CN1202891A - 新的对二氮萘二酮衍生物、其制备和在药物中的应用 - Google Patents
新的对二氮萘二酮衍生物、其制备和在药物中的应用 Download PDFInfo
- Publication number
- CN1202891A CN1202891A CN96198529A CN96198529A CN1202891A CN 1202891 A CN1202891 A CN 1202891A CN 96198529 A CN96198529 A CN 96198529A CN 96198529 A CN96198529 A CN 96198529A CN 1202891 A CN1202891 A CN 1202891A
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- CN
- China
- Prior art keywords
- trifluoromethyl
- phosphonic acid
- phenopiazine
- diketone
- tetrahydrochysene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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Abstract
本文公开了式(Ⅰ)新的对二氮萘二酮衍生物,其中R1、R5、R6和R7具有说明书中所述的含义,及其制备和在药物中的应用。
Description
本发明涉及对二氮萘二酮衍生物、其制备和在药物中的应用。
由大量的文献已知：对二氮萘衍生物对使君子氨酸(Quisqualat)-受体具有亲和性并且基于该亲和性而适合于作为药物用于中枢神经系统疾病的治疗。例如WO9308173中说明了6-甲基-1-烷基-取代的对二氮萘-2，3-二酮衍生物；EPA-0377112中说明了6-甲基-和7-乙基-1-羟基-对二氮萘-2，3-二酮。这些化合物的缺点为：它们不具备作为药物所必要的良好溶解性，同时对使君子氨酸-受体缺乏良好的亲和性。
因此提出了任务：合成新的化合物，它们易于溶解，对AMPA-受体具有特异性的拮抗作用并因此适于作为药物用于治疗兴奋性氨基酸的超活性所导致的疾病。
本发明化合物的通式为
其中R1为-(CH2)n-CR2H-(CH2)m-Z和R5为：C1-6-烷基，它可以被卤素、-OR8、-NR9R10、SO0-R11、COR12、任选取代的芳基或者任选取代的杂芳基取代；C2-6-链烯基，它可以被卤素、-OR8、-NR9R10、SO0-R11、COR12、任选取代的芳基或者任选取代的杂芳基取代；SOp-R13或-CH＝R15R6和R7相同或不相同，为氢原子、卤素、NO2、-氰基、NR16R17、-COR14、OR18、任选地被取代的芳基、任选地被取代的杂芳基、C1-6-烷基，它可以被卤素、-OR8、-NR9R10、SO0-R11、COR12、任选取代的芳基或者任选取代的杂芳基取代、C2-6-链烯基，它可以被卤素、-OR8、-NR9R10、SO0-R11、COR12、任选取代的芳基或者任选取代的杂芳基取代；SOp-R13或-CH＝R15，R2为氢原子或-(CH2)q-R3R3为氢原子、羟基、C1-6-烷氧基或NR19R20，n、m和q分别为0、1、2或3Z为POXY、OPOXY、SO2R21、CO2R22、氰基或四唑，R8和R18为氢原子、任选地被卤素取代的C1-6-烷基，o和p分别为0、1或2，R11和R13为氢原子、C1-6-烷基或任选地被取代的芳基，R12、R14、R21和R22为OH、C1-6-烷氧基或NR23R24，R15为氧原子、＝NOH或
X和Y相同或不同且为羟基、C1-6-烷氧基、C1-4-烷基或NR25R26，R9和R10、R16和R17、R19和R20、R23和R24、R25和R26相同或不同且为氢、C1-4-烷基、芳基；或者与氮原子共同构成5-7-元的饱和杂环，该杂环可以含有另一个氧-、硫-或氮原子和被取代或者构成不饱和的5-元杂环，该杂环可以含有1-3N-原子和被取代，以及其异构体或盐类，其中R5不为CF3或CH3。
通式I的化合物还包括可能的互变形式并包括E-或Z-异构体或在有手性中心的情况下的外消旋物或对映体。
取代基R5、R6和R7可以处于任意位置，优选在6-和/或7-位。
烷基为直链或分支的烷基残基例如甲基、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，在此优选C1-4-烷基。
如果烷基残基被卤代，则为一至多卤代甚至全卤代。
链烯基为例如乙烯基、1-丙烯基、2-丙烯基、3-甲基-2-丙烯基、1-丁烯基、甲代烯丙基。
卤素分别为氟、氯、溴和碘。
芳基残基分别有6-12个碳原子例如萘基、联苯基和尤其是苯基。杂芳基为任选地被取代的带有1-2个N-、O-或S-原子的5-环芳香杂环例如噻吩、呋喃、唑、噻唑或者为任选地被取代的带有1-3个N-原子的6-环芳香杂环如吡啶、嘧啶、三嗪、喹啉、异喹啉。
作为可1至3次出现的芳基-和杂芳基残基的取代基合适的有卤素、C1-4-烷氧基、硝基、三氟甲基或C1-4-烷基。
如果R9和R10、R16和R17、R19和R20、R23和R24或者R25和R26与氮原子共同构成饱和的杂环，则是例如哌啶、吡咯烷、吗啉、硫代吗啉、六氢化丫庚因或哌嗪。杂环可以被C1-4-烷基或一个任选地被卤素取代的苯基-、苄基-或苯甲酰基残基1-3重取代。例如所列举的N-甲基-哌嗪、2，6-二甲基吗啉、苯基哌嗪或4-(4-氟苯甲酰基)-哌啶。
如果R9和R10、R16和R17、R19和R20、R23和R24或者R25和R26与氮原子共同构成不饱和的杂环，则是例如咪唑、吡唑、吡咯和三唑，它们可以被氰基、C1-4-烷基、苯基或CO2C1-6烷基单或二取代。
优选考虑R5为烷基的化合物，该烷基可以被-OR8、-NR9R10、SO0-R11、COR12、任选地被取代的芳基或任选地被取代的杂芳基所取代。
