CN1075059C - 秋水仙素衍生物及其治疗用途 - Google Patents
秋水仙素衍生物及其治疗用途Info
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Abstract
本发明涉及通式为(1)的新秋水仙素衍生物,其中Y是-CH2-CH-NH-R3基团或-CH-CH2OR3基团并且其它变量如权利要求1所定义。该衍生物具有抗增生、抗肿瘤和抗炎活性。该新化合物与秋水仙素相比对人肿瘤细胞系具有细胞毒性,但与后者相比,这种新化合物毒性更小并特别是对通常药物有抵抗力的细胞更具有选择性。一些化合物对TNF和白介素2具有明显的活性,因此它是非常有效的抗炎剂。它们可包括在用于肠胃外、口服和局部给药的药剂中。
Description
本发明涉及具有抗增生、抗肿瘤和抗炎活性的新秋水仙素衍生物,它的制备方法以及含有该衍生物的药物组合物。秋水仙素是一种已知在治疗痛风疗法中普遍使用的长效伪生物碱;它能够非常迅速和特异性地起作用,即使由于它的毒性短期使用。此外,秋水仙素还是一种非常有效的抑菌剂,它的作用与阻断细胞分裂中有丝分裂纺锤体的形成的机理有关;就任何抗肿瘤活性来说后一方面已被完全研究过并且为该目的已制备了大量秋水仙素的衍生物。
在危险/有益比方面,由于秋水仙素本身和许多由其制得的衍生物的较高毒性,所以它们没被使用。只有一种秋水仙素衍生物脱甲秋水仙素在肿瘤学的一些时候被用于治疗一些白血病疾病。就有关抗炎领域中的应用而言,硫代秋水仙素是唯一上市的秋水仙素衍生物,它在C10有硫甲基基团并且在C3的羟基上有一个葡萄糖分子;这种衍生物的治疗用途与肌肉松弛和抗炎作用有关。在较高治疗指数方面本发明的产物不同于现有技术中的那些。在抗肿瘤领域,研究者已经把精力集中在对除了具有正常细胞毒性外,还对通常抑菌药剂有抵抗力的细胞系具有细胞毒性的产物研究上。
本发明的衍生物具有通式1其中:X是一个氧原子或硫原子;R1和R2可以相同也可以不同,它们是含有1到6个碳原子的支链或直链烷基或环烷基;或含有16到22个碳原子的饱和或不饱和酰基,或者是一个β-D-葡萄糖残基本身或一个β-D-葡萄糖残基其中用脂族或芳香族或杂芳族醛类保护4和6位羟基为螯合物;Y是-CH2-CH-NH-R3基团,其亚甲基结合到5位碳原子上且次甲基具有与秋水仙素相同的绝对构型并结合到环庚三烯酚酮环上,或是-CH-CH2-OR4基团,其次甲基结合到5位碳原子和环庚三烯酚酮环上并具有绝对构型S;R3是具有1到3个卤原子的2到6个碳原子的酰基,卤原子优选氟或氯,或天然氨基酸的酰基,其中氨基酸是游离的或保护为三氟乙酰胺或苯甲酰胺;R4是含有4到6个碳原子的二羧酸的酰基,或天然氨基酸的酰基,其中氨基是游离的或保护为三氟乙酰胺或苯甲酰胺,或由D-葡萄糖,D-半乳糖、L-岩藻糖或L-鼠李糖组成的苷类。在这种情况下,该糖作为趋药性物质(chemotactic)对黑素细胞瘤、肝细胞、成纤维细胞起作用或者它们使该衍生物具有药物前体的特征。
式1的优选化合物是X是硫的那些化合物。
R1和R2可以相同也可以不同,它们优选是氢或C1-C6的烷基。
Y优选如上所定义的通式为-CH2-CH-NHR3的基团。
为制备本发明产物,所用的起始物是天然物质秋水仙素(1;X=O;R1=R2=Me;Y=CH2-CH-NHAc),2-O-脱甲基秋水仙素(1;X=O;R1=H;R2=Me;Y=CH2-CH-NHAc),3-O-脱甲基秋水仙素(1;X=O;R1=Me;R2=H;Y=CH2-CH-NHAc),秋水仙碱甙(1;X=O;R1=Me;R2=β-D-葡萄糖;Y=CH2-CH-NHAc),这些能够按照文献中的已知步骤从蔬菜物质中收集得到。为了制备通式1的衍生物(其中X是硫),按照文献中的已知步骤把这些天然物质在碱溶液中用甲基硫醇处理可获得相应的用作合成子(syntones)的硫代衍生物。
