NO317096B1 - Nye forbindelser, farmasoytisk formulering inneholdende slike forbindelser, fremgangsmate for deres fremstilling, og anvendelse derav - Google Patents
Nye forbindelser, farmasoytisk formulering inneholdende slike forbindelser, fremgangsmate for deres fremstilling, og anvendelse derav Download PDFInfo
- Publication number
- NO317096B1 NO317096B1 NO20002848A NO20002848A NO317096B1 NO 317096 B1 NO317096 B1 NO 317096B1 NO 20002848 A NO20002848 A NO 20002848A NO 20002848 A NO20002848 A NO 20002848A NO 317096 B1 NO317096 B1 NO 317096B1
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- Norway
- Prior art keywords
- formula
- compound
- compounds
- thrombin
- pharmaceutically acceptable
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
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- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Use Of Switch Circuits For Exchanges And Methods Of Control Of Multiplex Exchanges (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9704543A SE9704543D0 (sv) | 1997-12-05 | 1997-12-05 | New compounds |
| PCT/SE1998/002187 WO1999029664A1 (en) | 1997-12-05 | 1998-12-01 | New compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO20002848D0 NO20002848D0 (no) | 2000-06-02 |
| NO20002848L NO20002848L (no) | 2000-08-07 |
| NO317096B1 true NO317096B1 (no) | 2004-08-09 |
Family
ID=20409280
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20002848A NO317096B1 (no) | 1997-12-05 | 2000-06-02 | Nye forbindelser, farmasoytisk formulering inneholdende slike forbindelser, fremgangsmate for deres fremstilling, og anvendelse derav |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US6337394B2 (hu) |
| EP (1) | EP1036061B1 (hu) |
| JP (1) | JP2001525394A (hu) |
| KR (1) | KR100587434B1 (hu) |
| CN (1) | CN100379722C (hu) |
| AT (1) | ATE250574T1 (hu) |
| AU (1) | AU748834B2 (hu) |
| BR (1) | BR9813410A (hu) |
| CA (1) | CA2312431C (hu) |
| DE (1) | DE69818510T2 (hu) |
| EE (1) | EE200000322A (hu) |
| HU (1) | HUP0102681A3 (hu) |
| ID (1) | ID28008A (hu) |
| IL (1) | IL136295A (hu) |
| IS (1) | IS5511A (hu) |
| NO (1) | NO317096B1 (hu) |
| NZ (1) | NZ504528A (hu) |
| PL (1) | PL341047A1 (hu) |
| SE (1) | SE9704543D0 (hu) |
| SK (1) | SK6992000A3 (hu) |
| TR (1) | TR200001554T2 (hu) |
| WO (1) | WO1999029664A1 (hu) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9602263D0 (sv) * | 1996-06-07 | 1996-06-07 | Astra Ab | New amino acid derivatives |
| US6323180B1 (en) * | 1998-08-10 | 2001-11-27 | Boehringer Ingelheim (Canada) Ltd | Hepatitis C inhibitor tri-peptides |
| AR023510A1 (es) | 1999-04-21 | 2002-09-04 | Astrazeneca Ab | Un equipo de partes, formulacion farmaceutica y uso de un inhibidor de trombina. |
| SE0001803D0 (sv) | 2000-05-16 | 2000-05-16 | Astrazeneca Ab | New compounds i |
| US6433186B1 (en) | 2000-08-16 | 2002-08-13 | Astrazeneca Ab | Amidino derivatives and their use as thormbin inhibitors |
| US7129233B2 (en) | 2000-12-01 | 2006-10-31 | Astrazeneca Ab | Mandelic acid derivatives and their use as thrombin inhibitors |