如果含有酸官能团，则有机和无机碱的生理耐受盐类为合适的盐例如易于溶解的碱金属盐和碱土金属盐以及与N-甲基-葡糖胺、二甲基-葡糖胺、乙基-葡糖胺、细胞溶素、1，6-己二胺、乙醇胺、葡糖胺、肌氨酸、丝氨醇、三-羟基-甲基-氨基-甲烷、氨基丙二醇、Sovak碱、1-氨基-2，3，4-丁三醇的盐类。
如果含有碱性官能团，则有机和无机酸的生理耐受盐类较为合适例如HCl、H2SO4、磷酸、柠檬酸、酒石酸等等。
式I的化合物以及其生理耐受盐类基于其对AMPA-受体的亲和性而可以作为药物应用。本发明化合物基于其作用方式而适合于治疗兴奋性氨基酸例如谷氨酸或天冬氨酸的超活性所引起的疾病。因为新的化合物起兴奋性氨基酸的拮抗剂作用并且对AMPA-受体有高的特异亲和性，其作用方式是将放射性标记的特异性的兴奋剂(RS)a-氨基-3-羟基-5-甲基-4-异唑丙酸盐(AMPA)由AMPA-受体排挤开，所以新的化合物尤其适合于治疗通过兴奋性氨基酸受体尤其是AMPA-受体而受到影响的疾病。
按照本发明的化合物可以应用于治疗由于AMPA-受体过度兴奋所引起的神经性和精神性障碍。可以从功能上和预防上进行治疗的神经性疾病例如有神经变性疾病如巴金森氏病、阿尔茨海默氏病、亨廷顿氏舞蹈病、肌萎缩性侧索硬化和橄榄脑桥小脑变性。本发明化合物可用于预防缺血后的细胞死亡、脑外伤后的细胞死亡，中风、低氧、缺氧和低血糖时的细胞死亡；可用于治疗老年性痴呆、艾滋病痴呆、与HIV(人类免疫缺陷病毒，即艾滋病病毒)-感染相关的神经病症状、多发梗塞痴呆以及癫痫和肌痉挛。属于精神性疾病有恐惧症、精神分裂症、偏头痛、疼痛症，以及治疗睡眠障碍和滥用药物后的戒断症状如戒酒、可卡因、苯并二氮杂或鸦片。本化合物此外还可以应用于预防在用镇静药物例如苯并二氮杂、巴比妥酸盐和吗啡长期治疗时的耐受形成。此外本化合物还可以作为麻醉药、止痛药或止吐药应用。
借助于下面说明的实验可以确定式I化合物的药理学作用：
使体重18-22g的雄性NMRI小鼠处于监控状态下(6：00-18：00明亮/黑暗节律，自由进食物和水)并且将它们随意分组。由5-16只动物组成组。在8：00和13：00之间观察动物。
将AMPA注射入可自由活动小鼠的左侧脑室内。注射器由带有使注射深度限制在3.2mm的不锈钢装置的套管针所组成。将注射器连结在注射泵上。按照Montemurro和Dukelow座标垂直于头颅表面导入注射针。观察动物直至出现阵挛性以及紧张性痉挛达180秒。持续时间长于5秒钟的阵挛性动作算作痉挛。将阵挛性痉挛的起始作为测定痉挛阈的终点。使痉挛阈升高和降低50％的必要剂量(THRD50)在4-5个实验中确定。THRD50-和置信界值用回归分析测定。
该实验的结果表明：式I的化合物及其酸加成盐影响AMPA-受体的功能障碍。因此它们适合用于制备药物用于对症性和预防性治疗由于AMPA-受体-复合物的功能改变而引起的疾病。
用本发明化合物的治疗阻止和延迟由于疾病而出现的细胞损伤和功能障碍并且减轻由此产生的症状。
通过常用的药理学实验可以表明适应症。
为了使本发明化合物作为药物应用，将之制备成药物制剂形式，它除含有活性物质以外还含有适合于经胃肠用药和胃肠外用药的制药学有机或无机惰性载体物质，例如水、明胶、阿拉伯胶、乳糖、淀粉、硬脂酸镁、滑石粉、植物油、聚亚烷基二醇等等。药物制剂可能是固态形式例如片剂、糖衣丸剂、栓剂、胶囊；或者是液体的形式例如溶液、悬浮液或乳剂。此外任选地还可以含有佐剂如贮藏剂、稳定剂、湿润剂或者乳化剂、改变渗透压盐或者缓冲剂。
适合于经胃肠外用药的尤其是注射液或悬浮液，尤其是活性化合物于多羟基乙氧基化的蓖麻油中的水溶液。
作为载体系统可以应用界面活性佐剂如胆酸盐类或者动植物磷脂、也可以是其混合物及脂质体或者其组成成份。
适合于口服用药的尤其是片剂、糖衣丸剂或胶囊，它们含有滑石和/或碳氢化合物载体或粘合剂，例如乳糖、玉米-或土豆淀粉。也可以液体的形式应用，例如作为任选地添加甜化剂的汁液。
活性物质的剂量按照用药途径、病人的年龄和体重、待治疗疾病的类型和严重程度以及类似因素而有所不同。每日剂量为0.5-1000mg，优选为50-200mg，在此该剂量可以作为一次给药的一次剂量或者分为一个或多个日剂量用药。
本发明化合物的制备按照本身已知的方法进行。例如按照以下方法可以得到式I化合物：将式II化合物其中R1、R5、R6和R7具有以上说明的含义，用草酸或反应性草酸衍生物环化，任选地接着皂化酯基、或者酯化或酰胺化酸基、或者导入四唑基、或者将醇氧化成醛或将硫醚氧化成亚砜或砜或将亚砜氧化成砜，或者将醛转化成肟或硝酮或者分离异构体或者生成盐。
获得式II化合物的方法例如是：在式III化合物中，其中R1具有以上说明的含义，R5′、R6′和R7′为一个离去基团或者为R5、R6和R7，用SR13或者用任选地被取代的C2-6-链烯基替代离去基团，需要时接着将链烯基的双键氢化或氧化分解，将醛转化成链烯基化合物或者将醛还原成醇；将OH-基转化成离去基团和亲核取代并接着还原硝基。
环化成式I化合物的反应按照已知的方法用草酸在酸性环境中一步法进行或者用反应性草酸衍生物一步法或二步法进行。优选考虑二步法：在极性溶剂中如在环状或非环状醚或者卤代碳氢化合物例如四氢呋喃、乙醚或二氯甲烷或者也可以是水中，按照Schotten Baumann方法在碱如有机胺例如三乙胺、吡啶、Huenig-碱或二甲氨基吡啶或者也可以是苏打或氢氧化钠溶液的存在下，将二胺与草酸衍生物如草酸酯半酰氯或反应性草酸衍生物例如咪唑化物(Imidazoliden)反应。接着的环化反应可以在碱性或酸性，优选在酸性环境中进行，其中可在反应混合物中添加增溶剂如乙醇或乙腈。
用于二步法中合适的碱也可以是碱金属氢化物如NaH，将它加入惰性溶剂如碳氢化合物或醚中。
作为化合物III的离去基团合适的有如氟、氯、溴、碘或O-甲磺酸酯、O-甲苯磺酸酯、O-三氟甲磺酸酯(Triflat)或O-Nonaflat。
