CN1091601C - 用苯酚取代的二磷酸酯作抗肿瘤剂 - Google Patents
用苯酚取代的二磷酸酯作抗肿瘤剂 Download PDFInfo
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- CN1091601C CN1091601C CN96196005A CN96196005A CN1091601C CN 1091601 C CN1091601 C CN 1091601C CN 96196005 A CN96196005 A CN 96196005A CN 96196005 A CN96196005 A CN 96196005A CN 1091601 C CN1091601 C CN 1091601C
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- butyl
- diphosphonic acid
- hydroxy phenyl
- tert
- ethenylidene
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Abstract
本发明提供用一种苯酚取代的偕-二磷酸酯制备治疗和预防肿瘤疾病特别是Ras依赖性癌症的药物,其中苯酚取代的偕-二磷酸酯选自通式(I)的化合物,通式(I)中Z1、Z2、Z3和Z4是相同或不同的,是OR,R是H、含有1到8个碳原子的直链、支链或环状烷基,OM中M是一个阳离子,NR2中R有如上定义的相同含意,Z1、Z2和Z3、Z4可以形成一种含有2到8个碳原子的亚烷基二氧环,X1、X2是相同或不同并是H、含有1到8个碳原子的直链、支链或环状烷基或烷氧基,X3是H、含有1到4个碳原子的烷基R1、酰基C(O)R1、氨甲酰基C(O)NHR1,其中R1如上所述,X3O和两种其他取代基X1或X2可以形成含有1到4个碳原子的亚烷基二氧环,A是-CH=CH-CH2-、-(CH2)m-、-O(CH2)n-、-S-、-SO2-、-S(CH2)n-、-SO2(CH2)n-,其中n是1到7的整数,或A与B形成一种通式为-(CH=CH)k-(CH2)d-CH=的亚烷基,其中k是0或1而d是从0到4的整数,B是H、一个含有1到4个碳原子的烷基,t是0或1,条件是A是-(CH=CH)k-(CH2)d-CH=其中k和d是如上所述的时候t是0。
Description
本发明涉及抗肿瘤剂,特别是用苯酚取代的偕-二磷酸酯衍生物治疗肿瘤疾病。更具体地说,本发明提供了用一些苯酚取代的偕-二磷酸酯衍生物制备用于治疗和预防癌症和转移并且特别是用于治疗和预防Ras肿瘤基因依赖性癌症和转移性侵袭的药物组合物。
已有的多数抗癌药物是对杀死肿瘤细胞缺乏特异性的细胞毒素类化合物并由此影响正常细胞,从而产生毒副作用。所以对开发作用于细胞传送信号通道造成抑制癌细胞增殖而不影响正常细胞增生的更特异性药剂是需要的(溶瘤细胞药物,J.R.Prous,特药物年报,1994版,第459页和在癌症化疗中使用Ras致肿瘤基因方法,G.Bolton等,Annual Reports inMedicinal Chemistry,1994:29:165-17)。
现已表明Ras肿瘤基因的突变存在于各种人肿瘤中并且这些突变可以对所有人类癌症的1/5起作用。人们现已发现50%以上的结肠癌和90%胰腺癌是由其引起的。所以人们认为Ras突变在触发癌症形成和发展中起重要作用(J.L.Bos,癌症研究.1989;49:4682-4689)。现在也已经确认Ras蛋白的突变形式仅存在于肿瘤中而不存在于癌症患者的正常组织中。所以,有吸引力的治疗剂是能阻断把正常细胞转化为癌细胞以及进一步促进癌细胞和肿瘤发展的Ras突变的活性。
相应于欧洲专利N°0,339,237的美国专利N°5,043,330(1991)公开了一类苯酚取代的偕-二磷酸酯衍生物和它们作为降脂剂的用途如治疗心血管疾病。
本申请人目前惊奇地发现在US 5,043,330中公开的这类二磷酸酯能够特异地抑制癌细胞增生以及诱发癌细胞的细胞程序死亡而对正常细胞没有毒性。所以,一方面,本发明提供了用化合物制备治疗肿瘤疾病的药物,该化合物具有下列通式(I):其中:-Z1、Z2、Z3和Z4是相同或不同的,并是-OR,其中R是H、含有1到8个碳原子的直链、支链或烷基,-OM,其中M是一个阳离子,-NR2,其中R有如上定义的相同含意,-Z1、Z2和Z3、Z4可以形成含有2到8个碳原子的亚烷基二氧环,-X1、X2是相同或不同并是H、卤原子、含有1到8个碳原子的直链、支链或环烷基或烷氧基,-X3是H、含有1到4个碳原子的烷基R1、酰基C(O)R1、氨甲酰基C(O)NHR1,其中R1如上所述,X3O和两种其他取代基X1或X22-可以形成含有1到4个碳原子的亚烷基二氧环,-A是-CH=CH-CH2-、-(CH2)n-、-O(CH2)n-、-S-、-SO2-、-S(CH2)n-、-SO2(CH2)n-,其中n是1到7的整数,或A与B形成通式为-(CH=CH)k-(CH2)d-CH=的亚烷基,其中k是0或1而d是从0到4的整数,-B是H、含有1到4个碳原子的烷基,-t是0或1,条件是当A是-(CH=CH)k-(CH2)d-CH=其中k和d是如上所述的时候t是0。
通式(I)的化合物可以盐存在,本文下列通式(I)的化合物包括化合物的盐形式,除非另有说明。盐的例子是通式(I)的化合物,其中Z1、Z2、Z3和Z4中的一个或多个基团是由OM或氨鎓NR4组成,其中M是碱金属或碱土金属离子或R具有如上所定义的相同含义。
另一方面,本发明提供了用如前所定义的通式(I)的化合物制备治疗固体肿瘤例如结肠、胰腺、甲状腺、肺、乳腺、脑部和颈部肿瘤的药物。
另一方面,本发明提供了用如前所定义的通式(I)的化合物制备治疗造血和免疫系统肿瘤例如淋巴瘤和白血病的药物。
再一方面,本发明提供了用如前所定义的通式(I)的化合物制备治疗最初肿瘤转移患者的药物。
又一方面,本发明提供了用前所定义的通式(I)的化合物制备预防正常细胞的转化或抑制癌细胞对正常细胞的转移侵袭的药物。
又一方面,本发明提供了治疗肿瘤疾病或预防癌转移的方法,特别是Ras依赖性癌症,该方法包括把有效治疗量的如上述所定义的式(I)化合物给予患有癌症或癌症潜在发展的患者。
本发明的范围中也包括选择性去除癌细胞的方法,该方法包括用通式(I)的化合物体外处理来自患者的癌细胞和正常细胞的混合物,然后再把该细胞转入患者体内。这样,按照该方法,能够从患者体内抽取血液、血浆或其它体液,用通式(I)的化合物体外处理,然后再转入患者体内。
在通式(I)的化合物中,Z1、Z2、Z3和Z4基团的例子包括羟基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基和叔丁氧基。优选的基团是异丙氧基。
本文优选Z1、Z2、Z3和Z4基团是相同的,本发明特别优选的实施方案是Z1、Z2、Z3和Z4基团都是异丙氧基。
基团X1和X2的例子包括氢、含1到5个碳原子的直链或支链烷基和烷氧基,特别优选1到4个碳原子的。X1和X2的优选基团是甲基、乙基、正丙基、异丙基、仲丁基、叔丁基、甲氧基和乙氧基,特别优选叔丁基。
