CN1302287A - 生物还原性细胞毒试剂 - Google Patents
生物还原性细胞毒试剂 Download PDFInfo
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- CN1302287A CN1302287A CN99806490A CN99806490A CN1302287A CN 1302287 A CN1302287 A CN 1302287A CN 99806490 A CN99806490 A CN 99806490A CN 99806490 A CN99806490 A CN 99806490A CN 1302287 A CN1302287 A CN 1302287A
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- Prior art keywords
- salt
- alkyl
- amino
- quinone
- compound
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- 230000029936 alkylation Effects 0.000 claims description 25
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- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical group [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 4
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
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- 235000015320 potassium carbonate Nutrition 0.000 description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
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- WLYDZHCJSPHCFM-UHFFFAOYSA-N 2-(chloromethyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione Chemical compound CC1=C(C)C(=O)C(CCl)=C(C)C1=O WLYDZHCJSPHCFM-UHFFFAOYSA-N 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract
一种化合物,其由带有吸电子基团的活化前烷基化部分、含有至少两个双键的生物还原性部分、以及将该活化前烷基化部分与该生物还原性部分连接的接头组成。
Description
发明背景
根据美国癌症协会提供的统计,自1990年以来已有近四百万人死于癌症,癌症已成为继心脏病后美国第二大致死病因。癌症治疗通常包括化疗、放疗、激素治疗、免疫治疗、以及外科手术治疗。化疗一直是优选疗法,特别是对于那些不能进行手术的癌症或转移性的癌症更是如此。
很多细胞毒试剂,包括抗代谢物、抗生素、烷基化试剂、以及有丝分裂抑制剂目前均应用于化疗。这些试剂通常对正常细胞和肿瘤细胞均造成破坏。人们希望开发一种对肿瘤细胞的破坏远甚于对正常细胞的破坏的抗肿瘤试剂。
肿瘤细胞由于它们的病理状况,使它们的周边血管分布的有序性比正常细胞大大降低,导致肿瘤部位的氧供应不足。或者说,肿瘤细胞的含氧量都很低(氧缺乏)。这种独特的生理特点为特异性针对肿瘤细胞的细胞毒试剂的设计提供了依据。
发明简述
本发明的一方面涉及由以下三种成分组成的细胞毒化合物:(1)带有吸电子基团的活化前烷基化部分;(2)含有至少两个双键的生物还原性部分;以及(3)连接该活化前烷基化部分和该生物还原性部分的接头。“活化前烷基化部分”指一种功能基团,它一旦活化,将用它的烷基之一以共价形式取代另一种化合物如DNA的活性氢原子。“生物还原性部分”指能体内实施还原作用(接受电子的反应)即生物还原作用的部分。生物还原性部分的双键可通过其自身或与接头的双键一起形成共轭体系。该共轭体系可通过还原生物还原性部分而使电子从生物还原性部分流向活化前烷基化部分的吸电子基团。这将使吸电子基团与接头之间的双键打断,并使活化前烷基化部分转化成活性烷基化化合物。
活化前烷基化部分的一个实例是已由一吸电子基团(如酯、氨基甲酸乙酯、或碳酸酯)和一双(卤乙基)氨基(如双(氯乙基)氨基或氮芥)取代了的芳香基(如苯基或萘基)。当所述芳香部分为苯基时,所述两种取代基优选互为间位或对位。苯基上的其它位置各自可任选地由烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、氨基、氨烷基、羟基、羟烷基、烷氧基、芳氧基、芳烷氧基、杂芳氧基、杂芳烷氧基、寡聚亚烷基二醇、酰氨基、酯、芳烷氧基羰氨基、脲基、硫代基、硫代烷基、硫代芳基、或硫代杂芳基取代。其中,优选烷基、烷氧基、寡聚亚烷基二醇、芳氧基、杂芳氧基、和氨基。优选以上每一个取代基位于双(卤乙基)氨基的邻位。
生物还原性部分经生物还原作用转化成另一烷基化试剂。所述生物还原性部分的某些实例有1,4-苯醌(即醌)、硝基苯、或1,2-二氧环己-3,5-双烯。当所述生物还原性部分为醌时,该醌环上的每个非氧代位置各自可任选地由烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、氨基、氨烷基、羟基、羟烷基、烷氧基、芳氧基、芳烷氧基、杂芳氧基、杂芳烷氧基、羧酸酯、酰氧烷基、酯、酰氨基、酰氨烷基、硫代酰氨基、磺酰基氨基、硫代基、硫代烷基、硫代芳基、硫代芳烷基、硫代杂芳基、或硫代杂芳烷基。优选取代基为烷基、氨基、氨烷基、烷氧基、羟烷基、和酰氧烷基。如果醌的2-C和3-C位或5-C和6-C位同时被取代,可由两个取代基共同形成一个环。如果醌上所有非氧代位置均已被取代,且每对取代基均形成一个稠环,则可与醌环一起形成两个稠环。该稠环既可以是脂肪环也可以是芳香环。还可以任选由烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、氨基、氨烷基、羟基、羟烷基、烷氧基、芳氧基、芳烷氧基、杂芳氧基、杂芳烷氧基、羧酸酯、酰氧烷基、酯、酰氨基、酰氨烷基、硫代酰氨基、磺酰基氨基、硫代基、硫代烷基、硫代芳基、硫代芳烷基、硫代杂芳基、或硫代杂芳烷基取代。该稠环可任选含有1-3个杂原子,如氮原子、氧原子、或硫原子。
将活化前烷基化部分和生物还原性部分连接在一起的接头可以是下述之一:亚甲基、含有一个双键的C3烃链、或含有两个间隔双键的C5烃链。该接头可任选由烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、或寡聚亚烷基二醇取代。如果该接头含有不止两个取代基,其中的两个取代基可以连接在一起形成一个5-6元环。此环可以是脂肪环或芳香环,并可任选由烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、或寡聚亚烷基二醇取代。三个如氮原子、氧原子、或硫原子这样的杂原子中的一个可成为环的一部分。
本发明的范围还包括细胞毒化合物的盐。例如,可在细胞毒化合物的氨基取代基与带负电的抗衡离子之间形成所述盐。合适的抗衡离子包括,但不限于,氯化物、氢氯化物、溴化物、碘化物、硫酸盐、硝酸盐、磷酸盐、或乙酸盐。同样地,本发明之化合物的带负电取代基如羧酸酯也可与下述阳离子形成盐:如钠离子或钾离子等碱金属阳离子;镁离子或钙离子等碱土金属阳离子;或可由一或多个有机基团如四甲基铵离子或二异丙基-乙基铵离子取代的铵阳离子。
术语“烷基”在本文中指含有1-8个碳原子的直链或支链烃链。或含有3-8个碳原子的环烃链。所述环烃链可能含有1-3个杂原子如氮原子、氧原子、或硫原子并可能还含有稠环。稠环是含有同一个碳-碳键的多个环。烷基的实例包括,但不限于,甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、己基、异己基、庚基、辛基、环丙基、环戊基、环己基、环庚基、降冰片基(norbornyl)、异冰片基、环己甲基、1-或2-环己乙基、1-,2-,或3-环己丙基、四氢呋喃基、四氢吡喃基、哌啶基、吗啉基以及吡咯烷基。
术语“链烯基”指含有2-8个碳原子的直链或支链烃链,或环烃链即含有3-8个碳原子的“环烯基”,其特征是具有一或多个双键。环烯基可能含有1-3个如氮原子、氧原子、或硫原子这样的杂原子,即“杂环烯基”并可能含有稠环。链烯基通常包括烯丙基、2-丁烯基、2-戊烯基、2-己烯基、环丙烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基、和降冰片烯基。