在碱如碱金属-或碱土金属氢氧化物或-碳酸盐存在的情况下在极性质子或非质子传递溶剂如水、乙醇或二甲基甲酰胺中使用相应的硫醇进行亲核取代以引入-S-R13-基团。
在过渡金属配合物如Pd(0)、例如四(三苯膦)合钯或Pd(2+)，例如钯-双三-o-甲苯基膦-二氯化物或镍(0)的催化下按照文献已知的方法任选地在碱的存在下通过链烯基化合物进行取代，并且通过优选在邻位的活性的吸电子基团如硝基、氰基、三氟甲基促进反应。
作为亲核试剂合适的例如有相应的硼酸或-硼烷或有机锡化合物、有机锌化合物、格利雅化合物或者链烯基化物。反应可以在极性溶剂例如二甲基甲酰胺、二甲基乙酰胺、乙腈，在碳氢化合物如甲苯或者在醚如四氢呋喃、二甲氧基乙烷或乙醚中进行。作为碱合适的有无机碱如碱金属-或碱土金属氢氧化物或-碳酸盐或有机碱如环状、非环状和芳香胺如吡啶、三乙胺、DBU、Huenig碱任选地加水。
链烯基化合物氧化分解生成醛的反应可以按照文献已知的方法进行。优选在溶剂如卤代的碳氢化合物或醇或其混合物中在-78℃至室温的温度下进行臭氧化。所产生的臭氧化物通过用硫脲、亚磷酸三烷基酯或优选用三芳基膦截获而还原裂解生成醛。
可以将醛进行链烯化反应例如Peterson链烯化、Wittig-或Wittig-Horner-反应，以产生任选地被取代的链烯基化合物。为此将醛与预先生成的阴离子例如相应被取代的盐或膦酸酯的阴离子在溶剂如甲苯、四氢呋喃、二乙醚或二甲氧基乙烷中反应。合适的碱有例如碱金属氢化物、碱金属氨化物、碱金属醇化物例如叔丁醇钾、碱金属或碱土金属碳酸盐或-氢氧化物，必要时存在相转移催化剂如冠醚或有机碱如三乙胺、二异丙基乙胺或二氮杂双环十一烷必要时存在盐如溴化锂。
可以按照文献已知的方法将醛还原成醇。优选在溶剂如乙醇中用复合金属氢化物例如硼氢化钠进行还原。
可以按照文献已知的各种方法将羟基转化成离去基团如氯、溴、碘、三氟甲磺酸根、甲磺酸根或甲苯磺酸根。优选在有碱如三乙胺、乙基二异丙胺或二甲基氨基吡啶存在的条件下在溶剂如卤代的碳氢化合物或醚中用甲苯磺酰氯转化成氯化物。
通过亲核试剂如胺或硫醇在溶剂如醇、卤代的碳氢化合物或酮中或没有溶剂条件下必要时添加碱如碱金属-或碱土金属氢氧化物或-碳酸盐或有机碱如三乙胺、乙基二异丙胺或二甲基氨基吡啶进行亲核取代。
硝基的还原可以按照通常的方式在催化条件下进行或者通过用铁粉在升温下或者在醇中用硫化钠和氢氧化铵还原。链烯基的还原按照通常的方式在催化条件下进行并且通常与硝基的还原一起进行。
按照文献已知的方法将硫醚氧化成亚砜或砜。例如通过在甲醇和水的混合物中用高碘酸钠氧化选择性获得亚砜。可以由相应的亚砜或由硫醚通过在四氯化碳、乙腈和水的混合物中在钌(III)的催化下用高碘酸钠氧化制得。
接着任选进行的酯基的皂化反应可以在碱性或优选酸性的环境中进行，方法是：在直至反应混合物的沸点的温度下在有酸如高浓度盐酸水溶液的条件下必要时在溶剂如三氟乙酸或乙醇中进行水解反应。水解膦酸酯优选在高浓度含水酸如浓盐酸中加热必要时添加醇或通过在惰性溶剂如乙腈中用三甲基甲硅烷基卤化物处理和接着用水处理来进行。
羧酸或膦酸的酯化反应按照已知的方式用相应的醇在有酸催化剂的条件下或有活化酸衍生物的条件下进行。作为活化酸衍生物例如可以考虑酰氯、酸咪唑化物或-酐。对于膦酸也可以通过在必要时添加催化剂如P-甲苯磺酸的条件下与原酸酯反应进行酯化反应。
游离酸或其反应性衍生物如酰氯、混合酐、咪唑化物或叠氮化物通过与相应的胺在室温下反应进行酰胺化。
四唑的导入如下进行：在必要时添加质子源如氯化铵或三乙基氯化铵的情况下在极性溶剂如二甲基甲酰胺、二甲基乙酰胺或N-甲基吡咯烷酮中在室温至溶剂的沸点温度下将相应的腈与叠氮化物如三甲基甲硅烷基叠氮化物、叠氮酸或叠氮化钠反应。
可以按照文献已知的方法进行醇的氧化。优选利用Jones方法(三氧化铬在硫酸中)在溶剂如丙酮中进行。
按照文献已知的方法用相应羟胺的氢氯化物必要时添加碱优选在溶剂如醇或芳香烃或其混合物中将醛转化成肟和硝酮。
可以按照通常的方法例如结晶、色谱分离或生成盐将异构体混合物分离成对映体或E/Z-异构体。
按照通常的方法制备盐，即：将式I化合物溶液与当量或过量的碱或酸，它必要时在溶剂中，反应和分离沉淀物或按照通常的方式处理溶液。
倘若起始化合物的制备未经说明，则为已知化合物或者类似于例如按照WO93/08173、WO94/25469的已知化合物或者可以按照在此说明的方法制备。
以下实施例能进一步说明本发明的方法：起始材料的制备：A.)将3.3g(30mmol)氨基甲膦酸与3.37g(31.8mmol)苏打一起加入至120ml水和120ml乙腈中和与7.8g(97％，30mmol)3-三氟甲基-4，6-二氯硝基苯混合并且在120℃浴温下在回流下搅拌4小时。在旋转蒸发器中抽去乙腈后用100ml醋酸乙酯萃取3次。用少许水洗涤有机相。它含有起始物，将它摒弃。将收集的水相用4N-盐酸调节至酸性pH1和分别用100ml醋酸乙酯萃取3次。将有机相用水洗涤、干燥、过滤和浓缩、得6.85g(理论值的68％)N-(2-硝基-4-三氟甲基-5-氯-苯基)-氨基甲膦酸，其熔点为207.3℃。B.)将1.67g N-(2-硝基-4-三氟甲基-5-氯-苯基)-氨基甲膦酸在25ml原甲酸三乙酯中与190mg P-甲苯磺酸混合和在150℃浴温下加热3小时。在真空中蒸发后吸收进25ml水中和分别用25ml醋酸乙酯萃取3次。将收集的醋酸乙酯相用水洗涤1次、干燥、过滤和浓缩。得2g(＞理论值的100％)N-(2-硝基-4-三氟甲基-5-氯-苯基)-氨基甲膦酸二乙酯。以类似的方法制备：N-(2-硝基-4-三氟甲基-5-苯硫基)-苯基-氨基甲膦酸二乙酯C.)将8.5g N-(2-硝基-4-三氟甲基-5-氯-苯基)-氨基甲膦酸二乙酯在250ml甲苯中与60ml乙醇、50ml 2M-苏打溶液、0.9g四(三苯基膦)钯和3.7g苯乙烯基硼酸混合和在氩气氛中在110℃浴温下加热7小时。浓缩后在醋酸乙酯和水中分配和将醋酸乙酯相干燥、过滤和浓缩。