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CN1181825C - 秋水仙醇衍生物在制备作为血管破坏剂的药物中的应用 - Google Patents

秋水仙醇衍生物在制备作为血管破坏剂的药物中的应用 Download PDF

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CN1181825C
CN1181825C CNB988069466A CN98806946A CN1181825C CN 1181825 C CN1181825 C CN 1181825C CN B988069466 A CNB988069466 A CN B988069466A CN 98806946 A CN98806946 A CN 98806946A CN 1181825 C CN1181825 C CN 1181825C
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G·多尔蒂
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Abstract

公开了式I所示的秋水仙醇衍生物及其可药用盐、溶剂化物和水合物，其中R1、R2、R3和R6分别独立地代表氢、任选取代的烷基、环烷基、链烯基、炔基、芳烷基、链烷酰基、PO3H2；X是羰基(CO)、硫代羰基(CS)、亚甲基(CH2)或CHR4；R4是OH、烷氧基或NR8R9；R5和R7分别独立地代表氢、烷基、卤素、羟基、烷氧基、硝基或氨基；R8是氢、任选取代的烷基、环烷基、链烷酰基、硫代链烷酰基、芳基、杂芳基、芳基羰基、杂芳基羰基、烷氧基羰基、芳氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、芳基氨基羰基、烷基磺酰基、芳基磺酰基、氨基磺酰基、烷基氨基磺酰基、二烷基氨基磺酰基或芳基氨基磺酰基；且R9是氢、烷基或环烷基。已发现这些物质能用于治疗涉及血管生成的疾病。其中一些所述化合物是新的。特别优选的是其中R6是PO3H2的化合物。

Description

秋水仙醇衍生物在制备作为血管破坏剂的药物中的应用
本发明涉及血管破坏剂，尤其是涉及其中一些是新化合物的秋水仙醇衍生物在制备用于治疗新血管形成的治疗剂中的应用。
由血管生成导致新血管组织的形成是数种疾病的主要病理学特征(J Folkman，《新英格兰医学杂志》(New England Journal ofMedicine)333，1757(1995))。例如，实体瘤要生长就必须形成主要依靠其供给氧和营养物的自己的血液供给系统；如果该血液供给系统被机械性切断，实体瘤就会坏死。新血管形成也是牛皮癣中的皮肤损伤、类风湿性关节炎患者关节中的侵袭性血管翳以及动脉粥样硬化性血小板的临床特征。视网膜新血管形成是黄斑变性和糖尿病性视网膜病的病理学特征。在所有这些疾病中，人们预计通过破坏新形成的血管内皮来逆转新血管形成会具有良好疗效。
秋水仙醇(colchinol)衍生物例如N-乙酰秋水仙醇是已知的。已经在动物模型中证实了其抗肿瘤作用(参见，例如JNCI(《国立癌症研究所杂志》(Journal National Cancer Institute))第379-392页，1952年，第13卷)。然而，所研究的作用只是总体破坏效果(出血、变软和坏死)，其中没有提出任何通过破坏新血管组织来治疗不适当的血管生成的建议。
基于下述结构的《化学文摘》(Chemical Abstracts)(1955后)检索展现了一些与秋水仙醇有关的结构。
因为微管蛋白结合剂可能会具有抗有丝分裂活性，并因此对肿瘤细胞有直接作用，所以已经研究了所有这些化合物的抗癌活性。
在进行本发明的研究过程中，研究了微管蛋白结合特性与可能的抗血管效力之间的相关性问题，但是没有发现任何可预测性。因此，微管蛋白结合剂-docetaxel(《柳叶刀》(Lancet)，344，1267-1271，1994)没有任何血管破坏作用，甚至以其最大耐受剂量给药时也是如此。甚至当本发明者测试了一些在结构上与本发明化合物相关的化合物时，也发现对于可能的临床有效性，治疗窗口(MTD(最大耐受剂量)与MED(最小有效剂量)的比值)太小。
本发明提供了秋水仙醇衍生物在制备用于治疗涉及血管生成的疾病的组合物中的应用，其中所述秋水仙醇衍生物是式I所示化合物及其可药用盐、溶剂化物和水合物，
