NO311361B1 - Peptidderivater, fremgangsmåte for fremstilling, farmasöytisk preparat og anvendelse av peptidderivatene - Google Patents
Peptidderivater, fremgangsmåte for fremstilling, farmasöytisk preparat og anvendelse av peptidderivatene Download PDFInfo
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- NO311361B1 NO311361B1 NO19942066A NO942066A NO311361B1 NO 311361 B1 NO311361 B1 NO 311361B1 NO 19942066 A NO19942066 A NO 19942066A NO 942066 A NO942066 A NO 942066A NO 311361 B1 NO311361 B1 NO 311361B1
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- GBCAVSYHPPARHX-UHFFFAOYSA-M n'-cyclohexyl-n-[2-(4-methylmorpholin-4-ium-4-yl)ethyl]methanediimine;4-methylbenzenesulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.C1CCCCC1N=C=NCC[N+]1(C)CCOCC1 GBCAVSYHPPARHX-UHFFFAOYSA-M 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940021317 other blood product in atc Drugs 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000009024 positive feedback mechanism Effects 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000006965 reversible inhibition Effects 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical group 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical class NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
- 229960003766 thrombin (human) Drugs 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- SZYJELPVAFJOGJ-UHFFFAOYSA-N trimethylamine hydrochloride Chemical compound Cl.CN(C)C SZYJELPVAFJOGJ-UHFFFAOYSA-N 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229910001845 yogo sapphire Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
- C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- 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)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9103612A SE9103612D0 (sv) | 1991-12-04 | 1991-12-04 | New peptide derivatives |
PCT/SE1992/000832 WO1993011152A1 (fr) | 1991-12-04 | 1992-12-01 | Nouveaux derives de peptides |
Publications (3)
Publication Number | Publication Date |
---|---|
NO942066D0 NO942066D0 (no) | 1994-06-03 |
NO942066L NO942066L (no) | 1994-06-03 |
NO311361B1 true NO311361B1 (no) | 2001-11-19 |
Family
ID=20384531
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO19942066A NO311361B1 (no) | 1991-12-04 | 1994-06-03 | Peptidderivater, fremgangsmåte for fremstilling, farmasöytisk preparat og anvendelse av peptidderivatene |
Country Status (27)
Country | Link |
---|---|
US (4) | US5614499A (fr) |
EP (1) | EP0618926B1 (fr) |
JP (1) | JP3306826B2 (fr) |
CN (1) | CN1076199A (fr) |
AP (1) | AP353A (fr) |
AT (1) | ATE190066T1 (fr) |
AU (2) | AU670052B2 (fr) |
CA (1) | CA2125175C (fr) |
CZ (2) | CZ333895A3 (fr) |
DE (1) | DE69230727T2 (fr) |
EE (1) | EE9400455A (fr) |
FI (1) | FI115770B (fr) |
HU (1) | HUT70431A (fr) |
IL (1) | IL103910A0 (fr) |
IS (1) | IS3954A (fr) |
MA (1) | MA22729A1 (fr) |
MX (1) | MX9206938A (fr) |
NO (1) | NO311361B1 (fr) |
NZ (2) | NZ280762A (fr) |
SE (1) | SE9103612D0 (fr) |
SI (1) | SI9200363A (fr) |
SK (1) | SK63194A3 (fr) |
TN (1) | TNSN92109A1 (fr) |
TW (1) | TW223078B (fr) |
WO (1) | WO1993011152A1 (fr) |