“芳基”是含有3-8个碳原子的环状芳香性部分并可能还含有稠环。稠环指与另一环状部分具有同一碳-碳键的芳香环。该环状部分可以是芳基、环烷基、或杂环烷基。芳基通常包括苯基、1-萘基、2-萘基、联苯基、菲基、和蒽基。“杂芳基”指含有1-3个杂原子的芳基。通常杂环芳香环包括香豆素基(coumarinyl)、吡啶基、吡嗪基、嘧啶基、呋喃基、吡咯基、噻吩基、噻唑基、恶唑基、咪唑基、吲哚基、苯并呋喃基和苯并噻唑基。芳烷基的一个实例是2-苯乙基。
术语“寡聚亚烷基二醇”指2-5个烷氧基的链。其中的烷氧基之间可以相同也可以不同。寡聚亚烷基二醇的一个实例是乙氧甲氧基。
如本文所用,诸如氨基、酰氨基、酯、硫代酰氨基、磺酰基氨基、以及脲基等取代基可以是未取代的,也可以由烷基、链烯基、芳基、芳烷基、杂芳基、或杂芳烷基取代。此外,诸如酰氨基或酯这样的二价取代基可从不同方向连接至它的两个相邻部分。环状基团如苯基的取代基可以在任何有效部位接受连接。
本发明的另一方面涉及包含一种上述细胞毒化合物(或它们的盐)以及一种可药用载体的组合物。所述化合物使用可有效治疗肿瘤的量。本发明还有一方面涉及治疗肿瘤的方法,其包括将有效量的上述细胞毒化合物或它们的盐施予有相应需要的患者。可用此方法治疗的肿瘤的某些实例包括白血病、肺癌、结肠癌、CNS癌、黑色素瘤、卵巢癌、肾癌、前列腺癌、和乳腺癌。这类细胞毒化合物在用于治疗上述肿瘤的药物的生产中的应用也包括在本发明的范围内。
本发明的其它特征和优点在以下对优选实施方案的描述、以及从所附权利要求中均较明显。
发明详述
本发明涉及细胞毒化合物,其有(1)带吸电子基团的活化前烷基化部分和(2)生物还原性部分。
生物还原性部分的实例包括:
注意,在上两类实例中,活化前烷基化部分的酯基团是吸电子基团。
如上述,本发明所公开的细胞毒化合物能通过生物还原作用转化成两种烷基化试剂。这一转变的机制通常分为两个阶段。以醌作为生物还原性部分、以亚甲基作为接头、并以双(氯乙基)-氨基-苯基酯作为活化前烷基化部分的细胞毒化合物在以下描述中作为实例使用。
第一阶段涉及生物还原性部分的还原。这通常由细胞的酶如细胞色素P450还原酶实现。醌可在两个单电子步骤中实施生物还原作用,其中第一次还原产生一个半醌自由基负离子,第二次还原产生一个氢醌。该半醌自由基负离子与氧进行反应的能力很强。事实上,在富含氧的正常组织中,大部分这类自由基负离子都已重新氧化为醌。
如背景部分所述,肿瘤部位的特征是其血管系统分布的有序性很低,这会造成比正常组织的环境氧含量更低(氧缺乏)。或者说,还原的化合物更不太可能遇到分子氧而被重新氧化。因此半醌自由基负离子半衰期加长,并可进一步还原以产生氢醌。
在第二个阶段,一对电子从氢醌的氧原子传递至醌环(见下图,其中吸电子基团为-O-(C=O)-(酯),而接头为-CH2-(亚甲基)),最后通过连接生物还原性部分和活化前烷基化部分的接头传递至活化前烷基化部分之吸电子基团的氧原子上。这一电子传递活性因此导致吸电子基团与接头之间的键被打断,从而将醌部分转变成甲基醌。甲基醌是已知能攻击亲核物质如DNA的烷基化试剂(见Lin等,医学化学杂志1972,15,127;医学化学杂志1973,16,1268;医学化学杂志1974,17,688;医学化学杂志1975,18,917;医学化学杂志1976,19,1336)。
此键断裂的后果是,该吸电子基团变成一种吸电子能力更弱的基团。这种转变进而可增加双(卤乙基)氨基的电子密度并使所述活化前烷基化部分变成烷基化试剂。实例为酯基团时,它的强吸电子特点(Hammet取代常数为σp=0.45和σm=0.37)使双(卤乙基)氨基的烷基化部分在去活化阶段保持稳定。当该酯基团变成羧酸酯(其吸电子能力更弱,σp=0和σm=-0.1)时,该双(卤乙基)氨基中氨基氮的电子密度加强,因此而导致其烷基化活性的增强。
一类本发明的细胞毒化合物如下式(Ⅰ)所表示:其中A、B、C、和D各自为-R1、-R-NR1R2、-O-R1、-R-OH、-C(=P)O-R1、-R-O-C(=O)R1、-C(=O)-NR1R2、-R-NR1-C(=O)R2、-SO2-NR1R2、-N-SO2、-S-R1、或-L-W-Ph-N(CH2CH2X)2。任选地,如果A和B均不是-L-W-Ph-N(CH2CH2X)2,那么A和B一起可与所述醌环形成一个5-6元稠环。类似地,如果C和D均不是-L-W-Ph-N(CH2CH2X)2,那么C和D可任选地连接在一起,与醌环形成一个5-6元稠环。所述稠环可任选地包含1-3个杂原子如氮原子、氧原子、或硫原子,并可任选地由烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、-R-NR1R2、-O-R1、-R-OH、-C(=O)O-R1、-R-O-C(=O)R1、-C(=0)-NR1R2、-R-NR1-C(=O)R2、-SO2-NR1R2、-N-SO2、或-S-R1取代。每个R可分别为烷基或为缺失。每个R1和R2各自为氢、烷基、链烯基、芳基、芳烷基、杂芳基、或杂芳烷基。L为-(CR3=CR4)n-CR5R6-,其中R3、R4、R5、和R6各自为氢、烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、或-(O-烷基)1-5;n为0、1、或2。“-(O-烷基)1-5”指烷氧基(“-(O-烷基)1”)或寡聚亚烷基二醇基(“-(O-烷基)2-5”)。R3和R4当n不为0时可任选地共同形成一个5元或6元环。此环可以是脂肪环或芳香环,并可任选地由烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、或-(O-烷基)1-5取代。1-3杂原子如氮原子、氧原子、或硫原子也可成为此环的一部分。W为-O-C(=O)-、-O-C(=O)-NR1-、或-O-C(=O)O-。pH为苯基,可任选地由烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、-R-NR1R2、-OH、-(O-烷基)1-5、-O-芳基、-O-芳烷基、-O-杂芳基、-O-杂芳烷基、-R-OH、-C(=O)O-R1、-O-C(=O)O-R1、-C(=O)-NR1R2、-NR1-C(=O)-R2、-NR1-C(=O)O-R2、-NR1-C(=O)NR1R2、或S-R1取代。X为卤素,如氟、氯、溴、或碘。
注意如果A和B,或C和D,均不与醌形成稠环,那么A、B、C、和D中至少一个是-L-W-Ph-N(CH2CH2X)2。而且,如果A、B、C、和D无一为-L-W-Ph-N(CH2CH2X)2,那么A和B,或C和D(包括A和B以及C和D)一起与醌环形成稠环。该稠环(或有两个稠环时至少其中一个稠环)在环上两个环原子之间包含一个双键,并在环上所述两个原子之一处由-L-W-Ph-N(CH2CH2X)2取代。此双键与醌上的双键一起形成一共轭体系,使电子可从一个双键流向另一个双键。
式(Ⅰ)的化合物的制备一般分为三个部分:(1)生物还原性醌部分的制备;(2)双(卤乙基)氨基-苯基部分的制备;和(3)使该生物还原性醌部分与该双(卤乙基)氨基-苯基部分偶联。(1)-(3)分部的一般合成过程如下述:
(1)含醌环的生物还原性部分的制备:
连接于受到适当保护的生物还原性部分上的接头的离去基团如卤化物必须与分部(3)中含双(卤乙基)氨基的目的苯基部分偶联。可通过如亲电取代反应将该离去基团和该接头导入醌环的非氧位。如实施例1中分部(1)所述,当氢醌与低聚甲醛反应后,一个羟甲基出现在3,5,6-三甲基-氢醌二甲酯的C2碳原子上。由于上述反应是在盐酸中发生的,因此该羟甲基还能进一步发生反应并致使羟基被氯离子取代。故这一反应产生一个氯甲基取代的醌。然后两个甲基酯保护基团以后可能通过水解去保护。
(2)含双(卤乙基)氨基的苯基部分的制备(在以下描述中氯即为所述卤素):
双(卤乙基)氨苯基部分可从例如硝基苯甲酸制备。羧酸酯可以以酯形式保护。苯环的合适取代基可偶联至或转换至此位点,如参见实施例1的分部(2)。然后可还原硝基以形成氨基。此氨基可随后与环氧乙烷反应,形成双取代的羟乙基氨基。在这一含有双(羟乙基)氨基的中间产物中加入氯化剂如亚硫酰氯,便可最终形成所述烷基化部分即双(氯乙基)氨基部分。与分部(1)中的去保护反应类似,这里的酯基团也通过水解除去。
(3)含醌环的生物还原性部分与含双(氯乙基)氨基的苯基部分的偶联反应:
在一典型实例中,一种含醌环部分如实施例1的2-氯甲基-3,5,6-三甲基苯醌,可与一种含双(氯乙基)氨基的苯基部分如3-[双-(2-氯-乙基)氨基-4-甲氧基苯甲酸,通过亲核取代反应偶联。用作亲核物的羧酸酯代替了卤化物离子并导致一酯键的形成。
