NO309649B1 - <alfa>-(substituerte alkylfenyl)-4-(hydroxydifenylmethyl)-1- piperidinbutanolderivater og deres anvendelse til fremstilling av antihistaminer, anti-allergimidler og bronchodilatorer - Google Patents
<alfa>-(substituerte alkylfenyl)-4-(hydroxydifenylmethyl)-1- piperidinbutanolderivater og deres anvendelse til fremstilling av antihistaminer, anti-allergimidler og bronchodilatorer Download PDFInfo
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- NO309649B1 NO309649B1 NO975130A NO975130A NO309649B1 NO 309649 B1 NO309649 B1 NO 309649B1 NO 975130 A NO975130 A NO 975130A NO 975130 A NO975130 A NO 975130A NO 309649 B1 NO309649 B1 NO 309649B1
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- Prior art keywords
- compound according
- compound
- formula
- acid
- hydroxydiphenylmethyl
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- 238000002360 preparation method Methods 0.000 title claims description 19
- 239000000739 antihistaminic agent Substances 0.000 title claims description 10
- 229940124630 bronchodilator Drugs 0.000 title description 6
- 239000000043 antiallergic agent Substances 0.000 title description 4
- 229940125715 antihistaminic agent Drugs 0.000 title description 4
- 239000000168 bronchodilator agent Substances 0.000 title description 4
- 125000005037 alkyl phenyl group Chemical group 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 70
- 239000000203 mixture Substances 0.000 claims description 28
- -1 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-2-methylphenethyl Chemical group 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
- 230000001387 anti-histamine Effects 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 230000003266 anti-allergic effect Effects 0.000 claims description 5
- 239000000969 carrier Substances 0.000 claims description 5
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- LJRYMPSOYXBUOX-UHFFFAOYSA-N 2-[4-[1-hydroxy-4-[4-[hydroxy(diphenyl)methyl]piperidin-1-yl]butyl]phenyl]propanoic acid Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 LJRYMPSOYXBUOX-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- JZFFNZUKADOQTB-UHFFFAOYSA-N ethyl 2-[4-[1-hydroxy-4-[4-[hydroxy(diphenyl)methyl]piperidin-1-yl]butyl]phenyl]propanoate Chemical compound C1=CC(C(C)C(=O)OCC)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 JZFFNZUKADOQTB-UHFFFAOYSA-N 0.000 claims 1
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- 229960000583 acetic acid Drugs 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 239000004305 biphenyl Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
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- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
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- 238000000967 suction filtration Methods 0.000 description 4
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- LEKWBQDHDMSNSM-UHFFFAOYSA-N ethyl 2-[4-[4-[4-[hydroxy(diphenyl)methyl]piperidin-1-yl]butanoyl]phenyl]propanoate Chemical compound C1=CC(C(C)C(=O)OCC)=CC=C1C(=O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 LEKWBQDHDMSNSM-UHFFFAOYSA-N 0.000 description 3
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- 125000006239 protecting group Chemical group 0.000 description 3