YU (1) | YU104592A (fr) |
ZA (1) | ZA929099B (fr) |
Families Citing this family (73)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5583146A (en) * | 1992-12-02 | 1996-12-10 | Bristol-Myers Squibb Company | Heterocyclic thrombin inhibitors |
US6534536B1 (en) | 1994-03-16 | 2003-03-18 | Bristol-Myers Squibb Company | Alkylsulfonamido heterocyclic thrombin inhibitors |
SE9900043D0 (sv) * | 1999-01-11 | 1999-01-11 | Astra Ab | New use |
US6984627B1 (en) | 1993-06-03 | 2006-01-10 | Astrazeneca Ab | Peptide derivatives |
SE9301916D0 (sv) * | 1993-06-03 | 1993-06-03 | Ab Astra | New peptides derivatives |
EP0648780A1 (fr) * | 1993-08-26 | 1995-04-19 | Bristol-Myers Squibb Company | Inhibiteurs hétérocycliques de thrombine |
GB9318637D0 (en) * | 1993-09-08 | 1993-10-27 | Ferring Res Ltd | Enzyme inhibitors |
US5602101A (en) * | 1994-03-04 | 1997-02-11 | Eli Lilly And Company | Antithrombotic agents |
US5707966A (en) * | 1994-03-04 | 1998-01-13 | Eli Lilly And Company | Antithrombotic agents |
US5885967A (en) * | 1994-03-04 | 1999-03-23 | Eli Lilly And Company | Antithrombotic agents |
US5439888A (en) * | 1994-03-04 | 1995-08-08 | Eli Lilly And Company | Antithrombotic agents |
ZA951618B (en) * | 1994-03-04 | 1996-08-27 | Lilly Co Eli | Antithrombotic agents |
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 |
ZA951617B (en) * | 1994-03-04 | 1997-02-27 | Lilly Co Eli | Antithrombotic agents. |
US5484772A (en) * | 1994-03-04 | 1996-01-16 | Eli Lilly And Company | Antithrombotic agents |
US5488037A (en) * | 1994-03-04 | 1996-01-30 | Eli Lilly And Company | Antithrombotic agents |
US5691356A (en) * | 1994-03-21 | 1997-11-25 | Bristol-Myers Squibb Company | Disubstituted heterocyclic thrombin inhibitors |
US5681844A (en) * | 1994-04-18 | 1997-10-28 | Corvas International, Inc. | Methionine sulfone and s-substituted cysteine sulfone derivatives as enzyme inhibitors |
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 |
DE4436772A1 (de) * | 1994-10-14 | 1996-04-18 | Boehringer Mannheim Gmbh | Neues Dipeptid-Derivat, Verfahren zu seiner Herstellung sowie diese Verbindung enthaltende Arzneimittel |
SE504185C2 (sv) * | 1994-11-08 | 1996-12-02 | Astra Ab | Lagringsstabil vattenlösning för infusion av trombininhibitorer |
SE9404196D0 (sv) * | 1994-12-02 | 1994-12-02 | Astra Ab | New antithrombotic formulation |
DE4443390A1 (de) * | 1994-12-06 | 1996-06-13 | Basf Ag | Neue dipeptidische p-Amidinobenzylamide mit N-terminalen Sulfonyl- bzw. Aminosulfonylresten |
SK104697A3 (en) * | 1995-02-17 | 1998-11-04 | Basf Ag | Novel dipeptide amidines as thrombin inhibitors |
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 |
DE19512484A1 (de) | 1995-04-04 | 1996-10-17 | Bayer Ag | Kohlenhydratmodifizierte Cytostatika |
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 |
SE9600216D0 (sv) * | 1996-01-18 | 1996-01-18 | Hans Arne Hansson | Styrning av läkningsprocesser |
CA2200163A1 (fr) * | 1996-03-22 | 1997-09-22 | Michael Robert Wiley | Diamides antithrombotiques |
US5811402A (en) * | 1996-03-22 | 1998-09-22 | Eli Lilly And Company | Antithrombotic diamides |
