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CN1219924A - 秋水仙素骨架化合物,其作为药物的用途以及含有该化合物的组合物 - Google Patents

秋水仙素骨架化合物,其作为药物的用途以及含有该化合物的组合物 Download PDF

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CN1219924A
CN1219924A CN97194988A CN97194988A CN1219924A CN 1219924 A CN1219924 A CN 1219924A CN 97194988 A CN97194988 A CN 97194988A CN 97194988 A CN97194988 A CN 97194988A CN 1219924 A CN1219924 A CN 1219924A
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E·鲍姆巴德利
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Abstract

本发明涉及秋水仙素和硫代秋水仙素衍生物,该物质可通过将这些分子的C－7功能基化成酮或功能基化成氨基制得。所述化合物对正常癌细胞和抗药表型均有显著的抑制增殖活性。本发明的化合物可通过注射和口服给药。

Description

秋水仙素骨架化合物， 其作为药物的用途以及含有该化合物的组合物
本发明涉及具有抗增殖、抗肿瘤和抗炎活性的新的秋水仙素衍生物、其制备方法以及含有该化合物的药物制剂。
秋水仙素是一种已知的伪生物碱，在相当长的时间内被广泛用于治疗痛风，秋水仙素对该疾病的作用非常迅速并且具有很高特异性，尽管如此，由于它的毒性，仍应短期使用。秋水仙素衍生物，即硫代秋水仙碱苷，被广泛由于治疗挛缩和骨骼肌炎症。此外，秋水仙素还是一种非常有效的抑制增殖剂，它可以在细胞分裂过程中阻断有丝分裂纺锤体的形成；在这方面，对抗肿瘤活性进行了深入的研究，并为此制备了大量的秋水仙素衍生物。秋水仙素及其大量衍生物的高毒性导致了其无法接受的危险性/有益效果比，因此不能用于临床。只有一种秋水仙素衍生物、即秋水仙胺在一定程度上在肿瘤学中用于治疗某些类型的白血病。
因此，存在的问题是如何得到具有令人满意的危险性/有益效果比、即治疗活性高而副作用小或无副作用的抗肿瘤药物。
抗肿瘤领域的另一个问题是以特定的表型产生的抗药性。
现已惊奇地发现，某些秋水仙素衍生物对正常癌细胞和相应的抗药性表型(MDR)具有很高的细胞毒性。
本发明的化合物是有效的细胞程序死亡的诱导剂，显著优于现有技术的化合物。由于该化合物的亲脂特性，其在口服给药后的生物利用度非常好。此外，本发明的化合物还可通过胃肠外或局部的途径给药。
本发明涉及式(Ⅰ)化合物
Figure A9719498800041
其中的R是甲氧基或甲硫基，R1是1-6个碳原子的直链或支链的烷基或链烯基，或脂环或杂环基团、饱和或不饱和的一元或二元羧酸或氨基酸的酰基残基或β-D-葡萄糖或6-脱氧半乳糖残基。
烷基的例子是甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、戊基、新戊基、己基。
链烯基的例子是丙烯基、1-丁烯基、2-丁烯基、1-戊烯基。
脂环基团的例子是环丙基、环丁基、环戊基、环己基。
杂环基团的例子是苯并三唑基、甲基四唑基。
酰基残基的例子是西门木烯酰基、琥珀酰基、天冬氨酰基。
式Ⅰ化合物从天然的秋水仙素或硫代秋水仙素或其C3-衍生物进行制备，该物质可购买到或可以通过文献中已知的方法制得。如文献所述，C3衍生物可通过将3-O-二甲基衍生物与烷基卤化物或酰卤反应进行制备。将所述化合物用强的无机酸水溶液水解，通过改变温度和反应时间，可以选择性地得到相应的N-二乙酰基衍生物。具体地讲，硫代秋水仙素或其C3衍生物的脱乙酰化反应可以通过将化合物酸水解来完成；对于硫代秋水仙素，用氢卤酸或更优选用硫酸(20％硫酸-120h)水解可以以近乎定量的收率得到N-脱乙酰基硫代秋水仙素和3-脱甲基-N-脱乙酰基硫代秋水仙素。
将N-脱乙酰基衍生物与4-甲酰基-1-甲基吡啶鎓对甲苯磺酸盐和1,8-二氮杂双环[5.4.0]壬-7-烯(DBU)反应制备式Ⅰ化合物。
或者，将N-脱乙酰基衍生物与2,3-二叔丁基-1,2-苯醌反应，得到式Ⅱ的化合物：其中的R和R1具
Figure A9719498800061
本发明另一方面涉及式Ⅱ的化合物。
本发明的化合物在体外和体内均表现出显著的抗肿瘤活性。
下表给出了与秋水仙素和紫杉酚相比，本发明化合物对于培养的正常(MCF-7)或对阿霉素和长春花碱均有抗药性的(MCF7-ADR)乳腺肿瘤外植体的抗有丝分裂活性。
                                       表5
   化合物                    IC50(nM)
MCF7-ADR     MCF-7  MCF7-ADR/MCF7
秋水仙素化合物Ia化合物Ib化合物Ic紫杉酚     12,0001540522,400     1.86.223172.3     6,6002.41.73.01,043
该表表明，本发明的化合物对于抗药性细胞系具有显著的优点，这些抗药性细胞系目前被认为是细胞毒性药物的主要靶点。
此外，本发明的化合物还具有抗炎和抗关节炎(变性类风湿性关节炎或类似的疾病)活性，可将其掺入用于治疗给定疾病的药物制剂中。可以方便地制备用于静脉内、口服、经皮、经上皮(epicutaneous)给药的制剂。
在用于制备上述制剂的赋形剂中，已证实天然的和合成的磷脂特别适于制备用于胃肠外和/或局部给药的脂质体形式。已证实该制剂可用于局部治疗皮肤的上皮癌和皮肤的过度增殖情况如牛皮癣。在抗肿瘤领域，除了磷脂能够使药物以脂质体形式给药外，某些表面活性剂如聚氧乙基化的蓖麻油或聚山梨醇酯可以对活性成分起到增效作用，因此特别有用。优选将活性成分微粒化以便将化合物溶于水中。非常有效的、方便的形式是这些化合物与环糊精的复合物。
