PT725641E - Novos inibidores da fosforilase da uridina (urdpase) e da desidrogenase do di-hidrouracilo (dhudase) - Google Patents
Novos inibidores da fosforilase da uridina (urdpase) e da desidrogenase do di-hidrouracilo (dhudase) Download PDFInfo
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- PT725641E PT725641E PT94929398T PT94929398T PT725641E PT 725641 E PT725641 E PT 725641E PT 94929398 T PT94929398 T PT 94929398T PT 94929398 T PT94929398 T PT 94929398T PT 725641 E PT725641 E PT 725641E
- Authority
- PT
- Portugal
- Prior art keywords
- phenylthio
- barbituric acid
- pyrimidine
- phenylselenenyl
- compounds
- Prior art date
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- 108010019092 Uridine phosphorylase Proteins 0.000 title claims abstract description 64
- 239000003112 inhibitor Substances 0.000 title claims description 55
- OIVLITBTBDPEFK-UHFFFAOYSA-N DIHYDRO-URACILE Natural products O=C1CCNC(=O)N1 OIVLITBTBDPEFK-UHFFFAOYSA-N 0.000 title description 8
- 102000006405 Uridine phosphorylase Human genes 0.000 title description 7
- 101710088194 Dehydrogenase Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 90
- 238000011282 treatment Methods 0.000 claims abstract description 36
- -1 methoxy, benzyl Chemical group 0.000 claims abstract description 35
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 24
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 14
- 230000001580 bacterial effect Effects 0.000 claims abstract description 14
- 230000002538 fungal effect Effects 0.000 claims abstract description 14
- 230000003612 virological effect Effects 0.000 claims abstract description 13
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 12
- 208000031888 Mycoses Diseases 0.000 claims abstract description 12
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- 208000036142 Viral infection Diseases 0.000 claims abstract description 12
- 206010017533 Fungal infection Diseases 0.000 claims abstract description 11
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 9
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 4
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 24
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- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 18
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- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical class O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims description 14
- 231100000419 toxicity Toxicity 0.000 claims description 13
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- 229940035893 uracil Drugs 0.000 claims description 13
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- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 claims description 10
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- YWWZCHLUQSHMCL-UHFFFAOYSA-N diphenyl diselenide Chemical compound C=1C=CC=CC=1[Se][Se]C1=CC=CC=C1 YWWZCHLUQSHMCL-UHFFFAOYSA-N 0.000 claims description 6
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- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 6
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims description 6
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- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- UTKBQCBAMCEBTL-UHFFFAOYSA-N 1-(2-hydroxyethoxymethyl)-5-phenylsulfanyl-1,3-diazinane-2,4,6-trione Chemical compound O=C1N(COCCO)C(=O)NC(=O)C1SC1=CC=CC=C1 UTKBQCBAMCEBTL-UHFFFAOYSA-N 0.000 claims description 5
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- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 claims description 5
- KFSPSGWABMNFIY-UHFFFAOYSA-N 1-(2-hydroxyethoxymethyl)-5-phenylselanylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)N(COCCO)C=C1[Se]C1=CC=CC=C1 KFSPSGWABMNFIY-UHFFFAOYSA-N 0.000 claims description 4
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- GQERGAYPZWJSAF-UHFFFAOYSA-N 1-(2-hydroxyethoxymethyl)-5-phenylselanyl-1,3-diazinane-2,4,6-trione Chemical compound O=C1N(COCCO)C(=O)NC(=O)C1[Se]C1=CC=CC=C1 GQERGAYPZWJSAF-UHFFFAOYSA-N 0.000 claims description 3
