。
5.式(I)表示的化合物:
其中,
R6是连接基团;
R1是H、吸电子基团或供电子基团;
R1’和R1”相同或不同,为H、吸电子基团或供电子基团;
R3和R4相同或不同,为具有1到10个碳原子的烷基或链烯基、具有3到10个碳原子的环烷基或环烯基、芳基或杂环;R4还可为-OC(CH3)3或由任何所述的烷基、链烯基、具有3到10个碳原子的环烷基、环烯基、芳基、或杂环形成的氨基甲酸酯;
R2和R5相同或不同,为H;杂环或芳基醚、酯或氨基甲酸酯;或具有1到10个碳原子的直链、支链或环状烷基或链烯基的酯或醚;或式-COX的氨基甲酸酯,其中X是含氮杂环如哌啶子基、吗啉代、哌嗪基、N-甲基哌嗪基;或式-CONR10R11的氨基甲酸酯,其中R10和R11相同或不同,为H、具有1到10个原子的直链、支链或环状烷基,或具有1到10个碳原子的单纯的或取代的芳基。
6.式(I)表示的化合物:
其中,
R3是连接基团;
R1是H、吸电子基团或供电子基团;
R1’和R1”相同或不同,为H、吸电子基团或供电子基团;
R4是具有1到10个碳原子的烷基或链烯基、具有3到10个碳原子的环烷基或环烯基、芳基或杂环;R4还可为-OC(CH3)3、或由任何所述的烷基、链烯基、具有3到10个碳原子的环烷基、环烯基、芳基、或杂环形成的氨基甲酸酯;
R2、R5和R6相同或不同,为H;杂环或芳基醚、酯或氨基甲酸酯;或具有1到10个碳原子的直链、支链或环状烷基或链烯基的酯或醚;或式-COX的氨基甲酸酯,其中X是含氮杂环如哌啶子基、吗啉代、哌嗪基、N-甲基哌嗪基;或式-CONR10R11的氨基甲酸酯,其中R10和R11相同或不同,为H、具有1到10个原子的直链、支链或环状烷基,或具有1到10个碳原子的单纯的或取代的芳基。
7.式(I)表示的化合物:
其中,
R4是连接基团;
R1是H、吸电子基团或供电子基团;
R1’和R1”相同或不同,为H、吸电子基团或供电子基团;
R3是具有1到10个碳原子的烷基或链烯基、具有3到10个碳原子的环烷基或环烯基、芳基或杂环;另外R4为-OC(CH3)3或由任何所述的烷基、链烯基、具有3到10个碳原子的环烷基、环烯基、芳基、或杂环形成的氨基甲酸酯;
R2、R5和R6相同或不同,为H;杂环或芳基醚、酯或氨基甲酸酯;或具有1到10个碳原子的直链、支链或环状烷基或链烯基的酯或醚;或式-COX的氨基甲酸酯,其中X是含氮杂环如哌啶子基、吗啉代、哌嗪基、N-甲基哌嗪基;或式-CONR10R11的氨基甲酸酯,其中R10和R11相同或不同,为H、具有1到10个原子的直链、支链或环状烷基,或具有1到10个碳原子的单纯的或取代的芳基。
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2003
- 2003-07-14 CA CA002494074A patent/CA2494074A1/en not_active Abandoned
- 2003-07-14 EP EP03766820A patent/EP1534674A4/en not_active Withdrawn
- 2003-07-14 AU AU2003247587A patent/AU2003247587B2/en not_active Ceased
- 2003-07-14 CN CNB038232480A patent/CN100522955C/zh not_active Expired - Fee Related
- 2003-07-14 KR KR1020057001946A patent/KR20050032110A/ko not_active Application Discontinuation
- 2003-07-14 JP JP2004526000A patent/JP2005539009A/ja active Pending
- 2003-07-14 WO PCT/US2003/019558 patent/WO2004013093A2/en active Application Filing
- 2003-07-14 MX MXPA05001390A patent/MXPA05001390A/es active IP Right Grant
- 2003-07-14 BR BR0313197-1A patent/BR0313197A/pt not_active IP Right Cessation
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2004
- 2004-08-26 US US10/926,192 patent/US7495114B2/en not_active Expired - Fee Related
- 2004-10-14 US US10/963,711 patent/US7414073B2/en not_active Expired - Fee Related
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103702686A (zh) * | 2011-02-15 | 2014-04-02 | 伊缪诺金公司 | 缀合物的制备方法 |
CN103702686B (zh) * | 2011-02-15 | 2016-11-23 | 伊缪诺金公司 | 缀合物的制备方法 |
WO2015096553A1 (zh) * | 2013-12-24 | 2015-07-02 | 于跃 | 抗多药耐药紫杉烷类抗肿瘤化合物及其制备方法 |
Also Published As
Publication number | Publication date |
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KR20050032110A (ko) | 2005-04-06 |
EP1534674A2 (en) | 2005-06-01 |
MXPA05001390A (es) | 2005-07-29 |
WO2004013093A3 (en) | 2004-07-01 |
CA2494074A1 (en) | 2004-02-12 |
CN100522955C (zh) | 2009-08-05 |
US7495114B2 (en) | 2009-02-24 |
NO20051108L (no) | 2005-05-02 |
US20050026997A1 (en) | 2005-02-03 |
US7414073B2 (en) | 2008-08-19 |
BR0313197A (pt) | 2005-08-09 |
AU2003247587A1 (en) | 2004-02-23 |
JP2005539009A (ja) | 2005-12-22 |
IL166624A0 (en) | 2006-01-15 |
WO2004013093A2 (en) | 2004-02-12 |
EP1534674A4 (en) | 2007-11-28 |
AU2003247587B2 (en) | 2009-07-09 |
US20050085513A1 (en) | 2005-04-21 |
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