Figure C9880694600081
其中
R1、R2、R3和R6分别独立地代表氢、任选取代的烷基、环烷基、链烯基、炔基、芳烷基、链烷酰基、PO3H2；
X是羰基(CO)、硫代羰基(CS)、亚甲基(CH2)或CHR4；
R4是OH、烷氧基或NR8R9；
R5和R7分别独立地代表氢、烷基、卤素、羟基、烷氧基、硝基或氨基；
R8是氢、任选取代的烷基、环烷基、链烷酰基、硫代链烷酰基、芳基、杂芳基、芳基羰基、杂芳基羰基、烷氧基羰基、芳氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、芳基氨基羰基、烷基磺酰基、芳基磺酰基、氨基磺酰基、烷基氨基磺酰基、二烷基氨基磺酰基或芳基氨基磺酰基；
且R9是氢、烷基或环烷基。
虽然不是限制本发明，但是据信，与一旦血管组织已经形成效果就变得很差的已知抗血管生成剂相比，本发明化合物能破坏新形成的血管组织，例如肿瘤的血管组织，因此能有效地逆转新血管生成过程。
其中一些本发明化合物是新的。在一个实施方案中，新化合物是其中R1、R2、R3和R6至少有一个为PO3H2的式I化合物。在一个特别优选的实施方案中，R6是PO3H2。特别优选的是式II所示化合物及其可药用盐、溶剂化物和水合物，
其中
R1、R2和R3分别独立地代表氢、任选取代的烷基、环烷基、链烯基、炔基、链烷酰基或PO3H2；
R6为PO3H2；
R4是H或NR8R9；
R5和R7分别独立地代表氢、烷基、卤素、烷氧基、硝基或氨基；
R8是氢、任选取代的烷基、环烷基、链烷酰基、硫代链烷酰基、芳基、杂芳基、芳基羰基、杂芳基羰基、烷氧基羰基、芳氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、芳基氨基羰基、烷基磺酰基、芳基磺酰基、氨基磺酰基、烷基氨基磺酰基、二烷基氨基磺酰基或芳基氨基磺酰基；
且R9是氢、烷基或环烷基。
另一方面，本发明提供了式IIA所示新化合物及其可药用盐、溶剂化物和水合物，
其中
R1、R2和R3分别独立地代表氢、任选取代的烷基、环烷基、链烯基、炔基、链烷酰基或PO3H2；
R6为氢、任选取代的烷基、环烷基、链烯基、炔基或PO3H2；
R4是H或NR8R9；
R5和R7分别独立地代表氢、烷基、卤素、硝基或氨基；
R8是氢、任选取代的烷基、环烷基、链烷酰基、硫代链烷酰基、芳基、杂芳基、芳基羰基、杂芳基羰基、烷氧基羰基、芳氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、芳基氨基羰基、烷基磺酰基、芳基磺酰基、氨基磺酰基、烷基氨基磺酰基、二烷基氨基磺酰基或芳基氨基磺酰基；
且R9是氢、烷基或环烷基，条件是：当R1、R2和R3都是甲基，并且R4是氢、乙酰氨基、乙酰基甲基氨基、氨基、甲氨基或二甲氨基时，则R6不是氢、甲基或羟乙基、或乙酰氧乙基。
用于本发明且作为本发明的优选化合物是其中R1、R2和R3是烷基的那些化合物以及其中R4是酰氨基的那些化合物。
本说明书所用术语“烷基”(包括涉及烷基的所有脂肪族结构)表示具有1-7个、优选最多4个碳原子的直链或支链基团，例如甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基和戊基。可存在于烷基上的任选的取代基包括一个或多个选自下述基团的取代基：卤素、氨基、一烷基氨基、二烷基氨基、羟基、烷氧基、烷硫基、烷基磺酰基、酰氨基、烷氧基羰基氨基、链烷酰基、酰氧基、羧基、硫酸基或磷酸基。烷氧基的实例有甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基和叔丁氧基。术语“卤素”表示氟、氯、溴或碘。
链烯基是具有2-7个碳原子的烯基，例如亚甲基、乙烯基、正丙烯基、异丙烯基、正丁烯基、异丁烯基、仲丁烯基和叔丁烯基。炔基是具有2-7个碳原子的炔基，例如乙炔基、丙炔基或丁炔基。
术语芳基无论单独地存在还是结合存在都表示未取代的苯基或具有一个或多个、优选1-3个取代基的苯基，所述取代基的实例有卤素、烷基、卤代烷基、羟基、硝基、氰基、氨基和烷氧基。卤代烷基可具有一个或多个卤素原子，卤代烷基的实例有三氟甲基和二氯甲基。
术语杂芳基在本说明书中定义为单环或二环芳基，其中含有1-4个选自N、S和O的杂原子以及最多9个碳原子。杂芳基的实例包括吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、吲哚基、苯并呋喃基、苯并噻吩基、苯并噻唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、咪唑基、三唑基、喹啉基和异喹啉基。
