CN1085908A - 断-核苷的脂核苷酸，它们的制备方法以及含有它们的具有抗病毒作用的药用组合物 - Google Patents
断-核苷的脂核苷酸，它们的制备方法以及含有它们的具有抗病毒作用的药用组合物 Download PDFInfo
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- CN1085908A CN1085908A CN93107987A CN93107987A CN1085908A CN 1085908 A CN1085908 A CN 1085908A CN 93107987 A CN93107987 A CN 93107987A CN 93107987 A CN93107987 A CN 93107987A CN 1085908 A CN1085908 A CN 1085908A
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- liponucleotide
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- amino
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Abstract
断-核苷的脂核苷酸，它们的制备方法以及含有
它们的具有抗病毒作用的药用组合物。本发明提供
了通式(I)脂核苷酸及其互变异构体以及与无机酸和
有机酸及碱形成的生理上适用的盐。
Description
本发明涉及连接类脂部分的断 - 核苷的新的磷脂类衍生物，它具有取代的C3碱结构，通过磷酸酯或硫代磷酸酯与断 - 核苷相连，本发明还涉及它们的制备方法，以及含有它们的具有抗病毒作用的药用组合物。
因此，根据本发明提供了通式（Ⅰ）化合物、它们的互变异构体，以及与无机和有机酸及碱生成的生理上适用的盐，
其中R1为可以由下述取代基1次或多次任意取代的含有直至20个碳原子的直链或支链、饱和的不饱和的脂肪族基团，取代基系选自苯基、卤素、C1- C6烷氧基、C1- C6烷硫基、C1- C6烷氧基羰基、C1- C6烷基亚磺酰基或C1- C6烷基磺酰基，
R2为可以由下述取代基1次或多次任意取代的含有直至20个碳原子的直链或支链、饱和或不饱和的脂肪族基团，取代基系选自苯基、卤素、C1- C6烷氧基、C1- C6烷硫基、C1- C6烷氧基羰基、C1- C6烷基亚磺酰基或C1-C6烷基磺酰基，
R3为氢原子，或者为由羟基任意取代的C1-C6烷基，
R4为氢原子、羟基或氨基，或者为由C1-C6烷基一次或两次取代的氨基，
R5为氢原子、羟基或氨基，或者为由C1-C6烷基一次或两次取代的氨基，
X为价键、氧或硫原子、亚磺酰基或磺酰基，
Y的定义同X，X和Y可以相同或不同，
Z为氧或硫原子。
由于通式Ⅰ化合物含有不对称碳原子，因此，所有具有旋光活性的化合物和外消旋混合物也是本发明的内容。
在J.Biol.Chem.，265，6112/1990和EP 0350287中叙述了作为抗病毒药物的脂核苷酸的制备和应用。但是，其内容仅研究和合成了二肉豆蔻酰磷脂酰和二棕榈酰磷脂酰与已知核苷例如AZT（叠氮胸苷）和ddc（二脱氧胞苷）的脂肪酸酯结构偶合的化合物。EP-0350287公开了丙三醇相应的二酯。
在J.Med.Chem.，33，1380/1990中叙述了硫醚类脂与二磷酸胞苷的核苷共轭物，它具有抗肿瘤作用，并且发现可用在肿瘤学方面。
在Chem.Pharm.Bull.，36，209/1988中叙述了具有抗白血病作用的5′-（3-SN-磷脂酰）-核苷，以及在具有转移酶作用的磷脂酶D存在下从相应的核苷和胆碱磷酸进行的酶的合成。
在国际专利申请PCT/EP91/01541中叙述了在核苷中有环状糖部分的脂核苷酸，它具有抗病毒作用。
在Acta Chem.Scand.，Ser.B，39，47/1985（也请参阅Organophosphorus Chem.，18，187/1987）中叙述了从L-α-二肉豆蔻酰磷脂酸与无环鸟苷得到的无环鸟苷-磷脂共轭物。
本发明的醚/硫醚类脂（X、Y为氧或硫）是新的，并且还表现出有价值的药理学作用。尤其是它们可用于治疗和预防由DNA病毒（例如单纯疱疹病毒、巨细胞病毒、人乳头瘤病毒、水痘-带状疱疹病毒或爱泼斯坦-巴尔疱疹病毒）引起的感染，或由RNA病毒（例如披膜病毒）引起的感染，或由逆转录病毒（例如肿瘤病毒HTLV Ⅰ和Ⅱ）引起的感染，以及由维斯那慢病毒和人免疫缺陷病毒HIV 1和2引起的感染。
