NO972482L - Nytt amidinonafthylderivat eller salt derav - Google Patents
Nytt amidinonafthylderivat eller salt deravInfo
- Publication number
- NO972482L NO972482L NO972482A NO972482A NO972482L NO 972482 L NO972482 L NO 972482L NO 972482 A NO972482 A NO 972482A NO 972482 A NO972482 A NO 972482A NO 972482 L NO972482 L NO 972482L
- Authority
- NO
- Norway
- Prior art keywords
- group
- formula
- represented
- chem
- hydrogen atom
- Prior art date
Links
- -1 amidinonaphthyl Chemical class 0.000 title abstract 4
- 150000003839 salts Chemical class 0.000 title abstract 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 3
- 125000003545 alkoxy group Chemical group 0.000 abstract 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 2
- 230000002401 inhibitory effect Effects 0.000 abstract 2
- 108010074860 Factor Xa Proteins 0.000 abstract 1
- 208000007536 Thrombosis Diseases 0.000 abstract 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 125000002947 alkylene group Chemical group 0.000 abstract 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 125000004430 oxygen atom Chemical group O* 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 abstract 1
- 229910052717 sulfur Inorganic materials 0.000 abstract 1
- 125000004434 sulfur atom Chemical group 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- 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
- C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (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)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29996394 | 1994-12-02 | ||
| JP10520595 | 1995-04-28 | ||
| JP19881695 | 1995-08-03 | ||
| PCT/JP1995/002458 WO1996016940A1 (en) | 1994-12-02 | 1995-12-01 | Novel amidinonaphthyl derivative or salt thereof |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO972482D0 NO972482D0 (no) | 1997-05-30 |
| NO972482L true NO972482L (no) | 1997-08-01 |
| NO309566B1 NO309566B1 (no) | 2001-02-19 |
Family
ID=27310425
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO972482A NO309566B1 (no) | 1994-12-02 | 1997-05-30 | Nytt amidinonaftylderivat eller salt derav og farmasöytisk preparat inneholdende dette |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US5869501A (no) |
| EP (1) | EP0798295B1 (no) |
| JP (1) | JP3004362B2 (no) |
| KR (1) | KR100383161B1 (no) |
| CN (1) | CN1087736C (no) |
| AT (1) | ATE233240T1 (no) |
| AU (1) | AU688628B2 (no) |
| CA (1) | CA2206532C (no) |
| DE (1) | DE69529770T2 (no) |
| ES (1) | ES2193202T3 (no) |
| FI (1) | FI115051B (no) |
| HU (1) | HUT77313A (no) |
| MX (1) | MX9704059A (no) |
| NO (1) | NO309566B1 (no) |
| NZ (1) | NZ296210A (no) |
| PL (1) | PL184824B1 (no) |
| PT (1) | PT798295E (no) |
| RU (1) | RU2154633C2 (no) |
| TW (1) | TW300888B (no) |
| WO (1) | WO1996016940A1 (no) |