基团X3的例子包括氢、C1-4烷基和C1-4链烷酰基,本文特别优选氢。
结构(Ia)的化合物包括例如是那些其中:-X1和X2是相同或不同并是含1到8个碳原子的烷基,-X3是氢,-A是CH=CH-CH2(CH2)n,S,SO2,S-(CH2)n,SO2-(CH2)n,其中n是1-7,-B是氢或C1-C4烷基,-Z1、Z2、Z3和Z4是相同或不同,并且是OH,含1到8个碳原子的烷氧基或Z1,Z2和Z3,Z4对的一个或两个是含2到8个碳原子的亚烷基二氧基。
结构(Ib)的化合物包括例如是那些其中:-X1和X2是相同或不同并是含1到8个碳原子的烷基,-X3是氢,-k是0或1,d是0到4,-Z1、Z2、Z3和Z4是相同或不同,并且是OH,含1到8个碳原子的烷氧基或Z1、Z2和Z3、Z4对的一个或两个是含2到8个碳原子的亚烷基二氧基。
用于本发明的通式(I)化合物的具体例子包括表1a和1b中的化合物。
本发明提供了式(I)偕-二磷酸酯治疗肿瘤疾病和预防癌症和转移、特别是那些Ras依赖性癌症的新用途。在特别优选的实施方案中,它提供了式(I)的化合物1制备用于治疗癌症的药物组合物的新用途,其中X1和X2都是叔丁基,分别在3-和5-位,X3是H,在4-位,A是CH2,B是H,t是1,Z1、Z2、Z3、Z4都是异丙氧基。该化合物1具有下列结构、通式和理化特性:2-(3,5-二叔丁基-4-羟基苯基)-亚乙基-1,1-二磷酸四异丙酯,C28H52O7P7,mp=104-105℃。
按照EP 0 339 237 A的所述的方法可制备本发明的化合物,本文把EP0 339 237 A引用为参考文献。
一些类似物是新的。所以,另一方面,本发明提供了新化合物,它们选自:2-(3,5-二异丙基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四异丙酯2-(3,5-二异丙基-4-羟基苯基)-亚乙基-1,1-二磷酸四异丙酯2-(3,4,5-三甲氧基苯基)-亚乙烯基-1,1-二磷酸四异丙酯2-(3,4,5-三甲氧基苯基)-亚乙基-1,1-二磷酸四异丙酯2-(3-叔丁基-4-羟基-5-甲基苯基)-亚乙烯基-1,1-二磷酸四异丙酯2-(3-叔丁基-4-羟基-5-甲基苯基)-亚乙基-1,1-二磷酸四异丙酯2-(3-乙氧基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四异丙酯2-(3-乙氧基-4-羟基苯基)-亚乙基-1,1-二磷酸四异丙酯2-(3,5-二-叔丁基-4-甲氧基苯基)-亚乙烯基-1,1-二磷酸四乙酯1-(3,5-二-叔丁基-4-羟基苯基)-亚丁基-2,2-二磷酸四异丙酯
式(I)化合物可口服或通过其它粘膜表面(如经鼻、颊、支气管或直肠粘膜),经皮转运,或通过注射(如皮下,腹膜内,静脉或肌内注射)给药。
当把通式(I)化合物用于口服给药时,可以把它们配制成如片剂、胶囊、颗粒剂、丸剂、糖衣药丸、锭剂、粉剂、溶液、乳液、糖浆、悬浮液或其它任何适于口服给药的制剂。如果需要的话,可以用一种或多种缓释包衣包裹口服剂型来控制活性化合物在肠道的特定部位释放。
可用标准方式把通式(I)的化合物和药物学上可接受的增溶剂、稀释剂或载体制备成片剂和其它固体或液体剂型。增溶剂、稀释剂或载体的例子包括糖类如乳糖、淀粉、纤维素及其衍生物、粉状西黄耆胶(tracaganth)、麦芽、明胶、滑石、硬脂酸、硬脂酸镁、硫酸钙、植物油、多元醇类如甘油、丙二醇和聚乙二醇、藻酸和藻酸盐、琼脂、无热源的水、等渗盐水、磷酸缓冲溶液和任选的其它药物学的赋型剂如崩解剂、润滑剂、湿润剂如十二烷基硫酸钠、着色剂、矫味剂和防腐剂等。
胶囊可以是硬或软的类型,含有固体、液体或半固体形式该活性化合物。一般这种胶囊是由明胶或等同物形成的并且可以包衣或不包衣。如果需要胶囊通过胃部进入肠道时释放该活性成分,可以提供具有pH敏感包衣的胶囊来适应在十二指肠或回肠pH中溶解。这种包衣的例子包括Eudragits,它的使用是本领域所熟知的。
注射剂通常由适当增溶剂如去污剂组成,它也包括化合物和赋型剂如可提供具有正确生理pH等渗溶液的缓冲剂。注射溶液一般无热源并提供含单位剂量化合物的密封的管瓶或安瓿。
本发明化合物的单位剂量一般含0.1%到99%重量的活性物质,更一般的是5%到75%的活性物质。作为举例,单位剂量可含1mg到1g的化合物,更一般的是10mg到500mg,例如50mg至400mg,一般剂量在100mg到200mg之间。
本发明化合物将以有效提供所需治疗作用的量给药。提供所需治疗作用的浓度根据疾病的准确特性、患者的大小、体重和年龄和疾病的严重程度这些因素而不同。
尽管在特定情况下,所治疗疾病的严重性需要以引起一些毒性症状的化合物的量给药,但优选给药剂量是对患者物无毒的。
一般,本发明的化合物以0.01mg/kg到100mg/kg体重的量,更优选以0.1mg/kg到10mg/kg体重并特别是1mg/kg到5mg/kg体重的量给药。对平均70kg体重的人来说,一般本发明化合物的每日剂量在70mg到700mg。这种剂量例如以每天两到四次给药。但是,给药剂量的大小和给药频率由治疗患者的医生判断。
实施例K用来详细说明发明人制备化合物1胶囊作用的代表性配方。
本发明化合物的药理活性可采用人膀胱癌T24(H-Ras)致肿瘤基因转染NIH 3T3细胞克隆,通过体外筛选模型证实。该细胞系(PAP2)已基于它高水平Ras表达特性和与高水平转移能力有关的Ras依赖活性筛选出来(S.A.Hill等,国立癌症研究所杂志1988,80:484-490和A.Champers等,在侵袭和转移中1990;10:225-240)。PAP2细胞系已表明其使参与转移过程的组织蛋白酶、半胱氨酸蛋白酶的Ras-依赖表达增加(A.Chambers等,癌基因分子学,1992;5:238-245)。因此PAP2细胞与人类癌症的病理过程有关。这些细胞用于体外试验以观察化合物对细胞增生、蛋白水解酶活性(转移)和下垂蛋白(程序细胞死亡)的作用。当皮下(s.c.)注射这些细胞到免疫缺陷(裸体)鼠时,迅速形成固体肿瘤,然后在口服受试化合物后体内测定受试化合物的抗癌活性。
一系列体外和体内试验结果导致了本发明发现,即代表性通式(I)化合物和特别是化合物1,
-抑制组织培养中的癌细胞生长,
-诱导组织培养中癌细胞的细胞程序死亡,
-抑制参与转移的癌细胞中的蛋白水解酶和
-在患有固体肿瘤的裸体鼠中显示了抗癌活性。
表1-7b中所示的试验结果提供了证据,即通式(I)的化合物,特别是化合物1可潜在性地用于治疗肿瘤疾病,这些肿瘤疾病包括造血和免疫系统的癌症如淋巴癌和白血病以及胰腺、结肠、乳腺、甲状腺、大脑、肺、头部和颈部的癌。最近发现的通式(I)化合物的抗癌活性是出人意料的并与以前报道的其降脂活性是无关的。
实施例1用通式(I)的化合物抑制Ras依赖性细胞增生
筛选一系列通式(I)的化合物测定最大活性的化合物和结构与活性的关系。选择PAP2细胞增生的抑制作初始筛选试验。