如上述,本发明的含有效量细胞毒化合物的药用组合物可用于治疗肿瘤。本发明的范围还包括通过将这类组合物施予病人而治疗肿瘤的方法。将细胞毒化合物(或该细胞毒化合物的盐)的有效量定义为通过施予有需要的病人而对接受治疗的病人产生疗效的化合物的量。施予病人的有效量一般取决于年龄、表面积、体重、和病人的状况。对动物和对人的剂量相互关系(基于每平方米体表面积的毫克数)如Freireich等,癌症化疗报道(CancerChemother.Rep.)1966,50,219所述。体表面积可从病人的身高和体重近似地测定。见如科学列表(Scientific Tables),Geigy Pharmaceuticals,Ardley,NewYork,1970,537。用于实施本发明的细胞毒化合物的有效量可为约0.1mg/kg-约250mg/kg。有效量也可根据给药途径、所用赋形剂、以及与其它治疗包括使用抗肿瘤制剂和放疗同时用药的可能性而变化,如本领域技术人员所认知。
所述药用组合物可通过非胃肠道途径给药,包括口服、局部用药、皮下用药、腹膜内用药、肌肉内用药、以及静脉用药。胃肠道用药剂型的实例包括活性试剂的水溶液,溶于等渗的生理盐水,5%葡萄糖或其它众所周知的可药用的赋形剂。增溶剂如环糊精,或本领域熟知的其它增溶剂可作为能运输所述药用化合物的药物赋形剂。
本发明的细胞毒化合物还可配制成适用于其它已知方法的给药途径的剂型。例如可将所述药用组合物配制成适于口服的胶囊、凝胶密封(gelseal)或片剂。胶囊可能包含任何已知的可药用物质如明胶或纤维素衍生物。片剂可按常规方法通过压缩本发明活性化合物与固体赋形剂、以及润滑剂的混合物而配制。固体赋形剂的实例包括淀粉和糖膨润土。所述细胞毒化合物还能以含有如乳糖或甘露糖醇作为黏合剂并含有常规填料以及压片剂的硬壳片剂或胶囊形式给药。
本发明化合物的抗肿瘤活性可用肿瘤生长消退试验作初步评估,该试验分析了所测化合物对已知小鼠体内已有实体瘤生长的抑制能力。该试验可如下进行:将肿瘤细胞植入裸鼠的脂肪足垫中,然后使肿瘤细胞生长,长至一定大小再给予所述细胞毒化合物。随后在数周如三周内监控肿瘤的体积。在试验期间同时还监控受试动物的总体健康水平。
我们相信,本领域技术人员无需进一步解释就能根据本文的描述全面并深入地实施本发明。故以下描述了本发明各种化合物的合成和生物学检验的具体实施例应被看成仅为举例说明,而非对本公开的任何意义上的限制。本文所引用的所有出版物包括专利均全文引入作为参考。
实施例1-7分别详细描述了七种本发明的细胞毒化合物的合成。每个实施例均分为三个分部:(1)生物还原性醌部分的制备,(2)双(氯乙基)氨基-苯基部分的制备,和(3)以上两个部分的偶联反应。
实施例1
化合物1的合成
(1)2-氯甲基-3,5,6-三甲基苯醌的合成
将氯化氢气体引入3,5,6-三甲基氢醌二甲醚(1g,5.5mmol)与低聚甲醛(lg)在含1NHCl的乙酸(30ml)中的混合物中。然后于60℃将反应混合物搅拌1小时。将混合物倾入400ml水中,过滤。残留物溶于100ml乙酸乙酯,用饱和NaCl溶液(100ml)洗涤。抽提物在硫酸镁上干燥,减压除去溶剂。获得甲基4-2-氯甲基-3,5,6-三甲基氢醌二甲醚的白色固体(0.8g,6%)。1H NMR(300MHz,CDCl3):4.47(s,2H),3.79(s,3H),3.66(s,3H),2.3(s,2H),2.20(s,3H),2.18(s,3H).Cl2H19ClO2的ESMS计算值为230.73;实际值为231.7(M+H)+。
将2-氯甲基-3,5,6-三甲基氢醌二甲酯溶于20ml乙腈。该溶液中加入含9.6g硝酸铵铈(Ⅳ)的200ml水后,用乙酸乙酯(100ml和50ml)抽提该混合物。合并的抽提物在硫酸镁上干燥,溶剂经减压除去。残留物中加50ml水,然后用乙酸乙酯(50ml)抽提该混合物。抽提物用饱和NaCl溶液(100ml)洗涤。使抽提物在硫酸镁上干燥,溶剂经减压除去,得2-氯甲基-3,5,6-三甲基氢醌黄色结晶。1H NMR(300MHz,CDCl3):4.47(s,2H),2.16(s,3H),2.06(s,3H),2.05(s,3H)C10H11ClO2的ESMS计算值为198.65;实际值为199.6(M+H)+。
(2)3-双(2’-氯乙基)氨基-4-甲氧基苯甲酸的合成
将甲基3-氨基-4-甲氧基苯甲酸酯(10.94g,0.06mol)与环氧乙烷(12.5g,0.28mol)在乙酸(150ml)中的反应混合物室温搅拌24小时。然后在旋转蒸发仪中浓缩至约80ml,用H2O(300ml)稀释,用二氯甲烷/乙酸乙酯(1∶1,6×300ml)抽提。浓缩该有机溶液,得到一种灰白色的油(8.6g,54%)。1H NMR(300MHz,CDCl3):7.85(m,2H),6.94(d,J=8.1Hz,1H),3.90(s,3H),3.84(s,3H),3.52(m,4H),3.24(m,4H).
向室温搅拌的甲基3-(2’-双(羟基-乙基)氨基)-4-甲氧基苯甲酸酯(2.80g,10.40mmol)之苯溶液(40ml)中缓慢加入亚硫酰氯(1.2ml)。之后将反应浆回流加热0.5小时。再用冰/H2O(100ml)处理反应混合物,并用乙酸乙酯(100ml)抽提。此乙酸乙酯溶液用碳酸氢钠(100ml)洗涤,在硫酸镁上干燥,并经浓缩得到灰白色固体产物(2.50g,79%)。1H NMR(300MHz,CDCl3):7.76(dd,J=8.4,2.4Hz,1H),7.69(d,J=2.4Hz,1H),6.90(d,J=8.4Hz,1H),3.90(s,3H),3.85(s,3H),3.52(s,8H).C13H17Cl2NO3的ESMS计算值为305.1;实际值为328.0(M+Na)+。
将甲基3-双(2’-氯乙基)氨基-4-甲氧基苯甲酸酯(2.70g,8.823mmol)的浓盐酸(37%重量比的水溶液,40ml)悬浮液在氮气下回流加热1小时。反应混合物用冰/H2O(200ml)处理,乙酸乙酯抽提(4×150ml)。浓缩有机溶液,得到白色固体(2.05g,80%)。C12H15Cl2NO3的ESMS计算值为291.0;实际值为292.0(M+H)+。
(3)使(1)和(2)所得的中间产物偶联
将3-双(2’-氯乙基)氨基-4-甲氧基苯甲酸(0.51g,1.750mmol)和2-氯甲基-3,5,6-三甲基苯醌(0.56g,2.819mmol)的丙酮溶液(25ml)在氮气下、有碳酸钾(2.0g)和碘化钠(1.2g)存在的情况下回流加热2小时。分离有机层,用乙酸乙酯(50ml)稀释,含水碳酸钾洗涤(2×50ml),硫酸镁干燥,浓缩成油。在硅胶上经急骤层析纯化得到粘性油(0.61g,77%)。1H NMR(300MHz,CDCl3):7.70(dd,J=8.4,1.8Hz,1H),7.65(d,J=1.8Hz,1H),6.86(d,J=8.4Hz,1H),5.25(s,3H),3.90(s,3H),3.50(s,8H),2.18(s,3H),2.06(s,3H),2.05(s,3H).C22H25Cl2NO5的ESMS计算值为453.1;实际值为454.1(M+H)+。
实施例2
化合物2的合成
(1)参见实施例1的分部(1)
(2)参见实施例1的分部(2),不同的是起始物质为3-氨基-4-甲基苯甲酸酯,而不是3-氨基-4-甲氧基苯甲酸酯。
(3)使(1)和(2)所得的中间产物偶联
将3-甲基-4-双(2’-氯乙基)氨基苯甲酸(830mg,3.02mmol)与2-氯甲基-3,5,6-三甲基苯醌(500mg,2.51mmol)溶于丙酮(20ml)并在有碳酸钾(1g)和碘化钠(80mg)存在的情况下加热1.5小时。将反应混合物倾入300ml水中并用乙酸乙酯抽提(100ml,4次)。抽提物在硫酸镁上干燥,然后减压浓缩。获得醌-芥A的油形式(800mg,72%)。1H NMR(300MHz,CDCl3):7.75(dd,J=2.19,2.19Hz,1H),7.63(m,1H),6.65(d,J=8.52,1H),5.22(s,2H),3.48(m,8H), 2.31(s,3H),2.15(s,3H),2.14(s,3H),2.04(s,3H).C22H25Cl2NO4的ESMS计算值为438.31;实际值为439.0(M+H)+。
实施例3
化合物3的合成
(1)参见实施例1的分部(1)
(2)4-双(2’-氯乙基)氨基-3-辛氧基苯甲酸的合成
将甲基3-羟基-4-硝基苯甲酸酯(5.5g,0.028mol)、碘辛烷(10.0g,0.042mol)和碳酸钾(20g)的DMF(100ml)浆液于100℃搅拌3小时。将反应混合物冷却至室温,加H2O(500ml)稀释,再用乙醚/乙酸乙酯(9/1,2×200ml)抽提。收集的有机溶液加H2O(400ml)洗涤,硫酸镁干燥,浓缩,得灰白色油(8.7g,100%)。
甲基4-硝基-3-辛氧基苯甲酸酯(8.7g,0.028mol)的甲醇溶液(150ml)于室温有10%Pd-C存在的情况下在氮气下搅拌29h。反应混合物经硅藻土过滤,浓缩,得灰白色固体(7.6g,96%)。1H NMR(300Mhz,CDCl3):7.25(d,J=2.1Hz,1H),C16H25NO3的MS计算值为279.2;实际值为279。
