CN1067059C - 用于制备一种药物活性化合物的中间体 - Google Patents
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- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 abstract description 6
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- 150000004677 hydrates Chemical class 0.000 abstract description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 11
- -1 4-carboxyl phenyl Chemical group 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
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- 238000000926 separation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- PNXMTCDJUBJHQJ-UHFFFAOYSA-N propyl prop-2-enoate Chemical compound CCCOC(=O)C=C PNXMTCDJUBJHQJ-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
Abstract
本发明涉及式(Ⅰ)的化合物及其水合物、溶剂化物和其盐。
Description
发明领域
本发明涉及可用于制备血管紧张肽Ⅱ(AⅡ)受体拮抗剂的关键中间体的亚硫酸氢盐加成化合物。
发明背景
公开于1994年3月31日的PCT申请WO 94/06776叙述了一种制备1-烷芳基-2-烷基-5-甲酰咪唑的方法，包括使2-卤代-2-丙烯醛-3-烷基醚，如2-溴-3-(1-甲基乙氧基)-2-丙烯醛，与N-(1-亚氨基烷基)氨基烷芳基化合物，如N-(1-亚氨基戊基)-4-(氨甲基)苯甲酸反应。尤其该PCT申请具体描述4-[(2-正丁基-5-甲酰基-1H-咪唑-1-基)甲基]苯甲酸的制备，它是制备(E)-3-[2-正丁基-1-{(4-羧基苯基)甲基-1H-咪唑-5-基]-2-(2-噻吩基)甲基-2-丙烯酸，一种高效AⅡ受体拮抗剂(Weinstock等，药物化学杂志(J.Med.Chem.)，第34卷，1514-1517页(1991年)的关键中间体。虽然在该PCT申请WO 94/06776叙述的方法以高产率和高纯度生产该关键中间体，但分离所述中间体过程包括由多次萃取组成的冗长步骤、用蒙脱土K-10粘土淤浆，和蒸馏/结晶步骤。因此，需要有其他方法分离4-[(2-正丁基-5-甲酰基-1H-咪唑-1-基)甲基]苯甲酸，尤其是在工业规模制备这一中间体用于合成(E)-3-[2-正丁基-1-{(4-羧基苯基)甲基-1H-咪唑-5-基]-2-(2-噻吩基)甲基-2-丙烯酸时更是如此。
现已发现通过将该中间体转化为其亚硫酸氢盐加成化合物，重结晶该加成化合物及将所述加成化合物再转化为4-[(2-正丁基-5-甲酰基-1H-咪唑-1-基)甲基]苯甲酸，可以获得精制的4-[(2-正丁基-5-甲酰基-1H-咪唑-1-基)甲基]苯甲酸。该亚硫酸氢盐加成化合物本身也可以直接用于(E)-3-[2-正丁基-1-{(4-羧基苯基)甲基-1H-咪唑-5-基]-2-(2-噻吩)甲基-2-丙烯酸乙酯的制备，它是(E)-3-[2-正丁基-1-{(4-羧基苯基)甲基-1H-咪唑-5-基]-2-(2-噻吩)甲基-2-丙烯酸的直接母体。利用4-[(2-正丁基-5-甲酰基-1H-咪唑-1-基)甲基]苯甲酸的亚硫酸盐加成化合物达到的后处理容易和分离过程高效化从商业观点考虑是极为有利的。
本发明概述
本发明提供了式(Ⅰ)化合物及水合物，溶剂化物和其盐。
本发明详述
本发明涉及式(Ⅰ)的化合物及水合物、溶剂化物和其盐。
本发明的具体化合物是4-[(2-正丁基-5-甲酰基-1H-咪唑-1-基)甲基]苯甲酸的亚硫酸氢盐加成化合物及水合物、溶剂化物和其盐。
通常该式(Ⅰ)的化合物由式(Ⅱ)的化合物与亚硫酸氢钠反应制备：
具体地说，该式(Ⅰ)的化合物由在方案Ⅰ中描述的方法制备。
方案Ⅰ
根据方案Ⅰ，在碱，例如，碳酸钾存在时，将N-(1-亚氨基戊基)-4-(氨甲基)苯甲酸(方案Ⅰ中的式(Ⅰ)化合物)与2-溴-3-(1-甲基乙氧基)-2-丙烯醛(方案Ⅰ中的式(2)化合物)反应，生成4-[2-正丁基-5-甲酰基-1H-咪唑-1-基)甲基]苯甲酸。(见PCT申请WO94/06776)。生成的5-甲酰基咪唑化合物(式(Ⅱ)化合物)不经分离，然后与亚硫酸氢钠反应，生成该亚硫酸氢盐加成化合物(方案Ⅰ中式(3))中间体钠盐。用盐酸水溶液(pH1.0-1.5)处理式(3)化合物导致形成方案Ⅰ中式(4)的化合物，也即式(Ⅰ)化合物。4-[(2-正丁基-5-甲酰基-1H-咪唑-1-基)甲基]苯甲酸然后也可以通过在氮气氛中使方案(Ⅰ)中式(4)化合物与水、醋酸和盐酸的混合物反应而再生。