在肿瘤学中，所述产品的使用剂量为1-100mg/m2。
用以下实施例进一步说明本发明。
实施例1从N-脱乙酰基硫代秋水仙素制备硫代秋水仙酮(thiocolchicone)(Ⅰb:R=OMe；R1=Me)
将100ml二氯甲烷和30ml DMF在氮气氛下混合，然后加入4g脱乙酰基秋水仙素(M.W.373,10.7mmol)和24.2g 4-甲酰基-1-甲基吡啶鎓对甲苯磺酸盐(M.W.279,15mmol)；将反应液回流3小时或一直回流到胺消失。将溶液于0℃下冷却，然后滴加1.94g DBU(M.W.152,12.8mmol)，得到深红色溶液。15分钟后，加入150ml草酸水溶液，将该混合物放置使其反应过夜，然后反复用二氯甲烷萃取；用硫酸钠干燥并蒸除溶剂至干。将残余物用乙酸乙酯结晶得到78％的收率。硫代秋水仙酮具有如下物理化学和波谱学特征。M.p.212℃MS(E.I.):372m/z(35％)-344(55％)-329(6％)-311(13％)-301(4％)-287(8％)-267(4％)-243(4％)-215(4％)-84(64％)-49(100％).1H-NMR(300MHz,CDCl3)ppm        molt        int     type       J(Hz)     J(Hz)    J(Hz)2.45       s           3H      SME2.68       ddd         1H      H-5eq.     13.4      4.8      1.92.81       ddd         1H      H-6ax      16.6      13.4     4.82.95       ddd         1H      H-6eq      16.6      5.5      1.93.11       ddd=td      1H      H-5ax      13.1      13.5     5.63.57       s           3H      OMe3.88       s           3H      OMe3.90       s           3H      OMe6.56       s           1H      H-46.96       s           1H      H-87.07       AB          1H      H-11       10.27.27       AB          1H      H-12       10.213C-NMR(300MHz,CDCl3):15.8ppm(SMe)-30.0(C-5)-48.0(C-6)-56.7(OMe-3)-61.8(OMe-2)-61.8(OMe-1)-107.8(C-4)-125.3(C-12b)-127.0(C-11)-130.7(C-8)-134.4(C-4a)-136.1(C-12a)-136.5(C-12)-142.3(C-2)-150.4(C-1)-152.6(C-7a)-154.6(C-3)-160.7(C-10)-182.9(C-9)-206.2(C-7).
实施例2从N-脱乙酰基-秋水仙素制备秋水仙酮(colchicone)(Ⅰa:R=SMe；R1=Me)
将3.58g N-脱乙酰基秋水仙素根据实施例1的方法进行处理。得到2.6g秋水仙酮，其具有如下物理化学和波谱学特征。MS(E.I.):356m/z(100％)-328(95％)-313(25％)-300(22％)-285(18％)-271(26％)-253(13％)-238(8％)-227(13％)-199(16％)-171(11％).1H-NMR(300MHz,CDCl3)ppm       molt      int      type   J(Hz)    J(Hz)    J(Hz)2.67      ddd       1H       H-5β      13.7     5.0      2.22.82      ddd       1H       H-6β      16.6     13.6     5.02.95      ddd       1H       H-6α      16.6     5.4      2.23.11      ddd       1H       H-5α      13.7     13.6     5.43.55      s         3H       OMe-13.86      s         3H       OMe-23.87      s         3H       OMe-34.00      s         3H       OMe-106.54      s         1H       H-46.85      d         1H       H-11    10.77.12      s         1H       H-87.24      d         1H       H-12    10.713C-NMR(300MHz,CDCl3):29.27ppm(C-5)-43.33(C-6)-55.96(OMe-10)-56.44(OMe-3)-61.07(OMe-2)-61.12(OMe-1)-106.96(C-4)-112.40(C-11)-124.50(C-12b)-132.00(C-4a)-132.80(C-8)-135.30(C-12)-136.15(C-12a)-141.80(C-2)-150.16(C-1)-151.83(C-7a)-153.70(C-3)-164.10(C-10)-179.40(C-9)-205.60(C-7).
实施例3硫代秋水仙素和3,5-二叔丁基-1,2-苯醌的缩合产物的制备(Ⅱa:R=SMe；R1=Me)