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- NAOPQRUHFCSBIC-UHFFFAOYSA-N 2-[4-[4-[4-[hydroxy(diphenyl)methyl]piperidin-1-yl]butanoyl]phenyl]propanoic acid;hydrate Chemical compound O.C1=CC(C(C(O)=O)C)=CC=C1C(=O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 NAOPQRUHFCSBIC-UHFFFAOYSA-N 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000001577 simple distillation Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- LGSAOJLQTXCYHF-UHFFFAOYSA-N tri(propan-2-yl)-tri(propan-2-yl)silyloxysilane Chemical compound CC(C)[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)C(C)C LGSAOJLQTXCYHF-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- KVWSBFXANGWHKO-LHKYRUFYSA-N tris[[(1S,2S,5R)-5-methyl-2-propan-2-ylcyclohexyl]methyl]alumane Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1C[Al](C[C@@H]1[C@@H](CC[C@@H](C)C1)C(C)C)C[C@@H]1[C@H](C(C)C)CC[C@@H](C)C1 KVWSBFXANGWHKO-LHKYRUFYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US43653595A | 1995-05-08 | 1995-05-08 | |
| PCT/US1996/005243 WO1996035667A1 (en) | 1995-05-08 | 1996-04-16 | Alpha-(substituted alkylphenyl)-4-(hydroxydiphenylmethyl)-1-piperidine butanol derivatives, their preparation and their use as anti-histamines, anti-allergy agents and bronchodilators |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO975130D0 NO975130D0 (no) | 1997-11-07 |
| NO975130L NO975130L (no) | 1998-01-06 |
| NO309649B1 true NO309649B1 (no) | 2001-03-05 |
Family
ID=23732797
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO975130A NO309649B1 (no) | 1995-05-08 | 1997-11-07 | <alfa>-(substituerte alkylfenyl)-4-(hydroxydifenylmethyl)-1- piperidinbutanolderivater og deres anvendelse til fremstilling av antihistaminer, anti-allergimidler og bronchodilatorer |
Country Status (16)
| Country | Link |
|---|---|
| US (4) | US20020016467A1 (xx) |
| EP (1) | EP0871614A1 (xx) |
| JP (1) | JPH11504650A (xx) |
| KR (1) | KR19990008406A (xx) |
| CN (1) | CN1183769A (xx) |
| AR (1) | AR002293A1 (xx) |
| AU (1) | AU705427B2 (xx) |
| CA (1) | CA2216877A1 (xx) |
| HU (1) | HUP9801254A3 (xx) |
| IL (1) | IL118161A0 (xx) |
| MX (1) | MX9708612A (xx) |
| NO (1) | NO309649B1 (xx) |
| NZ (1) | NZ306319A (xx) |
| TW (1) | TW412527B (xx) |
| WO (1) | WO1996035667A1 (xx) |
| ZA (1) | ZA963483B (xx) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6683094B2 (en) | 1998-07-02 | 2004-01-27 | Aventis Pharmaceuticals Inc. | Antihistaminic piperidine derivatives and intermediates for the preparation thereof |
| US6930197B2 (en) | 1998-07-02 | 2005-08-16 | Aventis Pharmaceuticals Inc. | Antihistaminic piperidine derivatives and intermediates for the preparation thereof |
| CN100522921C (zh) * | 1998-07-02 | 2009-08-05 | 阿旺蒂斯制药公司 | 抗组胺哌啶衍生物及制备其的中间体 |
| AU2007200674C1 (en) * | 1998-07-02 | 2011-02-24 | Aventisub Llc | Novel antihistaminic piperidine derivatives and intermediates for the preparation thereof |
| PT1311482E (pt) * | 2000-08-08 | 2007-04-30 | Ortho Mcneil Pharm Inc | Ariloxipiperidinas não imidazólicas como ligandos do receptor h3 |
| EP2578570A1 (en) | 2011-10-07 | 2013-04-10 | Almirall, S.A. | Novel process for preparing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(r)-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one via novel intermediates of synthesis. |
| EP2641900A1 (en) | 2012-03-20 | 2013-09-25 | Almirall, S.A. | Novel polymorphic Crystal forms of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy) hexyl]amino}-1-(R)-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one, heminapadisylate as agonist of the ß2 adrenergic receptor. |
| BR112016022829B1 (pt) * | 2014-04-02 | 2022-03-03 | Chembio Diagnostic Systems, Inc | Dispositivo de teste para determinar a presença de um primeiro ligante em uma amostra líquida, e método para testar uma amostra quanto à presença de um primeiro ligante |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3965257A (en) * | 1972-01-28 | 1976-06-22 | Richardson-Merrell Inc. | Compositions and methods for the treatment of the symptoms of histamine induced allergic reactions |
| US3878217A (en) * | 1972-01-28 | 1975-04-15 | Richardson Merrell Inc | Alpha-aryl-4-substituted piperidinoalkanol derivatives |