通式Ⅰ化合物表现为特别适合用于治疗人的疱疹病毒感染的临床表现。通式Ⅰ化合物具有抗病毒作用，在药理学相关的剂量下没有细胞毒性。
通式Ⅰ的特征还在于，它具有良好的口服适合性，同时具有良好的生物利用度。
根据本发明的化合物和含有它们的药用组合物还可以与其他治疗和预防上述感染的药物结合使用。可以用于治疗和预防HIV感染以及HIV伴随疾病的其他药物的实例包括，例如3′-叠氮-3′-脱氧胸苷（AZT），2′，3′-二脱氧核苷，如2′，3′-二脱氧胞苷（ddc）、2′，3′-二脱氧腺苷和2′，3′-二脱氧肌苷（ddI），以及非核苷类RT抑制剂如HEPT、nevirapin和L-697661及相应的衍生物。在各种情况下，本发明化合物和其他的药物可以以单一的或两个独立的制剂单独地服用、或同时服用、或者在不同的时间服用。
关于通式Ⅰ化合物的可能的盐，特别优选的是碱金属盐、碱土金属盐和磷酸酯基的铵盐。优选的碱金属盐是锂盐、钠盐和钾盐，优选的碱土金属盐特别是镁盐和钙盐。本发明所述的铵盐，可以理解为所含铵离子可由至多四个含有直到4个碳原子的烷基和/或芳烷基（优选苄基）取代的盐。这里取代基可以是相同的，或者是不同的。
式Ⅰ化合物含有与合适的有机酸或无机酸反应可以转变成酸加成盐的碱性基团，特别是氨基。关于酸，可以应用的有例如盐酸、氢溴酸、硫酸、磷酸、富马酸、琥珀酸、酒石酸、柠檬酸、乳酸、马来酸和甲磺酸。
在通式Ⅰ中，R1优选直链C9-C14烷基，该烷基也可以由C1-C6烷氧基或C1-C6烷硫基取代。特别是R1可以是癸基、十一烷基、十二烷基、十三烷基或十四烷基。作为R1的取代基C1-C6烷氧基，优选的有甲氧基、乙氧基、丁氧基和己氧基。如果R1由C1-C6烷硫基取代，那么优选的有甲硫基、乙硫基、丙硫基、丁硫基或己硫基。
R2优选直链C9-C14烷基，该烷基也可以由C1-C6烷氧基或C1-C6烷硫基取代。作为R2的取代基C1-C6烷氧基，优选的有甲氧基、乙氧基、丙氧基、丁氧基和己氧基。如果R2由C1-C6烷硫基取代，那么优选的取代基有甲硫基、乙硫基、丁硫基或己硫基。
在R3的定义中，优选的烷基是直链或支链的烷基，特别好的是具有直到4个碳原子的，例如甲基、乙基、正丙基、异丙基或正丁基。上述烷基最好由1个或2个羟基取代，例如羟甲基、2-羟乙基或3-羟丙基。
一般来讲，C1-C6烷基意指含有直到4个碳原子的直链或支链烷基，例如甲基、乙基、正丙基、异丙基、正丁基或异丁基。
R4优选是羟基或氨基，R5特别是氢原子或羟基或氨基，X和Y是氧或硫原子较好，Z优选是氧原子。
在通式Ⅰ脂核苷酸中，特别优选的偶合的断-核苷是更昔洛韦和无环鸟苷。
本发明的通式Ⅰ化合物可以按下法制备，例如
1.用缩合剂如二环己基碳二亚胺（DCC）于吡啶中、或在2，4，6-三异丙基苯磺酰氯和叔氮碱（如吡啶或二甲基吡啶）存在下，在惰性溶剂（如甲苯）中或直接在吡啶中，使通式（Ⅱ）化合物与通式（Ⅲ）化合物反应，在水解进行之后，用核苷化学中常用的方法脱去氧保护基，
其中R1、R2、X、Y和Z的定义同上，
其中R3、R4和R5的定义同上，或者
2.在磷脂酶D存在下，于惰性溶剂（如氯仿）中，在合适的缓冲液存在下，使通式（Ⅳ）化合物与通式（Ⅲ）化合物（其中R3、R4和R5的定义同上）反应，在反应进行之后，用核苷化学中常用的方法脱去氧保护基，
其中R1、R2、X、Y和Z的定义同上。
通式（Ⅱ）和（Ⅳ）化合物的制备方法已在DE 3929217.7和WO91/05558中叙述。通式（Ⅲ）化合物的制备方法在Progress in Medicinal Chemistry，23，187/1986和上面引用的文献中有叙述。无环鸟苷和更昔洛韦是可以购买到的。
用于治疗病毒感染的含有通式（Ⅰ）化合物的药用组合物可以按液体或固体形式经肠道或非胃肠道途径给药。为此，可以应用常用的给药剂型，例如片剂、胶囊、糖锭、糖浆、溶液和混悬液。作为注射剂介质最好应用水，在注射溶液剂情况下，水中含有常用的添加剂，例如稳定剂、增溶剂和缓冲液。上述添加剂包括例如酒石酸盐和柠檬酸盐缓冲液、乙醇、复合的构成如乙二胺四乙酸及其无毒盐，用作粘稠度调节剂的高分子量聚合物如液体聚环氧乙烷。用作为注射溶液剂的液体载体必须是无菌的，并且最好装入安瓿。固体载体包括例如淀粉、乳糖、甘露糖醇、甲基纤维素、滑石、高度分散的硅酸、高分子量脂肪酸（如硬脂酸）、明胶、琼脂、磷酸钙、硬脂酸镁、动物和植物脂肪、高分子量固体聚合物（如聚乙二醇）等。如果需要，适用于口服给药的组合物可以含有调味剂或甜味剂。