将剩余物2次经硅胶色谱层析，首先用展开剂甲苯∶醋酸乙酯＝1∶1和然后将相应的合并的馏分首先用环己烷以分离三苯膦然后用醋酸乙酯洗脱。得5.8g(理论值的58％)N-(4-硝基-2-三氟甲基-5-苯乙烯基)-苯基-氨基甲膦酸二乙酯。D.)将1g N-[(2-硝基-4-三氟甲基-5-苯乙烯基)-苯基]-氨基甲膦酸二乙酯溶于100ml乙醇中和在室温下在正常压力下用2g阮内镍氢化。经硅藻土吸滤去催化剂和浓缩滤液后得885mg N-(2-氨基-4-三氟甲基-5-苯乙基)-苯基-氨基甲膦酸二乙酯，它不需进一步提纯而直接用于下一步。以类似的方法制备：N-(2-氨基-4-三氟甲基-5-(4-氯苯乙基)-苯基)-氨基甲膦酸二乙酯。N-(2-氨基-4-三氟甲基-5-(4-甲氧基苯乙基)-苯基)-氨基甲膦酸二乙酯。N-(2-氨基-4-三氟甲基-5-(4-氟苯乙基)-苯基)-氨基甲膦酸二乙酯。N-(2-氨基-4-三氟甲基-5-(吡啶-2-基乙基)-苯基)-氨基甲膦酸二乙酯。E.)将2.96g N-(2-硝基-4-三氟甲基-5-苯乙烯基)-苯基-氨基甲膦酸二乙酯-酯溶于140ml甲醇和140ml二氯甲烷中和冷却至-78℃。然后将臭氧导入溶剂中15分钟。在用DC-监控起始物消失后，加入2.8g三苯膦。使温度升至室温和浓缩。将剩余物用丙酮∶己烷＝1∶1硅胶色谱层析。得1.8g N-(2-硝基-4-三氟甲基-5-甲酰)-苯基-氨基甲膦酸二乙酯。F.)将2.56g N-(2-硝基-4-三氟甲基-5-甲酰)-苯基-氨基甲膦酸二乙酯溶于130ml甲醇中和缓慢分批地与260mg硼氢化钠混合。在添加结束后在室温下搅拌2小时。接着浓缩和分配于醋酸乙酯和1N盐酸中。将醋酸乙酯相用水洗涤、干燥、过滤和浓缩。将剩余物用丙酮∶己烷＝1∶1硅胶色谱层析。得2.2g N-(2-硝基-4-三氟甲基-5-羟基甲基)-苯基氨基甲膦酸-二乙酯。G.)将0.76g N-(2-硝基-4-三氟甲基-5-羟基甲基)-苯基氨基甲膦酸-二乙酯在75ml乙醇中在氢正常压力和室温下用0.24g钯/碳(10％)氢化。经硅藻土吸滤除去催化剂后将滤液浓缩。0.73g N-(2-氨基-4-三氟甲基-5-羟基甲基)-苯基-氨基甲膦酸二乙酯剩余物将不需进一步提纯而直接用于下一步。以类似的方法制备：N-(2-氨基-4-三氟甲基-5-N-吗啉代甲基)-苯基-氨基甲膦酸二乙酯。N-(2-氨基-4-三氟甲基-5-(2-乙酯基乙-1-基)-苯基-氨基甲膦酸二乙酯(由N-(2-硝基-4-三氟甲基-5-(2-乙酯基乙烯-1-基)-苯基-氨基甲膦酸二乙酯制备)。H.)将1.75g N-(2-硝基-4-三氟甲基-5-羟基甲基)-苯基-氨基甲膦酸二乙酯溶于60ml二氯甲烷中并先后与634mg二甲基氨基吡啶和980mg甲苯磺酰氯混合。在室温下搅拌过夜。然后再次加入266mg二甲基氨基吡啶和400mg甲苯磺酰氯并且在室温下继续搅拌7小时。用二氯甲烷稀释，分别用1N盐酸和饱和食盐溶液洗涤。将有机相干燥、过滤和浓缩。将剩余物用醋酸乙酯作为展开剂硅胶色谱层析。得1.4g N-(2-硝基-4-三氟甲基-5-氯甲基)-苯基-氨基甲膦酸二乙酯。I.)将550mg N-(2-硝基-4-三氟甲基-5-氯甲基)-苯基-氨基甲膦酸二乙酯在10ml乙醇中氩气氛中首先用317mg碳酸钾然后以滴加方式与0.12ml乙硫醇混合。在室温下搅拌1.5小时。用水稀释、用1N-盐酸中和并用醋酸乙酯萃取。将醋酸乙酯相浓缩和将剩余物用醋酸乙酯作为展开剂经硅胶层析。得460mg N-(2-硝基-4-三氟甲基-5-乙硫基甲基)-苯基-氨基甲膦酸二乙酯。K.)将356mg N-(2-硝基-4-三氟甲基-5-乙硫基甲基)-苯基-氨基甲膦酸二乙酯溶于14ml甲醇中并且滴进与140mg铁粉混合的212mg氯化铵于14ml水中的溶液内。在添加完后在80℃加热1小时。经硅藻土吸滤后将滤液浓缩。剩余物不需进一步提纯而直接用于下一步。以类似的方法制备：N-(2-氨基-4-三氟甲基-5-苯硫基)-苯基-氨基甲膦酸二乙酯。L.)向60mg氢化钠(80％与油中)于1ml二甲氧基乙烷中的悬浮液中滴进0.5ml膦酸乙酸三乙酯于1ml二甲氧基乙烷中的溶液。室温下搅拌1小时后将384mg N-(2-氨基-4-三氟甲基-5-甲酰基-苯基)-氨基甲膦酸二乙酯在8ml二甲氧基乙烷中的溶液滴加入反应混合物中，在添加结束后在80℃浴温下加热4小时。接着加至冰上，将二甲氧基乙烷蒸馏去和用醋酸乙酯萃取。将有机相干燥、过滤和浓缩并且将剩余物通过丙酮∶己烷＝1∶1硅胶作为洗脱剂经硅胶色谱分离。得350mg N-(2-氨基-4-三氟甲基-5-(2-乙酯基乙烯-1-基)-苯基-氨基甲膦酸二乙酯。M.)将1.6g N-(2-硝基-4-三氟甲基-5-氟苯基)-氨基甲膦酸溶于20ml水中和与1.6g碳酸钠混合。然后与660mg苯硫酚混合和在120℃浴温下加热1.25小时。冷却后首先用醋酸乙酯萃取。将萃取液摒弃。将水相用4N-盐酸调节至酸性和用醋酸乙酯萃取3次。将收集的醋酸乙酯相干燥、过滤和浓缩并且不需进一步提纯而直接用于酯化过程B.)。N.)将1.1g N-(2-硝基-4-三氟甲基-5-氯甲基)-苯基氨基甲膦酸乙酯于25ml吗啉中在60℃加热2小时。浓缩，将剩余物用醋酸乙酯吸收和用1N氢氧化钠萃取。醋酸乙酯相用水洗涤、干燥、过滤和浓缩。将剩余物通过丙酮∶己烷＝1∶1作为洗脱剂经硅胶色谱分离。得600mg N-(2-硝基-4-三氟甲基-5-(N-吗啉代-甲基)-苯基-氨基甲膦酸二乙酯。O.)将1.58 N-(2-硝基-4-三氟甲基-5-甲酰基)-苯基氨基甲膦酸二乙酯在氩气氛下加入160ml无水甲苯中并与4.65g 2-甲基吡啶基三苯基氯化物和氨化钠的混合物混合。将反应混合物在室温下搅拌2小时。用醋酸乙酯稀释后用水萃取2次。将醋酸乙酯相浓缩。将剩余物通过丙酮∶己烷＝1∶1作为洗脱剂经硅胶色谱分离。得915mg N-(2-硝基-4-三氟甲基-5-(吡啶基-2-基-乙烯基)-苯基)-氨基甲膦酸二乙酯。P.)将500mg N-(2-硝基-4-三氟甲基-5-甲酰基)-苯基氨基甲膦酸二乙酯加进50ml无水甲苯中，与1.36g 4-甲氧基苄基三苯基 氯化物混合，冷却至0℃和与370mg叔丁醇钾混合。然后在室温下搅拌3小时。用水混合和萃取。将合并的有机相用饱和的食盐溶液洗涤、过滤和浓缩。将剩余物通过丙酮∶己烷＝1∶1作为洗脱剂经硅胶色谱分离。得370mg N-(2-硝基-4-三氟甲基-5-(4-甲氧基(苯乙烯基)-苯基)-氨基甲膦酸二乙酯。以类似的方法制备：N-(2-硝基-4-三氟甲基-5-(4-氟(苯乙烯基)-苯基)-氨基甲膦酸二乙酯N-(2-硝基-4-三氟甲基-5-(4-氯(苯乙烯基)-苯基)-氨基甲膦酸二乙酯实施例1