Families Citing this family (66)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996028427A1 (en) | 1995-03-10 | 1996-09-19 | Berlex Laboratories, Inc. | Benzamidine derivatives their preparation and their use as anti-coagulants |
| SE9602646D0 (sv) | 1996-07-04 | 1996-07-04 | Astra Ab | Pharmaceutically-useful compounds |
| HUP9904363A3 (en) | 1996-08-15 | 2000-12-28 | Schering Corp | Piperidine ether muscarinic antagonists and pharmaceutical compositions containing them |
| EP0842941A1 (de) * | 1996-11-16 | 1998-05-20 | Roche Diagnostics GmbH | Neue Phosphonate, Verfahren zu ihrer Herstellung und Arzneimittel |
| US6653340B1 (en) | 1997-06-03 | 2003-11-25 | Biocryst Pharmaceuticals, Inc. | Compounds useful in the complement, coagulat and kallikrein pathways and method for their preparation |
| US6060491A (en) * | 1997-06-19 | 2000-05-09 | Dupont Pharmaceuticals | 6-membered aromatics as factor Xa inhibitors |
| WO1998057934A1 (en) * | 1997-06-19 | 1998-12-23 | The Du Pont Merck Pharmaceutical Company | (AMIDINO)6-MEMBERED AROMATICS AS FACTOR Xa INHIBITORS |
| ZA986594B (en) * | 1997-07-25 | 1999-01-27 | Abbott Lab | Urokinase inhibitors |
| US6258822B1 (en) | 1997-08-06 | 2001-07-10 | Abbott Laboratories | Urokinase inhibitors |
| WO1999011617A1 (en) * | 1997-09-01 | 1999-03-11 | Yamanouchi Pharmaceutical Co., Ltd. | Novel naphthamide derivatives or salts thereof |
| US6686364B2 (en) | 1997-12-08 | 2004-02-03 | Berlex Laboratories, Inc. | Benzamidine derivatives and their use as anti-coagulants |
| DE19754490A1 (de) * | 1997-12-09 | 1999-06-10 | Boehringer Ingelheim Pharma | Durch einen Aminocarbonylrest substituierte Bicyclen, ihre Herstellung und ihre Verwendung als Arzneimittel |
| EP1048652A4 (en) * | 1997-12-26 | 2001-05-09 | Mochida Pharm Co Ltd | AROMATIC COMPOUNDS WITH A CYCLIC AMINO GROUP OR THEIR SALTS |
| AU2074699A (en) * | 1998-01-26 | 1999-08-09 | Yamanouchi Pharmaceutical Co., Ltd. | Novel benzene-fused heterocyclic derivatives or salts thereof |
| EP0937723A1 (de) * | 1998-02-18 | 1999-08-25 | Roche Diagnostics GmbH | Neue Sulfonamide, Verfahren zu ihrer Herstellung sowie diese enthaltende Arzneimittel |
| EP1066272A4 (en) * | 1998-03-27 | 2002-03-13 | Biocryst Pharm Inc | NEW CONNECTIONS USEFUL IN THE COMPLEMENT, COAGULATE AND KALLIKREIN REACTION WAY AND METHOD FOR THEIR PRODUCTION |
| NZ508101A (en) * | 1998-04-10 | 2002-12-20 | Japan Tobacco Inc | Amidine compounds useful as factor Xa inhibitors and as anticoagulants |
| US6284796B1 (en) | 1998-08-06 | 2001-09-04 | Abbott Laboratories | Ukokinase inhibitors |
| US6504031B1 (en) | 1998-08-06 | 2003-01-07 | Milan Bruncko | Naphthamidine urokinase inhibitors |
| US6262088B1 (en) | 1998-11-19 | 2001-07-17 | Berlex Laboratories, Inc. | Polyhydroxylated monocyclic N-heterocyclic derivatives as anti-coagulants |
| EP1140862A4 (en) | 1998-12-23 | 2004-07-28 | Bristol Myers Squibb Pharma Co | THROMBIN OR Xa FACTOR INHIBITORS |