将甲基4-氨基-3-辛氧基苯甲酸酯(3.47g,12.4mmol)与环氧乙烷(4.5g,198mol)在乙酸(100ml)中的反应混合物于室温搅拌12小时。加H2O(500ml)稀释,用氯仿/甲醇(95/5,4×100ml)抽提。将有机溶液浓缩为棕色油。急骤层析纯化(硅胶,含5%-10%甲醇的氯仿溶液),所得产物为灰白色油(2.25g,42%)。1H NMR(300MHz,CDCl3):7.62(dd,J=8.1,2.1Hz,1H),7.55(d,J=2.1Hz,1H),7.12(d,J=8.4Hz,1H),4.06(t,J=6.9Hz,2H),3.90(s,3H),3.64(t,J=5.1Hz,4H),3.38(t,J=5.1Hz,4H),1.86(J=5.1Hz,2H),1.30(m,10H),0.89(t,J=6.9Hz,3H).C20H13NO5的ESMS计算值为367.2;实际值为390.3(M+Na)+。
向室温搅拌的甲基4-双(2’-羟乙基)氨基-3-辛氧基苯甲酸酯(2.20g,6.0mol)之苯溶液(50ml)中缓慢加入亚硫酰氯(1.2ml,l6mmol)。之后将反应回流加热1.5小时。将反应混合物冷却至室温,用冰/H2O(100ml)处理,并用乙酸乙酯(50ml)抽提。有机溶液用碳酸氢钠(20ml)、H2O(50ml)洗涤,在硫酸镁上干燥,并经浓缩得到灰白色固体产物(2.1g,87%)。1H NMR(300MHz,CDCl3):7.58(dd,J=8.1,1.8Hz,lH),7.51(d,J=l.8Hz,1H),6.92(d,J=8.1Hz,1H),4.03(t,J=6.9Hz,1H),3.89(s,3H),3.60(m,8H),1.85(J=7.2Hz,2H),1.30(m,10H),0.89(t,J=6.9Hz,3H).C20H31Cl2NO3的ESMS计算值为403.2;实际值为404.2(M+H)+。
将甲基4-双(2’-氯乙基)氨基-3-辛氧基苯甲酸酯(1.8g,4.5mmol)的浓盐酸(37%重量比的H2O溶液,50ml)悬浮液在氮气下回流加热0.5小时。反应混合物用冰/H2O(100ml)处理,氯仿抽提(3×50ml)。浓缩有机溶液,得到棕色油。急骤层析纯化(硅胶,含2%甲醇的氯仿溶液)得灰白色固体产物(1.58g,88%)1H NMR(300MHz,CDCl3):7.67(dd,J=8.1,1.5Hz,1H),7.56(d,J=1.5Hz,1H),6.93(d,J=8.4Hz,1H),4.40(t,J=6.6Hz,2H),3.65(m,8H),1.85(J=7.8Hz,2H),1.35(m,10H),0.90(t,J=6.6Hz,3H).C29H29Cl2NO3的ESMS计算值为389.2;实际值为390.2(M+H)+。
(3)使(1)和(2)所得的中间产物偶联
相同方法如实施例1和2的分部(3)中所述。1H NMR:δ7.76(dd,J=8.and1.8Hz,1H),7.68(d,J=1.8Hz,1H),6.98(d,J=8.Hz,1H),5.25(s,2H),3.53(brs,8H),3.6(t,J=5.0Hz,2H),2.13(s,3H),2.0(s,3H),2.02(s,3H),1.86(J=5.0Hz,3H),1.30(m,10H),0.89(t,J=6.9Hz,3H).C29H39Cl2NO5的ESMS计算值为552.2;实际值为553.1(M+H)+。
实施例4
化合物4的合成
(1)参见实施例1的分部(1)
(2)2-双(2’-氯乙基)氨基-3,5-二甲基苯甲酸的合成
将甲基2-氨基-3,5-二甲基苯甲酸酯(7.0g,0.039mol)与环氧乙烷(10g,0.23mol)在乙酸(150ml)中的反应混合物于室温搅拌19小时。然后在旋转蒸发仪上将其浓缩至约100ml,加H2O(300ml)稀释,用氯仿(5×200ml)抽提。将有机溶液浓缩为灰白色油(10.0g,96%)。1H NMR(300MHz,CDCl3):7.31(br,s,1H),7.16(brs,1H),3.91(s,3H),3.73(m,2H),3.63(m,2H),3.26(brm,4H),2.32(s,3H),2.30(s,3H).
向室温搅拌的甲基2-双(2’-羟乙基)氨基-3,5-二甲基苯甲酸酯(7.0g,0.026mol)之苯溶液(200ml)中缓慢加入亚硫酰氯(12ml,0.16mmol)。之后将反应浆室温搅拌12小时。再将反应混合物用冰/H2O(500ml)处理,并用乙酸乙酯(2×300ml)抽提。该乙酸乙酯溶液用H2O(300ml)、碳酸氢钠(200ml)洗涤,在硫酸镁上干燥,并经浓缩得到清亮的油(5.6g,71%)。1H NMR(300MHz,CDC13):7.31(d,J=2.1Hz,1H),7.17(d,J=2.1Hz,1H),3.88(s,3H),3.53(m,4H),3.37(brm,4H),2.35(s,3H),2.30(s,3H).C14H19Cl2NO2的ESMS计算值为303.1;实际值为304.1(M+H)+。
将甲基2-双(2’-氯乙基)氨基-3,5-二甲基苯甲酸酯(5.6g,0.018mol)的浓盐酸(37%重量比的H2O溶液,150ml)悬浮液在氮气下回流加热3小时。反应混合物用冰/H2O(200ml)处理,氯仿抽提(3×150ml)。浓缩有机溶液,得到白色固体(5.1g,96%)1H NMR(300MHz,CDC13):8.01(d,J=1.5Hz,1H),7.23(dd,J=1.5,0.6Hz,1H),3.6(m,8H),2.43(s,3H),2.35(s,3H).C13H17Cl2NO2的ESMS计算值为289.1。
(3)使(1)和(2)所得的中间产物偶联
将2-双(2’-氯乙基)氨基-3,5-二甲基苯甲酸(0.45g,1.551mmol)的丙酮(15ml)溶液在有碳酸钾(1.5g)和碘化钠(1.0g)存在的情况下在氮气下回流加热。向其中缓慢加入2-氯甲基-3,5,6-三甲基苯醌(0.45g,2.413mmol)的丙酮溶液(5ml)。回流加热20分钟后,将反应混合物冷却至室温,加H2O(50ml)稀释,并用乙酸乙酯抽提(50ml)。有机层加H2O(50ml)洗涤,在硫酸镁上干燥,浓缩得油。在硅胶上急骤层析获得粘性油(0.52g,76%)。1H NMR(300MHz,CDCl3):7.25(d,J=2.1Hz,1H),7.17(d,J=2.1Hz,1H),5.24(s,2H),3.49(m,4H),3.38(brm,4H),2.33(s,3H),2.28(s,3H),2.20(s,3H),2.07(s,3H),2.06(s,H).C23H27Cl2NO4的ESMS计算值为451.1;实际值为452.2(M+H)+。
实施例5
化合物5的合成
(1)参见实施例1的分部(1),用2-(2-乙酰氧乙基)-苯醌作为起始物质。
(2)参见实施例1的分部(2),用4-硝基苯甲酸作为起始物质。
(3)将2-氯甲基-5-(2’-乙酰氧乙基)苯醌(110mg,0.453mmol)与4-双(2’-氯乙基)氨基苯甲酸(80mg,0.305mmol)的二噁烷(6ml)溶液在有碳酸钾存在的情况下室温搅拌5小时。反应混合物用己烷(15ml)稀释,经硅藻土垫过滤。有机相经浓缩成油。在硅胶上急骤层析纯化得黄色固体(18mg,12%)。1H NMR(300MHz,CDCL3):7.97(d,J=9.0Hz,2H),6.80(m,4H),5.20(d,J=1.8Hz,2H),4.26(t,J=6.3Hz,2H),3.83(t,J=6.6Hz,4H),3.68(t,J=6.6Hz,2H),2.76(dt,J=6.0,1.2Hz,2H),2.03(s,3H).C22H23Cl2NO6的ESMS计算值为467.1;实际值为490.0(M+Na)+。
实施例6
化合物6的合成
(1)参见实施例1的分部(1)关于2,3-二甲基苯醌之合成的类似方法。
(2)参见实施例1的分部(2)。
(3)将3-双(2’-氯乙基)氨基-4-甲氧基苯甲酸(180mg,0.618mmol)溶于丙酮(10ml)并在有碳酸钾(0.58g)的情况下回流加热。向其中滴加2,3-二氯甲基-5,6-二甲基苯醌(75mg,0.323mmol)的丙酮溶液(5ml)。将反应混合物冷却至室温,加乙酸乙酯(15ml)稀释,并含水碳酸钾洗涤(2×50ml),在硫酸镁上干燥,浓缩得油。在硅胶上急骤层析获得粘石油(85mg,37%)。1H NMR(300MHz,CDCl3):7.59(m,4H),6.75(d,J=9.0Hz,2H),5.39(s,4H),3.86(s,6H),3.48(m,16H),2.08(s,6H).C34H38Cl4N2O8的ESMS计算值为742.1;实际值为789.1(M+2Na-H)+。
实施例7
化合物7的合成
(1)参见实施例1的分部(1)。
(2)甲基4-双(2’-氯乙基)氨基-3-(2’-(2”-甲氧基乙氧基)乙氧基)苯甲酸的合成