将870mg N-[(2-氨基-4-三氟甲基-5-苯乙基)-苯基]-氨基甲膦酸二乙酯溶于50ml无水四氢呋喃中和与0.57g三乙胺混合。于该溶液中在室温下滴进0.6g草酸乙酯酰氯于12ml无水四氢呋喃中的溶液。添加结束后在室温下继续搅拌4小时。吸滤除去沉淀物和将滤液浓缩。将剩余物吸收进50ml 1N-盐酸和50ml乙醇中并在120℃浴温下搅拌3小时。吸滤沉淀物和摒弃滤液。用乙醇重结晶后得230mg(理论值的60％)N-[(6-三氟甲基-7-苯乙基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯。以类似的方法制备：[(6-三氟甲基-7-(4-(氯苯基乙基)-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯。[(6-三氟甲基-7-(4-(氟苯基乙基)-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯。[(6-三氟甲基-7-(4-(甲氧基苯基乙基)-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯。[(6-三氟甲基-7-羟基甲基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯。[(6-三氟甲基-7-乙硫基甲基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯。[(6-三氟甲基-7-苯硫基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯。[(6-三氟甲基-7-(N-吗啉代甲基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯。[(6-三氟甲基-7-(2-羟基羰基乙-1-基)-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯(原本存在的羧酸酯在反应条件下被皂化)。[(6-三氟甲基-7-(2-吡啶基乙基)-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯。实施例2
将150mg[(6-三氟甲基-7-苯硫基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯溶于10ml甲醇中和与110mg高碘酸钠于3ml水中的溶液混合并在室温下搅拌10小时。然后用水稀释和用醋酸乙酯振荡萃取3次。将有机相浓缩和经硅胶色谱分离2次：首先用洗脱剂甲苯∶醋酸∶水＝10∶10∶1，第二次用二氯甲烷∶乙醇＝10∶1。得121mg 6-三氟甲基-7-亚磺酰基(sulfoxy)苯基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯。以类似的方法制备：6-三氟甲基-7-(乙基亚磺酰基(sulfoxy)甲基)-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯实施例3
将122mg 6-三氟甲基-7-苯硫基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯溶于2ml乙腈中然后先后与2ml四氯化碳、4ml水、160mg高碘酸钠和一刮匀尖三氯化钌混合。在室温下搅拌8小时后用30ml水稀释、分别用30ml醋酸乙酯振荡萃取3次。将收集的有机相通过硅藻土过滤、浓缩和将剩余物用二氯甲烷∶乙醇＝10∶1硅胶色谱分离，有必要将色谱柱上的剩余化合物用甲醇洗涤。得98mg 6-三氟甲基-7-苯基磺酰基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯。以类似的方法制备：6-三氟甲基-7-(乙基磺酰基甲基)-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯。实施例4
将220mg[(6-三氟甲基-7-苯基乙基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯于20ml浓盐酸中在120℃浴温下加热3小时。浓缩后得200mg[(6-三氟甲基-7-苯基乙基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸，其熔点为260℃。以类似的方法制备：[(6-三氟甲基-7-羟基羰基乙基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸。[(6-三氟甲基-7-苯基磺酰基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸。[(6-三氟甲基-7-苯硫基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸。[(6-三氟甲基-7-甲酰基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸。[(6-三氟甲基-7-(4-氯苯基)-乙基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸。[(6-三氟甲基-7-(4-氟苯基)-乙基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸。实施例5