将500mg脱乙酰硫代基秋水仙素(M.W.373,1.34mmol)和590mg3,5-二叔丁基-1,2-苯醌(M.W.220,2.69mmol)于常压下溶于50ml甲醇。
通过TLC(二氯甲烷∶丙酮 30∶1)监测反应，约18小时后真空蒸除溶剂。
将热的粗产物溶于1体积的乙酸乙酯中，加入1-1.5体积的己烷并将该混合物用冰冷却。过滤回收反应产物，收率为70％。该化合物具有如下物理化学和波谱学特征。M.P.238℃，分解。MS(E.I.):573m/z(33％)-558(1％)-545(100％)-530(9％)-514(7％)-314(4％)-301(4％)-265(7％)-249(7％).1H-NMR(300MHz,CDCl3)ppm          molt       int        type        J(Hz)     J(Hz)1.30         s          9H         tBu1.40         s          9H         tBu2.45         s          3H         SMe3.05         dd         1H         H-5         14.0       4.03.30         dd         1H         H-5         14.0       4.03.55         s          3H         OMe3.83         s          3H         OMe3.87         s          3H         OMe3.86         t          1H         H-6          4.06.65         s          1H         H-47.08         d          1H         H-11         11.07.20         d          1H         H-5′        2.07.26         d          1H         H-3′        2.07.28         d          1H         H-12         11.07.33         s          1H         H-813C-NMR(300MHz,CDCl3):15.71 ppm (SMe)-30.33(C(CH3)3)-31.95(C(CH3)3)-34.96((C(CH3)3)-35.25(C(CH3)3)-36.60(C-5)-56.41(OMe-3)-61.81(OMe-1)-61.64(OMe-2)-76.47(C-6)-109.80(C-4)-123.56(C-5′)-124.61(C-3′)-125.75(C-12b)-126.80(C-11)-132.28(C-4′)-133.58(C-6′)-135.13(C-8)-135.47(C-4a)-136.10(C-12)-137.01-(C-12a)-142.35(C-2)-143.21(C-7a)-144.88(C-2′)-147.19(C-1′)-152.06(C-1)-153.78(C-3)-159.85(C-10)-164.68(C-7)-182.26(C-9).
实施例4含有化合物(Ⅰa)的片剂的制备化合物Ⅰa                                         25mg乳糖                                              47mg微晶纤维素                                        20mg交联羧甲基纤维素钠                                5mg胶性二氧化硅                                      1mg滑石                                              1mg硬脂酸镁                                          1mg
实施例5含有化合物(Ⅱa)的脂质体霜剂的制备化合物Ⅱa                                         0.20g磷脂酰胆碱                                        20.00g胆甾醇                                            0.50g丁基羟基甲苯                                      0.01g95％乙醇                                          8.00g依地酸二钠                                        0.15g咪唑烷基脲                                        0.30g脱氢乙酸钠                                        0.20g羟乙基纤维素(Natrsol 250 HHX-Aqualon)             2.00g蒸馏水                                            67.75
实施例6含有化合物(Ⅰa)的可注射溶液的制备化合物Ⅰa                                              15mgPEG-660 12-羟基硬脂酸酯                                2.500mg丙二醇                                                 1.000mg乙醇适量至                                             5ml