术语芳烷基在本说明书中定义为，其中一个氢原子被上述芳基或杂芳基取代的上述烷基。
当式I、II、IIA化合物中的一个或多个官能团具有足够的碱性或酸性时，就可以形成盐。合适的盐包括可药用盐，例如酸加成盐，包括盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、硫氢酸盐、烷基磺酸盐、芳基磺酸盐、乙酸盐、苯甲酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、乳酸盐和酒石酸盐，衍生自无机碱的盐，包括碱金属盐如钠盐或钾盐、碱土金属盐如镁盐或钙盐，以及衍生自有机胺的盐例如吗啉盐、哌啶盐或二甲胺盐。
本领域技术人员应当认识到，式I、II、IIA化合物能以立体异构体和/或几何异构体形式存在，因此本发明包括所有这些异构体及其混合物。
一组有用的化合物包括其中R1、R2和R3分别是烷基的那些化合物。
另一组有用的化合物包括其中R1、R2和R3分别是烷基并且R5和R7分别是氢的那些化合物。在该组化合物中，特别有用的是其中R1、R2和R3分别是甲基并且R6是氢、烷基或PO3H2的那些化合物。
特别有用的本发明化合物包括：
N-乙酰基秋水仙醇-O-磷酸酯及其盐、溶剂化物和水合物。
式I、II或IIA化合物可通过多种如下一般描述、并且在后面实施例中更具体描述的方法制得。在下述方法的描述中，除非另外指出，用在反应式中的符号R1、R2、R3、R4、R5、R6和R7代表上面对式I、II或IIA化合物所述的那些基团。在下述反应方案中，可能需要利用保护基，然后将保护基在合成的最后阶段除去。这种保护基的适当应用及其除去方法对本领域技术人员来说是显而易见的。
因此，依据本发明的另一方面，其中R5、R6和R7分别是氢的式II或IIA化合物可通过用碱过氧化氢处理式(2)化合物制得。该反应一般可在氢氧化钠水溶液中、在不存在或存在共溶剂如醇例如乙醇条件下、于例如0-100℃、优选60℃或接近60℃温度下进行。
式(2)中间体可通过将式(3)化合物用酸水解制得；该反应一般在酸水溶液如盐酸中、于升高的温度下如在100℃或接近100℃温度下进行。
Figure C9880694600122
式(3)化合物是已知的或可用秋水仙碱按常规方法制得。
式I、II或IIA化合物也可以由其它式I、II或IIA化合物通过化学修饰制得。可采用的化学修饰的实例有一般的烷基化、芳化、杂芳化、酰化、硫代酰化、磺酰化、硫酸化、磷酰化、芳卤化和偶合反应。这些反应可用于添加新取代基或修饰已有的取代基。或者，可通过例如氧化、还原、消除、水解或其它断裂反应将式I、II或IIA化合物上已有的取代基修饰以生成其它式I、II或IIA化合物。
因此，例如含有氨基的式II或IIA化合物可通过在碱如叔胺碱例如三乙胺存在下、在例如溶剂如烃类溶剂例如二氯甲烷中、在例如-30-120℃、通常在室温或接近室温下用例如酰卤或酸酐处理而将氨基酰化。
在相互转化的另一一般的实例内，可通过在碱如叔胺碱例如三乙胺存在下、在例如溶剂如烃类溶剂例如二氯甲烷中、在例如-30-120℃、通常在室温或接近室温下、用例如烷基或芳基磺酰氯或烷基或芳基磺酸酐处理来将式II或IIA化合物上的氨基磺酰化。
在另一一般实例内，可将含有羟基的式II或IIA化合物通过下述处理来转化成相应的二氢磷酸酯：在适当催化剂如四唑存在下、在溶剂如醚类溶剂例如四氢呋喃中、于-40-40℃、通常是室温或接近室温下用例如二乙基氨基磷酸二叔丁酯处理；然后用氧化剂例如3-氯过苯甲酸在-78-40℃、优选-40℃--10℃温度下处理；将所得磷酸三酯中间体在溶剂如氯化熔剂例如二氯甲烷中、在-30-40℃、通常在0℃或接近0℃温度下用酸例如三氟乙酸处理，生成了含有二氢磷酸酯的式(2)化合物。
在另一一般实例内，可将含有酰胺的式(2)化合物在溶剂如醇例如甲醇中、于升高的温度下、通常是回流温度下用酸例如盐酸处理来使其水解。
在另一一般实例内，通过与三溴化硼在溶剂如氯化溶剂例如二氯甲烷中、于低温下例如约-78℃反应，O-烷基可裂解成相应的醇(OH)。
在另一一般实例内，式II或IIA化合物可通过与适当烷化剂例如卤代烷、甲苯磺酸烷基酯、甲磺酸烷基酯或三氟甲基磺酸烷基酯反应而烷基化。烷基化反应可在碱如无机碱例如碳酸盐如碳酸铯或碳酸钾、氢化物如氢化钠或醇盐例如叔丁醇钾存在下、在适当溶剂如非质子传递溶剂例如二甲基甲酰胺或醚类溶剂例如四氢呋喃中、于-10-80℃温度下进行。