将200mg[(6-三氟甲基-7-羟基甲基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯加入9ml乙腈中并与0.44ml三甲基溴硅烷混合。在室温下搅拌8小时，接着与水混合和浓缩。将剩余物用水充分搅拌和吸滤。得80mg[(6-三氟甲基-7-羟基甲基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸。以类似的方法制备：[(6-三氟甲基-7-乙硫基甲基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸。[(6-三氟甲基-7-乙基磺酰基甲基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸。[(6-三氟甲基-7-吗啉代甲基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸。[(6-三氟甲基-7-(2-吡啶基乙基)-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸。[(6-三氟甲基-7-(4-甲氧基苯基)-乙基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸。实施例6
将650mg[(6-三氟甲基-7-羟基甲基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯加入10ml丙酮中和与1.2ml Jones试剂(由26.7g三氧化铬、23ml浓硫酸制备用水充盈至100ml)在室温下搅拌4小时。然后与3ml异丙醇混合和再搅拌10分钟。然后浓缩和分配在醋酸乙酯∶水中。将有机相干燥、过滤和浓缩。将剩余物用甲苯∶醋酸∶水＝10∶10∶1硅胶色谱分离。得160mg[(6-三氟甲基-7-甲酰基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯，此外还回收375mg起始物。实施例7
将215mg[(6-三氟甲基-7-甲酰基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯加入10ml苯中并先后与0.1ml三乙胺以及63mg N-异丙基羟基胺氢氯化物混合。室温下搅拌8小时。然后将固态物质吸滤出。将固态物质用甲苯∶醋酸∶水＝10∶10∶1硅胶色谱分离。得120mg[(6-三氟甲基-7-[N-氧基-(N-异丙基甲酰基亚氨基)]-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯。以类似的方法制备：[(6-三氟甲基-7-[N-氧基-(N-异丙基甲酰基亚氨基)]-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸。
Claims (4)
1.式I化合物
其中R1为-(CH2)n-CR2H-(CH2)m-Z和R5为：C1-6-烷基，它可以被卤素、-OR8、-NR9R10、SO0-R11、COR12、任选取代的芳基或者任选取代的杂芳基取代；C2-6-链烯基，它可以被卤素、-OR8、-NR9R10、SO0-R11、COR12、任选取代的芳基或者任选取代的杂芳基取代；SOp-R13或-CH＝R15R6和R7相同或不相同，为氢原子、卤素、NO2、-氰基、NR16R17、-COR14、OR18、任选地被取代的芳基、任选地被取代的杂芳基、C1-6-烷基，它可以被卤素、-OR8、-NR9R10、SO0-R11、COR12、任选取代的芳基或者任选取代的杂芳基取代、C2-6-链烯基，它可以被卤素、-OR8、-NR9R10、SO0-R11、COR12、任选取代的芳基或者任选取代的杂芳基取代；SOp-R13或-CH＝R15，R2为氢原子或-(CH2)q-R3R3为氢原子、羟基、C1-6-烷氧基或NR19R20，n、m和q分别为0、1、2或3Z为POXY、OPOXY、SO2R21、CO2R22、氰基或四唑，R8和R18为氢原子、任选地被卤素取代的C1-6-烷基，o和p分别为0、1或2，R11和R13为氢原子、C1-6-烷基或任选地被取代的芳基，R12、R14、R21和R22为OH、C1-6-烷氧基或NR23R24，R15为氧原子、＝NOH或
X和Y相同或不同且为羟基、C1-6-烷氧基、C1-4-烷基或NR25R26，R9和R10、R16和R17、R19和R20、R23和R24、R25和R26相同或不同且为氢、C1-4-烷基、芳基；或者与氮原子共同构成5-7-元的饱和杂环，该杂环可以含有另一个氧-、硫-或氮原子和被取代或者构成不饱和的5-元杂环，该杂环可以含有1-3N-原子和被取代，以及其异构体或盐类，其中R5不为CF3或CH3。
2.N-[(6-三氟甲基-7-苯乙基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯[(6-三氟甲基-7-苯硫基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯[(6-三氟甲基-7-(2-吡啶基乙基)-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸二乙酯[(6-三氟甲基-7-苯基乙基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸[(6-三氟甲基-7-乙硫基甲基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸[(6-三氟甲基-7-吗啉代甲基-1，2，3，4-四氢对二氮萘-2，3-二酮)-1基]-甲膦酸