| AR035216A1 (es) * | 2000-12-01 | 2004-05-05 | Astrazeneca Ab | Derivados de acido mandelico ,derivados farmaceuticamente aceptables, uso de estos derivados para la fabricacion de medicamentos, metodos de tratamiento ,procesos para la preparacion de estos derivados, y compuestos intermediarios |
| AU2002230836A1 (en) | 2000-12-18 | 2002-07-01 | Merck & Co., Inc. | Benzylamine derivatives and their use as thrombin inhibitors |
| WO2002064559A2 (en) | 2001-02-09 | 2002-08-22 | Merck & Co., Inc. | Thrombin inhibitors |
| SE0101762D0 (sv) * | 2001-05-18 | 2001-05-18 | Astrazeneca Ab | New use |
| AR034517A1 (es) | 2001-06-21 | 2004-02-25 | Astrazeneca Ab | Formulacion farmaceutica |
| SE0201661D0 (sv) | 2002-05-31 | 2002-05-31 | Astrazeneca Ab | New salts |
| SE0201659D0 (sv) | 2002-05-31 | 2002-05-31 | Astrazeneca Ab | Modified release pharmaceutical formulation |
| CN103204903A (zh) * | 2003-05-21 | 2013-07-17 | 贝林格尔.英格海姆国际有限公司 | 丙型肝炎抑制剂化合物 |
| US7781424B2 (en) * | 2003-05-27 | 2010-08-24 | Astrazeneca Ab | Modified release pharmaceutical formulation |
| UY29016A1 (es) * | 2004-07-20 | 2006-02-24 | Boehringer Ingelheim Int | Analogos de dipeptidos inhibidores de la hepatitis c |
| EP1771454B1 (en) * | 2004-07-20 | 2011-06-15 | Boehringer Ingelheim International GmbH | Hepatitis c inhibitor peptide analogs |
| TW200827336A (en) * | 2006-12-06 | 2008-07-01 | Astrazeneca Ab | New crystalline forms |
| US20090061000A1 (en) * | 2007-08-31 | 2009-03-05 | Astrazeneca Ab | Pharmaceutical formulation use 030 |
Family Cites Families (43)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU178398B (en) | 1979-06-12 | 1982-04-28 | Gyogyszerkutato Intezet | Process for producing new agmatine derivatives of activity against haemagglutination |
| HU192646B (en) | 1984-12-21 | 1987-06-29 | Gyogyszerkutato Intezet | Process for preparing new n-alkyl-peptide aldehydes |
| CA1341029C (en) | 1985-02-04 | 2000-06-20 | Michael Kolb | Peptidase inhibitors |
| US5187157A (en) | 1987-06-05 | 1993-02-16 | Du Pont Merck Pharmaceutical Company | Peptide boronic acid inhibitors of trypsin-like proteases |
| EP0362002B1 (en) | 1988-09-01 | 1995-07-26 | Merrell Dow Pharmaceuticals Inc. | HIV protease inhibitors |
| ZA897515B (en) | 1988-10-07 | 1990-06-27 | Merrell Dow Pharma | Novel peptidase inhibitors |
| TW201303B (hu) | 1990-07-05 | 1993-03-01 | Hoffmann La Roche | |
| CA2075154A1 (en) | 1991-08-06 | 1993-02-07 | Neelakantan Balasubramanian | Peptide aldehydes as antithrombotic agents |
| SE9102462D0 (sv) | 1991-08-28 | 1991-08-28 | Astra Ab | New isosteric peptides |
| NZ245039A (en) | 1991-11-12 | 1994-12-22 | Lilly Co Eli | N-phenylalanyl and n-phenylglycyl derivatives of the dipeptide of l-azetidine-2-carboxylic acid and l-arginine aldehyde; anti-blood clotting compositions |
| SE9103612D0 (sv) | 1991-12-04 | 1991-12-04 | Astra Ab | New peptide derivatives |
| US5760235A (en) | 1992-03-04 | 1998-06-02 | Gyogyszerkutato Intezet Kft. | Anticoagulant peptide derivatives and pharmaceutical compositions containing the same as well as a process for preparation thereof |
| TW223629B (hu) | 1992-03-06 | 1994-05-11 | Hoffmann La Roche | |