式(Ⅰ)的化合物可以以水合的或溶剂化的形式存在。任何和所有这类水合物和溶剂化物都包括在本发明范围内。
从无机碱，包括碱金属和碱土金属碱，如，锂、钠和钾的氢氧化物、碳酸氢盐和碳酸盐和有机碱，如三乙胺、丁胺、哌嗪，胆碱和二乙醇胺用已知方法可制备式(Ⅰ)化合物的盐类，如方案(Ⅰ)中式(3)的化合物。
在合成有效的血管紧张肽Ⅱ受体拮抗剂的过程中，使用本发明的化合物提供了分离和提纯关键中间体的新方法。这种通过形成4-[(2-正丁基-5-甲酰基-1H-咪唑-1-基)甲基]苯甲酸的亚硫酸氢盐加成化合物的分离/纯化方法便于以简化的方式来生产该关键中间体，这种方法特别适用于在工业规模制备该中间体过程。
通过下面实施例说明本发明，该实施例无意限制本发明以上说明和以下要求保护的范围。
实施例1
4-[(2-丁基-5-甲酰基-1H-咪唑-1-基)甲基]苯甲酸亚硫酸氢盐加成化合物的合成
在氮气氛中将N-(1-亚氨基戊基)-4-(氨基甲基)苯甲酸(80mMol，19.13g，80％)、2-溴-3-(1-甲基乙氧基)-2-丙烯醛(88mMol，18.9g，90％)、碳酸钾(104mMol，14.42g)，四氢呋喃(90ml)和水(10ml)混合，剧烈搅拌、回流。回流3小时后，再加入2-溴-3-(1-甲基乙氧基)-2-丙烯醛(12mMol，2.6g，90％)和碳酸钾(15mMol，2.1 g)。回流4.5小时后，再加入2-溴-3-(1-甲基乙氧基)-2-丙烯醛(6.0mMol，1.3g，90％)和碳酸钾(7.5mMol，1.05g)。回流6-7小时后，反应冷却至环境温度。该混合物用水(25ml)稀释，用冰醋酸调节pH值至6.0-6.5(需要的话)。用叔-丁基甲基醚(90ml)稀释该中和的反应体系。亚硫酸氢钠(20g)和氯化钠(16g)加入到充分搅拌的混合物中。该混合物被冷却到0-5℃，搅拌2小时，该亚硫酸氢盐加成化合物(方案Ⅰ中式(3)的化合物)的中间体钠盐经过真空过滤分离。将该中间体盐溶解在水(275ml)中，该生成的溶液用盐酸酸化至pH1.0-1.5。形成的混合物被冷却至3-7℃2-3小时，所需的亚硫酸氢盐加成化合物(方案Ⅰ中式(4)化合物)经真空过滤分离成白色、亲水(water-wet)固体，粗产率70％。在90℃用冰醋酸(40ml)重结晶该湿固体制得真空干燥后为白色固体的标题化合物(29.5g)，产率60％。
IR(FT，KBr)：3600-3100，N-H和O-H(羟基)伸缩；3300-2800，O-H(酸)伸缩；3100-2800，-C-H和=C-H伸缩；2800-2400，NH+伸缩；1708，C=O(羧酸)伸缩；1614，C=N和C=C伸缩；1250-1160，C-O和O-H(羟基)伸缩，C-O(酸)伸缩，和SO2伸缩，1040和1014，C-O和O-H(羟基)伸缩和SO3振动(cm-1)。
应该理解本发明不限于上述实施方案，并保留对所述实施方案及所有在下面的权利要求书范围内的修改的权利。
Claims (2)
1、式(Ⅰ)的化合物：
2、如权利要求1定义的式(Ⅰ)的化合物的制备方法，该方法包括使式(Ⅱ)的化合物与亚硫酸氢钠反应：
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24643194A | 1994-05-20 | 1994-05-20 | |
| US08/246,431 | 1994-05-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1151734A CN1151734A (zh) | 1997-06-11 |
| CN1067059C true CN1067059C (zh) | 2001-06-13 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95193895A Expired - Fee Related CN1067059C (zh) | 1994-05-20 | 1995-05-04 | 用于制备一种药物活性化合物的中间体 |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US5719293A (zh) |
| EP (1) | EP0850225B1 (zh) |
| JP (1) | JPH10500681A (zh) |
| KR (1) | KR100369417B1 (zh) |
| CN (1) | CN1067059C (zh) |
| AT (1) | ATE247091T1 (zh) |
| AU (1) | AU690270B2 (zh) |
| BR (1) | BR9507668A (zh) |
| CZ (1) | CZ289968B6 (zh) |
| DE (1) | DE69531507T2 (zh) |
| DK (1) | DK0850225T3 (zh) |
| ES (1) | ES2204950T3 (zh) |
| HK (1) | HK1014939A1 (zh) |
