CN1138759C - 新的方法 - Google Patents
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- CN1138759C CN1138759C CNB00806198XA CN00806198A CN1138759C CN 1138759 C CN1138759 C CN 1138759C CN B00806198X A CNB00806198X A CN B00806198XA CN 00806198 A CN00806198 A CN 00806198A CN 1138759 C CN1138759 C CN 1138759C
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- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 8
- -1 silicon azide metals Chemical class 0.000 claims description 7
- GARJITDFQFOYKD-UHFFFAOYSA-N [N-]=[N+]=[N-].[Li+].[Si+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] Chemical class [N-]=[N+]=[N-].[Li+].[Si+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] GARJITDFQFOYKD-UHFFFAOYSA-N 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- TVCXVUHHCUYLGX-UHFFFAOYSA-N 2-Methylpyrrole Chemical compound CC1=CC=CN1 TVCXVUHHCUYLGX-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-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
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical group [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
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Abstract
本发明涉及某些有药物活性的吡啶基化合物的制备方法。
Description
本发明涉及某些药物的改进的制备方法。
EP 0633 879 B1公开了据说具有NMDA受体拮抗活性的化合物。该化合物称为(S)-1-苯基-2-(2-吡啶基)乙胺，特别是在治疗中风中是特别有用的。然而，在EP 0633 879 B1中公开的制备该化合物的方法存在某些缺点，例如，需要使用丁基锂，在大规模生产中使用丁基锂不方便。
现在已经研究出制备(S)-1-苯基-2-(2-吡啶基)乙胺的新方法，不必使用丁基锂，因此该方法更适合于大规模生产中的应用。由于本发明方法取消了使用丁基锂的要求，因而它还有其它优点，即不再受由于放出丁烷而产生的环境问题的困扰。此外，令人惊奇地发现本发明的方法仅使用催化量的碱(相对于式(II)的2-甲基吡啶)便可实施，而不是象EP 0633 879 B1中那样需使用化学计量的碱。因此，从各个方面来说，本发明要求保护的方法比EP 0633 879 B1中的方法是更有效的、更安全的、更符合环境要求的和更经济的。
第一方面，本发明提供了制备式(I)化合物或其可药用盐的方法：该方法包括：在六甲基二硅叠氮化金属存在下使式(II)化合物与式(III)化合物反应，并且任选地拆分式(I)化合物的对映体及形成可药用盐，
式(III)化合物可由苯甲醛和六甲基二硅叠氮化金属、优选六甲基二硅叠氮化锂(LHMDS)制得。优选式(III)化合物在降低温度、即低于35℃、并且优选低于25℃的条件下制得。
化合物(II)和(III)的反应适于在升高温度，例如约40℃条件下进行。该反应可以在惰性溶剂、优先在醚类溶剂、例如叔丁基甲基醚或更优选的四氢呋喃中进行。六甲基二硅叠氮化金属优先是六甲基二硅叠氮化锂(LHMDS)，并且该碱相对于式(II)的2-甲基吡啶按催化量使用，例如约10mol％。反应混合物经酸处理得到所需要的式(I)化合物。
本发明化合物可以形成可药用溶剂化物和盐。式(I)化合物可与酸、例如常规可药用酸、如苹果酸、盐酸、氢溴酸、磷酸、乙酸、富马酸、水杨酸、柠檬酸、乳酸、扁桃酸、酒石酸、三氟乙酸和甲磺酸形成酸加成盐。优选的盐是苹果酸盐和盐酸盐。
特别优选的盐是EP 0691 977 B1中公开的用手性酸制备得到的式(I)化合物单个对映体的盐。优选地式(I)化合物的外消旋体用(S)-苹果酸处理得到(S)-1-苯基-2-(2-吡啶基)乙胺(S)-苹果酸盐。
另一方面，当用本发明的方法制备时，本发明提供了(S)-1-苯基-2-(2-吡啶基)乙胺及其盐，特别是(S)-苹果酸盐。
本发明用下面的实施例加以说明.