式II或IIA化合物的单一对映体或适当时非对映异构体的制备可从对映异构纯的原料或中间体进行合成，或可通过用常规方法将终产物拆分来实现。
式II或IIA化合物的酸加成盐可按照常规方法、用约1当量的可药用酸处理式II或IIA游离碱的溶液或悬浮液制得。衍生于无机碱或有机碱的式I、II或IIA化合物的盐可按照常规方法、用约1当量的可药用无机碱或有机碱处理式I、II或IIA游离酸的溶液或悬浮液制得。或者，酸加成盐或衍生于碱的盐都可通过将母化合物用适当的离子交换树脂以标准方式处理制得。采用常规浓缩和重结晶技术来分离这些盐。
本发明化合物能破坏肿瘤脉管系统和已经新形成的脉管系统而不影响正常、成熟的脉管系统。在下述实施例中描述的试验可证实本发明化合物的这种功能。
因此，本发明化合物特别适用于预防和治疗涉及实体瘤的癌症，以及预防和治疗发生不适当新血管形成的疾病例如糖尿病性视网膜病、牛皮癣、类风湿性关节炎、动脉粥样硬化和黄斑变性。
本发明化合物可单独给药治疗，或者与其它治疗结合起来进行。为了治疗实体瘤，本发明化合物可与放疗结合起来进行给药，或可与选自下述活性剂的其它抗肿瘤物质联合给药：核分裂抑制剂，例如长春碱、紫杉醇和docetaxel；烷化剂，例如顺铂、卡铂和环磷酰胺；抗代谢物，例如5-氟尿嘧啶、阿糖胞苷和羟基脲；嵌入剂，例如阿霉素和博来霉素；酶，例如天冬酰胺酶；拓扑异构酶抑制剂，例如依托泊苷、托泊替堪和伊利替康；胸苷酸合成酶抑制剂，例如raltitrexed；生物反应调节剂，例如干扰素；抗体，例如edrecolomab；和抗激素，例如他莫昔酚。这种联合治疗可包括将各治疗剂同时或依次给药。
为了治疗和预防疾病，本发明化合物可作为依据欲采用的给药途径和标准药物惯例所选择的药物组合物给药。这种药物组合物可以是适于口服给药、颊给药、鼻内给药、局部给药、直肠给药或非胃肠道给药的剂型，并且可按照常规方法用常用赋形剂制得。例如，口服给药的药物组合物可以制成片剂或胶囊。对于鼻内给药或吸入给药，化合物可以粉末或溶液形式方便地给药。局部给药剂型可以是软膏或乳膏，直肠给药剂型可以是栓剂。对于非胃肠道注射(包括静脉内注射、皮下注射、肌内注射、血管内注射或输注)，组合物可以制成例如无菌溶液、悬浮液或溶液。
预防或治疗具体疾病所需本发明化合物的剂量与所选的化合物、给药途径、疾病的类型和严重程度、以及化合物是单独给药还是与其它药物联合给药有关。因此精确剂量应由给药医师确定，但是日剂量通常为0.001-100mg/kg、优选为0.1-50mg/kg。
生物活性
进行下述试验以证实本发明化合物的活性和选择性。
用放射性示踪物测定的抗肿瘤脉管系统的活性
下述试验证实了本发明化合物选择性地破坏肿瘤脉管系统的能力。
将含有约106个细胞的0.05ml粗制肿瘤细胞悬浮液注射到12-16周大小的小鼠的后背皮肤下面，来引发皮下CaNT肿瘤。大约3-4周后，当其肿块长到5.5-6.5mm的几何平均直径时，选择小鼠进行治疗。将化合物溶解在无菌生理盐水中，并以0.1ml/10g体重的剂量腹膜内注射。腹膜内给药6小时后，通过86RbCI提取技术(Sapirstein，《美国生理学杂志》(Amer J Physiol)，193，161-168，1958)测定肿块、肾、肝脏、皮肤、肌肉、肠和脑中的血液灌注量。静脉内注射86RbCI 1分钟后，测定组织放射性来计算作为心输出量比例的相对血流量(Hill和Denekamp，《英国放射学杂志》(BritJ Radiol)，55，905-913，1982)。对照组和治疗组使用5只小鼠。以用载体治疗的小鼠的相应组织中的血流量百分比来表示结果。
荧光染料测定的抗肿瘤脉管系统的活性
下述试验进一步证实了本发明化合物破坏肿瘤脉管系统的能力。
按照Smith等人的方法(《英国癌症杂志》(Brit J Cancer)，57，247-253，1988)，用荧光染料Hoechst 33342测定长有CaNT肿瘤的小鼠中的肿瘤机能血管体积。对照组和治疗组使用5只小鼠。将荧光染料以6.25mg/ml的比例溶解在生理盐水中，并且在腹膜内给药治疗6小时后，以10mg/kg体重的量静脉内注射。1分钟后，处死小鼠，切除肿瘤并冷冻；在3个不同水平切10μm的切片，并用配有外荧光计的Olympus显微镜在UV照射下观察。以其荧光轮廓确定血管，按照Chalkley描述的点打分系统(《国立癌症研究所杂志》(J NatlCancer Inst)，4，47-53，1943)来定量表示血管体积。所有评价都是基于在3个不同水平切的切片上计数最少100个区域。以50mg/kg或低于50mg/kg剂量给药，本发明化合物使肿瘤机能血管体积减小了20％以上。