为制备R1和R2是烷基或酰基的式1衍生物,所用的起始产物是秋水仙素或在2或3位脱甲基的硫代秋水仙素合成子。这些合成子可用所熟知的苯酚衍生方法进行烷基化或酰化。相似的,从秋水仙素或在2或3位脱甲基的硫代秋水仙素合成子制备R1和R2是β-D-葡萄糖残基或者4或6位羟基用脂族或芳香醛保护成螯合物的β-D-葡萄糖残基的通式1的衍生物。这些合成子可与α-溴代-四乙酰基-D-葡萄糖或含有在4和6位为羟基的螯合物基团的2,3-二-O-二氯乙酰基-β-D-葡萄糖反应(参考加拿大专利956939)。用文献中所描述的已知方法除去保护性酰基,得到本发明的2或3位葡萄糖甙化的衍生物。
Y是-CH2-CH-NH-R3基团的式1衍生物是用酸性催化剂使2和3位有甲氧基或羟基的秋水仙素或硫代秋水仙素经过N-去乙酰化,接着用含有1到3个氟或氯原子或天然氨基酸的酸性反应活性衍生物把伯氨基酰化制备的,氨基酸的氨基是游离或保护为三氟乙酰胺或苯甲酰胺。由此制得R3有上述所定义的式1衍生物。获得Y是-CH-CH2-OR4基团的式1衍生物是秋水仙素或使在2和3位的甲氧基或羟基的硫代秋水仙素合成子经过N-去乙酰化,接着用亚硝酸钠和乙酸处理收缩环庚烷环伴随着形成Y=-CH-CH2-OH的式1合成子(J.Med.Chem.36,544,1993)。把所得到的伯醇基团与适当活化的二羧酸,或活化的天然氨基酸,其中的氨基酸可是游离的或保护为三氟乙酰胺或苯甲酰胺,或反应活性形式的糖类D-葡萄糖、D-半乳糖、L-岩藻糖或L-鼠李糖反应,得到Y=-CH-CH2-OR4,R4如上述所定义的式1衍生物。
下表显示了本发明的一些衍生物对肿瘤细胞系的抗有丝分裂活性。紫杉醇和秋水仙素是对照物质。
表--一些新秋水仙素衍生物的体外细胞毒性活性物质 IC50(nM)
细胞系
卵巢 结肠 乳房 肺 细胞抵抗力紫杉醇 6.1 3.5 3.2 1.7 299秋水仙素 5.3 3.9 4.4 16 112化合物ⅠZ 4.2 2.6 6.2 8 26化合物ⅡZ 9.4 1.8 5.0 19 11化合物ⅣZ 6.1 2.2 4.1 12 7
该表证实了新衍生物对有抵抗力的细胞系具有显著益处,这正是细胞毒性药物的主要目标。本发明产物能够掺入用于给药的药物组合物中。一般可制成胃肠外、口腔、经皮、上表皮给药的制剂。
在用于制备上述制剂的赋型剂中,天然和合成的磷脂证实特别适用于制备胃肠外、经皮或上表皮途径的脂质体形式。;后两种制剂特别适用于关节病或外周静脉炎的治疗;该制剂也适合于上皮癌和高度增生病如牛皮癣的局部治疗。在特殊抗肿瘤领域里,以脂质体形式给药的药剂中除了磷脂外,一些表面活性剂如聚乙氧基化的蓖麻油象Cremoform L50或聚山梨酸盐如Tween与活性成分起增效作用证实是具体用途。在肿瘤学上,该产物以1到100mg/m2的剂量使用,而作为抗炎剂以每天两次每单位剂量1到20mg的范围给药。用大部分该衍生物能够制备所有的药物剂型如小瓶装制剂、胶囊、霜剂等。
下列实施例进一步详细说明本发明。实施例Ⅰ-N-去乙酰基-N-三氟乙酰基-3-O-去甲基-3-O-环戊基-硫代秋水仙素,化合物ⅠZ(1;X=S;R1=Me;R2=C5H9;Y=CH2CHNH-COCF3)的制备
把20g3-O-去甲基硫代秋水仙素(1;X=S;R1=Me;R2=H;Y=CH2CHNHAc)溶于300ml的20%硫酸中并在氮气下100℃处理36小时。中和反应混合物,分离得到12g的N-脱乙酰基-3-O-去甲基硫代秋水仙素(1;X=S;R1=Me;R2=H;Y=CH2CHNH2)。把该产物溶于丙酮中并在无水Na2CO3存在下剧烈搅拌将其与3当量的三氟乙酸酐反应。两小时后,过滤该反应混合物并将该溶液蒸干。在含有NH4Cl的甲醇中水解由3-O-去甲基-N-3-O-双三氟乙酰基硫代秋水仙素组成的残余物。在真空下把反应混合物蒸干并把剩余物溶于丙酮中。过滤丙酮溶液并在碳酸钠存在下与5当量的环戊基溴化物回流加热8小时。滤除盐,把溶液蒸干并在硅胶柱上用乙酸乙酯作洗脱液用色谱层析法纯化剩余物。从丙酮/己烷中结晶得到8.6g的产物,M+am/z523。实施例Ⅱ-N-去乙酰基-N-三氟乙酰基-3-O-去甲基-3-O-异丙基-硫代秋水仙素的化合物ⅡZ(1;X=S;R1=Me;R2=iPr;Y=CH2CHNH-COCF3)的制备