| US5583146A (en) | 1992-12-02 | 1996-12-10 | Bristol-Myers Squibb Company | Heterocyclic thrombin inhibitors |
| AU675981B2 (en) | 1992-12-02 | 1997-02-27 | Bristol-Myers Squibb Company | Guanidinyl-substituted heterocyclic thrombin inhibitors |
| JPH06340619A (ja) | 1993-05-03 | 1994-12-13 | Bristol Myers Squibb Co | グアニジニルまたはアミジニル置換メチルアミノ複素環トロンビン抑制剤 |
| US5780631A (en) | 1993-06-03 | 1998-07-14 | Astra Aktiebolag | Starting materials in the synthesis of thrombin and kininogenase inhibitors |
| SE9301916D0 (sv) | 1993-06-03 | 1993-06-03 | Ab Astra | New peptides derivatives |
| EP0648780A1 (en) | 1993-08-26 | 1995-04-19 | Bristol-Myers Squibb Company | Heterocyclic thrombin inhibitors |
| TW394760B (en) | 1993-09-07 | 2000-06-21 | Hoffmann La Roche | Novel Carboxamides, process for their preparation and pharmaceutical composition containing the same |
| AU1025795A (en) | 1994-01-27 | 1995-08-03 | Mitsubishi Chemical Corporation | Prolineamide derivatives |
| US5726159A (en) | 1994-03-04 | 1998-03-10 | Eli Lilly And Company | Antithrombotic agents |
| US5705487A (en) | 1994-03-04 | 1998-01-06 | Eli Lilly And Company | Antithrombotic agents |
| US5707966A (en) | 1994-03-04 | 1998-01-13 | Eli Lilly And Company | Antithrombotic agents |
| ZA951617B (en) | 1994-03-04 | 1997-02-27 | Lilly Co Eli | Antithrombotic agents. |
| US5561146A (en) | 1994-06-10 | 1996-10-01 | Bristol-Myers Squibb Company | Modified guanidino and amidino thrombin inhibitors |
| DE4421052A1 (de) | 1994-06-17 | 1995-12-21 | Basf Ag | Neue Thrombininhibitoren, ihre Herstellung und Verwendung |
| US5510369A (en) | 1994-07-22 | 1996-04-23 | Merck & Co., Inc. | Pyrrolidine thrombin inhibitors |
| DE4443390A1 (de) | 1994-12-06 | 1996-06-13 | Basf Ag | Neue dipeptidische p-Amidinobenzylamide mit N-terminalen Sulfonyl- bzw. Aminosulfonylresten |
| BR9607412A (pt) | 1995-02-10 | 1998-07-07 | Basf Ag | Inibidor de trombina e composto |
| EA199700186A1 (ru) * | 1995-02-17 | 1998-02-26 | Басф Акциенгезельшафт | Новые дипептидные амидины, используемые в качестве ингибиторов тромбина |
| US5914319A (en) | 1995-02-27 | 1999-06-22 | Eli Lilly And Company | Antithrombotic agents |
| US5710130A (en) | 1995-02-27 | 1998-01-20 | Eli Lilly And Company | Antithrombotic agents |
| EP0820453A4 (en) | 1995-04-04 | 2001-08-29 | Merck & Co Inc | THROMBIN INHIBITORS |
| US5629324A (en) | 1995-04-10 | 1997-05-13 | Merck & Co., Inc. | Thrombin inhibitors |
| SA96170106A (ar) | 1995-07-06 | 2005-12-03 | أسترا أكتيبولاج | مشتقات حامض أميني جديدة |
| AR005245A1 (es) | 1995-12-21 | 1999-04-28 | Astrazeneca Ab | Prodrogas de inhibidores de trombina, una formulación farmaceutica que las comprende, el uso de dichas prodrogas para la manufactura de un medicamento y un procedimiento para su preparacion |
| SE9602263D0 (sv) * | 1996-06-07 | 1996-06-07 | Astra Ab | New amino acid derivatives |
| JPH1095898A (ja) | 1996-09-25 | 1998-04-14 | Sumitomo Bakelite Co Ltd | 難燃性樹脂組成物およびこれを用いた積層板 |
| SE9602646D0 (sv) | 1996-07-04 | 1996-07-04 | Astra Ab | Pharmaceutically-useful compounds |
| DE19632772A1 (de) | 1996-08-14 | 1998-02-19 | Basf Ag | Neue Benzamidine |