简要地说,以每孔3×104的浓度把PAP2细胞接种到24孔平皿上并使其附着24小时。试验化合物以在1%乙醇溶液中最终浓度为10和20μM被加入。温育48小时后将细胞胰蛋白酶化并对可见细胞(除了锥虫兰)计数。对化合物(Ia)和(Ib)系列来说,得到的结果分别列在表1a和1b中。
在试验中筛选的化合物可以按照相应于欧洲专利0 339 237的美国专利5,043,330(1991)中描述的步骤合成。提供一些实施例(实施例A-J)来更详细地说明按照上述现有技术中所述的步骤合成新衍生物。
表1a苯酚取代的偕-二磷酸酯(Ia)对PAP2细胞的作用
化合物 | X1 | X2 | X3 | A | B | Z1 | Z2 | Z3 | Z4 | 细胞(%计数对照) | |
10μM | 20μM | ||||||||||
1 | 3-t-Bu | 5-t-Bu | 4-H | CH2 | H | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | -70 | -100 |
2 | 3-t-Bu | 5-t-Bu | 4-H | CH2 | H | OH | OH | OH | OH | -31 | -45 |
3 | 3-t-Bu | 5-t-Bu | 4-H | CH2 | H | OMe | OMe | OMe | OMe | -21 | -17 |
4 | 3-t-Bu | 5-t-Bu | 4-H | CH2 | H | OEt | OEt | OEt | OEt | -30 | -22 |
5 | 3-t-Bu | 5-t-Bu | 4-H | CH2 | H | On-Pr | On-Pr | On-Pr | On-Pr | -22 | -89 |
6 | 3-t-Bu | 5-t-Bu | 4-H | CH2 | H | On-Bu | On-Bu | On-Bu | On-Bu | -26 | -51 |
7 | 3-s-Bu | 5-s-Bu | 4-H | CH2 | H | OEt | OEt | OEt | OEt | -6 | +3 |
8 | 3-s-Bu | 5-s-Bu | 4-H | CH2 | H | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | -21 | -45 |
9 | 3-i-Pr | 5-i-Pr | 4-H | CH2 | H | OEt | OEt | OEt | OEt | -16 | -31 |
10 | 3-i-Pr | 5-i-Pr | 4-H | CH2 | H | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | -20 | -51 |
11 | 3-t-Bu | 5-Me | 4-H | CH2 | H | OEt | OEt | OEt | OEt | -14 | -37 |
12 | 3-t-Bu | 5-Me | 4-H | CH2 | H | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | -3 | -27 |
13 | 3-t-Bu | 5-t-Bu | 4-H | S | H | OEt | OEt | OEt | OEt | -19 | -39 |
14 | 3-t-Bu | 5-t-Bu | 4-H | S | H | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | -53 | -90 |
15 | 3-OMe | 5-OMe | 4-Me | CH2 | H | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | -23 | -5 |
16 | 3-OEt | 5-H | 4-H | CH2 | H | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | -2 | +5 |
17 | 3-t-Bu | 5-t-Bu | 4-H | CH2 | H | OEt | OEt | On-Bu | On-Bu | -6 | -95 |
18 | 3-t-Bu | 5-t-Bu | 4-H | CH2 | H | OEt | OEt | Oi-Pr | Oi-Pr | -46 | -59 |
19 | 3-t-Bu | 5-t-Bu | 4-H | CH2 | Et | OEt | OEt | OEt | OEt | -21 | -36 |
20 | 6-Cl | 34-O | CH2 | CH2 | H | OEt | OEt | OEt | OEt | +20 | -9 |
21 | 3-t-Bu | 5-t-Bu | 4-H | CH2 | H | O(CH2)3 | O | O(CH2)3 | O | -32 | -28 |
22 | 3-OMe | 5-OMe | 4-H | CH2 | H | OEt | OEt | OEt | OEt | ||
23 | 3-OMe | 5-OMe | 4-H | CH2 | H | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | ||
24 | 3-t-Bu | 5-t-Bu | 4-H | CH2 | Et | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | -25 | -40 |
表1b苯酚取代的偕-二磷酸酯(Ib)对PAP2细胞的作用
实施例2体外试验结果Ras依赖性细胞增生的抑制细胞培养
化合物 | X1 | X2 | X3 | k | d | Z1 | Z2 | Z3 | Z4 | 细胞数(%对照) | |
10μM | 20μM | ||||||||||
25 | 3-t-Bu | 5-t-Bu | 4-H | 0 | 0 | OH | OH | OH | OH | ||
26 | 3-t-Bu | 5-t-Bu | 4-H | 0 | 0 | OMe | OMe | OMe | OMe | -33 | -17 |
27 | 3-t-Bu | 5-t-Bu | 4-H | 0 | 0 | OEt | OEt | OEt | OEt | -48 | -45 |
28 | 3-t-Bu | 5-t-Bu | 4-H | 0 | 0 | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | -28 | -46 |
29 | 3-t-Bu | 5-t-Bu | 4-H | 0 | 0 | On-Pr | On-Pr | On-Pr | On-Pr | -51 | -63 |
30 | 3-t-Bu | 5-t-Bu | 4-H | 0 | 0 | On-Bu | On-Bu | On-Bu | On-Bu | -13 | -31 |
31 | 3-s-Bu | 5-s-Bu | 4-H | 0 | 0 | OEt | OEt | OEt | OEt | -30 | -44 |