甲基3-羟基-4-硝基苯甲酸酯(5.5g,0.028mol)、1-溴-2-(2-甲氧基乙氧基)乙烷(10.0g,0.055mol)和碳酸钾(20g)在DMF(100ml)中的浆液于90-100℃搅拌2小时。将反应混合物冷却至室温,用H2O(100ml)稀释。所得固体经过滤收集,用H2O(100ml)洗,并干燥,得到白色固体状的产物(6.2g,74%)。1H NMR(300MHz,CDCl3):7.82(d,J=8.1Hz,1H),7.78(d,J=1.2Hz,1H),7.69(dd,J=8.1,1.2Hz,1H),4.33(t,J=4.5Hz,2H),3.95(s,3H),3.92(t,d,J=4.8Hz,2H),3.73(m,2H),3.55(m,2H),3.38(s,3H).C13H17NO7的ESMS计算值为299.1;实际值为300.1(M+H)+。
于室温下有10%Pd-C和乙酸(10ml)存在时将甲基3-(2’-(2”-甲氧基乙氧基)乙氧基)-4-硝基苯甲酸酯(6.0g,0.020mol)的甲醇溶液于H2气中搅拌20h。反应混合物经硅藻土过滤,浓缩,得到灰白色固体(5.0g,93%)。1H NMR(300MHz,CDCl3):7.55(d,J=8.7,2.4Hz,1H),7.47(d,J=1.8Hz,1H),6.67(d,J=8.7Hz,1H),4.22(t,J=4.8Hz,2H),3.87(m,2H),3.85(s,3H),3.70(t,J=4.8Hz,2H),3.58(t,J=4.8Hz,2H),3.39(s,3H).C13H19NO5的MS计算值为269.1;实际值为270.1(M+H)+。
将4-氨基-3-(2’-(2”-甲氧基乙氧基)乙氧基)苯甲酸酯(5.0g,18.6mmol)和环氧乙烷(8.8g,200mol)在乙酸(150ml)中的反应混合物于室温搅拌12小时。用H2O(300ml)稀释,氯仿/甲醇(95/5,4×200ml)抽提。有机溶液经浓缩得灰白色油(6.1g,92%)。1H NMR(300MHz,CDCl3):7.62(dd,J=8.l,2.1Hz,1H),7.52(d,J=2.1Hz,1H),7.05(d,J=7.2Hz,1H),4.22(m,4H),3.89(s,3H),3.9-3.8(m,4H),3.68(m,6H),3.58(m,2H),3.38(m,2H),3.37(s,1H).C17H27NO7的ESMS计算值为357.2;实际值为358.3(M+H)+。
向室温搅拌的甲基4-双(2’-羟乙基)氨基-3-(2’-(2”-甲氧基乙氧基)乙氧基)笨甲酸酯(5.0g,13.3mol)之苯溶液(100ml)中缓慢加入亚硫酰氯(5.1ml,68mmol)。之后将反应室温搅拌16小时。再将反应混合物用冰/H2O(500ml)处理,并用乙酸乙酯(2×300ml)抽提。合并的乙酸乙酯溶液用碳酸氢钠(20ml)、H2O(50ml)洗涤,在硫酸镁上干燥,并经浓缩得到灰白色油(3.9g,74%)。1H NMR(300MHz,CDCl3)7.58(dd,J=8.7,2.1Hz,1H),7.49(d,J=2.1Hz,1H),6.88(d,J=8.1Hz,1H),4.18(m,2H),3.87(m,2H),3.86(s,3H),3.69(m,2H),3.63(m,8H),3.56(m,2H),3.37(s,1H).C17H25Cl2NO5的ESMS计算值为393.1;实际值为395.2(M+H)+。
甲基4-双(2’-氯乙基)氨基-3-(2’-(2”-甲氧基乙氧基)乙氧基)苯甲酸酯(3.0g,7.64mmol)在浓盐酸(37%重量比的H2O溶液,50ml)中的悬浮液于氮气下回流加热2小时。。反应混合物用冰/H2O(100ml)处理,氯仿抽提(2×100ml)。浓缩有机溶液,得到白色固体(2.8g,97%)。1H NMR(300MHz,CDCl3):7.68(dd,J=8.4,2.1Hz,1H),7.55(d,J=2.1Hz,1H),6.92(d,J=8.7Hz,1H),4.22(m,1H),3.89(m,2H),3.67(m,10H),3.62(m,2H),3.39(s,3H).C16H23Cl2NO5的ESMS计算值为379.1;实际值为408.2(M+H)+。
(3)将分部(1)和(2)的中间产物偶联
利用如实施例1分部(3)中所述的相同方法。1H NMR:δ7.58(dd,J=8.7,2.1Hz,1H),7.9(d,J=2.1Hz,1H),6.88(d,J=8.1Hz,1H),5.26(s,2H),1.8(m,2H),3.87(m,2H),3.69(m,2H),3.63(m,8H),3.56(m,2H),3.37(s,3H),2.12(s,3H),2.05(s,3H),2.02(s,3H).C26H33Cl2NO5的ESMS计算值为52.2;实际值为53.1(M+H)+。
以下化合物用类似于上述这些实施例的方法合成。
实施例8
化合物8的合成1H NMR:δ7.59(dd,J=8.,2.1Hz,1H),7.1(d,J=2.1Hz,1H),6.88(d,J=8.Hz,1H),5.23(s,3H),3.87(d,J=6.6Hz,2H),2.63(q,J=7.2Hz,H),3.65(s,8H),1.30(m,1H),1.10(t,J=7.2Hz,6H),0.68(m,2H),0.38(m,2H).C28H36Cl2N2O5的ESMS计算值为551.2;实际值为552.1(M+H)+。
实施例9
化合物9的合成1H NMR:δ7.58(dd,J=8.7,2.1Hz,1H),7.49(d,J=2.1Hz,1H),6.88(d,J=8.1Hz,1H),5.06(q,J=7Hz,1H),3.92(t,7Hz,1H),3.63(m,8H),3.56(m,2H),2.12(s,2H),2.05(s,2H),2.02(s,3H),1.80(m,2H),1.45(s,2H),1.00(d,J=7Hz,3H).C26H33Cl2NO5的ESMS计算值为510.1;实际值为511.2(M+H)+。
实施例10
化合物10的合成1H NMR:δ7.62(dd,J=8.,2.1Hz,1H),7.5(d,J=2.1Hz,1H),37.30(d,J=Hz,1H),6.85(d,J=8.Hz,1H),6.0(d,J=Hz,1H),625(d,J=Hz,1H),5.23(s,2H),.50(S,2H),3.85(s,6H),3.65(s,8H),2.05(s,3H),2.00(s,3H).C27H30Cl2N2O6的ESMS计算值为59.2;实际值为550.1(M+H)+。
实施例11
化合物11的合成1H NMR:δ7.58(dd,J=8.7,2.1Hz,1H),7.9(d,J=2.1Hz,1H),6.88(d,J=8.1Hz,1H),5.26(s,2H),.13(m,2H),3.92(s,3H),3.87(m,2H),3.69(m,2H),3.63(m,8H),3.56(m,2H),3.37(s,3H),2.05(s,3H),2.02(s,3H)C26H33Cl2NO8的ESMS计算值为558.2;实际值为559.1(M+H)+。
实施例12
化合物12的合成1H NMR:δ7.52(dd,J=8.4,2.1Hz,1H),7.7(d,J=2.1Hz,1H),7.7(d,J=2.1Hz,1H),6.86(d,J=8.1Hz,1H),5.25(s,2H),3.98(d,J=6.9Hz,2H),3.60(m,8H),2.82(m,1H),2.25-2.1(m,2H),2.18(s,3H),2.05(s,3H),2.0(s,3H),2.0-1.7(m,H).C26H33Cl2NO8的ESMS计算值为558.2;实际值为559.1(M+H)+。
实施例13
化合物13的合成1H NMR:δ7.59(dd,J=8.4,2.1Hz,1H),7.1(d,J=2.1Hz,1H),6.88(d,J=8.4Hz,1H)5.23(s,3H),3.87(d,J=6.6Hz,2H),2.63(q,J=7.2Hz,H),3.65(s,8H),2.15(s,3H),2.08(s,3H),2.0(s,3H),1.30(m,1H),1.10(t,J=7.2Hz 6H),0.68(m,2H),0.38(m,2H).C28H36Cl2N2O5的ESMS计算值为551.2;实际值为552.1(M+H)+。
实施例14
化合物14的合成1H NMR:δ7.4(dd,J=8.7,1.8Hz,1H),7.0(d,J=1.8Hz,1H),6.75(d,J=8.7Hz,1H)5.38(s,2H),3.96(t,J=6.6Hz,2H),3.56(m,8H),2.08(s,3H),2.0(s,3H),1.80(m,2H),1.8(m,2H),0.99(t,J=7.2Hz,3H).C25H29Cl2N3O5的ESMS计算值为522.2;实际值为523.1(M+H)+。
实施例15