下述非限制性实施例对本发明举例说明。在实施例中，除非另外指明，所有1Hnmr都是在300MHz下测定的。柱色谱法是在硅胶上进行的。所有温度单位都是℃。使用的下述缩写表示：THF-四氢呋喃；DMSO-二甲亚砜；MCPBA-3-氯过苯甲酸。
实施例1
N-乙酰秋水仙醇-O-磷酸酯
在氮气下，将N-乙酰秋水仙醇(260mg，0.76mmol)的无水THF(2ml)溶液用二乙基氨基磷酸二叔丁酯(189mg，0.75mmol)和1(H)-四唑(0.14g，1.99mmol)处理，并将溶液在20℃搅拌0.5小时。将溶液冷却至-40℃，以溶液温度能维持在-10℃以下的速度加入85％的MCPBA(202mg，0.99mmol)的无水二氯甲烷(2ml)溶液。将溶液的温度升至室温，加入乙醚(30ml)，把所得溶液依次用10％的焦亚硫酸钠水溶液(洗两次，每次25ml)、5％的碳酸氢钠水溶液(洗两次，每次25ml)、5％的柠檬酸水溶液(30ml)、5％的碳酸氢钠水溶液和盐水洗涤。将有机溶液减压浓缩，把剩余物进行柱色谱处理，获得了含有N-乙酰秋水仙醇-O-二叔丁基磷酸酯的白色泡沫状物(170mg)，将其再溶解在二氯甲烷(5ml)中，冷却至0℃并用三氟乙酸(0.5ml)处理。
将溶液的温度升至室温，搅拌1小时，然后减压浓缩，用乙醚研制，得到了标题化合物(110mg)为白色固体，熔点为233-235℃。δH(d6-DMSO)8.38(d，1H，J＝8Hz)，7.27(d，1H，J＝7Hz)，7.12(d，1H，J＝8Hz)，7.10(s，1H)，6.77(s，1H)，4.48(m，1H)，3.81(s，3H)，3.76(s，3H)，3.49(s，3H)，2.5(被DMSO峰部分覆盖的单峰)，1.9-2.2(m，2H)，1.86(s，3H)。
通过上述放射性示踪物分析法测定该磷酸酯化合物的活性：本实施例化合物以125mg/kg给药时使肿瘤中血流量下降了65％，而皮肤、肌肉、肝脏、肾、肠和心脏中的血流量没有显著下降。
比较该磷酸酯化合物与母化合物N-乙酰秋水仙醇的最大耐受剂量(MTD)(三只动物中没有发生死亡)、通过上述荧光染料技术测定的最小有效剂量(MED)和治疗窗口(MTD/MED)。
                            MTD            MED            治疗窗口
                            mg/kg体重      mg/kg体重      (MTD/MED)
N-乙酰秋水仙醇              125            30             4
N-乙酰秋水仙醇-O-磷酸酯     750            50             15
虽然该磷酸酯的MED有少量增加，但是“治疗窗口”显著增大。这是出乎意料的。该磷酸酯还具有更好的溶解性。
比较秋水仙碱(与本发明化合物结构最相似的活性剂)和docetaxel(微管蛋白结合药物，商品名为“Taxotere”，无血管破坏活性)的“治疗窗口”，试验数据列在下表中：
表1-其它微管蛋白结合剂的治疗窗口(通过荧光染料技术测定的)
化合物                           MED                       MTD              MTD/MED
                                 (mg/kg体重)               (mg/kg体重)
docetaxel                        ＞30(在30时无任何作用)    30               ＜1
秋水仙碱                         2.5                       5                2
实施例2
N-乙基秋水仙醇
在冰浴冷却下，用15分钟将N-乙酰秋水仙醇(500mg，1.4mmol)的THF(15ml)溶液滴加到氢化铝锂(106mg，2.74mmol)的THF(10ml)溶液中。将混合物加热回流15小时，冷却至室温，再用氢化铝锂(53mg，1.4mmol)处理，然后再加热回流3小时。将混合物冷却(冰浴)，滴加水(10ml)，然后用乙酸乙酯萃取3次。合并萃取液并干燥(MgSO4)，然后减压浓缩，得到了绿色胶状物，然后用乙醚研制，得到了标题化合物，为浅绿色固体。熔点为185℃(分解温度)，m/e 343(M+)。