| HU (1) | HU221905B1 (zh) |
| MX (1) | MX9605794A (zh) |
| NO (1) | NO306673B1 (zh) |
| NZ (1) | NZ285588A (zh) |
| PL (1) | PL185858B1 (zh) |
| PT (1) | PT850225E (zh) |
| WO (1) | WO1995032189A1 (zh) |
| ZA (1) | ZA954053B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR011125A1 (es) * | 1997-02-14 | 2000-08-02 | Smithkline Beecham Corp | Procedimiento para preparar eprosartano |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1214324A (fr) * | 1957-11-16 | 1960-04-07 | Merck Ag E | Procédé de préparation du pyridoxal et de ses dérivés à groupe aldéhyde protégé |
| US3798172A (en) * | 1969-05-26 | 1974-03-19 | Dan River Inc | Dyeing textile materials with vat and sulfur dyes and reducing agent stabilizers for same |
| JPS518934B2 (zh) * | 1972-02-04 | 1976-03-22 | ||
| US4024067A (en) * | 1976-01-07 | 1977-05-17 | The United States Of America As Represented By The Secretary Of The Navy | Processes for the preparation of bis-benzoins and bis-benzils |
| JPS55104254A (en) * | 1979-02-05 | 1980-08-09 | Kuraray Co Ltd | N-substituted-alpha-cyano-3-phenoxybenzylamine |
| JPS55167274A (en) * | 1979-06-14 | 1980-12-26 | Banyu Pharmaceut Co Ltd | Forphenicine derivative and its preparation |
| JPS5671074A (en) * | 1979-11-12 | 1981-06-13 | Takeda Chem Ind Ltd | 1,2-disubstituted-4-halogenoimidazole-5-acetic acid derivative |
| US5185351A (en) * | 1989-06-14 | 1993-02-09 | Smithkline Beecham Corporation | Imidazolyl-alkenoic acids useful as angiotensin II receptor antagonists |
| CA2059000C (en) * | 1989-06-30 | 1998-01-20 | Robert John Ardecky | Fused-ring aryl substituted imidazoles |
| JPH03112940A (ja) * | 1989-09-26 | 1991-05-14 | Nkk Corp | （±）―４―ホルミル―α―アルキルベンジルアルコール類の製造方法 |
-
1995
- 1995-05-04 AU AU24737/95A patent/AU690270B2/en not_active Ceased
- 1995-05-04 KR KR1019960706579A patent/KR100369417B1/ko not_active IP Right Cessation
- 1995-05-04 HU HU9603205A patent/HU221905B1/hu not_active IP Right Cessation
- 1995-05-04 PL PL95317538A patent/PL185858B1/pl not_active IP Right Cessation
- 1995-05-04 NZ NZ285588A patent/NZ285588A/en not_active IP Right Cessation
- 1995-05-04 BR BR9507668A patent/BR9507668A/pt not_active Application Discontinuation
