EE05080B1 - Pruvaatdehdrogenaasi aktiivsust t?stvad asendatud N-fenl-2-hdroks-2-metl-3,3,3-trifluoropropaanamiidi derivaadid - Google Patents
Pruvaatdehdrogenaasi aktiivsust t?stvad asendatud N-fenl-2-hdroks-2-metl-3,3,3-trifluoropropaanamiidi derivaadidInfo
- Publication number
- EE05080B1 EE05080B1 EEP200200113A EEP200200113A EE05080B1 EE 05080 B1 EE05080 B1 EE 05080B1 EE P200200113 A EEP200200113 A EE P200200113A EE P200200113 A EEP200200113 A EE P200200113A EE 05080 B1 EE05080 B1 EE 05080B1
- Authority
- EE
- Estonia
- Prior art keywords
- droxy
- phenyl
- substituted
- methyl
- dehydrogenase activity
- Prior art date
Links
- 101710088194 Dehydrogenase Proteins 0.000 title 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 title 1
- 230000000694 effects Effects 0.000 title 1
- 230000002708 enhancing effect Effects 0.000 title 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
-
- 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
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
-
- 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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
- C07C317/42—Y being a hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C317/50—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
- C07C323/65—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfone or sulfoxide groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Obesity (AREA)
- Hospice & Palliative Care (AREA)
- Neurology (AREA)
- Urology & Nephrology (AREA)
- Emergency Medicine (AREA)
- Vascular Medicine (AREA)
- Endocrinology (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9920814.2A GB9920814D0 (en) | 1999-09-04 | 1999-09-04 | Chemical compounds |
| GB0006641A GB0006641D0 (en) | 2000-03-21 | 2000-03-21 | Chemical compounds |
| PCT/GB2000/003314 WO2001017956A1 (en) | 1999-09-04 | 2000-08-30 | Substituted n-phenyl 2-hydroxy-2-methyl-3,3,3-trifluoropropanamide derivatives which elevate pyruvate dehydrogenase activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EE200200113A EE200200113A (et) | 2003-06-16 |
| EE05080B1 true EE05080B1 (et) | 2008-10-15 |
Family
ID=26243905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EEP200200113A EE05080B1 (et) | 1999-09-04 | 2000-08-30 | Pruvaatdehdrogenaasi aktiivsust t?stvad asendatud N-fenl-2-hdroks-2-metl-3,3,3-trifluoropropaanamiidi derivaadid |
Country Status (32)
| Country | Link |
|---|---|
| US (1) | US6689909B1 (ru) |
| EP (1) | EP1214296B1 (ru) |
| JP (1) | JP2003508515A (ru) |
| KR (1) | KR100692232B1 (ru) |
| CN (1) | CN1235877C (ru) |
| AR (1) | AR035163A1 (ru) |
| AT (1) | ATE262507T1 (ru) |
| AU (1) | AU760061B2 (ru) |
| BG (1) | BG65099B1 (ru) |
| BR (1) | BR0013694A (ru) |
| CA (1) | CA2381581A1 (ru) |
| CO (1) | CO5190690A1 (ru) |
| CZ (1) | CZ2002773A3 (ru) |
| DE (1) | DE60009319T2 (ru) |
| DK (1) | DK1214296T3 (ru) |
| EE (1) | EE05080B1 (ru) |
| ES (1) | ES2216940T3 (ru) |
| HK (1) | HK1045496B (ru) |
| HU (1) | HUP0202725A3 (ru) |
| IL (2) | IL148111A0 (ru) |
| IS (1) | IS2069B (ru) |
| MX (1) | MXPA02002319A (ru) |
| MY (1) | MY127036A (ru) |
| NO (1) | NO20021040L (ru) |
| NZ (1) | NZ517147A (ru) |
| PL (1) | PL353887A1 (ru) |
| PT (1) | PT1214296E (ru) |
| RU (1) | RU2255085C2 (ru) |
| SK (1) | SK286774B6 (ru) |