| ZA728544B (en) * | 1972-01-28 | 1974-02-27 | Richardson Merrell Inc | Alpha-aryl-4-substituted piperidinoalkanol derivatives |
| US3806526A (en) * | 1972-01-28 | 1974-04-23 | Richardson Merrell Inc | 1-aroylalkyl-4-diphenylmethyl piperidines |
| US4285957A (en) * | 1979-04-10 | 1981-08-25 | Richardson-Merrell Inc. | 1-Piperidine-alkanol derivatives, pharmaceutical compositions thereof, and method of use thereof |
| US4254129A (en) * | 1979-04-10 | 1981-03-03 | Richardson-Merrell Inc. | Piperidine derivatives |
| US4254130A (en) * | 1979-04-10 | 1981-03-03 | Richardson-Merrell Inc. | Piperidine derivatives |
| US4285958A (en) * | 1979-04-10 | 1981-08-25 | Richardson-Merrell Inc. | 1-Piperidine-alkylene ketones, pharmaceutical compositions thereof and method of use thereof |
| GB8321157D0 (en) * | 1983-08-05 | 1983-09-07 | Fordonal Sa | Piperidine derivatives |
| IT1205685B (it) * | 1987-05-26 | 1989-03-31 | Erregierre Spa | Processo per la preparazione di alfa-(alchilfenil)-4-(idrossi difenilmetil)-1-piperidina butanolo |
| US4863931A (en) * | 1988-09-15 | 1989-09-05 | Schering Corporation | Antihistaminic fluoro substituted benzocycloheptapyridines |
| CN1168717C (zh) * | 1993-06-25 | 2004-09-29 | 默里尔药物公司 | 用于制备抗组胺哌啶衍生物的新中间体 |
| US6174216B1 (en) * | 1999-08-03 | 2001-01-16 | Mattel, Inc. | Stretchable two-headed toy figure |
-
1996
- 1996-04-16 JP JP8534075A patent/JPH11504650A/ja not_active Ceased
- 1996-04-16 CN CN96193789A patent/CN1183769A/zh active Pending
- 1996-04-16 KR KR1019970707933A patent/KR19990008406A/ko not_active Application Discontinuation
- 1996-04-16 NZ NZ306319A patent/NZ306319A/xx not_active IP Right Cessation
- 1996-04-16 HU HU9801254A patent/HUP9801254A3/hu unknown
- 1996-04-16 AU AU54860/96A patent/AU705427B2/en not_active Ceased
- 1996-04-16 CA CA002216877A patent/CA2216877A1/en not_active Abandoned
- 1996-04-16 EP EP96911782A patent/EP0871614A1/en not_active Withdrawn
- 1996-04-16 WO PCT/US1996/005243 patent/WO1996035667A1/en not_active Application Discontinuation
- 1996-04-16 MX MX9708612A patent/MX9708612A/es unknown
- 1996-05-02 ZA ZA963483A patent/ZA963483B/xx unknown
- 1996-05-03 AR ARP960102432A patent/AR002293A1/es not_active Application Discontinuation
- 1996-05-03 TW TW085105337A patent/TW412527B/zh active
- 1996-05-06 IL IL11816196A patent/IL118161A0/xx unknown
-
1997
- 1997-11-07 NO NO975130A patent/NO309649B1/no not_active IP Right Cessation
-
2001
- 2001-10-02 US US09/968,961 patent/US20020016467A1/en not_active Abandoned
-
2002
- 2002-10-03 US US10/263,869 patent/US20030065186A1/en not_active Abandoned
-
2004
- 2004-03-01 US US10/790,284 patent/US20040167169A1/en not_active Abandoned
-
2005
- 2005-06-09 US US11/149,106 patent/US20050239834A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| HUP9801254A3 (en) | 1998-09-28 |
| NO975130L (no) | 1998-01-06 |
| AU5486096A (en) | 1996-11-29 |
| WO1996035667A1 (en) | 1996-11-14 |
| AR002293A1 (es) | 1998-03-11 |
| MX9708612A (es) | 1998-02-28 |
| NZ306319A (en) | 1999-08-30 |
| CA2216877A1 (en) | 1996-11-14 |
| ZA963483B (en) | 1996-11-13 |
| US20050239834A1 (en) | 2005-10-27 |
| EP0871614A1 (en) | 1998-10-21 |
| US20030065186A1 (en) | 2003-04-03 |
| TW412527B (en) | 2000-11-21 |
| US20040167169A1 (en) | 2004-08-26 |
| CN1183769A (zh) | 1998-06-03 |
| KR19990008406A (ko) | 1999-01-25 |
| HUP9801254A2 (hu) | 1998-08-28 |
| US20020016467A1 (en) | 2002-02-07 |
| AU705427B2 (en) | 1999-05-20 |
| JPH11504650A (ja) | 1999-04-27 |
| NO975130D0 (no) | 1997-11-07 |
| IL118161A0 (en) | 1996-09-12 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM1K | Lapsed by not paying the annual fees |