剂量可以根据不同的因素（如给药的方式、种类、年龄或患者的健康情况）而定。本发明化合物通常以0.1-100毫克/公斤体重/天的剂量给药，优选为0.2-80毫克/公斤体重/天。优选将每天剂量分成2-5次服用，因此，在每次服药的情况下，给予有效物质含量为0.5-500毫克的片剂1片或2片。片剂还可以是延效的，因此每天服用的片数可以减至1-3片。延效片剂的有效物质含量可以是2-1000毫克。有效物质还可以以连续输注的方式给药，因此，每天的剂量为5-1000毫克通常是足够的。
在本发明的内容中，除了以下实便所述化合物和通过权利要求书中涉及的所有定义的取代基组合得到的化合物之外，下述通式（Ⅰ）化合物也是优选的：
1.2′-[9-乙氧基甲基）-鸟嘌呤]-磷酸（3-十二烷硫基-2-癸氧基）-1-丙基酯
2.2′-（9-｛[（1-羟甲基）乙氧基]-甲基｝-鸟嘌呤）-磷酸（3-十二烷基亚磺酰基-2-癸氧基）-1-丙基酯
3.2′-（9-｛[（1-羟甲基）-乙氧基]-甲基｝-鸟嘌呤）-磷酸（3-十二烷基磺酰基-2-癸氧基）-1-丙基酯
4.2′-（9-｛[（1-羟甲基）-乙氧基]-甲基｝-鸟嘌呤）-磷酸（3-十二烷硫基-2-癸氧基）-1-丙基酯
5.2′-[9-乙氧基甲基）-鸟嘌呤]-磷酸（3-十一烷硫基-2-癸氧基）-1-丙基酯
6.2′-[9-乙氧基甲基）-鸟嘌呤]-磷酸（3-十二烷氧基-2-癸氧基）-1-丙基酯
7.2′-（9-｛[（1-羟甲基）-乙氧基]-甲基｝-鸟嘌呤）-磷酸（3-十二烷硫基-2-壬氧基）-1-丙基酯
8.2′-（9-｛[（1-羟甲基）-乙氧基]-甲基｝-鸟嘌呤）-磷酸（3-十二烷硫基-2-癸氧基）-1-丙基酯
9.2′-（9-｛[（1-羟甲基）-乙氧基]-甲基｝-鸟嘌呤）-磷酸（3-十一烷硫基-2-癸氧基）-1-丙基酯
10.2′-[9-乙氧基甲基）-鸟嘌呤]-磷酸（3-十三烷硫基-2-癸氧基）-1-丙基酯
11.2′-（9-｛[（1-羟甲基）-乙氧基]-甲基｝-鸟嘌呤）-磷酸（3-十三烷硫基-2-癸氧基）-1-丙基酯
12.2′-[9-乙氧基甲基）-鸟嘌呤]-磷酸（3-十二烷硫基-2-十二烷氧基）-1-丙基酯
13.2′-[9-乙氧基甲基）-鸟嘌呤]-磷酸（3-十二烷硫基-2-十一烷氧基）-1-丙基酯
14.2′-（9-｛[（1-羟甲基）-乙氧基]-甲基｝-鸟嘌呤）-磷酸（2，3-双（十二烷硫基））-1-丙基酯
15.2′-（9-｛[（1-羟甲基）-乙氧基]-甲基｝-鸟嘌呤）-磷酸（3-癸硫基-2-十二烷氧基）-1-丙基酯
16.2′-[9-乙氧基甲基）-鸟嘌呤]-磷酸（3-十一烷硫基-2-十二烷氧基）-1-丙基酯
17.2′-[9-乙氧基甲基）-鸟嘌呤]-磷酸（3-癸基磺酰基-2-十二烷氧基）-1-丙基酯
18.2′-[9-乙氧基甲基）-鸟嘌呤]-磷酸（3-癸氧基-2-癸氧基）-1-丙基酯
19.2′-[9-乙氧基甲基）-鸟嘌呤]-磷酸（3-十二烷硫基-2-十二烷氧基）-1-丙基酯
20.2′-（9-｛[（1-羟甲基）-乙氧基]-甲基｝-鸟嘌呤）-磷酸（3-十四烷硫基-2-癸氧基）-1-丙基酯
21.2′-[9-乙氧基甲基）-鸟嘌呤]-磷酸（3-十五烷硫基-2-癸氧基）-1-丙基酯
22.2′-（9-｛[（1-羟甲基）-乙氧基]-甲基｝-鸟嘌呤）-磷酸（3-十三烷硫基-2-癸氧基）-1-丙基酯
23.2′-[9-乙氧基甲基）-鸟嘌呤]-磷酸（3-十二烷硫基-2-辛氧基）-1-丙基酯
给出以下实施例，以便详细叙述本发明。
实施例1
磷酸（3-十二烷硫基-2-癸烷氧基）-1-丙基酯
在室温下将4.26克五氧化二磷在60ml无水吡啶中的混悬液与13ml六甲基二硅氧烷混合，并加热至100℃再保持1小时。然后将反应混合物稍冷却，与25克3-十二烷硫基-2-癸氧基-1-丙醇混合，并加热至100℃再保持2.5小时。完全冷至室温和真空下除去容易挥发的成分之后，从残余物的水混悬液中用乙醚提取磷酸酯。蒸发乙醚相后的残余物经硅胶60或RP 18柱层析纯化。得18.7克（理论值的63%）;薄板层析：Merck 5715（硅胶60）上，Rf＝0.66（二氯甲烷/甲醇/水，6.5∶2.5∶0.4 V/V/V）。