元素分析C20H25NO4H2O
计算值：C，66.46；H，7.53；N，3.88；
实测值：C，66.50；H，7.17；N，3.79。
实施例3
N-苄氧基羰基秋水仙醇
将氯甲酸苄酯(0.566ml，3.97mmol)滴加到秋水仙醇(625mg，1.98mmol)的无水吡啶(10ml)溶液中，将混合物搅拌16小时。减压除去溶剂，加入水，将所得混合物用氯仿萃取3次。合并萃取液并干燥(MgSO4)，然后减压浓缩，得到了棕色胶状物，然后进行硅胶柱色谱处理，用50％的乙酸乙酯/石油醚洗脱。将得到的橙色胶状物用乙醚/石油醚重结晶，得到了标题化合物(346mg)，为浅黄色固体。熔点为79-81℃，m/e 449(M+)。
元素分析C26H27NO60.33H2O
计算值：C，68.57；H，6.07；N，3.08；
实测值：C，68.71；H，6.18；N，2.91。
实施例4
N-(苯基氨基甲酰基)秋水仙醇
将异氰酸苯酯(0.151ml，1.39mmol)滴加到秋水仙醇(400mg，1.27mmol)的无水吡啶(10ml)溶液中，将混合物搅拌18小时，然后加热回流2小时。减压除去溶剂，加入水，将所得混合物用氯仿萃取3次。合并萃取液并干燥(MgSO4)，然后减压浓缩，得到了深棕色胶状物，然后进行硅胶柱色谱处理，用35％的乙酸乙酯/石油醚洗脱。将得到的胶状物用乙醚/石油醚重结晶，得到了标题化合物(261mg)，为浅橙色固体。熔点为145-146℃，m/e 434(M+)。
实施例5
N-甲磺酰基秋水仙醇
用氢氧化钠(40mg，1mmol)处理N，O-二甲磺酰基秋水仙醇(234mg，0.5mmol)的甲醇(8ml)溶液，将混合物加热回流3小时。减压除去溶剂，加入水(5ml)。加入1M的盐酸将溶液中和，并用二氯甲烷萃取3次。合并萃取液并干燥(MgSO4)，然后减压浓缩，得到了标题化合物(123mg)，为粉红色固体。熔点为234-236℃，m/e 393(M+)。
所用原料N，O-二甲磺酰基秋水仙醇是按照下述方法制得的：用甲磺酰氯(0.135ml，1.7mmol)处理秋水仙醇(500mg，1.6mmol)的无水吡啶(15ml)溶液，将混合物在室温下搅拌36小时。再加入甲磺酰氯(0.135ml，1.7mmol)并再搅拌16小时。减压除去溶剂，加入水(5ml)。将溶液用氯仿萃取3次，合并萃取液并干燥(MgSO4)，然后减压浓缩，得到了棕色胶状物，然后进行硅胶柱色谱处理，用乙酸乙酯洗脱，得到了N，O-二甲磺酰基秋水仙醇(292mg)，为浅橙色固体。
实施例6
N-二甲基氨基磺酰基秋水仙醇
用二甲基氨基磺酰氯处理秋水仙醇(50mg，0.16mmol)在无水乙腈(3ml)和三乙胺(0.022ml，0.16mmol)中的溶液，将混合物搅拌30分钟，然后加热回流15小时。减压除去溶剂，加入水，并用氯仿萃取3次。合并萃取液并干燥(Na2SO4)，然后减压浓缩，得到了深棕色胶状物，然后进行硅胶柱色谱处理，用乙酸乙酯洗脱。得到了标题化合物(46mg)，为固化的浅橙色胶状物。熔点为82-85℃，m/e 422(M+)。
实施例7
N-乙酰基-O-甲氧基羰基甲基秋水仙醇
在0℃用溴乙酸甲酯(322mg，2.1mmol)和氢化钠(84mg 60％的油悬浮液，2.1mmol)处理N-乙酰秋水仙醇(500mg，1.4mmol)的无水DMF(5ml)溶液，将混合物搅拌30分钟。加入水(50ml)，将所得混合物用乙酸乙酯萃取4次。合并萃取液，依次用水洗涤4次、用氯化钠饱和水溶液洗涤2次，干燥(MgSO4)，然后减压除去溶剂，得到了标题化合物(280mg)，为白色固体。熔点为82-83℃，m/e429.2(M+)。
元素分析C23H27NO70.33H2O
计算值：C，63.45；H，6.40；N，3.22；
实测值：C，63.53；H，6.29；N，3.17。
实施例8
N-乙酰基-O-羧甲基秋水仙醇
用氢氧化钾水溶液(1.0M，5ml)处理N-乙酰基-O-甲氧基羰基甲基秋水仙醇(140mg，0.33mmol)的乙腈(5ml)溶液，将混合物在80℃加热30分钟。将混合物冷却，加入2M盐酸将其pH调至3，将混合物用乙酸乙酯萃取4次。合并萃取液，用氯化钠饱和水溶液洗涤2次，干燥(MgSO4)，然后减压浓缩.加入丙酮(2ml)和己烷(1ml)，得到了标题化合物(58mg)，为白色固体。熔点为220-221℃，m/e 415.3(M+)。