32 | 3-s-Bu | 5-s-Bu | 4-H | 0 | 0 | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | -13 | -54 |
33 | 3-i-Pr | 5-i-Pr | 4-H | 0 | 0 | OEt | OEt | OEt | OEt | -5 | +13 |
34 | 3-i-Pr | 5-i-Pr | 4-H | 0 | 0 | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | -26 | -62 |
35 | 3-t-Bu | 5-Me | 4-H | 0 | 0 | OEt | OEt | OEt | OEt | -14 | -14 |
36 | 3-t-Bu | 5-Me | 4-H | 0 | 0 | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | -24 | -7 |
37 | 3-OMe | 5-OMe | 4-H | 0 | 0 | OEt | OEt | OEt | OEt | -3 | -28 |
38 | 3-OMe | 5-OMe | 4-H | 0 | 0 | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | ||
39 | 3-OMe | 5-OMe | 4-Me | 0 | 0 | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | -17 | -34 |
40 | 3-OEt | 5-H | 4-H | 0 | 0 | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | -30 | -23 |
41 | 3-t-Bu | 5-t-Bu | 4-H | 1 | 0 | OEt | OEt | OEt | OEt | -40 | -77 |
42 | 3-t-Bu | 5-t-Bu | 4-H | 1 | 0 | Oi-Pr | Oi-Pr | Oi-Pr | Oi-Pr | -36 | -71 |
43 | 3-t-Bu | 5-t-Bu | 4-H | 0 | 0 | OEt | OEt | On-Bu | On-Bu | -18 | -54 |
44 | 3-t-Bu | 3-t-Bu | CH2 | 0 | 0 | OEt | OEt | Oi-Pr | Oi-Pr | -17 | -28 |
45 | 3-t-Bu | 5-t-Bu | 4-Me | 0 | 0 | OEt | OEt | OEt | OEt | -10 | -33 |
46 | H | 3,4- | OCH2 | 0 | 0 | OEt | OEt | OEt | OEt | -22 | -26 |
47 | H | 3,4- | (OCH2)2 | 0 | 0 | OEt | OEt | OEt | OEt | -11 | -30 |
在Dulbecco的改良型Eagle培养基(DMEM)中37℃5%CO2气氛中使H-Ras-转染的NIH 3T3细胞(PAP2)(S.A.Hill等;国立癌症研究所杂志1988;80:484-490)生长,其中的培养基含有25mM HEPES和10%胎牛血清。将PAP2细胞胰蛋白酶化并在融合前再培养两次。1.细胞增生的抑制
用两种方法监测化合物1对细胞增生的作用:
-用血细胞计数器的细胞计数法和合并的DNA测定
-用比色计测定法估计细胞的数目。1.1细胞计数和DNA含量
简要地说,在加入增加浓度的受试化合物前4小时把PAP2细胞以每孔3×104的浓度接种在24孔的平皿上。隔一天后把细胞胰蛋白酶化。用一台血细胞计数器对等份的细胞悬浮液计数。在0.01N NaOH中溶解所保留的细胞并用4,6-二氨基-2-苯吲哚作荧光染料和牛犊胸腺DNA作标准物通过荧光分光光度计测定DNA浓度。
表2a
化合物1对PAP2细胞增生的抑制
(细胞数/孔)
所计算的化合物1对PAP2细胞生长抑制的IC50值是1.02μM。
化合物1的浓度 | ||||||
0 | 0.1μM | 0.5μM | 1.0μM | 5.0μM | 10μM | |
细胞数/孔sem%变化p | 2737509437 | 2562507465-60.196 | 2087504270-240.001 | 18625015861-320.003 | 1025005951-630.001 | 712508260-740.001 |
表2b
在培养的PAP2细胞中化合物1所产生的DNA浓度的降低
DNA(mg/孔)
所计算的化合物1对PAP2 DNA含量降低的IC50值是2.77μM。
化合物1的浓度 | ||||||
0 | 0.1μM | 0.5μM | 1.0μM | 5.0μM | 10μM | |
DNA(mg/孔)sem%变化p | 4.620.14 | 4.400.18-50.375 | 4.040.42-130.240 | 1.990.14-570.001 | 1.660.07-640.001 | 0.340.04-930.001 |
表2a和2b中的结果表明通式(I)的化合物特别是化合物1能够在培养基中抑制PAP2细胞的生长。1.2.比色的MTT测定法
用基本上如T.Mosman在免疫方法杂志1983;65:55-63中所述的MTT测定法估算细胞数。
简要地说,在加入试验药物前5小时,以每孔1×104的浓度把PAP2细胞接种到96孔的平皿(Falcon)上。温育24小时、48小时或72小时后,向每个孔中加入10μl以5mg/ml溶于PBS的MTT[3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物]并在37℃温育4小时。然后除去培养基并向每个孔中加入100μ1 0.04N HCl异丙醇溶液。用扣除620nm背景的微板计数器测定570nm处转化染料的吸收值。
如MTT法所测定的(温育72小时后),所计算的化合物1对PAP2细胞增生抑制的IC50值是8.05μM。用另一测定法得到的表3a、3b和3c中的结果证实通式(I)的化合物特别是化合物1能够在培养基中抑制PAP2细胞的生长。
用MTT测定法测得的化合物1对PAP2细胞增生的作用
表3a
化合物1温育24小时
(在570nm的OD)
化合物1的浓度 | ||||||
0 | 1.0μM | 2.5μM | 5μM | 10μM | 25μM | |
ODsem%变化p | 39.92.10 | 39.54.6-10.942 | 37.61.2-60.370 | 35.91.0-100.109 | 28.91.1-280.001 | 21.41.0-460.001 |
表3b
化合物1温育48小时
(在570nm的OD)
化合物1的浓度 | ||||||
0 | 1.0μM | 2.5μM | 5μM | 10μM | 25μM | |