为了制备该衍生物,用异丙基溴替代环戊基溴作试剂重复实施例Ⅰ的步骤。在硅胶柱上纯化反应粗产物后,结晶得到7.6g产物,M+am/z497.实施例Ⅲ-N-去乙酰基-N-三氟乙酰基-硫代秋水仙碱甙化合物ⅢZ(1;X=S;R1=Me;R2=β-D-葡糖基;Y=CH2-CH-NHCOCF3)的制备
把10g的N-去乙酰基-硫代秋水仙碱甙(1;X=S;R1=Me;R2=β-D-葡糖基;Y=CH2-CH-NH2)溶于丙酮并在10℃下用3当量的三氟乙酸酐处理2小时。把该混和物蒸干并将剩余物从异丙醇中接着从乙醇中结晶。得到8.5g产物,M+am/z617。实施例Ⅳ-N-(N-三氟乙酰基-α-苯基甘氨酰基)-去乙酰基硫代秋水仙素,化合物ⅣZ(1;X=S;R1=R2=Me;Y=CH2-CH-NH-CO-CH(NHCOCF3)Ph)的制备
在氮气下把400mg的N-去乙酰基-硫代秋水仙甙(1;X=S;R1=R2=Me;Y=CH2-CH-NH2)(1.07mmol)与265mg(1.07mmol)的L-N-三氟乙酰基-α-苯基甘氨酸一起溶于10ml的二氯甲烷中。向溶液中加入221mg(1.07mmol)的N,N-二环己基碳化二亚胺,同时搅拌直到试剂消失为止。把该反应混合物冷却到-30℃并滤除沉淀的脲。浓缩该二氯甲烷溶液并通过在硅胶柱上过滤用二氯甲烷/甲醇98∶2混合物洗脱来纯化。得到350mg产物,M+am/z602。实施例Ⅴ-N-(N-三氟乙酰基-L-丙氨酰基-)-去乙酰基硫代秋水仙素的化合物ⅤZ(1;X=S;R1=R2=Me;Y=CH2-CH-NH-CO-CH(NHCOCF3)CH3)的制备
在氮气下10ml二氯甲烷中用1当量的N-三氟乙酰基-L-丙氨酸和1当量的N,N-二环己基碳化二亚胺处理400mgN-去乙酰基-硫代秋水仙素(1.07mmol)直到试剂消失为止。把该反应混合物冷却到-30℃并滤除沉淀的脲。浓缩该二氯甲烷溶液并通过在硅胶柱上过滤用二氯甲烷/甲醇98∶2混合物洗脱来纯化。从二氯甲烷/乙醚中结晶得到94mg产物,M+am/z540。实施例Ⅵ-N-(N-三氟乙酰基蛋氨酰基)-去乙酰基硫代秋水仙素,化合物ⅥZ(1;X=S;R1=R2=Me;Y=CH2-CH-NHCO-CH(NHCOCF3)CH2-CH2-SMe)的制备
重复实施例Ⅳ的步骤,与N-三氟乙酰基蛋氨酸反应。在把反应残余物色谱层析纯化后用分级结晶法从400mg的N-去乙酰基硫代秋水仙素中得到84mg的产物,M+am/z600。实施例Ⅶ-N-(α-苯基甘氨酰基)-去乙酰基硫代秋水仙素,化合物ⅦZ(1;X=S;R1=R2=Me;Y=CH2-CH-NHCO-CHNH2-Ph)的制备
在120mg碳酸钾存在下把400mg实施例Ⅳ中得到的产物溶于5ml的50%丙酮中并在60℃搅拌下加热5小时。冷却反应混合物,用NaCl饱和并用氯仿萃取。在无水硫酸钠上干燥有机相,然后浓缩至干并在硅胶上用二氯甲烷/甲醇98∶2的混合物色谱层析残余物,得到160mg的产物,M+am/z506。实施例Ⅷ-N-去乙酰基-N-三氟乙酰基-3-O-去甲基-3-O-西门木炔酰基(Ximeninyl)硫代秋水仙素的化合物ⅧZ(1;X=S;R1=Me;R2=CO(CH2)7C≡C-CH=CH-(CH2)5CH3;Y=CH2-CH-NH-CO-CF3)的制备