元素分析C22H25NO70.33H2O
计算值：C，62.71；H，6.14；N，3.32；
实测值：C，62.63；H，6.02；N，3.26。
实施例9
N-乙酰基-O-环戊基秋水仙醇
在0℃依次用氢化钠(33mg 60％的油悬浮液，0.84mmol)和溴环戊烷(125mg，0.84mmol)处理N-乙酰秋水仙醇(200mg，0.56mmol)的无水DMF(2ml)溶液，将混合物搅拌1小时.再加入氢化钠(17mg 60％的油悬浮液，0.42mmol)和溴环戊烷(63mg，0.42mmol)，将混合物在室温下搅拌过夜。加入水(10ml)，将混合物用乙酸乙酯萃取4次。合并萃取液，用氯化钠饱和水溶液洗涤2次，干燥(MgSO4)，然后减压浓缩。得到了标题化合物(160mg)，为白色固体。熔点为89-94℃，m/e 425.3(M+)。
元素分析C25H31NO5
计算值：C，70.54；H，7.35；N，3.29；
实测值：C，70.55；H，7.35；N，3.25。
实施例10
N-乙酰基-10-硝基秋水仙醇
缓慢地用20ml浓硝酸(0.34ml)的乙酸(100ml)溶液处理N-乙酰秋水仙醇(100mg，0.27mmol)的冰醋酸(20ml)溶液，将温度维持在约12℃。将混合物在室温下搅拌18小时，在加入1ml硝酸/乙酸溶液，并继续搅拌2小时。将混合物倒入冰中，用乙酸乙酯萃取3次。合并萃取液，用氯化钠饱和水溶液洗涤2次，干燥(MgSO4)，然后减压浓缩。用硅胶纯化产物，用乙酸乙酯洗脱，得到了标题化合物(50mg)，为浅黄色固体。熔点为117-118℃，m/e 401.9(M+)。
元素分析C20H22N2O70.33H2O
计算值：C，58.82；H，5.56；N，6.86；
实测值：C，58.87；H，5.66；N，6.55。
实施例11
使用上述荧光染料技术测定以50mg/kg给药的实施例1-10化合物与N-乙酰秋水仙醇抗肿瘤脉管系统的活性。
实施例化合物                      血管体积减少的百分比(％)
    1                                 89
    2                                 38
    3                                 43
    4                                 37
    5                                 38
    6                                 30
    7                                 12
    8                                 49
    9                                 59
    10                                28
    N-乙酰秋水仙醇                    78

Claims (17)

1.秋水仙醇衍生物在制备用于治疗涉及血管形成的疾病的组合物中的应用，其中所述秋水仙醇衍生物是式I所示化合物或其可药用盐，
其中
R1、R2、R3和R6分别独立地代表氢、PO3H2或选自以下基团的烷基基团：C1-7烷基、环戊基和C1-7烷酰基，其中该烷基基团是未取代的或带有一个或多个选自以下基团的取代基：羟基、羧基和C1-7烷氧基羰基；
X是羰基、亚甲基或CHR4；
R4是OH或NR8R9；
R5和R7分别独立地代表氢、C1-7烷氧基或硝基；
R8是氢；选自以下基团的芳基基团：苄氧基羰基、苯基羰基和苯基氨基羰基，其中任一苯环是未取代的或带有一个或多个选自卤素的取代基；或选自以下基团的烷基基团：C1-7烷基、C1-7烷酰基、C1-7烷氧基羰基、C1-7烷基氨基羰基、C1-7烷基磺酰基和二(C1-7烷基)氨基磺酰基，其中该烷基基团是未取代的或带有一个或多个选自以下基团的取代基：卤素、羟基、羧基、C1-7单烷基氨基和二(C1-7烷基)氨基；
且R9是氢。
2.权利要求1的应用，其中R1、R2、R3和R6中至少有一个是PO3H2。