| TR (1) | TR200200550T2 (ru) |
| TW (1) | TW577867B (ru) |
| WO (1) | WO2001017956A1 (ru) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001017942A1 (en) | 1999-09-04 | 2001-03-15 | Astrazeneca Ab | Amides as inhibitors for pyruvate dehydrogenase |
| GB0012012D0 (en) * | 2000-05-19 | 2000-07-05 | Astrazeneca Ab | Chemical compound |
| GB0120471D0 (en) * | 2001-08-23 | 2001-10-17 | Astrazeneca Ab | Chemical compounds |
| WO2003055850A1 (fr) * | 2001-12-27 | 2003-07-10 | Daiichi Pharmaceutical Co., Ltd. | Inhibiteurs de la production/secretion de la proteine amyloide-$g(b) |
| WO2012151448A1 (en) * | 2011-05-03 | 2012-11-08 | Agios Pharmaceuticals, Inc. | Pyruvate kinase activators for use in therapy |
| AU2013342203B2 (en) | 2012-11-08 | 2017-11-23 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions and their use as PKM2 modulators |
| WO2014139144A1 (en) | 2013-03-15 | 2014-09-18 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
| ES2944545T3 (es) | 2017-08-15 | 2023-06-22 | Agios Pharmaceuticals Inc | Moduladores de piruvato quinasa y uso de los mismos |
| CN109096186B (zh) * | 2018-09-29 | 2020-08-04 | 中南大学 | 一种2-芳磺酰基喹啉衍生物的合成方法 |
| AR126913A1 (es) * | 2021-09-01 | 2023-11-29 | Japan Tobacco Inc | Compuesto tricíclico que contiene nitrógeno y su uso farmacéutico |
Family Cites Families (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0002309B1 (en) | 1977-10-12 | 1982-12-01 | Imperial Chemical Industries Plc | Acylanilides, process for their manufacture and pharmaceutical and veterinary compositions containing them |
| US4191775A (en) | 1977-12-15 | 1980-03-04 | Imperial Chemical Industries Limited | Amide derivatives |
| NZ197008A (en) | 1980-05-22 | 1984-10-19 | Ici Ltd | Acylanilide derivatives and pharmaceutical compositions |
| AU8961382A (en) | 1981-11-06 | 1983-05-12 | Imperial Chemical Industries Plc | Amide derivatives |
| US4537618A (en) | 1982-05-26 | 1985-08-27 | Ciba Geigy Corporation | N-phenylsulfonyl-N'-pyrimidinylureas |
| ATE28864T1 (de) | 1982-07-23 | 1987-08-15 | Ici Plc | Amide-derivate. |
| GB8617653D0 (en) | 1986-07-18 | 1986-08-28 | Ici Plc | Amide derivatives |
| GB8617652D0 (en) | 1986-07-18 | 1986-08-28 | Ici Plc | Acylanilide derivatives |
| GB9214120D0 (en) * | 1991-07-25 | 1992-08-12 | Ici Plc | Therapeutic amides |
| EP0539329A1 (de) | 1991-10-25 | 1993-04-28 | Ciba-Geigy Ag | Acetylen-Verbindungen, verwendbar als Leukotrien-Antagonisten |
| SE9103397D0 (sv) | 1991-11-18 | 1991-11-18 | Kabi Pharmacia Ab | Nya substituerade salicylsyror |
| IL105558A (en) | 1992-05-18 | 1998-04-05 | Zeneca Ltd | Tertiary carbinols with channel activity potassium process for their preparation and pharmaceutical preparations containing them |
| GB9305295D0 (en) | 1993-03-15 | 1993-05-05 | Zeneca Ltd | Therapeutic compounds |
| GB9309716D0 (en) | 1993-05-12 | 1993-06-23 | Zeneca Ltd | Heterocyclic derivatives |
| GB9310069D0 (en) | 1993-05-17 | 1993-06-30 | Zeneca Ltd | Heterocyclic compounds |
| GB9310095D0 (en) | 1993-05-17 | 1993-06-30 | Zeneca Ltd | Therapeutic compounds |
| GB2278054A (en) * | 1993-05-18 | 1994-11-23 | Zeneca Ltd | Compounds for the treatment of urinary incontinence |
| GB9505082D0 (en) | 1995-03-14 | 1995-05-03 | Zeneca Ltd | Medicament |