| AU771776B2 (en) | 1999-01-13 | 2004-04-01 | Genentech Inc. | Serine protease inhibitors |
| JP4599714B2 (ja) * | 1999-01-22 | 2010-12-15 | アステラス製薬株式会社 | 経口吸収改善医薬用組成物 |
| EP1159273A1 (en) | 1999-03-02 | 2001-12-05 | Boehringer Ingelheim Pharmaceuticals Inc. | Compounds useful as reversible inhibitors of cathepsin s |
| FR2793247B1 (fr) * | 1999-05-04 | 2001-06-22 | Synthelabo | Derives de 6-[[(aryl et heteroaryl)oxy]methyl]naphtalene-2- carboximidamide, leur preparation et leur application en therapeutique |
| US6858599B2 (en) * | 1999-06-30 | 2005-02-22 | Mochida Pharmaceutical Co., Ltd. | Tricyclic compound having spiro union |
| AU5570900A (en) * | 1999-07-01 | 2001-01-22 | Sankyo Company Limited | Indoline or tetrahydroquinoline derivatives |
| US6350761B1 (en) | 1999-07-30 | 2002-02-26 | Berlex Laboratories, Inc. | Benzenamine derivatives as anti-coagulants |
| US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
| CN1572882A (zh) * | 1999-10-28 | 2005-02-02 | 三共株式会社 | 苯甲脒衍生物 |
| EP1095933A1 (en) * | 1999-10-30 | 2001-05-02 | Aventis Pharma Deutschland GmbH | Novel N-guanidinoalkylamides, their preparation, their use, and pharmaceutical preparations comprising them |
| US20020065303A1 (en) * | 2000-02-01 | 2002-05-30 | Bing-Yan Zhu | Bivalent phenylene inhibitors of factor Xa |
| US6376515B2 (en) | 2000-02-29 | 2002-04-23 | Cor Therapeutics, Inc. | Benzamides and related inhibitors of factor Xa |
| EP1272483A2 (en) * | 2000-03-24 | 2003-01-08 | Millenium Pharmaceuticals, Inc. | OXINDOLE INHIBITORS OF FACTOR Xa |
| AU776053B2 (en) * | 2000-03-31 | 2004-08-26 | Astellas Pharma Inc. | Diazepan derivatives or salts thereof |
| US6495562B1 (en) | 2000-04-25 | 2002-12-17 | Abbott Laboratories | Naphthamidine urokinase inhibitors |
| US6410733B1 (en) | 2000-09-11 | 2002-06-25 | Genentech, Inc. | Amidine inhibitors of serine proteases |
| CN1283626C (zh) | 2000-11-22 | 2006-11-08 | 安斯泰来制药有限公司 | 取代苯衍生物或其盐 |
| US6710061B2 (en) | 2001-03-09 | 2004-03-23 | Ortho-Mcneil Pharamceutical, Inc. | Aminopyrrolidine sulfonamides as serine protease inhibitors |
| CA2440389A1 (en) | 2001-03-09 | 2002-10-03 | Ortho-Mcneil Pharmaceutical, Inc. | Aminopyrrolidine sulfonamides as serine protease inhibitors |
| US7312235B2 (en) | 2001-03-30 | 2007-12-25 | Millennium Pharmaceuticals, Inc. | Benzamide inhibitors of factor Xa |
| PL363961A1 (en) | 2001-04-05 | 2004-11-29 | Sankyo Company, Limited | Benzamidine derivative |
| PL207295B1 (pl) * | 2002-01-29 | 2010-11-30 | Serono Lab | Podstawione pochodne metylenoamidowe , ich zastosowanie i sposób ich wytwarzania oraz kompozycja farmaceutyczna |
| RU2226392C1 (ru) * | 2002-10-23 | 2004-04-10 | Биологический факультет Московского государственного университета им. М.В. Ломоносова | Способ ингибирования агрегации тромбоцитов |