- 1995-05-04 MX MX9605794A patent/MX9605794A/es not_active IP Right Cessation
- 1995-05-04 JP JP7530315A patent/JPH10500681A/ja active Pending
- 1995-05-04 DE DE69531507T patent/DE69531507T2/de not_active Expired - Lifetime
- 1995-05-04 AT AT95919025T patent/ATE247091T1/de not_active IP Right Cessation
- 1995-05-04 WO PCT/US1995/005664 patent/WO1995032189A1/en active IP Right Grant
- 1995-05-04 ES ES95919025T patent/ES2204950T3/es not_active Expired - Lifetime
- 1995-05-04 CN CN95193895A patent/CN1067059C/zh not_active Expired - Fee Related
- 1995-05-04 EP EP95919025A patent/EP0850225B1/en not_active Expired - Lifetime
- 1995-05-04 CZ CZ19963403A patent/CZ289968B6/cs not_active IP Right Cessation
- 1995-05-04 PT PT95919025T patent/PT850225E/pt unknown
- 1995-05-04 US US08/737,699 patent/US5719293A/en not_active Expired - Lifetime
- 1995-05-04 DK DK95919025T patent/DK0850225T3/da active
- 1995-05-18 ZA ZA954053A patent/ZA954053B/xx unknown
-
1996
- 1996-11-19 NO NO964921A patent/NO306673B1/no not_active IP Right Cessation
-
1998
- 1998-12-31 HK HK98119267A patent/HK1014939A1/xx not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0850225A4 (zh) | 1998-07-01 |
| CN1151734A (zh) | 1997-06-11 |
| ATE247091T1 (de) | 2003-08-15 |
| NO964921D0 (no) | 1996-11-19 |
| DE69531507T2 (de) | 2004-06-17 |
| AU690270B2 (en) | 1998-04-23 |
| ES2204950T3 (es) | 2004-05-01 |
| ZA954053B (en) | 1996-01-19 |
| HK1014939A1 (en) | 1999-10-08 |
| NZ285588A (en) | 1997-12-19 |
| HU221905B1 (hu) | 2003-02-28 |
| PT850225E (pt) | 2003-11-28 |
| HU9603205D0 (en) | 1997-01-28 |
| PL185858B1 (pl) | 2003-08-29 |
| JPH10500681A (ja) | 1998-01-20 |
| KR100369417B1 (ko) | 2003-04-23 |
| MX9605794A (es) | 1997-12-31 |
| HUT75714A (en) | 1997-05-28 |
| EP0850225B1 (en) | 2003-08-13 |
| CZ289968B6 (cs) | 2002-05-15 |
| CZ340396A3 (en) | 1997-03-12 |
| PL317538A1 (en) | 1997-04-14 |
| DK0850225T3 (da) | 2003-12-01 |
| AU2473795A (en) | 1995-12-18 |
| NO306673B1 (no) | 1999-12-06 |
| BR9507668A (pt) | 1997-10-07 |
| DE69531507D1 (de) | 2003-09-18 |
| EP0850225A1 (en) | 1998-07-01 |
| US5719293A (en) | 1998-02-17 |
| NO964921L (no) | 1996-11-20 |
| WO1995032189A1 (en) | 1995-11-30 |
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