化合物15的合成1H NMR:δ7.4(dd,J=8.7,1.8Hz,1H),7.0(d,J=1.8Hz,1H),6.75(d,J=8.7Hz,1H),5.38(s,2H),.67(m,2H),3.96(t,J=6.6Hz,2H),3.91(s,3H),3.56(m,8H),2.23(s,3H),2.08(s,3H),1.80(m,2H),1.8(m,2H),0.99(t,J=7.2Hz,3H),C28H3Cl2N2O6的ESMS计算值为565.2;实际值为566.1(M+H)+。
实施例16
化合物16的合成1H NMR:δ7.4(dd,J=2.19,2.19Hz,1H),7.63(m,1H),6.65(d,J=8.52,1H),5.22(s,2H),3.8(m,8H),2.31(s,3H),2.15(s,3H)2.(s,3H),2.0(s,3H).C22H25Cl2NO的ESMS计算值为38.31;实际值为39.0(M+H)+。
实施例17
化合物17的合成1H NMR:δ7.76(dd,J=8.and1.8Hz,1H),7.68(d,J=1.8Hz,1H),6.98(d,J=8.Hz,1H),5.30(s,2H),3.53(brs,8H),2.35(s,3H),2.18(s,3H),2.0(s,3H),2.02(s,3H).C22H25Cl2NO的ESMS计算值为22.1;实际值为823.1(M+H)+。
实施例18
化合物18的合成1H NMR:δ7.70(dd,J=8.,1.8Hz,1H),7.65(d,J=1.8Hz.1H),6.86(d,J=8Hz,1H),5.25(s,3H),3.90(s,3H),3.50(s,8H),2.18(s,3H),2.06(s,3H),2.05(s,3H).C22H25Cl2NO5的ESMS计算值为53.l;实际值为5.1(M+H)+。
实施例19
化合物19的合成1H NMR:δ7.76(dd,J=8.and1.8Hz,1H),7.68(d,J=1.8Hz,1H),6.98(d,J=8.Hz,1H),5.22(s,2H),3.68-3.80(brm,H),3.53(brs,8H),3.6(t,J=5.0Hz,2H),2.58-2.6(bm,H),2.0(s,3H),2.02(s,3H),1.86(J=5.0Hz,2H),1.30(m,10H),0.89(t,J=6.9Hz,3H).C31HCl2N2O6的ESMS计算值为611.2;实际值为612.1(M+H)+。
实施例20
化合物20的合成1H NMR:δ7.4(dd,J=2.19,2.19Hz,1H),7.63(m,1H),6.65(d,J=8.52,1H),5.22(s,2H),3.90(s,3H),3.8(m,8H),2.0(t,J=7Hz),2.15(s,3H),2.0(s.3H),2.0(s,3H),1.65(m,2H),1.3(m,2H),0.92(t,J=8Hz).C26H32Cl2N2O6的ESS计算值为539.2;实际值为50.1(M+H)+。
实施例21
化合物21的合成1H NMR:δ7.4(dd,J=2.19,2.19Hz,1H),7.63(m,1H),7.20(m,5H),6.65(d,J=8.52,1H),5.22(s,2H),5.18(s,2H),3.80(s,6H),3.8(m,8H),2.15(s,3H),2.(s,3H),2.0(s,3H).C30H33Cl2N3O6的ESMS计算值为502.2;实际值为603.1(M+H)+。
实施例22
化合物22的合成1H NMR:δ8.20(d,J=7.0Hz,1H),8.11(d,J=7.0Hz,1H),7.70(dd,J=8.,1.8Hz),7.65(d,J=1.8Hz,1H),7.53(m,2H),6.86(d,J=8.Hz,1H),5.25(s,3H),3.90(s,3H),3.50(s,8H),2.18(s,3H).C2H23Cl2NO5的ESMS计算值为76.1;实际值为77.0(M+H)+。
实施例23
化合物23的合成1H NMR:δ7.76(dd,J=8.4,1.8Hz,1H),7.55(d,J=1.8Hz,1H),7.02(s,1H),6.86(d,J=8.Hz,1H),5.23(s,2H),3.90(s,3H),3.50(s,8H),2.26(s,3H),2.03(s,3H).C23H23Cl2NO6的ESMS计算值为80.1;实际值为81.2(M+H)+。
实施例241H NMR:δ7.4(dd,J=8.7,1.8Hz,2H),7.0(d,J=1.8Hz,2H),6.75(d,J=8.7Hz,2H)5.38(s,H),3.96(t,J=6.6Hz,H),3.56(m,16H),1.80(sexet,J=7.5Hz,H),1.8(sexet,J=7.5Hz,H),0.99(t,J=7.2Hz,6H).C0H50ClN2O8的ESMS计算值为826.2;实际值为827.1(M+H)+。
实施例25
化合物25的合成1H NMRδ7.80(dd,J=2.19and2.19Hz,1H),7.53(m,1H),6.6(d,J=8.52,1H),5.22(s,2H),3.80(s,3H),3.8(m,8H),2.3(s,3H),2.31(s,3H),2.15(s,3H),2.(s,3H).C2H28Cl2N2O的ESMS计算值为08.2;实际值为09.1(M+H)+。
实施例26
生物学检验
将裸鼠体内能生长为实体瘤的人乳腺癌(MDA-35)肿瘤细胞通过注射一种肿瘤细胞在介质中的悬浮液(3-5×106细胞)而植入雌性裸鼠(Taconic实验室)的脂肪足垫。每组5只小鼠。移植的两至三周后,当肿瘤长至可触及时,给动物静脉注射本发明的细胞毒化合物,每周三次,以MTD的剂量。期间以及停药后两周内每周用卡尺测量肿瘤的体积。半椭圆形的肿瘤体积用以下等式计算:
体积=1/2(L/2×W/2×H)/3π
其中L为肿瘤的长度,W为肿瘤的宽度,H为肿瘤的高度。试验期间对动物称体重并监控一般性健康状况。当肿瘤直径达到约15mm(约800mm3)或肿瘤坏死或动物濒临死亡时,将该动物用CO2窒息法行安乐死。
计算用本发明的各种细胞毒化合物处理的动物体内的肿瘤体积,并与用chlorumbucil(一种含有芳香族氮芥的抗癌药物)处理的动物以及未处理的动物的肿瘤体积进行比较。所测的本发明细胞毒化合物经证实在抑制肿瘤生长方面有出乎意料的高效力。
其它实施方案
本领域技术人员可根据如上所述轻易地明了本发明的本质特征,并且在不违背其宗旨或超出其范围的前提下,可以对本发明作出各种改变和修饰以适应各种应用和具体情况。例如,含有杂原子的接头如-CH=N-CH2-或-N=N-CH2-,尽管在上文中没有描述,但也能作为本发明细胞毒化合物的共轭体系的一部分使用。因此,其它实施方案也均包括在权利要求范围内。
Claims (45)
1.一种化合物或其盐,其由带有吸电子基团的活化前烷基化部分、含有至少两个双键的生物还原性部分、以及将该活化前烷基化部分与该生物还原性部分连接的接头组成,其中所述接头为亚甲基,含双键的C3烃链,含有两个可替换双键的C5烃链;所述生物还原性部分的双键,当接头为亚甲基时通过它们自己,或与C3接头的双键或C5接头的双键一起形成共轭体系,该体系可通过使该生物还原性部分还原而使电子从该生物还原性部分流向该活化前烷基化部分的吸电子基团,从而打断吸电子基团与接头之间的键并使该活化前烷基化部分转变为活性烷基化化合物。
2.权利要求1的化合物或其盐,其中所述活化前烷基化部分为取代有酯、氨基甲酸乙酯、或碳酸酯的芳基,和取代有双(卤以及)氨基的芳基;而该芳基的其它每一位置各自可任选地由烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、氨基、氨烷基、羟基、羟烷基、烷氧基、寡聚亚烷基二醇、芳氧基、芳烷氧基、杂芳氧基、杂芳烷氧基、酯、酰氨基、芳烷氧基羰基氨基、脲基、硫代基、硫代烷基、硫代芳基、硫代芳烷基、硫代杂芳基、或硫代杂芳烷基取代。
3.权利要求1的化合物或其盐,其中所述生物还原性部分经还原可成为烷基化化合物。
4.权利要求3的化合物或其盐,其中所述生物还原性部分是醌,所述醌的每个非氧位置各自可任选地由烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、氨基、氨烷基、羟基、羟烷基、烷氧基、芳氧基、芳烷氧基、杂芳氧基、杂芳烷氧基、羧酸酯、酰氧基烷基、酯、酰氧基烷基、酰氨基、酰氨烷基、硫酰氨基、磺胺基、硫代基、硫代烷基、硫代芳基、硫代芳烷基、硫代杂芳基、或硫代杂芳烷基取代;如果2-C和3-C位置或5-C和6-C位置均有取代,那么可任选地将这两个取代基连接在一起形成一个任选取代的环。
5.权利要求4的化合物或其盐,其中所述醌的每个非氧位置各自任选地取代有烷基、氨基、氨烷基、烷氧基、酰氧基烷基、或羟基烷基。