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- 208000001297 phlebitis Diseases 0.000 description 1
- RGCLLPNLLBQHPF-HJWRWDBZSA-N phosphamidon Chemical compound CCN(CC)C(=O)C(\Cl)=C(/C)OP(=O)(OC)OC RGCLLPNLLBQHPF-HJWRWDBZSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 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
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000010902 straw Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/146,838 US5476855A (en) | 1993-11-02 | 1993-11-02 | Enzyme inhibitors, their synthesis and methods for use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PT725641E true PT725641E (pt) | 2001-05-31 |
Family
ID=22519188
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PT94929398T PT725641E (pt) | 1993-11-02 | 1994-09-30 | Novos inibidores da fosforilase da uridina (urdpase) e da desidrogenase do di-hidrouracilo (dhudase) |
Country Status (9)
| Country | Link |
|---|---|
| US (3) | US5476855A (enExample) |
| EP (1) | EP0725641B1 (enExample) |
| JP (1) | JP3621102B2 (enExample) |
| AT (1) | ATE198046T1 (enExample) |
| AU (1) | AU699914B2 (enExample) |
| DE (1) | DE69426423T2 (enExample) |
| ES (1) | ES2155093T3 (enExample) |
| PT (1) | PT725641E (enExample) |
| WO (1) | WO1995012400A1 (enExample) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5476855A (en) * | 1993-11-02 | 1995-12-19 | Mahmoud H. el Kouni | Enzyme inhibitors, their synthesis and methods for use |
| DE69430587T2 (de) * | 1994-02-28 | 2003-01-09 | Sunkyong Industries Co. Ltd., Suwon | Pyrimidin-acyclonukleosid-derivate |
| US5811073A (en) * | 1995-06-19 | 1998-09-22 | President And Fellows Of Harvard College | Method for radioisotopic detection and localization of inflammation in a host |
| US5719132A (en) * | 1996-06-27 | 1998-02-17 | Bristol-Myers Squibb Company | Compositions and methods of treating HIV with d4T, 5-fluorouracil/tegafur, and uracil |
| US6306909B1 (en) | 1997-03-12 | 2001-10-23 | Queen's University At Kingston | Anti-epileptogenic agents |
| US6177437B1 (en) * | 1998-09-04 | 2001-01-23 | University Of Massachusetts Medical Center | Inhibitors of Herpes Simplex virus uracil-DNA glycosylase |
| DK1255738T3 (da) * | 2000-01-25 | 2012-06-25 | Neurocrine Biosciences Inc | Gonadotropin-frigivende hormonreceptor-antagonister og fremgangsmåder relateret dertil |
| US7501429B2 (en) * | 2001-04-11 | 2009-03-10 | Queen's University At Kingston | Pyrimidine compounds as anti-ictogenic and/or anti-epileptogenic agents |
| JP2004536071A (ja) * | 2001-05-25 | 2004-12-02 | クイーンズ ユニバーシティ アット キングストン | 複素環ベータアミノ酸およびそれらの抗癲癇誘発剤としての使用 |
| WO2005012309A1 (fr) * | 2003-08-04 | 2005-02-10 | Valery Khazhmuratovich Zhilov | Bioisosteres cycliques issus d'un systeme purine et composition pharmaceutique a base desdits bioisosteres |
| EP1827443A1 (en) * | 2004-12-03 | 2007-09-05 | Adherex Technologies, Inc. | Methods for administering dpd inhibitors in combination with 5-fu and 5-fu prodrugs |
| US20100158967A1 (en) * | 2005-05-24 | 2010-06-24 | Ted Reid | Selenium-based biocidal formulations and methods of use thereof |
| AU2006269657B2 (en) * | 2005-05-24 | 2012-04-19 | Selenbio, Inc. | Selenium-based biocidal formulations and methods of use thereof |
| US9370187B2 (en) | 2005-05-24 | 2016-06-21 | Selenium, Ltd. | Selenium-based biocidal formulations and methods of use thereof |
| US20100158966A1 (en) * | 2005-05-24 | 2010-06-24 | Ted Reid | Selenium-based biocidal formulations and methods of use thereof |
| NZ565955A (en) | 2005-08-22 | 2011-08-26 | Melior Pharmaceuticals I Inc | Methods and formulations for modulating lyn kinase activity and treating related disorders |
| CN101686686A (zh) * | 2007-02-20 | 2010-03-31 | 梅里奥尔医药I公司 | 鉴别Lyn激酶激活剂的方法 |
| CA2693809A1 (en) * | 2007-07-23 | 2009-01-29 | Melior Discovery, Inc. | Methods of activating irs-1 and akt |
| AU2009223453B2 (en) | 2008-03-03 | 2014-05-01 | Tosk, Inc. | Methotrexate adjuvants to reduce toxicity and methods for using the same |