3.含有按照权利要求1式I化合物的药物。
4.式I化合物的制备方法，其特征为：将式II化合物其中R1、R5、R6和R7具有以上说明的含义，用草酸或反应性草酸衍生物环化，任选地接着皂化酯基、或者酯化或酰胺化酸基、或者导入四唑基、或者将醇氧化成醛或将硫醚氧化成亚砜或砜或将亚砜氧化成砜，或者将醛转化成肟或硝酮或者分离异构体或者生成盐。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19545251.8 | 1995-11-24 | ||
| DE19545251A DE19545251A1 (de) | 1995-11-24 | 1995-11-24 | Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln |
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| Publication Number | Publication Date |
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| CN1202891A true CN1202891A (zh) | 1998-12-23 |
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| CN96198529A Pending CN1202891A (zh) | 1995-11-24 | 1996-11-15 | 新的对二氮萘二酮衍生物、其制备和在药物中的应用 |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0876357A1 (zh) |
| JP (1) | JP2000500471A (zh) |
| KR (1) | KR19990071596A (zh) |
| CN (1) | CN1202891A (zh) |
| AU (1) | AU720083B2 (zh) |
| CA (1) | CA2238023A1 (zh) |
| CZ (1) | CZ160498A3 (zh) |
| DE (1) | DE19545251A1 (zh) |
| EE (1) | EE9800163A (zh) |
| HU (1) | HUP9902041A3 (zh) |
| IL (1) | IL124534A0 (zh) |
| IS (1) | IS4740A (zh) |
| MX (1) | MX9804068A (zh) |
| NO (1) | NO982349L (zh) |
| NZ (1) | NZ330492A (zh) |
| PL (1) | PL326844A1 (zh) |
| SK (1) | SK68298A3 (zh) |
| TR (1) | TR199800904T2 (zh) |
| WO (1) | WO1997019066A1 (zh) |
| ZA (1) | ZA969832B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106619953A (zh) * | 2016-10-31 | 2017-05-10 | 山东省海盟生化科技有限公司 | 一种用于皮肤病的外用中药组合物及其制备方法和应用 |
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| DE19737446A1 (de) * | 1997-08-22 | 1999-02-25 | Schering Ag | Verfahren zur Herstellung von Phosphonsäurederivaten |
| EP2338492A1 (en) | 2009-12-24 | 2011-06-29 | Universidad del Pais Vasco | Methods and compositions for the treatment of alzheimer |
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| NO179551C (no) * | 1987-11-10 | 1996-10-30 | Novo Nordisk As | Analogifremgangsmåte for fremstilling av terapeutisk virksomme kinoxalinforbindelser |
| DK69790D0 (da) * | 1990-03-16 | 1990-03-16 | Novo Nordisk As | Heterocykliske forbindelser, deres fremstilling af anvendelse |
| PT101004B (pt) * | 1991-10-26 | 1999-10-29 | Schering Ag | Derivados da quinoxalina, processo para a sua preparacao e composicoes farmaceuticas que os contem |
| IL109397A0 (en) * | 1993-04-28 | 1994-07-31 | Schering Ag | Quinoxalinedione derivatives, processes for the preparation thereof and pharmaceutical compositions containing the same |