实施例2
2′-（9-｛[（1-羟甲基）-乙氧基]甲基｝-鸟嘌呤）-磷酸（3-十二烷硫基-2-癸氧基）-1-丙基酯
将1.45克（3毫摩尔）磷酸（3-十二烷硫基-2-癸氧基）-1-丙基酯和770毫克（3毫摩尔）更昔洛韦与无水吡啶混合2次（20ml×2）并蒸发。残余物溶于20ml无水吡啶中，在氮气氛下与2.7克（8.5毫摩尔）2，4，6-三异丙基苯磺酰氯混合，并于40℃搅拌24小时。然后加入10ml水，反应混合物再在室温下搅拌2小时，并用旋转蒸发器除去溶剂。与甲苯一起蒸发，使油状残余物从吡啶残余物中分离出来，经RP 18柱层析纯化，用甲醇/水7/3-9.5/0.5作为洗脱剂进行线性梯度洗脱。得到0.75克（理论值的34%）油状物;薄板层析：在RP 18上，Rf＝0.73（水/甲醇，0.5∶9.5 V/V）;在Merck 5715（硅胶50）上，Rf＝0.30（二氯甲烷/甲醇/水，6.5∶2.5∶0.4 V/V/V）。
实例3
2′-[9-乙氧基甲基）-鸟嘌呤]-磷酸（3-十二烷硫基-2-癸氧基）-1-丙基酯
按与实例1类似的方法，由无环鸟苷制备本实例化合物，产率为理论值的47%，为油状物;薄板层析：在RP 18上，Rf＝0.77（水/甲醇，0.5∶9.5 V/V），在Merck 5715（硅胶60）上，Rf＝0.35（二氯甲烷/甲醇/水，6.5∶2.5∶0.4 V/V/V）。
Claims (14)
1、通式Ⅰ脂核苷酸及其互变异构体以及与无机酸和有机酸及碱形成的生理上适用的盐，
其中R1为可以由下述取代基1次或多次任意取代的含有直至20个碳原子的直链或支链、饱和或不饱和的烷基，取代基系选自苯基、卤素、C1-C6烷基、C1-C6烷基、C1-C6烷氧基羰基、C1-C6烷基亚磺酰基或C1-C6烷基磺酰基，
R2为可以由下述取代基1次或多次任意取代的含有直至20个碳原子的直链或支链、饱和或不饱和的烷基，取代基系选自苯基、卤素、C1-C6烷氧基、C1-C6烷硫基、C1-C6烷氧基羰基、C1-C6烷基亚磺酰基或C1-C6烷基磺酰基，
R3为氢原子，或者为由羟基任意取代的C1-C6烷基，
R4为氢原子、羟基或氨基，或者为由C1-C6烷基一次或两次取代的氨基，
R5为氢原子、羟基或氨基，或者为由C1-C6烷基一次或两次取代的氨基，
X为价键、氧或硫原子、亚磺酰基或磺酰基，
Y的定义同X，因此X和Y可以相同或不同，
Z为氧或硫原子。
2、按照权利要求1的脂核苷酸，其中R1为可以由C1-C6烷氧基或C1-C6烷硫基取代的直链C9-C14烷基。
3、按照权利要求2的脂核苷酸，其中R1为可以由甲氧基、乙氧基、丁氧基、己氧基、甲硫基、乙硫基、丙硫基、丁硫基或己硫基取代的癸基、十一烷基、十二烷基、十三烷基或十四烷基。
4、按照上述权利要求中任何一项的脂核苷酸，其中R2为可以由C1-C6烷氧基或C1-C6烷硫基取代的直链C9-C14烷基。
5、按照权利要求4所述的脂核苷酸，其中R2为可以由甲氧基、乙氧基、丙氧基、丁氧基、己氧基、甲硫基、乙硫基、丁硫基或己硫基取代的癸基、十一烷基、十二烷基、十三烷基或十四烷基。
6、按照上述权利要求中任何一项的脂核苷酸，其中R3为氢原子或羟基-C1～C6烷基。
7、按照上述权利要求中任何一项的脂核苷酸，其中R4为羟基或氨基。
8、按照权利要求1-7中任何一项的脂核苷酸，其中R5为氢或氨基。
9、按照权利要求1的脂核苷酸，该脂核苷酸是上面特别提到的。
10、制备权利要求1-9中任何一项的通式Ⅰ脂核苷酸的方法，其中
a）用缩合剂于惰性溶剂中使通式（Ⅱ）化合物与通式（Ⅲ）化合物反应，在水解进行之后，用核苷化学中常用的方法脱去可能存在的氧保护基，
其中R1、R2、X、Y和Z的定义同上，
其中R3、R4和R5的定义同上，或者
b）在磷脂酶D存在下，于惰性溶剂中，在合适的缓冲液存在下，使通式（Ⅳ）化合物与通式（Ⅲ）化合物（其中R3、R4和R5的定义同上）反应，反应进行之后，用核苷化学中常用的方法脱去可能存在的氧保护基，然后如果需要，将得到的通式（Ⅰ）化合物转变成生理上合适的盐，
11、实质上按以上所述和举例说明，制备权利要求1的通式（Ⅰ）脂核苷酸的方法。
12、按照权利要求10或11的方法制备的权利要求1的通式Ⅰ脂核苷酸。