| US8552184B2 (en) * | 2008-07-03 | 2013-10-08 | Melior Pharmaceuticals I, Inc. | Compounds and methods for treating disorders related to glucose metabolism |
| WO2010080086A1 (en) * | 2009-01-12 | 2010-07-15 | Selenium, Ltd. | Anti-microbial orthodontic compositions and appliances and methods of production and use thereof |
| US8658618B2 (en) * | 2009-10-14 | 2014-02-25 | Adherex Technologies, Inc. | Methods for preventing or reducing neurotoxicity associated with administering DPD inhibitors in combination with 5-FU and 5-FU prodrugs |
| US20130158055A1 (en) | 2010-05-28 | 2013-06-20 | Andrew G. Reaume | Prevention Of Pancreatic Beta Cell Degeneration |
| KR102634575B1 (ko) | 2017-04-10 | 2024-02-06 | 멜리어 파마슈티칼스 아이, 인코포레이티드 | 지방세포의 처리 |
| US11446303B2 (en) | 2019-06-21 | 2022-09-20 | Tosk, Inc. | Uridine phosphorylase (UPase) inhibitors for treatment of liver conditions |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3755295A (en) * | 1969-10-24 | 1973-08-28 | Syntex Corp | 1-(2-amino-2-deoxy-{62 -d-ribofuranosyl) pyrimidines and derivatives thereof |
| US3687931A (en) * | 1970-03-19 | 1972-08-29 | Syntex Corp | Halogenated purine and pyrimidine nucleosides and process therefor |
| JPS5738774A (en) * | 1980-08-19 | 1982-03-03 | Chugai Pharmaceut Co Ltd | Uracil derivative and its preparation |
| US4868187A (en) * | 1980-09-16 | 1989-09-19 | Syntex (U.S.A.) Inc. | Anti-viral N-substituted pyrimidines |
| US4613604A (en) * | 1985-07-31 | 1986-09-23 | Brown University Research Foundation | Hydroxymethyl derivatives of 5-benzylacyclouridine and 5-benzoyloxybenzylacyclouridine and their use as potentiators for 5-fluoro-2'-deoxyuridine |
| DD283613A5 (de) * | 1988-03-31 | 1990-10-17 | ��@���������@�������k�� | Verfahren zur herstellung von in 6-stellung substituierte acyclopyrimidin-nucleosid-derivaten |
| US5077280A (en) * | 1988-04-12 | 1991-12-31 | Brown University Research Foundation | Treatment of viral infections |
| EP0449726B1 (en) * | 1990-03-29 | 1997-06-11 | Mitsubishi Chemical Corporation | Pyrimidine nucleoside derivative and antiviral agent containing the derivative as active ingredient |
| US5141943A (en) * | 1990-04-12 | 1992-08-25 | Brown University Research Foundation | 5-benzyl barbiturate derivatives |
| US5476855A (en) * | 1993-11-02 | 1995-12-19 | Mahmoud H. el Kouni | Enzyme inhibitors, their synthesis and methods for use |
| KR0151811B1 (ko) * | 1993-12-21 | 1998-10-15 | 강박광 | 신규한 항바이러스성 2,4-피리미딘디온 유도체 및 그의 제조방법 |
-
1993
- 1993-11-02 US US08/146,838 patent/US5476855A/en not_active Ceased
-
1994
- 1994-09-30 DE DE69426423T patent/DE69426423T2/de not_active Expired - Lifetime
- 1994-09-30 EP EP94929398A patent/EP0725641B1/en not_active Expired - Lifetime
- 1994-09-30 ES ES94929398T patent/ES2155093T3/es not_active Expired - Lifetime
- 1994-09-30 WO PCT/US1994/011173 patent/WO1995012400A1/en not_active Ceased
- 1994-09-30 JP JP51321195A patent/JP3621102B2/ja not_active Expired - Fee Related
- 1994-09-30 PT PT94929398T patent/PT725641E/pt unknown
- 1994-09-30 AT AT94929398T patent/ATE198046T1/de not_active IP Right Cessation
- 1994-09-30 AU AU78476/94A patent/AU699914B2/en not_active Ceased
-
1995
- 1995-06-06 US US08/466,470 patent/US5721241A/en not_active Expired - Lifetime
-
1997
- 1997-12-01 US US08/980,629 patent/USRE37623E1/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| DE69426423T2 (de) | 2001-07-12 |
| ES2155093T3 (es) | 2001-05-01 |
| AU7847694A (en) | 1995-05-23 |
| JPH09507054A (ja) | 1997-07-15 |
| DE69426423D1 (de) | 2001-01-18 |
| US5721241A (en) | 1998-02-24 |
| AU699914B2 (en) | 1998-12-17 |
| EP0725641A4 (enExample) | 1996-09-04 |
| ATE198046T1 (de) | 2000-12-15 |
| WO1995012400A1 (en) | 1995-05-11 |
| EP0725641B1 (en) | 2000-12-13 |
| US5476855A (en) | 1995-12-19 |
| JP3621102B2 (ja) | 2005-02-16 |
| EP0725641A1 (en) | 1996-08-14 |
| USRE37623E1 (en) | 2002-04-02 |
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