| AU2003284596A1 (en) | 2002-11-22 | 2004-06-18 | Takeda Pharmaceutical Company Limited | Imidazole derivative, process for producing the same, and use |
| HUE025683T2 (hu) | 2002-12-03 | 2016-04-28 | Pharmacyclics Llc | VIIA faktor inhibitor 2-(2-hidroxi-bifenil-3-il)-1H-benzoimidazol-5-karboxamidin-származékok |
| WO2004058728A1 (ja) * | 2002-12-24 | 2004-07-15 | Daiichi Pharmaceutical Co., Ltd. | 新規なエチレンジアミン誘導体 |
| US7250447B2 (en) | 2003-05-20 | 2007-07-31 | Genentech, Inc. | Acylsulfamide inhibitors of factor VIIa |
| JP2007500221A (ja) | 2003-05-20 | 2007-01-11 | ジェネンテック・インコーポレーテッド | 第VIIa因子のベンゾフラン阻害剤 |
| CN1886398A (zh) | 2003-10-09 | 2006-12-27 | 米伦纽姆医药公司 | 作为Xa因子抑制剂的经硫醚取代的苯甲酰胺 |
| TWI396686B (zh) | 2004-05-21 | 2013-05-21 | Takeda Pharmaceutical | 環狀醯胺衍生物、以及其製品和用法 |
| JP5020073B2 (ja) | 2004-06-18 | 2012-09-05 | ミレニアム ファーマシューティカルズ インク. | 第Xa因子阻害剤 |
| WO2006055951A2 (en) | 2004-11-19 | 2006-05-26 | Portola Pharmaceuticals, Inc. | Tetrahydroisoquinolines as factor xa inhibitors |
| US7678913B2 (en) | 2004-12-07 | 2010-03-16 | Portola Pharmaceuticals, Inc. | Ureas as factor Xa inhibitors |
| WO2006063293A2 (en) * | 2004-12-07 | 2006-06-15 | Portola Pharmaceuticals, Inc. | THIOUREAS AS FACTOR Xa INHIBITORS |
| JP4900238B2 (ja) | 2005-02-02 | 2012-03-21 | 味の素株式会社 | 新規ベンズアミジン化合物 |
| US7598276B2 (en) | 2005-11-08 | 2009-10-06 | Millenium Pharmaceuticals, Inc. | Pharmaceutical salts and polymorphs of a factor Xa inhibitor |
| JP2009531364A (ja) * | 2006-03-28 | 2009-09-03 | ノバルティス アクチエンゲゼルシャフト | アミド誘導体およびgタンパク質関連疾患の処置のためのそれらの使用 |
| WO2008044731A1 (en) * | 2006-10-12 | 2008-04-17 | Institute Of Medicinal Molecular Design. Inc. | N-phenyloxamidic acid derivative |
| ES2382055T3 (es) | 2006-11-02 | 2012-06-04 | Millennium Pharmaceuticals, Inc. | Métodos para sintetizar sales farmacéuticas de un inhibidor del factor Xa |
| WO2008066102A1 (en) | 2006-11-30 | 2008-06-05 | Takeda Pharmaceutical Company Limited | Sustained release preparation |
| US8633245B2 (en) * | 2008-04-11 | 2014-01-21 | Institute Of Medicinal Molecular Design, Inc. | PAI-1 inhibitor |
| WO2010005087A1 (ja) | 2008-07-11 | 2010-01-14 | 味の素株式会社 | アミジン誘導体 |
| EA015918B1 (ru) | 2010-03-03 | 2011-12-30 | Дмитрий Геннадьевич ТОВБИН | УРЕТАНЫ, МОЧЕВИНЫ, АМИДЫ И РОДСТВЕННЫЕ ИНГИБИТОРЫ ФАКТОРА Xa |
| WO2019241213A1 (en) * | 2018-06-11 | 2019-12-19 | The Regents Of The University Of Colorado, A Body Corporate | 2-naphthimidamides, analogues thereof, and methods of treatment using same |
| CN117304076B (zh) * | 2023-11-28 | 2024-02-20 | 苏州大学 | 一种n-磺酰基脒化合物的制备方法 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4443462A (en) * | 1979-08-06 | 1984-04-17 | Merrell Dow Pharmaceuticals Inc. | Antipsychotic 4-(naphthalenyloxy)piperidine derivatives |
| AU527371B2 (en) * | 1980-09-16 | 1983-03-03 | Torii & Co., Ltd. | Amidine |
| JPS59139357A (ja) * | 1983-01-28 | 1984-08-10 | Torii Yakuhin Kk | アミジン誘導体 |