实施例
(S)-α-苯基-2-吡啶乙胺(S)-苹果酸盐
将六甲基二硅叠氮化锂(在四氢呋喃中的1100ml的1.0M溶液，1.1mol)溶液在氮气氛和冷却条件下滴加到搅拌的苯甲醛(102ml，1.0mol)在四氢呋喃(305ml)中的溶液中，同时维持温度低于25℃。所得溶液在20℃搅拌30分钟，然后一次加入2-甲基吡淀(101ml，1.0mol)，接着加入四氢呋喃(102ml)。然后将反应混合物用30分钟加热到40℃，并在40℃保持90分钟。然后将溶液用10分钟冷却到20℃，滴加到浓盐酸(420ml，5.0mol)在去离子水(900ml)中的溶液中，其间保持冷却，以便维持温度在10℃和20℃之间。所得混合物(pH 1)在20℃搅拌15分钟，然后分层。分出较低的水层并用乙酸乙酯(2×900ml)洗涤，然后加入氢氧化钠(200g，5.0mol)在去离子水(830ml)中的溶液进行碱化，同时保持冷却，以便将温度维持在10℃至20℃范围内。所得混合物(pH 12)在20℃搅拌15分钟，然后用乙酸乙酯(2×800ml)提取。将乙酸乙酯溶液加到S-苹果酸(120.7g，0.9mol)在乙醇(1060ml)中的溶液中，然后加入标题化合物的籽晶(0.2g)。将该混合物在20℃搅拌30分钟，然后冷却至0℃，并在0℃搅拌20小时。过滤悬浮液并用乙醇(530ml)洗涤，得到白色固体，将其在40℃真空箱中干燥过夜，得到(S)-α-苯基-2-吡啶乙胺(S)-苹果酸盐胺(S)-苹果酸盐(119.07g，35.8％)，为白色固体，与已知物质相同。
Claims (5)
1.式(I)化合物或其可药用盐的制备方法，该方法包括：使式(II)化合物
在六甲基二硅叠氮化金属存在下与式(III)化合物反应
并且然后任选地通过与(S)-苹果酸反应拆分式(I)化合物的对映体和形成可药用盐。
2.根据权利要求1的方法，其中六甲基二硅叠氮化金属是六甲基二硅叠氮化锂。
3.根据权利要求1的方法，其中化合物(II)和(III)在醚类溶剂中反应。
4.根据权利要求1至3中之一的方法，其中六甲基二硅叠氮化锂相对于式(II)化合物以催化量使用。
5.根据权利要求4的方法，其中式(II)化合物与六甲基二硅叠氮化锂的摩尔比是约10∶1。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE99013401 | 1999-04-15 | ||
| SE9901340A SE9901340D0 (sv) | 1999-04-15 | 1999-04-15 | Novel process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1370145A CN1370145A (zh) | 2002-09-18 |
| CN1138759C true CN1138759C (zh) | 2004-02-18 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB00806198XA Expired - Fee Related CN1138759C (zh) | 1999-04-15 | 2000-04-14 | 新的方法 |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US6518432B1 (zh) |
| EP (1) | EP1492769B1 (zh) |
| JP (1) | JP4676064B2 (zh) |
| KR (1) | KR100663811B1 (zh) |
| CN (1) | CN1138759C (zh) |
| AT (1) | ATE333444T1 (zh) |
| AU (1) | AU773962B2 (zh) |
| BR (1) | BR0009795B1 (zh) |
| CA (1) | CA2367410C (zh) |
| DE (1) | DE60029493T2 (zh) |
| ES (1) | ES2267526T3 (zh) |
| IL (2) | IL145585A0 (zh) |
| NO (1) | NO320810B1 (zh) |
| NZ (1) | NZ514586A (zh) |
| SE (1) | SE9901340D0 (zh) |
| TW (1) | TWI248433B (zh) |
| WO (1) | WO2000063175A2 (zh) |
| ZA (1) | ZA200108374B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ593282A (en) | 2008-12-24 | 2013-06-28 | Astrazeneca Ab | Ethanamine compounds and their use for treating depression |
| JP6479834B2 (ja) | 2013-11-05 | 2019-03-06 | アストラゼネカ・アクチエボラーグＡｓｔｒａｚｅｎｅｃａ Ａｋｔｉｅｂｏｌａｇ | Ｎｍｄａアンタゴニストプロドラッグ |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9320273D0 (en) | 1993-04-01 | 1993-11-17 | Fisons Corp | Compound useful in therapy |
| US5455259A (en) * | 1987-02-06 | 1995-10-03 | Fisons Corporation | Compounds for the treatment of neurodegenerative disorders |
| WO1993020052A1 (en) | 1992-04-03 | 1993-10-14 | Fisons Corporation | Enantiomeric 1-phenyl-2-(2-pyridinyl)ethylamine for the treatment of neurodegenerative disorders |