| GB9607458D0 (en) | 1996-04-10 | 1996-06-12 | Zeneca Ltd | Enzymatic process for stereoselective preparation of therapeutic amides |
| GB9804648D0 (en) * | 1998-03-06 | 1998-04-29 | Zeneca Ltd | Chemical compounds |
| GB9805520D0 (en) * | 1998-03-17 | 1998-05-13 | Zeneca Ltd | Chemical compounds |
| GB9811427D0 (en) | 1998-05-29 | 1998-07-22 | Zeneca Ltd | Chemical compounds |
-
2000
- 2000-08-30 TR TR2002/00550T patent/TR200200550T2/xx unknown
- 2000-08-30 ES ES00956672T patent/ES2216940T3/es not_active Expired - Lifetime
- 2000-08-30 WO PCT/GB2000/003314 patent/WO2001017956A1/en active Application Filing
- 2000-08-30 PT PT00956672T patent/PT1214296E/pt unknown
- 2000-08-30 HU HU0202725A patent/HUP0202725A3/hu unknown
- 2000-08-30 BR BR0013694-8A patent/BR0013694A/pt not_active Application Discontinuation
- 2000-08-30 DK DK00956672T patent/DK1214296T3/da active
- 2000-08-30 SK SK300-2002A patent/SK286774B6/sk not_active IP Right Cessation
- 2000-08-30 IL IL14811100A patent/IL148111A0/xx active IP Right Grant
- 2000-08-30 NZ NZ517147A patent/NZ517147A/en unknown
- 2000-08-30 CZ CZ2002773A patent/CZ2002773A3/cs unknown
- 2000-08-30 JP JP2001521703A patent/JP2003508515A/ja active Pending
- 2000-08-30 DE DE60009319T patent/DE60009319T2/de not_active Expired - Fee Related
- 2000-08-30 KR KR1020027002841A patent/KR100692232B1/ko not_active IP Right Cessation
- 2000-08-30 PL PL00353887A patent/PL353887A1/xx not_active Application Discontinuation
- 2000-08-30 CA CA002381581A patent/CA2381581A1/en not_active Abandoned
- 2000-08-30 MY MYPI20004037 patent/MY127036A/en unknown
- 2000-08-30 CN CNB008152446A patent/CN1235877C/zh not_active Expired - Fee Related
- 2000-08-30 RU RU2002108508/04A patent/RU2255085C2/ru not_active IP Right Cessation
- 2000-08-30 MX MXPA02002319A patent/MXPA02002319A/es active IP Right Grant
- 2000-08-30 AT AT00956672T patent/ATE262507T1/de not_active IP Right Cessation
- 2000-08-30 EE EEP200200113A patent/EE05080B1/xx not_active IP Right Cessation
- 2000-08-30 AU AU68543/00A patent/AU760061B2/en not_active Ceased
- 2000-08-30 EP EP00956672A patent/EP1214296B1/en not_active Expired - Lifetime
- 2000-08-30 US US10/069,994 patent/US6689909B1/en not_active Expired - Fee Related
- 2000-09-01 CO CO00065992A patent/CO5190690A1/es not_active Application Discontinuation
- 2000-09-04 AR ARP000104623A patent/AR035163A1/es unknown
- 2000-09-04 TW TW089118053A patent/TW577867B/zh not_active IP Right Cessation
-
2002
- 2002-02-11 IL IL148111A patent/IL148111A/en not_active IP Right Cessation
- 2002-02-26 IS IS6285A patent/IS2069B/xx unknown
- 2002-03-01 NO NO20021040A patent/NO20021040L/no not_active Application Discontinuation
- 2002-03-14 BG BG106520A patent/BG65099B1/bg active Active
- 2002-09-25 HK HK02107004.7A patent/HK1045496B/zh not_active IP Right Cessation
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| ES1044451Y (es) | Gavion perfeccionado. | |
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| FR2769001B1 (fr) | Caisse garde-objets, notamment garde-meubles | |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| KB4A | Valid patent at the end of a year |
Effective date: 20081231 |
|
| MM4A | Lapsed by not paying the annual fees |
Effective date: 20090830 |