13、含有至少一种权利要求1－9和12中任何一项的通式（Ⅰ）脂核苷酸以及其他常规药用辅剂和载体物质的药用组合物。
14、应用权利要求1－9和12中任何一项的通式（Ⅰ）脂核苷酸制备治疗病毒和逆转录病毒感染的药用组合物。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4226279.8 | 1992-08-08 | ||
| DE4226279A DE4226279A1 (de) | 1992-08-08 | 1992-08-08 | Liponucleotide von Seco-Nucleosiden, deren Herstellung sowie deren Verwendung als antivirale Arzneimittel |
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| Publication Number | Publication Date |
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| CN1085908A true CN1085908A (zh) | 1994-04-27 |
| CN1040984C CN1040984C (zh) | 1998-12-02 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN93107987A Expired - Fee Related CN1040984C (zh) | 1992-08-08 | 1993-08-07 | 断-核苷的脂核苷酸,它们的制备方法以及含有它们的具有抗病毒作用的药用组合物 |
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| EP (1) | EP0654036B1 (zh) |
| JP (1) | JP3479299B2 (zh) |
| KR (1) | KR100243440B1 (zh) |
| CN (1) | CN1040984C (zh) |
| AT (1) | ATE152114T1 (zh) |
| AU (1) | AU672994B2 (zh) |
| CA (1) | CA2141030A1 (zh) |
| DE (2) | DE4226279A1 (zh) |
| DK (1) | DK0654036T3 (zh) |
| ES (1) | ES2104163T3 (zh) |
| FI (1) | FI109699B (zh) |
| GR (1) | GR3023960T3 (zh) |
| HU (1) | HUT72605A (zh) |
| IL (1) | IL106588A (zh) |
| MX (1) | MX9304676A (zh) |
| NO (1) | NO304986B1 (zh) |
| NZ (1) | NZ254813A (zh) |
| TW (1) | TW306924B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6599887B2 (en) | 1988-07-07 | 2003-07-29 | Chimerix, Inc. | Methods of treating viral infections using antiviral liponucleotides |
| US6252060B1 (en) | 1988-07-07 | 2001-06-26 | Nexstar Pharmaceuticals, Inc. | Antiviral liponucleosides: treatment of hepatitis B |
| US5817638A (en) * | 1988-07-07 | 1998-10-06 | Nexstar Pharmaceuticals, Inc. | Antiviral liponucleosides: treatment of hepatitis B |
| DE4402492A1 (de) * | 1994-01-28 | 1995-08-03 | Boehringer Mannheim Gmbh | Verfahren zur Herstellung von unsymmetrischen Phosphorsäurediestern |