平均值sem%变化p | 71.35.20 | 66.54.9-70.516 | 59.42.5-170.059 | 52.83.1-260.009 | 37.31.9-480.001 | 15.10.7-790.001 |
表3c
化合物1温育72小时
(在570nm的OD)
3.对DNA合成的抑制
化合物1的浓度 | ||||||
0 | 1.0μM | 2.5μM | 5μM | 10μM | 25μM | |
平均值sem%变化p | 366.030.3 | 336.819.0-80.427 | 334.418.6-90.388 | 287.416.5-210.039 | 136.615.5-630.001 | 29.06.3-920.001 |
把用氘标记的胸苷掺入培养PAP2细胞的三乙酸(TCA)沉淀物质中来测定DNA的合成。把PAP2细胞以每孔3×104个细胞接种到24孔平皿中两天。然后用溶于乙醇的化合物1预温育后,加入0.5μCi的甲基-[3H]-胸苷(特异活性82Ci/mmol)并标记4小时。然后用1ml的冷磷酸酯缓冲盐水(PBS)洗涤该细胞。用0.2ml 4%的十二烷基硫酸钠溶解。用1ml 30%TCA沉淀细胞提取物并冰浴保存1小时。在玻璃纤维滤纸上过滤收集沉淀物并用5ml 5%TCA洗涤。用液晶闪烁计数器对滤纸上的放射活性计数。
表4
化合物1对Ras转染细胞(PAP2)中DNA合成的抑制
把3H-胸苷掺入DNA(cpm)
所计算的化合物1对PAP2细胞中DNA合成抑制的IC50值是3.75μM。
化合物1的浓度 | ||||||
0 | 0.5μM | 2μM | 5μM | 10μM | 25μM | |
cpmsem%变化p | 5302172960 | 456075354-140.427 | 371302590-300.075 | 302263945-430.016 | 187721481-650.009 | 141002766-730.005 |
表4中的结果表明通式(I)的化合物特别是化合物1能够抑制Ras转染细胞中DNA的合成。4.细胞程序死亡的诱导
现已表明通式(I)的化合物在5μM或更高浓度对PAP2细胞系中促进细胞死亡具有选择性作用。在用化合物1处理的其它两种人癌细胞系(HepG2和SW480)中证实了这种选择性促进癌细胞中细胞程序死亡的特异作用,这表明这些化合物不仅抑制细胞成长而且还产生癌细胞自身的破坏(表5)。这已被显示DNA片段和细胞程序死亡的检验印迹的凝胶电泳所证实。
表5
化合物对人癌细胞系中细胞生存力的作用
·处理前,细胞在24孔平皿中培养了48小时。·10μM化合物处理24小时。·计数:把细胞胰蛋白酶化并对生存的细胞计数。5.化合物1对较广范围的人癌细胞系的作用
细胞系 | 在0小时生存的细胞数 | 在24小时生存的细胞数 | %变化 |
SW480 | 38′800 | 0 | -100.0% |
HepG2 | 214′700 | 82 000 | -61.8% |
在较广范围的已建立的来源于人的癌细胞系中对化合物1的抗增殖活性进行了试验以证实这些化合物对与在人相关的癌症中的潜在用途(表6)。结果表明化合物1在所试验的50个人癌细胞系中对90%以上细胞系降低细胞增生有效。所以,可以认为通式(I)的化合物能够用于治疗较广范围的具有和没有Ras突变的人癌症。
表6
化合物1对来自人肿瘤的细胞系的抗增殖作用
实施例2体内的结果肿瘤生长的抑制
肿瘤类型 | 细胞系 | 增殖的抑制率(%对照) |
白血病 | CCRF-CEM | -61.8 |
白血病 | HL-60(tb) | -95.3 |
白血病 | K-562 | -61.2 |
非-小细胞肺癌 | A549/ATCC | -55.0 |
非-小细胞肺癌 | EKVX | -27.0 |
非-小细胞肺癌 | HOP-62 | -13.8 |
非-小细胞肺癌 | HOP-92 | -85.1 |
非-小细胞肺癌 | NCl-H23 | -21.8 |
非-小细胞肺癌 | NCl-H322M | -12.5 |
非-小细胞肺癌 | NCl-H460 | -40.7 |
非-小细胞肺癌 | NCL-H522 | -59.8 |
结肠癌 | COLO 205 | -55.9 |
结肠癌 | HCC-2998 | -50.7 |
结肠癌 | HCT-116 | -68.7 |
结肠癌 | HCT-15 | -19.5 |
结肠癌 | HT29 | -83.0 |
结肠癌 | KM12 | -32.5 |
结肠癌 | SW-620 | -21.4 |
CNS癌 | SF-268 | -21.2 |
CNS癌 | SF-295 | -49.6 |
CNS癌 | SF-539 | -1.5 |
CNS癌 | SNB-19 | -55.8 |
CNS癌 | SNB-75 | -54.4 |
CNS癌 | U251 | -41.6 |
黑素瘤 | LOX IMVI | -18.7 |
黑素瘤 | MALME-3M | -20.4 |
黑素瘤 | M14 | -66.7 |
黑素瘤 | SK-MEL-2 | -6.1 |
黑素瘤 | SK-MEL-28 | -25.0 |
黑素瘤 | SK-MEL-5 | -51.8 |
黑素瘤 | UACC-257 | -26.9 |
黑素瘤 | UACC-62 | -30.9 |
卵巢癌 | IGROV1 | -24.4 |
卵巢癌 | OVCAR-3 | -47.3 |
卵巢癌 | OVCAR-4 | -18.9 |
卵巢癌 | OVCAR-5 | -17.6 |
卵巢癌 | OVCAR-8 | -37.6 |
卵巢癌 | SK-OV-3 | -28.1 |
肾癌 | 786-0 | -28.7 |
肾癌 | ACHN | -43.4 |
肾癌 | CAKI-1 | -31.1 |
肾癌 | SN12C | -1.0 |
肾癌 | TK-10 | -18.6 |
肾癌 | UO-31 | -35.9 |
前列腺癌 | PC-3 | -75.9 |
前列腺癌 | DU-145 | -21.3 |
乳腺癌 | MCF-7 | -57.0 |
乳腺癌 | MCF-7/ADR-RES | -49.3 |
乳腺癌 | MDA-MB-231/ATCC | -50.9 |
乳腺癌 | MDA-MB-435 | -51.6 |
乳腺癌 | MDA-N | -43.3 |
乳腺癌 | BT-549 | -51.3 |
乳腺癌 | T-47D | -62.1 |
当天将0.5ml的PAP2细胞(每0.5mlDMEM 5×10个细胞)皮下(s.c.)注射到7到9周雌性裸鼠(Swiss nu/nu)。在同一天用化合物1口服治疗(50mg/kg)。治疗组(n=18)得到混合有食物的化合物1(0.03%w/w),对照组(n=22)得到未加化合物的饮食。在第15天,给该鼠称重、杀死并摘除肿瘤称重。
表7a
用化合物1口服治疗(50mg/kg)对皮下注射
PAP2细胞的裸鼠所产生的肿瘤重量的作用
动物组 | 体重(g)(平均±sem) | 肿瘤重量(g)(平均±sem) |