| DE4439493A1 (de) * | 1994-10-25 | 1996-05-02 | Schering Ag | Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln |
| DE4439492A1 (de) * | 1994-10-25 | 1996-05-02 | Schering Ag | Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln |
| DE19519979A1 (de) * | 1995-05-24 | 1996-11-28 | Schering Ag | Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln |
-
1995
- 1995-11-24 DE DE19545251A patent/DE19545251A1/de not_active Withdrawn
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1996
- 1996-11-15 SK SK682-98A patent/SK68298A3/sk unknown
- 1996-11-15 EE EE9800163A patent/EE9800163A/xx unknown
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- 1996-11-15 IL IL12453496A patent/IL124534A0/xx unknown
- 1996-11-15 TR TR1998/00904T patent/TR199800904T2/xx unknown
- 1996-11-15 EP EP96946000A patent/EP0876357A1/de not_active Withdrawn
- 1996-11-15 KR KR1019980703872A patent/KR19990071596A/ko not_active Application Discontinuation
- 1996-11-15 CN CN96198529A patent/CN1202891A/zh active Pending
- 1996-11-15 PL PL96326844A patent/PL326844A1/xx unknown
- 1996-11-15 CA CA002238023A patent/CA2238023A1/en not_active Abandoned
- 1996-11-15 HU HU9902041A patent/HUP9902041A3/hu unknown
- 1996-11-15 WO PCT/DE1996/002227 patent/WO1997019066A1/de not_active Application Discontinuation
- 1996-11-15 AU AU18674/97A patent/AU720083B2/en not_active Ceased
- 1996-11-15 JP JP9519292A patent/JP2000500471A/ja active Pending
- 1996-11-22 ZA ZA969832A patent/ZA969832B/xx unknown
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1998
- 1998-05-13 IS IS4740A patent/IS4740A/is unknown
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106619953A (zh) * | 2016-10-31 | 2017-05-10 | 山东省海盟生化科技有限公司 | 一种用于皮肤病的外用中药组合物及其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR19990071596A (ko) | 1999-09-27 |
| IS4740A (is) | 1998-05-13 |
| SK68298A3 (en) | 1998-12-02 |
| CA2238023A1 (en) | 1997-05-29 |
| EP0876357A1 (de) | 1998-11-11 |
| ZA969832B (en) | 1997-06-17 |
| WO1997019066A1 (de) | 1997-05-29 |
| JP2000500471A (ja) | 2000-01-18 |
| IL124534A0 (en) | 1998-12-06 |
| AU1867497A (en) | 1997-06-11 |
| EE9800163A (et) | 1998-12-15 |
| HUP9902041A2 (hu) | 2000-04-28 |
| HUP9902041A3 (en) | 2000-07-28 |
| TR199800904T2 (xx) | 1998-08-21 |
| PL326844A1 (en) | 1998-10-26 |
| CZ160498A3 (cs) | 1998-09-16 |
| MX9804068A (es) | 1998-09-30 |
| DE19545251A1 (de) | 1997-05-28 |
| NO982349D0 (no) | 1998-05-22 |
| AU720083B2 (en) | 2000-05-25 |
| NZ330492A (en) | 1999-10-28 |
| NO982349L (no) | 1998-07-01 |
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