6.权利要求5的化合物或其盐,其中所述活化前烷基化部分为取代有互为间位或对位的酯基和双(氯乙基)氨基的苯基;该苯基上其它每一位置各自可任选地取代有烷基、烷氧基、寡聚亚烷基二醇、芳氧基、杂芳氧基、或氨基。
7.权利要求6的化合物或其盐,其中所述苯基在所述双(氯乙基)氨的邻位取代有烷基、烷氧基、或寡聚亚烷基二醇。
8.权利要求4的化合物或其盐,其中2-C和3-C位或5-C和6-C位均已取代,且这两个取代基连接在一起形成一个可任选地取代的环。
9.权利要求8的化合物或其盐,其中所述活化前烷基化部分是取代有互为间位或对位的酯基和双(氯乙基)氨基的苯基;而该苯基上其它每一位置各自可任选地取代有烷基、烷氧基、寡聚亚烷基二醇、芳氧基、杂芳氧基、或氨基。
10.权利要求9的化合物或其盐,其中所述苯基在双(氯乙基)氨的邻位取代有烷基、烷氧基、或寡聚亚烷基二醇。
11.权利要求4的化合物或其盐,其中所述活化前烷基化部分为取代有酯、氨基甲酸乙酯、或碳酸酯以及双(卤乙基)氨基的苯基;苯基上其它每一位置各自可任选地取代有烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、氨基、氨烷基、羟基、羟烷基、烷氧基、寡聚亚烷基二醇、芳氧基、芳烷氧基、杂芳氧基、杂芳烷氧基、酯、酰氨基、芳烷氧基羰基氨基、脲基、硫代基、硫代烷基、硫代芳基、硫代芳烷基、硫代杂芳基、或硫代杂芳烷基。
12.权利要求11的化合物或其盐,其中所述双(卤乙基)氨基为双(氯乙基)氨基。
13.权利要求12的化合物或其盐,其中所述苯基取代有酯。
14.权利要求13的化合物或其盐,其中所述酯在双(氯乙基)氨基的对位或间位。
15.权利要求14的化合物或其盐,其中所述苯基在双(氯乙基)氨基的邻位取代有烷基、芳基、杂芳基、烷氧基、芳氧基、杂芳氧基、或寡聚亚烷基二醇。
16.权利要求1的化合物或其盐,其中所述活化前烷基化部分为取代有酯、氨基甲酸乙酯、或碳酸酯和双(卤乙基)氨基的苯基;苯基上其它每一位置各自可任选地取代有烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、氨基、氨烷基、羟基、羟烷基、烷氧基、寡聚亚烷基二醇、芳氧基、芳烷氧基、杂芳氧基、杂芳烷氧基、酯、酰氨基、芳烷氧基羰基氨基、脲基、硫代基、硫代烷基、硫代芳基、硫代芳烷基、硫代杂芳基、或硫代杂芳烷基。
17.权利要求16的化合物或其盐,其中所述苯基取代有酯和双(氯乙基)氨基;且所述酯在所述双(氯乙基)氨基的对位或间位。
18.权利要求17的化合物或其盐,其中所述苯基在双(氯乙基)氨基的邻位取代有烷基、芳基、杂芳基、烷氧基、芳氧基、杂芳氧基、或寡聚亚烷基二醇。
19.权利要求18的化合物或其盐,其中所述生物还原性部分为一种醌,该醌的每个非氧位置各自可任选地取代有烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、氨基、氨烷基、羟基、羟烷基、烷氧基、芳氧基、芳烷氧基、杂芳氧基、杂芳烷氧基、羧酸酯、酰氧基烷基、酯、酰氧基烷基、酰氨基、酰氨烷基、硫酰氨基、磺胺基、硫代基、硫代烷基、硫代芳基、硫代芳烷基、硫代杂芳基、或硫代杂芳烷基;而且如果2-C和3-C位或5-C和6-C位均有取代,那么这两个取代基可任选地连接在一起形成一个可任选地取代的环。
20.权利要求19的化合物或其盐,其中所述醌的每个非氧位置各自可任选地取代有烷基、氨基、氨烷基、烷氧基、酰氧基烷基、或羟烷基。
21.权利要求19的化合物或其盐,其中2-C和3-C位或5-C和6-C位均有取代而且这两个取代基连接在一起形成一个可任选地取代的环。
其中A、B、C、和D各自为-R1、-R-NR1R2、-O-R1、-R-OH、-C(=O)O-R1、-R-O-C(=O)R1、-C(=O)-NR1R2、-R-NR1-C(=O)R2、-SO2-NR1R2、-N=SO2、-S-R1、或-L-W-Ph-N(CH2CH2X)2;任选地,如果A和B均不是-L-W-Ph-N(CH2CH2X)2,那么A和B一起可与所述醌环形成一个5-6元稠环;如果C和D均不是-L-W-Ph-N(CH2CH2X)2,那么C和D可一起与醌环形成一个5-6元稠环;其中每个R可各自为烷基或为缺失;每个R1和R2各自为氢、烷基、链烯基、芳基、芳烷基、杂芳基、或杂芳烷基;L为-(CR3=CR4)n-CR5R6,其中R3、R4、R5、和R6各自为氢、烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、或-(O-烷基)1-5;n为0、1、或2;W为-O-C(=O)-、-O-C(=O)-NR1-、或-O-C(=O)O-;Ph为苯基,可任选地由烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、-R-NR1R2、-OH、-(O-烷基)1-5、-O-芳基、-O-芳烷基、-O-杂芳基、-O-杂芳烷基、-R-OH、-C(=0)O-R1、-O-C(=O)-R1、-C(=O)-NR1R2、-NR1-C(=O)-R2、-NR1-C(=O)O-R2、-NR1-C(=O)-NR1R2、或S-R1取代;X为卤素;条如果A和B,或C和D,均不与醌形成稠环,那么A、B、C、或D中至少一个是-L-W-Ph-N(CH2CH2X)2;而且,如果A、B、C、和D无一为-L-W-Ph-N(CH2CH2X)2,那么A和B,或C和D与醌环形成稠环,其中该稠环在两个环原子之间含有一个双键并在这两个环原子之一上取代有-L-W-Ph-N(CH2CH2X)2,此双键与醌上的双键一起形成一共轭体系。
23.权利要求22的醌衍生物或其盐,其中A、B、C、和D各自为-R1、-R-NR1R2、-O-R1、-R-O-C(=O)R1、或-R-OH。
24.权利要求23的醌衍生物或其盐,其中W为-O-C(=O)-,X为氯,n为0。
25.权利要求24的醌衍生物或其盐,其中W和N(CH2CH2X)2互为对位或间位。
26.权利要求25的醌衍生物或其盐,其中Ph在N(CH2CH2X)2的邻位取代有烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、-(O-烷基)1-5、-O-芳基、-O-芳烷基、-O-杂芳基、-O-杂芳烷基。
27.权利要求22的醌或其盐,其中A、B、C、和D中至少一个是-L-W-Ph-N(CH2CH2X)2。
28.权利要求27的醌衍生物或其盐,其中A和B,或C和D均不与所述醌环形成稠环,而且A、B、C、和D中只有一个是-L-W-Ph-N(CH2CH2X)2。
29.权利要求28的醌衍生物或其盐,其中W为-O-C(=O)-,X为氯,n为O,W和N(CH2CH2X)2互为对位或间位,Ph在N(CH2CH2X)2的邻位取代有烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、-(O-烷基)1-5、-O-芳基、-O-芳烷基、-O-杂芳基、-O-杂芳烷基。
30.权利要求22的醌衍生物或其盐,其中A和B或C和D与所述醌环形成稠环。
31.权利要求30的醌衍生物或其盐,其中W为-O-C(=O)-,X为氯,n为0。
32.权利要求31的醌衍生物或其盐,其中W和N(CH2CH2X)2互为对位或间位。
33.权利要求32的醌衍生物或其盐,其中Ph在N(CH2CH2X)2的邻位取代有烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、-(O-烷基)1-5、-O-芳基、-O-芳烷基、-O-杂芳基、-O-杂芳烷基。
34.权利要求30的醌衍生物或其盐,其中A、B、C、和D都不是-L-W-Ph-N(CH2CH2X)2。
35.权利要求34的醌衍生物或其盐,其中W为-O-C(=0)-,X为氯,n为0,W和N(CH2CH2X)2互为对位或间位,Ph在N(CH2CH2X)2的邻位取代有烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、-(O-烷基)1-5、-O-芳基、-O-芳烷基、-O-杂芳基、-O-杂芳烷基。
36.权利要求35的醌衍生物或其盐,其中W为-O-C(=O)-,X为氯,n为0。
37.权利要求36的醌衍生物或其盐,其中W和N(CH2CH2X)2互为对位或间位。
38.权利要求37的醌衍生物或其盐,其中Ph在N(CH2CH2X)2的邻位取代有烷基、链烯基、芳基、芳烷基、杂芳基、杂芳烷基、-(O-烷基)1-5、-O-芳基、-O-芳烷基、-O-杂芳基、-O-杂芳烷基。
39.权利要求38的醌衍生物或其盐,其中A、B、C、和D各自为-R1、-R-NR1R2、-O-R1、-R-O-C(=0)R1、或-R-OH。
40.权利要求39的醌或其盐,其中A、B、C、和D中至少一个是-L-W-Ph-N(CH2CH2X)2。
41.权利要求40的醌衍生物或其盐,其中A和B,或C和D均不与所述醌环形成稠环,而且A、B、C、和D中只有一个是-L-W-Ph-N(CH2CH2X)2。
42.权利要求38的醌衍生物或其盐,其中A和B或C和D与所述醌环形成稠环。