对照组(n=21) | 24.2±0.5 | 0.228±0.041 |
治疗组(n=18) | 24.6±0.7 | 0.053±0.016 |
%变化 | +2 | -77 |
p | 0.6470 | 0.0006 |
表7a的结果显示在治疗组中平均的肿瘤重量显著下降,这表明化合物1是有效的抗肿瘤剂。在对照组和治疗组中小鼠的重量相同,所以确定化合物1无毒性。
在另一例试验中,以12.50和100mg/kg的剂量试验化合物1。表7b的结果显示化合物1在低至12.5mg/kg剂量时抑制肿瘤生长并以依赖剂量方式抑制裸鼠的肿瘤生长。这些结果证实通式(I)的化合物特别是化合物1是有效的口服活性抗肿瘤化合物并对正常细胞、组织或器官不具有毒性作用。
表7b
用不同剂量的化合物1口服治疗注射有
PAP2细胞的裸鼠观察肿瘤重量的降低
实施例A2-(3,5-二异丙基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四异丙酯
动物组 | 体重(g)(平均±sem) | 肿瘤重量(g)(平均±sem) |
对照组(n=14) | 24.7±0.6 | 0.276±0.056 |
治疗组,12.5mg/kg(n=5)%变化p | 23.9±0.8-30.4562 | 0.053±0.026-810.0472 |
治疗组,50mg/kg(n=6)%变化p | 27.2±1.0+100.0523 | 0.037±0.020-870.0211 |
治疗组,100mg/kg(n=6)%变化p | 24.5±0.3-10.7619 | 0.025±0.011-910.0151 |
把四氯化钛(13.83g,73mmol)滴加到无水THF(80ml),在0℃保持。在0℃把所得到的混合物按顺序用3,5-二异丙基-4-羟基苯甲醛(5.0g,24mmol)、亚甲基二磷酸四异丙酯(10.85g,32mmol)和N-甲基吗啉(14.71g,146mmol)处理。在室温下把该反应混合物搅拌12小时并加80ml水。用二乙醚(3×60ml)萃取淬灭的反应混合物,用饱和的NaCl溶液萃取合并的醚部分直到水溶液洗到中性pH。在MgSO4上干燥后,蒸发有机溶剂并在硅胶上用CH2Cl2∶MeOH(95∶5)的混合物作洗脱剂进行柱色谱层析纯化该残余物,得到8g(62%)的固体;mp=87-88℃。MS:m/e=532:M+:367:M+-PO3iPr2NMR(CDCl3)δ=8.22(dd,J=31和48Hz,1H):Ph-CH=C-P2
7.7(s,2H):芳香H,
5.6(s,1H):OH,
4.85-4.63(2m,4H):P-O-CHMe2,
3.16(分开的,2H):Ph-CHMe2,
1.39,1.36,1.27,1.23和1.16(8d,36H总共):P-O-CHMe2和Ph-CHMe2。
把2-(3,5-二异丙基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四异丙酯(5g,9.4mmol)溶于乙醇(50ml)并在室温50psi在2g10%钯/碳上氢化溶液4小时。过滤结晶,蒸发溶剂并在硅胶上用CH2Cl2∶MeOH(95∶5)的混合物作洗脱剂进行柱色谱层析纯化该残余物,得到2.5g(50%)的固体;mp=90-91℃。MS:m/e=534:M+,369:M+-PO3iPr2NMR(CDCl3)δ=6.94(m,2H):芳香H,
4.8-4.7(m,5H):P-O-CHMe2和OH,
3.2-3.1(几个m,总共6H):Ph-CH2-CH和Ph-CHMe2,
2.51(tt,J=6和24H,1H):Ph-CH2-CH,
1.33-1.21(几个d,总共36H):P-O-CHMe2和Ph-CHMe2。
按照实施例A中所描述的在THF中用四氯化钛、亚甲基二磷酸四异丙酯和N-甲基吗啉处理3,4,5-三甲氧基苯甲醛(7g,35.7mmol)得到11.5g(62%)的标题化合物。MS:m/e=522:M+:357:M+-PO3iPr2NMR(CDCl3)δ=8.21(dd,J=30和48Hz,1H):Ph-CH=C-P2
7.28(s,2H):芳香H,
4.85-4.63(2m,4H):P-O-CHMe2,
3.9(t,9H):Ph-OMe,
1.4,1.36和1.22(4d,总共24H):P-O-CHMe2。实施例D2-(3,4,5-三甲氧基苯基)-亚乙基-1,1-二磷酸四异丙酯
如实施例B中所描述的在10%Pd/C上氢化2-(3,4,5-三甲氧基苯基)-亚乙烯基-1,1-二磷酸四异丙酯(7g,13.4mmol)得到5.7g(81%)的标题化合物。MS:m/e=524:M+,359:M+-PO3iPr2NMR(CDCl3)δ=6.55(s,2H):芳香H,
4.8-4.7(m,4H):P-O-CHMe2,
3.85和3.81(2s,9H):Ph-OMe,
3.17(dt,J=6和16Hz,2H):Ph-CH2-CH,
2.50(tt,J=6和24Hz,1H):Ph-CH2-CH,
1.33-1.26(几个d,总共24H):P-O-CHMe2。
按照实施例A中所描述的在THF中用四氯化钛、亚甲基二磷酸四异丙酯和N-甲基吗啉处理3-叔丁基-4-羟基-5-甲基苯甲醛(6g,31.3mmol)得到4.2g(62%)的标题化合物。MS:m/e=518:M+:353:M+-PO3iPr2NMR(CDCl3)δ=8.19(dd,J=30和48Hz,1H):Ph-CH=C-P2
7.71-7.76(m,2H):芳香H,
5.6(s,1H):OH,
4.8-4.7(2m,4H):P-O-CHMe2,
2.26(s,3H):Ph-Me,
1.40(s,9H):Ph-t-Bu,
1.38,1.36,1.24和1.20(8d,总共24H):P-O-CHMe2。
按照实施例B中所描述的在10%Pd/C上氢化2-(3-叔丁基-4-羟基-5-甲基苯基)-亚乙烯基-1,1-二磷酸四异丙酯(5g,9.6mmol)氢化得到2.9g(58%)的标题化合物。MS:m/e=520:M+:355:M+-PO3iPr2NMR(CDCl3)δ=7.02和6.92(2m,2H):芳香H,
4.8-4.7(m,5H):P-O-CHMe2和OH,
3.11(dt,J=6和17Hz,2H):Ph-CH2-CH,
2.49(tt,J=6和24Hz,1H):Ph-CH2-CH,
2.21(s,3H):Ph-Me,
1.39(s,9H):Ph-t-Bu,
1.31,1.26和1.24(3d,24H):P-O-CHMe2。
按照实施例A中所描述的在THF中用四氯化钛、亚甲基二磷酸四异丙酯和N-甲基吗啉处理3-乙氧基-4-羟基苯甲醛(6g,36.1mmol)得到4.2g(62%)的标题化合物。MS:m/e=492:M+:327:M+-PO3iPr2NMR(CDCl3)δ=8.19(dd,J=31和48Hz,1H):Ph-CH=C-P2
7.9,7.3和6.91(3m,3H):芳香H,
6.2(s,1H):OH,
4.85-4.63(2m,4H):P-O-CHMe2,
4.19(q,J=7Hz):Ph-OCH2-CH3,