把500mg的N-去乙酰基-N-三氟乙酰基-3-O-去甲基-硫代秋水仙素(1;X=S;O;R2=H;Y=CH2-CH-NHCOCF3)溶于2.5ml的吡啶中并在0℃加入500mg的西门木炔酰氯。反应混合物在室温下放置过夜,然后到在冰上。分离所得到沉淀并从丙酮/己烷中结晶,M+am/z715。实施例Ⅸ-5,6-二氢-6(S)-[(β-D-葡糖吡喃糖酰氧)甲基]-1,2,3-三甲氧基-9-(甲硫基)-8H-环庚[a]萘-8-酮,化合物ⅨZ(1;X=S;R1=R2=Me;Y=CH-CH2-β-D-葡萄糖)的制备
按照J.Med.Chem.,36,544,1993中所述的方法把10g的N-去乙酰基硫代秋水仙素用亚硝酸钠处理得到4g5,6-二氢-6(S)-(羟甲基)-1,2,3-三甲氧基-9-甲硫基-8H-环庚[a]萘-8-酮。把所得到的产物在85g氰化汞存在下与26gα-溴代四乙酰基葡萄糖在乙腈中回流加热处理12小时。滤除盐并把溶液蒸干,用70%丙酮溶解并用15%碳酸钠处理2小时。把混合物中和,用乙酸乙酯萃取并在硅胶上用二氯甲烷-乙醇9∶1的混合物洗脱进行色谱层析。得到2.1g产物,M+am/z536。实施例X-5,6-二氢-6(S)-(羟甲基)-1,2,3-三甲氧基-9-(甲硫基)-8H-环庚[a]萘-8-酮琥珀酰酯,化合物XZ(1;X=S;R1=R2=Me;Y=CH-CH2-OCOCH2CH2CO2H)的制备
象实施例Ⅸ一样处理10gN-去乙酰基硫代秋水仙素。把所得到的奈-8-酮溶于吡啶中并在回流加热下用琥珀酸酐处理24小时。冷却反应混合物,倒入足量的水中并用二氯甲烷萃取。把有机相浓缩成少量并在硅胶上用二氯甲烷-水-甲醇70∶30∶5混合物洗脱纯化。从甲醇中结晶后,得到7g产物,M+am/z474。
Claims (9)
1.式1化合物其中:X是氧原子或硫原子;R1、R2可以相同也可以不同,分别是含有1到6个碳原子的支链或直链烷基或环烷基;或含有16到22个碳原子的饱和或不饱和酰基,或者是B-D-葡萄糖基或β-D-葡萄糖基,其中用脂族或芳香族或杂芳香醛将4和6位的羟基保护为螯合物;Y是-CH2-CH-NH-R3基团,其亚甲基结合到5位碳原子上,具有与秋水仙素相同的绝对构型的次甲基结合到环庚三烯酚酮环上;R3是具有1到3个卤原子的2到6个碳原子的酰基,或天然氨基酸的酰基,其中氨基酸是游离的或保护为三氟乙酰胺或苯甲酰胺;条件是当R1和R2为甲基,X为氧或硫原子时,R3不为COCH2F,COCH2Cl,COCH2Br,COCH2I;当R1和R2为甲基,X为氧原子时,R3不为COCl3,COCHCl2,COCHF2,COCH2CHClCH3;COCH2CH2CHBrCH3;或由D-葡萄糖,D-半乳糖、L-岩藻糖或L-鼠李糖组成的苷。
2.根据权利要求1的化合物,其中X是硫。
3.根据权利要求1的化合物,其中X是氧。
4.根据权利要求2或权利要求3的化合物,其中R1和R2可以是相同也可以不同,它们是含有1到6个碳原子的直链或支链的烷基或环烷基。
5.根据权利要求1-3任何一个要求的化合物,其中所述卤原子选自氟或氯。
6.一种制备权利要求1-5的化合物的方法,它包括使秋水仙素、2-O-去甲基秋水仙素、3-O-去甲基秋水仙素、秋水仙碱甙进行下列一种或多种反应:a)在碱溶液中与甲基硫醇反应;b)将苯酚基团烷基化、酰化或糖基化;c)用酸性催化剂N-去乙酰化并接着用R3如权利要求1中所定义的R3-COOH酸或其反应活性衍生物将伯氨基功能团酰化;d)N-去乙酰化,接着用亚硝酸钠和乙酸处理得到化合物1,其中Y是Y-CH-CH2-OH并随后与氨基酸的二羧酸衍生物或与D-葡萄糖,D-半乳糖、L-岩藻糖或L-鼠李糖的反应活性衍生物反应。
7.一种药物组合物,它含有权利要求1-5中的化合物作活性成分及适当的载体。
8.权利要求7的药物组合物,其中载体选自天然或合成磷脂。
9.权利要求1-5的化合物在制备具有抗增生、抗肿瘤和抗炎活性的药物中的用途。
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GB9714249D0 (en) | 1997-07-08 | 1997-09-10 | Angiogene Pharm Ltd | Vascular damaging agents |