Claims (21)

1．式Ⅰ化合物
Figure A9719498800021
其中的R是甲氧基或甲硫基，R1是1-6个碳原子的直链或支链的烷基或链烯基，或脂环或杂环基团、饱和或不饱和的一元或二元羧酸或氨基酸的酰基残基或β-D-葡萄糖或6-脱氧半乳糖残基。
2．根据权利要求1的化合物，其中的R是甲氧基。
3．根据权利要求1的化合物，其中的R是甲硫基。
4．根据权利要求2的化合物，其中的R1是甲基。
5．根据权利要求3的化合物，其中的R1是甲基。
6．式Ⅱ的化合物：其中的R和R1具有权利要求1所定义的含义。
7．根据权利要求6的化合物，其中的R是甲氧基。
8．根据权利要求6的化合物，其中的R是甲硫基。
9．根据权利要求8的化合物，其中的R1是甲基。
10．权利要求1-5的化合物的制备方法，该方法包括将N-脱乙酰基秋水仙素或N-脱乙酰基硫代秋水仙素与4-甲酰基-1-甲基吡啶鎓对甲苯磺酸盐和1,8-二氮杂双环[5.4.0]壬-7-烯(DBU)反应。
11．权利要求6-9的化合物的制备方法，该方法包括将N-脱乙酰基秋仙素或N-脱乙酰基硫代秋水仙素与3,5-二叔丁基-1,2-苯醌反应。
12．权利要求1-9的化合物作为药物的用途。
13．权利要求1-9的化合物在生产具有抗肿瘤或抗增殖活性的药物中的用途。
14．权利要求1-9的化合物在生产具有抗炎和抗关节炎活性的药物中的用途。
15．药物组合物，含有有效量的权利要求1-9的化合物。
16．根据权利要求15的组合物，所述组合物适于胃肠外给药。
17．根据权利要求15的组合物，所述组合物适于经肠给药。
18．根据权利要求15的组合物，所述组合物适于局部给药。
19．根据权利要求16或18的组合物，所述组合物为脂质体制剂的形式。
20．根据权利要求15-19中任意一项的组合物，所述组合物含有表面活性剂如聚氧乙基化的蓖麻油或聚山梨醇酯。
21．根据权利要求15-19中任意一项的组合物，所述组合物含有与环糊精的复合物形式的活性成分。
CN97194988A 1996-06-07 1997-05-21 秋水仙素骨架化合物,其作为药物的用途以及含有该化合物的组合物 Expired - Fee Related CN1122657C (zh)

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