| DK0612314T3 (da) * | 1991-10-30 | 2000-05-29 | Astra Ab | 2-pyrazinylethylaminderivater og deres anvendelse som lægemidler |
-
1999
- 1999-04-15 SE SE9901340A patent/SE9901340D0/xx unknown
-
2000
- 2000-04-05 TW TW089106214A patent/TWI248433B/zh not_active IP Right Cessation
- 2000-04-14 US US09/555,050 patent/US6518432B1/en not_active Expired - Lifetime
- 2000-04-14 AU AU44447/00A patent/AU773962B2/en not_active Ceased
- 2000-04-14 BR BRPI0009795-0A patent/BR0009795B1/pt not_active IP Right Cessation
- 2000-04-14 EP EP00925816A patent/EP1492769B1/en not_active Expired - Lifetime
- 2000-04-14 WO PCT/SE2000/000713 patent/WO2000063175A2/en active IP Right Grant
- 2000-04-14 IL IL14558500A patent/IL145585A0/xx active IP Right Grant
- 2000-04-14 JP JP2000612269A patent/JP4676064B2/ja not_active Expired - Fee Related
- 2000-04-14 CA CA002367410A patent/CA2367410C/en not_active Expired - Fee Related
- 2000-04-14 ES ES00925816T patent/ES2267526T3/es not_active Expired - Lifetime
- 2000-04-14 NZ NZ514586A patent/NZ514586A/en not_active IP Right Cessation
- 2000-04-14 CN CNB00806198XA patent/CN1138759C/zh not_active Expired - Fee Related
- 2000-04-14 AT AT00925816T patent/ATE333444T1/de not_active IP Right Cessation
- 2000-04-14 KR KR1020017013069A patent/KR100663811B1/ko not_active IP Right Cessation
- 2000-04-14 DE DE60029493T patent/DE60029493T2/de not_active Expired - Lifetime
-
2001
- 2001-09-24 IL IL145585A patent/IL145585A/en not_active IP Right Cessation
- 2001-10-08 NO NO20014889A patent/NO320810B1/no not_active IP Right Cessation
- 2001-10-11 ZA ZA200108374A patent/ZA200108374B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200108374B (en) | 2003-08-06 |
| CA2367410C (en) | 2009-08-11 |
| NO20014889D0 (no) | 2001-10-08 |
| ATE333444T1 (de) | 2006-08-15 |
| NO320810B1 (no) | 2006-01-30 |
| US6518432B1 (en) | 2003-02-11 |
| CA2367410A1 (en) | 2000-10-26 |
| AU4444700A (en) | 2000-11-02 |
| JP4676064B2 (ja) | 2011-04-27 |
| NO20014889L (no) | 2001-10-08 |
| DE60029493T2 (de) | 2007-01-11 |
| IL145585A (en) | 2006-12-31 |
| DE60029493D1 (de) | 2006-08-31 |
| ES2267526T3 (es) | 2007-03-16 |
| BR0009795A (pt) | 2002-01-08 |
| EP1492769A2 (en) | 2005-01-05 |
| WO2000063175A2 (en) | 2000-10-26 |
| CN1370145A (zh) | 2002-09-18 |
| IL145585A0 (en) | 2002-11-10 |
| BR0009795B1 (pt) | 2011-12-27 |
| WO2000063175A3 (en) | 2004-11-11 |
| KR20010113799A (ko) | 2001-12-28 |
| TWI248433B (en) | 2006-02-01 |
| KR100663811B1 (ko) | 2007-01-03 |
| SE9901340D0 (sv) | 1999-04-15 |
| EP1492769B1 (en) | 2006-07-19 |
| JP2003524625A (ja) | 2003-08-19 |
| NZ514586A (en) | 2003-09-26 |
| AU773962B2 (en) | 2004-06-10 |
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