1.46(t,J=7Hz):Ph-OCH2-CH3,
1.39,1.36,1.23和1.21(4d,总共24H):P-O-CHMe2。
按照实施例B中所描述的在10%Pd/C上氢化2-(3-乙氧基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四异丙酯(5g,10.16mmol)得到4.5g(90%)的标题化合物。MS:m/e=494:M+:329:M+-PO3iPr2NMR(CDCl3)δ=6.85和6.75(几个m,3H):芳香H,
5.65(s,1H):OH,
4.8-4.7(m,4H):P-O-CHMe2,
4.10(q,J=7Hz):Ph-OCH2-CH3,
3.14(dt,J=6和16Hz,2H):Ph-CH2-CH,
2.45(tt,J=6和24Hz,1H):Ph-CH2-CH,
1.43(t,J=7Hz):Ph-OCH-CH3,
1.32-1.25(4个部分重叠的d,总共24H):P-O-CHMe2。
按照实施例A中所描述的在THF中用四氯化钛、亚甲基二磷酸四异丙酯和N-甲基吗啉处理3,5-二叔丁基-4-甲氧基苯甲醛(2.0g,8.1mmol)得到3.0g(72%)的标题化合物。mp=66-67℃MS:m/e=518:M+:381:M+-PO3Et2NMR(CDCl3)δ=8.26(dd,J=30和48Hz,1H):Ph-CH=C-P2
7.8(s,2H):芳香H,
4.25-4.00(2m,8H):P-O-CH2-CH3,
3.69(s,3H):Ph-OMe.
1.44(s,18H):Ph-t-Bu,
1.38和1.70(2t,12H):Ph-OCH2-CH3。实施例J1-(3,5-二叔丁基-4-羟基苯基)-亚丁基-2,2-二磷酸四异丙酯
通过在NaH存在下于THF中将亚甲基二磷酸四异丙酯与3当量的碘乙烷反应来制备亚丙基-1,1-二磷酸四异丙酯。
把亚丙基-1,1-二磷酸四异丙酯(2.2g,6.0mmol)加入60%NaH(0.5g,12.0mmol)的20ml无水THF悬浮液中并把混合物搅拌到NaH消失。加入在10ml THF中的3,5-二叔丁基-4-羟基苄氯(1.5g,6mmol)并把混合物回流一夜。完成后,在硅胶上用CHCl3∶AcOEt(8∶2)作洗脱剂柱色谱层析得到1.5g(42%)的标题化合物。MS:m/e=590:M+:425:M+-PO3Pr2,基峰341:M+-2×propenmp=131-132℃
实施例K化合物制剂的典型例活性成分:化合物1非活性成分:预胶凝化的淀粉NF3号不透明的暗兰色明胶胶囊
代表性的配方
一般一批2000个胶囊
组分 | g/每批 | ||
1mg | 10mg | 50mg | |
化合物1 | 2.0 | 20.0 | 100.0 |
预胶凝化的淀粉NF | 431.6 | 408.8 | 291.0 |
总共 | 433.6 | 428.8 | 391.0 |
Claims (16)
1.苯酚取代的偕-二磷酸酯在制备治疗或预防肿瘤疾病的药物中用途,其中苯酚取代的偕-二磷酸酯选自通式为(I)的化合物,其中:-Z1、Z2、Z3和Z4是相同或不同的,并是-OR,其中R是H、含有1到8个碳原子的直链、支链或环状烷基,-OM,其中M是一个阳离子,-NR2,其中R有如上定义的相同含意,-Z1、Z2和Z3、Z4可以形成一种含有2到8个碳原子的亚烷基二氧环,-X1、X2是相同或不同并是H、卤原子、含有1到8个碳原子的直链、支链或环烷基或烷氧基,-X3是H、含有1到4个碳原子的烷基R1、酰基C(O)R1、氨甲酰基C(O)NHR1,其中R1如上所述,X3O和两种其他取代基X1或X2之一可以形成含有1到4个碳原子的亚烷基二氧环,-A是-CH=CH-CH2-、-(CH2)n-、-O(CH2)n-、-S-、-SO2-、-S(CH2)n-、-SO2(CH2)n-,其中n是1到7的整数,或A与B形成通式为-(CH=CH)k-(CH2)d-CH=的亚烷基,其中k是0或1而d是从0到4的整数,-B是H、含有1到4个碳原子的烷基,-t是0或1,条件是当A是-(CH=CH)k-(CH2)d-CH=其中k和d是如上所述的时候t是0。
2.根据权利要求1的用途,其中的肿瘤疾病选自造血和免疫系统的癌症,包括淋巴瘤和白血病,以及胰腺、结肠、乳腺、甲状腺、大脑、肺、头部和颈部癌。
3.根据权利要求1的用途,选自于式〔I〕化合物中的二磷酸酯用于制备预防癌细胞对正常细胞的转移性侵袭的药物。
4.根据权利要求1到3中的任一用途,苯酚取代的亚烷基二磷酸酯选自式(Ia)化合物其中X1、X2、X3、A、B、Z1、Z2、Z3和Z4如权利要求1中所定义。
5.根据权利要求1到3中的任一用途,苯酚取代的亚链烯基二磷酸酯选自式(Ib)化合物其中X1、X2、X3、k、d、Z1、Z2、Z3和Z4如权利要求1中所定义。
6.根据上述权利要求中的任何一个用途,其中Z1、Z2、Z3和Z4是相同或不同的并选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基和叔丁基。
7.根据权利要求6的用途,其中Z1、Z2、Z3和Z4是相同的。
8.根据权利要求7的用途,其中Z1、Z2、Z3和Z4是异丙基。
9.根据上述权利要求中的任何一个用途,其中X1和X2是相同或不同的并选自具有1到5个碳原子的直链或支链烷基和烷氧基。
10.根据权利要求9用途,其中X1和X2是相同或不同的并选自甲基、乙基正丙基、仲丁基、叔丁基、甲氧基和乙氧基。
11.根据权利要求10的用途,其中X1和X2是相同的。
12 根据权利要求1的用途,其中X1和X2都是叔丁基。
13.根据上述权利要求中的任何一个用途,其中X3选自氢、C1-4烷基和C1-4烷酰基。
14.根据权利要求13的用途,其中X3是氢原子。
15.根据权利要求1到3中的任一用途,其中式(I)的化合物是2-(3,5-二-叔丁基-4-羟基苯基)-亚乙基-1,1-二磷酸四异丙酯。
16.根据权利要求1到3中的任一用途,其中苯酚取代的偕-二磷酸酯选自:2-(3,5-二叔丁基-4-羟基苯基)-亚乙基-1,1-二磷酸2-(3,5-二叔丁基-4-羟基苯基)-亚乙基-1,1-二磷酸四甲酯2-(3,5-二叔丁基-4-羟基苯基)-亚乙基-1,1-二磷酸四乙酯2-(3,5-二叔丁基-4-羟基苯基)-亚乙基-1,1-二磷酸四正丙酯2-(3,5-二叔丁基-4-羟基苯基)-亚乙基-1,1-二磷酸四正丁酯2-(3,5-二叔丁基-4-羟基苯基)-亚乙基-1,1-二磷酸四异丙酯2-(3,5-二仲丁基-4-羟基苯基)-亚乙基-1,1-二磷酸四异丙酯2-(3,5-二异丙基-4-羟基苯基)-亚乙基-1,1-二磷酸四乙酯2-(3,5-二异丙基-4-羟基苯基)-亚乙基-1,1-二磷酸四异丙酯2-(3-叔丁基-4-羟基-5-甲基苯基)-亚乙基-1,1-二磷酸四乙酯2-(3-叔丁基-4-羟基-5-甲基苯基)-亚乙基-1,1-二磷酸四异丙酯3,5-二叔丁基-4-羟基-苯基-硫代亚甲基-1,1-二磷酸四乙酯3,5-二叔丁基-4-羟基-苯基-硫代亚甲基-1,1-二磷酸