| US7517858B1 (en) * | 1995-06-07 | 2009-04-14 | The Regents Of The University Of California | Prodrugs of pharmaceuticals with improved bioavailability |
| KR100389558B1 (ko) * | 2000-10-11 | 2003-06-27 | 주식회사 한스환경엔지니어링 | 유리섬유 강화플라스틱 성형품의 표면처리용 직물 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5223263A (en) * | 1988-07-07 | 1993-06-29 | Vical, Inc. | Liponucleotide-containing liposomes |
| DE4026265A1 (de) * | 1990-08-20 | 1992-02-27 | Boehringer Mannheim Gmbh | Neue phospholipid-derivate von nucleosiden, deren herstellung sowie deren verwendung als antivirale arzneimittel |
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Also Published As
| Publication number | Publication date |
|---|---|
| GR3023960T3 (en) | 1997-09-30 |
| ZA935718B (en) | 1995-02-06 |
| ES2104163T3 (es) | 1997-10-01 |
| IL106588A0 (en) | 1993-12-08 |
| WO1994003465A1 (de) | 1994-02-17 |
| JP3479299B2 (ja) | 2003-12-15 |
| CN1040984C (zh) | 1998-12-02 |
| KR950702998A (ko) | 1995-08-23 |
| DK0654036T3 (da) | 1997-11-03 |
| NZ254813A (en) | 1996-05-28 |
| IL106588A (en) | 1998-01-04 |
| HU9500374D0 (en) | 1995-03-28 |
| FI950533A (fi) | 1995-02-07 |
| EP0654036A1 (de) | 1995-05-24 |
| AU4708293A (en) | 1994-03-03 |
| CA2141030A1 (en) | 1994-02-09 |
| DE59306286D1 (de) | 1997-05-28 |
| ATE152114T1 (de) | 1997-05-15 |
| MX9304676A (es) | 1994-03-31 |
| FI950533A0 (fi) | 1995-02-07 |
| AU672994B2 (en) | 1996-10-24 |
| NO304986B1 (no) | 1999-03-15 |
| KR100243440B1 (ko) | 2000-03-02 |
| FI109699B (fi) | 2002-09-30 |
| NO950445L (no) | 1995-02-07 |
| TW306924B (zh) | 1997-06-01 |
| HUT72605A (en) | 1996-05-28 |
| NO950445D0 (no) | 1995-02-07 |
| JPH08500345A (ja) | 1996-01-16 |
| EP0654036B1 (de) | 1997-04-23 |
| DE4226279A1 (de) | 1994-02-10 |
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