| US4563527A (en) * | 1984-07-19 | 1986-01-07 | Torii & Co., Ltd. | Amidine compounds |
| ZA928276B (en) * | 1991-10-31 | 1993-05-06 | Daiichi Seiyaku Co | Aromatic amidine derivates and salts thereof. |
-
1995
- 1995-12-01 TW TW084112820A patent/TW300888B/zh active
- 1995-12-01 AU AU39942/95A patent/AU688628B2/en not_active Ceased
- 1995-12-01 DE DE69529770T patent/DE69529770T2/de not_active Expired - Fee Related
- 1995-12-01 CN CN95196546A patent/CN1087736C/zh not_active Expired - Fee Related
- 1995-12-01 PL PL95320486A patent/PL184824B1/pl not_active IP Right Cessation
- 1995-12-01 PT PT95938625T patent/PT798295E/pt unknown
- 1995-12-01 EP EP95938625A patent/EP0798295B1/en not_active Expired - Lifetime
- 1995-12-01 CA CA002206532A patent/CA2206532C/en not_active Expired - Fee Related
- 1995-12-01 RU RU97108576/04A patent/RU2154633C2/ru not_active IP Right Cessation
- 1995-12-01 NZ NZ296210A patent/NZ296210A/en unknown
- 1995-12-01 HU HU9702028A patent/HUT77313A/hu unknown
- 1995-12-01 JP JP8518590A patent/JP3004362B2/ja not_active Expired - Fee Related
- 1995-12-01 KR KR1019970703620A patent/KR100383161B1/ko not_active Expired - Fee Related
- 1995-12-01 WO PCT/JP1995/002458 patent/WO1996016940A1/ja not_active Ceased
- 1995-12-01 AT AT95938625T patent/ATE233240T1/de not_active IP Right Cessation
- 1995-12-01 US US08/849,391 patent/US5869501A/en not_active Expired - Fee Related
- 1995-12-01 ES ES95938625T patent/ES2193202T3/es not_active Expired - Lifetime
- 1995-12-01 MX MX9704059A patent/MX9704059A/es not_active IP Right Cessation
-
1997
- 1997-05-30 NO NO972482A patent/NO309566B1/no not_active IP Right Cessation
- 1997-06-02 FI FI972326A patent/FI115051B/fi not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0798295A1 (en) | 1997-10-01 |
| PL320486A1 (en) | 1997-09-29 |
| EP0798295B1 (en) | 2003-02-26 |
| WO1996016940A1 (en) | 1996-06-06 |
| CN1087736C (zh) | 2002-07-17 |
| TW300888B (no) | 1997-03-21 |
| DE69529770T2 (de) | 2003-12-24 |
| CN1167484A (zh) | 1997-12-10 |
| ATE233240T1 (de) | 2003-03-15 |
| NZ296210A (en) | 1998-05-27 |
| PT798295E (pt) | 2003-07-31 |
| PL184824B1 (pl) | 2002-12-31 |
| FI972326A0 (fi) | 1997-06-02 |
| NO309566B1 (no) | 2001-02-19 |
| HUT77313A (hu) | 1998-03-30 |
| CA2206532C (en) | 2006-07-11 |
| RU2154633C2 (ru) | 2000-08-20 |
| FI115051B (fi) | 2005-02-28 |
| MX9704059A (es) | 1997-08-30 |
| DE69529770D1 (de) | 2003-04-03 |
| AU688628B2 (en) | 1998-03-12 |
| EP0798295A4 (en) | 1998-03-04 |
| NO972482D0 (no) | 1997-05-30 |
| AU3994295A (en) | 1996-06-19 |
| CA2206532A1 (en) | 1996-06-06 |
| US5869501A (en) | 1999-02-09 |
| JP3004362B2 (ja) | 2000-01-31 |
| ES2193202T3 (es) | 2003-11-01 |
| FI972326A7 (fi) | 1997-06-02 |
| KR100383161B1 (ko) | 2003-12-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM1K | Lapsed by not paying the annual fees |