四异丙酯2-(3,4,5-三甲氧基苯基)-亚乙基--1,1-二磷酸四异丙酯2-(3,5-二叔丁基-4-羟基苯基)-亚乙基-1,1-二磷酸二丁基二乙酯2-(3,5-二叔丁基-4-羟基苯基)-亚乙基-1,1-二磷酸二乙基二异丙酯1-(3,5-二叔丁基-4-羟基苯基)-亚丁基-2,2-二磷酸四乙酯2-(3,5-二叔丁基-4-羟基苯基)-亚乙基-1,1-二(2-氧代-1,3,2-dioxaphosphorinan)1-(3,5-二叔丁基-4-羟基苯基)-亚丁基-2,2-二磷酸四异丙酯2-(3,5-二叔丁基-4-羟基苯基)-亚乙烯基-1,1-二磷酸2-(3,5-二叔丁基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四甲酯2-(3,5-二叔丁基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四乙酯2-(3,5-二叔丁基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四异丙酯2-(3,5-二叔丁基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四正丙酯2-(3,5-二叔丁基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四正丁酯2-(3,5-二仲丁基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四乙酯2-(3,5-二仲丁基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四异丙酯2-(3,5-二异丙基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四异丙酯2-(3-叔丁基-4-羟基-5-甲基苯基)-亚乙烯基-1,1-二磷酸四乙酯2-(3-叔丁基-4-羟基-5-甲基苯基)-亚乙烯基-1,1-二磷酸四异丙酯2-(3,5-二甲氧基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四乙酯2-(3,5-二甲氧基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四异丙酯2-(3,4,5-三甲氧基苯基)-亚乙烯基-1,1-二磷酸四异丙酯2-(3-乙氧基-4-羟基苯基)-亚乙烯基-1,1-二磷酸四异丙酯4-(3,5-二叔丁基-4-羟基苯基)-1,3-亚丁间二烯基-1,1-二磷酸四乙酯4-(3,5-二叔丁基-4-羟基苯基)-1,3-亚丁间二烯基-1,1-二磷酸四异丙酯2-(3,5-二叔丁基-4-羟基苯基)-亚乙烯基-1,1-二磷酸二丁基二乙酯2-(3,5-二叔丁基-4-羟基苯基)-亚乙烯基-1,1-二磷酸二乙基二异丙酯2-(3,5-二叔丁基-4-甲氧基苯基)-亚乙烯基-1,1-二磷酸四乙酯2-(3,4-亚甲基二氧基苯基)-亚乙烯基-1,1-二磷酸四乙酯和2-(3,4-亚乙基二氧基苯基)-亚乙烯基-1,1-二磷酸四乙酯。
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- 1996-07-26 CA CA002228212A patent/CA2228212A1/en not_active Abandoned
- 1996-07-26 AU AU67874/96A patent/AU723094B2/en not_active Ceased
- 1996-07-26 WO PCT/EP1996/003301 patent/WO1997004785A1/en active IP Right Grant
- 1996-07-26 DE DE69619117T patent/DE69619117T2/de not_active Expired - Fee Related
- 1996-07-26 ES ES96928381T patent/ES2172675T3/es not_active Expired - Lifetime
- 1996-07-26 DK DK96928381T patent/DK0845991T3/da active
- 1996-07-26 CN CN96196005A patent/CN1091601C/zh not_active Expired - Fee Related
- 1996-07-26 US US09/011,247 patent/US6127350A/en not_active Expired - Fee Related
- 1996-07-26 EP EP96928381A patent/EP0845991B1/en not_active Expired - Lifetime
- 1996-07-26 PT PT96928381T patent/PT845991E/pt unknown
- 1996-07-26 AT AT96928381T patent/ATE212847T1/de not_active IP Right Cessation
- 1996-07-26 JP JP9507232A patent/JPH11511127A/ja active Pending
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Also Published As
Publication number | Publication date |
---|---|
DK0845991T3 (da) | 2002-05-27 |
JPH11511127A (ja) | 1999-09-28 |
US6127350A (en) | 2000-10-03 |
CH690163A5 (fr) | 2000-05-31 |
PT845991E (pt) | 2002-07-31 |
AU723094B2 (en) | 2000-08-17 |
ZA966364B (en) | 1997-02-11 |
EP0845991B1 (en) | 2002-02-06 |
DE69619117T2 (de) | 2002-09-19 |
AU6787496A (en) | 1997-02-26 |
DE69619117D1 (de) | 2002-03-21 |
ES2172675T3 (es) | 2002-10-01 |
EP0845991A2 (en) | 1998-06-10 |
HK1015686A1 (en) | 1999-10-22 |
CN1192148A (zh) | 1998-09-02 |
WO1997004785A1 (en) | 1997-02-13 |
CA2228212A1 (en) | 1997-02-13 |
ATE212847T1 (de) | 2002-02-15 |
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