| DE19632773A1 (de) | 1996-08-14 | 1998-02-19 | Basf Ag | Neue Thrombininhibitoren |
| AR013084A1 (es) | 1997-06-19 | 2000-12-13 | Astrazeneca Ab | Derivados de amidino utiles como inhibidores de la trombina, composicion farmaceutica, utilizacion de dichos compuestos para la preparacion demedicamentos y proceso para la preparacion de los compuestos mencionados |
-
1997
- 1997-12-05 SE SE9704543A patent/SE9704543D0/xx unknown
-
1998
- 1998-12-01 AT AT98962750T patent/ATE250574T1/de not_active IP Right Cessation
- 1998-12-01 TR TR2000/01554T patent/TR200001554T2/xx unknown
- 1998-12-01 NZ NZ504528A patent/NZ504528A/en unknown
- 1998-12-01 DE DE69818510T patent/DE69818510T2/de not_active Expired - Lifetime
- 1998-12-01 CA CA002312431A patent/CA2312431C/en not_active Expired - Fee Related
- 1998-12-01 KR KR1020007006078A patent/KR100587434B1/ko not_active IP Right Cessation
- 1998-12-01 BR BR9813410-8A patent/BR9813410A/pt not_active Application Discontinuation
- 1998-12-01 JP JP2000524261A patent/JP2001525394A/ja active Pending
- 1998-12-01 HU HU0102681A patent/HUP0102681A3/hu unknown
- 1998-12-01 EE EEP200000322A patent/EE200000322A/xx unknown
- 1998-12-01 EP EP98962750A patent/EP1036061B1/en not_active Expired - Lifetime
- 1998-12-01 ID IDW20001009A patent/ID28008A/id unknown
- 1998-12-01 AU AU17912/99A patent/AU748834B2/en not_active Ceased
- 1998-12-01 US US09/214,143 patent/US6337394B2/en not_active Expired - Fee Related
- 1998-12-01 SK SK699-2000A patent/SK6992000A3/sk unknown
- 1998-12-01 CN CNB988134756A patent/CN100379722C/zh not_active Expired - Fee Related
- 1998-12-01 PL PL98341047A patent/PL341047A1/xx not_active Application Discontinuation
- 1998-12-01 WO PCT/SE1998/002187 patent/WO1999029664A1/en active IP Right Grant
-
2000
- 2000-05-22 IL IL136295A patent/IL136295A/en not_active IP Right Cessation
- 2000-05-26 IS IS5511A patent/IS5511A/is unknown
- 2000-06-02 NO NO20002848A patent/NO317096B1/no not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0102681A3 (en) | 2002-01-28 |
| SE9704543D0 (sv) | 1997-12-05 |
| PL341047A1 (en) | 2001-03-26 |
| CN100379722C (zh) | 2008-04-09 |
| NZ504528A (en) | 2002-03-01 |
| TR200001554T2 (tr) | 2001-01-22 |
| US20010046981A1 (en) | 2001-11-29 |
| AU748834B2 (en) | 2002-06-13 |
| HUP0102681A2 (hu) | 2001-12-28 |
| KR20010024676A (ko) | 2001-03-26 |
| US6337394B2 (en) | 2002-01-08 |
| NO20002848L (no) | 2000-08-07 |
| ID28008A (id) | 2001-05-03 |
| EE200000322A (et) | 2001-08-15 |
| JP2001525394A (ja) | 2001-12-11 |
| KR100587434B1 (ko) | 2006-06-08 |
| DE69818510T2 (de) | 2004-06-24 |
| BR9813410A (pt) | 2000-10-10 |
| NO20002848D0 (no) | 2000-06-02 |
| IL136295A (en) | 2009-02-11 |
| EP1036061B1 (en) | 2003-09-24 |
| AU1791299A (en) | 1999-06-28 |
| IS5511A (is) | 2000-05-26 |
| EP1036061A1 (en) | 2000-09-20 |
| WO1999029664A1 (en) | 1999-06-17 |
| CA2312431C (en) | 2008-01-22 |
| SK6992000A3 (en) | 2001-02-12 |
| ATE250574T1 (de) | 2003-10-15 |
| CN1284063A (zh) | 2001-02-14 |
| DE69818510D1 (de) | 2003-10-30 |
| CA2312431A1 (en) | 1999-06-17 |
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| MM1K | Lapsed by not paying the annual fees |