43.权利要求42的醌衍生物或其盐,其中A、B、C、和D中都不是-L-W-Ph-N(CH2CH2X)2。
45.权利要求22的醌衍生物,具有以下结构:
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US8642998P | 1998-05-22 | 1998-05-22 | |
US09/083,652 | 1998-05-22 | ||
US60/086,429 | 1998-05-22 | ||
US09/083,652 US5969133A (en) | 1998-05-22 | 1998-05-22 | Bioreductive cytotoxic agents |
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KR (1) | KR20010074498A (zh) |
CN (1) | CN1302287A (zh) |
AU (1) | AU750381B2 (zh) |
BR (1) | BR9911066A (zh) |
CA (1) | CA2332806A1 (zh) |
HR (1) | HRP20000794A2 (zh) |
HU (1) | HUP0102932A3 (zh) |
NO (1) | NO20005880L (zh) |
PL (1) | PL344257A1 (zh) |
WO (1) | WO1999061409A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103781753A (zh) * | 2011-05-26 | 2014-05-07 | 印第安纳大学研究及科技有限公司 | 用于治疗ape1介导的疾病的醌化合物 |
CN111039764A (zh) * | 2018-10-12 | 2020-04-21 | 山东大学 | 一种双亲乙烯衍生物及制备方法 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6137003A (en) * | 1998-10-28 | 2000-10-24 | Shionogi Bioresearch | Bis (haloethyl) aminobenzene derivatives |
GB0517957D0 (en) | 2005-09-03 | 2005-10-12 | Morvus Technology Ltd | Method of combating infection |
GB0526552D0 (en) | 2005-12-29 | 2006-02-08 | Morvus Technology Ltd | New use |
GB2442202A (en) | 2006-09-30 | 2008-04-02 | Morvus Technology Ltd | Vermin poison |
CN113365616A (zh) | 2018-10-17 | 2021-09-07 | Ptc医疗公司 | 用于抑制和治疗α-突触核蛋白病、tau蛋白病及其他疾病的2,3,5-三甲基-6-壬基环己-2,5-二烯-1,4-二酮 |
KR20240032997A (ko) | 2021-07-08 | 2024-03-12 | 피티씨 테라퓨틱스, 인크. | 2,3,5-트리메틸-6-노닐사이클로헥사-2,5-디엔-1,4-디온을 포함하는 약제학적 조성물 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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GB9501052D0 (en) * | 1995-01-19 | 1995-03-08 | Cancer Res Campaign Tech | Improvements relating to prodrugs |
US5786488A (en) * | 1996-11-13 | 1998-07-28 | Sugen, Inc. | Synthetic methods for the preparation of indolyquinones |
WO1997023456A1 (en) * | 1995-12-21 | 1997-07-03 | British Technology Group Ltd. | Indoloquinone derivatives as bioreductive agents |
-
1999
- 1999-05-20 CA CA002332806A patent/CA2332806A1/en not_active Abandoned
- 1999-05-20 EP EP99924405A patent/EP1080066A4/en not_active Withdrawn
- 1999-05-20 HU HU0102932A patent/HUP0102932A3/hu unknown
- 1999-05-20 JP JP2000550818A patent/JP2002516304A/ja active Pending
- 1999-05-20 CN CN99806490A patent/CN1302287A/zh active Pending
- 1999-05-20 WO PCT/US1999/011199 patent/WO1999061409A1/en not_active Application Discontinuation
- 1999-05-20 BR BR9911066-0A patent/BR9911066A/pt not_active Application Discontinuation
- 1999-05-20 AU AU40913/99A patent/AU750381B2/en not_active Ceased
- 1999-05-20 PL PL99344257A patent/PL344257A1/xx unknown
- 1999-05-20 KR KR1020007013155A patent/KR20010074498A/ko not_active Application Discontinuation
-
2000
- 2000-11-20 HR HR20000794A patent/HRP20000794A2/hr not_active Application Discontinuation
- 2000-11-21 NO NO20005880A patent/NO20005880L/no not_active Application Discontinuation
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103781753A (zh) * | 2011-05-26 | 2014-05-07 | 印第安纳大学研究及科技有限公司 | 用于治疗ape1介导的疾病的醌化合物 |
CN103781753B (zh) * | 2011-05-26 | 2016-08-17 | 印第安纳大学研究及科技有限公司 | 用于治疗ape1介导的疾病的醌化合物 |
CN111039764A (zh) * | 2018-10-12 | 2020-04-21 | 山东大学 | 一种双亲乙烯衍生物及制备方法 |
Also Published As
Publication number | Publication date |
---|---|
KR20010074498A (ko) | 2001-08-04 |
NO20005880L (no) | 2001-01-09 |
EP1080066A1 (en) | 2001-03-07 |
CA2332806A1 (en) | 1999-12-02 |
HUP0102932A2 (hu) | 2001-12-28 |
HUP0102932A3 (en) | 2002-12-28 |
BR9911066A (pt) | 2001-02-13 |
WO1999061409A1 (en) | 1999-12-02 |
EP1080066A4 (en) | 2004-12-22 |
PL344257A1 (en) | 2001-10-22 |
AU4091399A (en) | 1999-12-13 |
HRP20000794A2 (en) | 2001-10-31 |
JP2002516304A (ja) | 2002-06-04 |
AU750381B2 (en) | 2002-07-18 |
NO20005880D0 (no) | 2000-11-21 |
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