FR2779147B1 (fr) * | 1998-05-27 | 2000-06-30 | Synthelabo | Derive de thiocolchicoside sa preparation et son application en therapeutique |
US6433187B1 (en) | 1998-12-17 | 2002-08-13 | Tularik Inc. | Certain polycyclic compounds useful as tubulin-binding agents |
GB9900334D0 (en) | 1999-01-07 | 1999-02-24 | Angiogene Pharm Ltd | Tricylic vascular damaging agents |
US6399093B1 (en) | 1999-05-19 | 2002-06-04 | Advanced Medical Instruments | Method and composition to treat musculoskeletal disorders |
US6720323B2 (en) | 2000-07-07 | 2004-04-13 | Angiogene Pharmaceuticals Limited | Colchinol derivatives as angiogenesis inhibitors |
WO2002004434A1 (en) * | 2000-07-07 | 2002-01-17 | Angiogene Pharmaceuticals Limited | Colchinol derivatives as vascular damaging agents |
US6624317B1 (en) | 2000-09-25 | 2003-09-23 | The University Of North Carolina At Chapel Hill | Taxoid conjugates as antimitotic and antitumor agents |
ITMI20031144A1 (it) * | 2003-06-06 | 2004-12-07 | Indena Spa | Analoghi del colchicoside. |
PT2128170E (pt) * | 2008-05-28 | 2011-02-23 | Indena Spa | Processo para a glicosidação de colchicina e tiocolchicina |
JP2013502441A (ja) * | 2009-08-26 | 2013-01-24 | アルバータ・ヘルス・サービシーズ | 新規コルヒチン誘導体、方法、およびその使用 |
WO2016059650A1 (en) | 2014-10-14 | 2016-04-21 | Council Of Scientific & Industrial Research | 10-substituted colchicinoids as potent anticancer agents |
WO2023077977A1 (zh) * | 2021-11-08 | 2023-05-11 | 天津市昕晨投资发展有限公司 | 秋水仙碱衍生物的制备方法及其用途 |
CN114907228B (zh) * | 2022-06-27 | 2023-11-28 | 深圳市锦泰医药科技合伙企业(有限合伙) | 一种秋水仙碱和厚朴酚复合物及其合成方法以及在抗新冠病毒方面的应用 |
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