3.权利要求2的应用，其中R6是PO3H2。
4.权利要求1-3中任一项的应用，其中R1、R2和R3是C1-7烷基。
5.权利要求1的应用，其中R4是酰氨基。
6.权利要求1的应用，其中R6是PO3H2，R1、R2和R3是C1-7烷基，且R4是酰氨基。
7.式I化合物或其可药用盐，
其中
R1、R2、R3和R6分别独立地代表氢、PO3H2或选自以下基团的烷基基团：C1-7烷基、环戊基和C1-7烷酰基，其中该烷基基团是未取代的或带有一个或多个选自以下基团的取代基：羟基、羧基和C1-7烷氧基羰基；
X是羰基、亚甲基或CHR4；
R4是OH或NR8R9；
R5和R7分别独立地代表氢、C1-7烷氧基或硝基；
R8是氢；选自以下基团的芳基基团：苄氧基羰基、苯基羰基和苯基氨基羰基，其中任一苯环是未取代的或带有一个或多个选自卤素的取代基；或选自以下基团的烷基基团：C1-7烷基、C1-7烷酰基、C1-7烷氧基羰基、C1-7烷基氨基羰基、C1-7烷基磺酰基和二(C1-7烷基)氨基磺酰基，其中该烷基基团是未取代的或带有一个或多个选自以下基团的取代基：卤素、羟基、羧基、C1-7单烷基氨基和二(C1-7烷基)氨基；
且R9是氢；
条件是R1、R2、R3和R6中至少一个是PO3H2。
8.权利要求7的化合物或其可药用盐，其中R6是PO3H2。
9.权利要求8的化合物或其可药用盐，其中R1、R2和R3是C1-7烷基，且R4是酰氨基。
10.式II所示的化合物或其可药用盐，
Figure C988069460004C1
其中
R1、R2和R3分别独立地代表氢、PO3H2或选自以下基团的烷基基团：C1-7烷基、环戊基和C1-7烷酰基，其中该烷基基团是未取代的或带有一个或多个选自以下基团的取代基：羟基、羧基和C1-7烷氧基羰基；R6为PO3H2；
R4是H或NR8R9；
R5和R7分别独立地代表氢、C1-7烷氧基或硝基；
R8是氢；选自以下基团的芳基基团：苄氧基羰基、苯基羰基和苯基氨基羰基，其中任一苯环是未取代的或带有一个或多个选自卤素的取代基；或选自以下基团的烷基基团：C1-7烷基、C1-7烷酰基、C1-7烷氧基羰基、C1-7烷基氨基羰基、C1-7烷基磺酰基和二(C1-7烷基)氨基磺酰基，其中该烷基基团是未取代的或带有一个或多个选自以下基团的取代基：卤素、羟基、羧基、C1-7单烷基氨基和二(C1-7烷基)氨基；且R9是氢。
11.式IIA化合物或其可药用盐，
其中
R1、R2和R3分别独立地代表氢、PO3H2或选自以下基团的烷基基团：C1-7烷基、环戊基和C1-7烷酰基，其中该烷基基团是未取代的或带有一个或多个选自以下基团的取代基：羟基、羧基和C1-7烷氧基羰基；
R6为氢、PO3H2或选自以下基团的烷基基团：C1-7烷基和环戊基，其中该烷基基团是未取代的或带有一个或多个选自以下基团的取代基：羟基、羧基和C1-7烷氧基羰基；
R4是H或NR8R9；
R5和R7分别独立地代表氢或硝基；
R8是氢；选自以下基团的芳基基团：苄氧基羰基、苯基羰基和苯基氨基羰基，其中任一苯环是未取代的或带有选自卤素的一个或多个取代基；或选自以下基团的烷基基团：C1-7烷基、C1-7烷酰基、C1-7烷氧基羰基、C1-7烷基氨基羰基、C1-7烷基磺酰基和二(C1-7烷基)氨基磺酰基，其中该烷基基团是未取代的或带有一个或多个选自以下基团的取代基：卤素、羟基、羧基、C1-7单烷基氨基和二(C1-7烷基)氨基；
且R9是氢；条件是：当R1、R2和R3都是甲基，并且R4是氢、乙酰氨基、氨基或甲氨基时，则R6不是氢、甲基或羟乙基。
12.权利要求11的化合物或其可药用盐，其中R1、R2和R3是C1-7烷基，且R4是酰氨基。
13.一种药用组合物，包含权利要求7-12中任一项的化合物和赋形剂。
14.权利要求13的药用组合物，其中化合物是N-乙酰秋水仙醇-O-磷酸酯。
15.化合物N-乙酰秋水仙醇-O-磷酸酯或其可药用盐。
16.N-乙酰秋水仙醇-O-磷酸酯或其可药用盐在制备用于治疗涉及血管形成的疾病的组合物中的应用。
17.制备权利要求7-12和15中任一项的化合物的方法，该制备方法通过用碱过氧化氢处理式(2)化合物来进行，
Figure C988069460006C1
其中R1、R2、R3、R4、R5、R6和R7如权利要求7-12和15中任一项定义；或者
通过对权利要求1、10和11中任一项的式I、II或IIA化合物进行化学修饰来进行。
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