SE9602263D0 (sv) | 1996-06-07 | 1996-06-07 | Astra Ab | New amino acid derivatives |
AU3496297A (en) * | 1996-06-25 | 1998-01-14 | Eli Lilly And Company | Anticoagulant agents |
US6200967B1 (en) | 1996-06-25 | 2001-03-13 | Eli Lilly And Company | Anticoagulant agents |
SE9602646D0 (sv) | 1996-07-04 | 1996-07-04 | Astra Ab | Pharmaceutically-useful compounds |
SE9603724D0 (sv) * | 1996-10-11 | 1996-10-11 | Astra Ab | New pharmaceutical parenteral formulation of a thrombin inhibitor |
US5877156A (en) * | 1997-04-24 | 1999-03-02 | Akzo Nobel, N.V. | Thrombin inhibitors |
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 |
SE9704543D0 (sv) | 1997-12-05 | 1997-12-05 | Astra Ab | New compounds |
HUP0100082A3 (en) | 1998-01-26 | 2001-12-28 | Abbott Gmbh & Co Kg | Thrombin inhibitor, peptide derivatives, pharmaceutical compositions comprising thereof and their use |
JP2003529528A (ja) * | 1998-04-24 | 2003-10-07 | 3−ディメンショナル ファーマシューティカルズ, インコーポレイテッド | プロテアーゼインヒビターとしてのアミノ酸アミジノヒドラゾン、アルコキシグアニジン、およびアミノグアニジン |
SE9802938D0 (sv) | 1998-09-01 | 1998-09-01 | Astra Ab | Improved stability for injection solutions |
SE9802973D0 (sv) | 1998-09-03 | 1998-09-03 | Astra Ab | Immediate release tablet |
SE9804313D0 (sv) | 1998-12-14 | 1998-12-14 | Astra Ab | New compounds |
TR200102037T2 (tr) | 1999-01-13 | 2001-10-22 | Astrazeneca Ab | Yeni amidinobenzilamin türevleri ve trombin engelleyiciler olarak kullanılmaları. |
KR20000060566A (ko) * | 1999-03-17 | 2000-10-16 | 이경하 | 치환된 방향족 아미딘 유도체 및 이를 함유하는 의약조성물 |
AR023510A1 (es) | 1999-04-21 | 2002-09-04 | Astrazeneca Ab | Un equipo de partes, formulacion farmaceutica y uso de un inhibidor de trombina. |
AR023819A1 (es) * | 1999-05-03 | 2002-09-04 | Astrazeneca Ab | FORMULACIoN FARMACEUTICA, KIT DE PARTES Y UTILIZACION DE DICHA FORMULACION |
US6290662B1 (en) * | 1999-05-28 | 2001-09-18 | John K. Morris | Portable, self-contained apparatus for deep vein thrombosis (DVT) prophylaxis |
SE9902202D0 (sv) * | 1999-06-10 | 1999-06-10 | Astra Ab | Production of aggregates |
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 |
JP2002155086A (ja) * | 2000-11-16 | 2002-05-28 | Ube Ind Ltd | 7a−アルコキシ−4H−ピラノ[3,2−d]−オキサゾール−2(3H)−オン類、及びその製造法 |
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 |
AR034517A1 (es) | 2001-06-21 | 2004-02-25 | Astrazeneca Ab | Formulacion farmaceutica |
SE0201659D0 (sv) | 2002-05-31 | 2002-05-31 | Astrazeneca Ab | Modified release pharmaceutical formulation |
SE0201661D0 (sv) | 2002-05-31 | 2002-05-31 | Astrazeneca Ab | New salts |
US7332227B2 (en) * | 2003-03-14 | 2008-02-19 | Becton, Dickinson And Company | Non-volatile lubricant system for medical devices |
US7641623B2 (en) | 2003-04-11 | 2010-01-05 | Hill-Rom Services, Inc. | System for compression therapy with patient support |
US7795205B2 (en) | 2004-04-12 | 2010-09-14 | Canyon Pharmaceuticals, Inc. | Methods for effecting regression of tumor mass and size in a metastasized pancreatic tumor |
GB0507577D0 (en) | 2005-04-14 | 2005-05-18 | Novartis Ag | Organic compounds |
US8070678B2 (en) * | 2005-10-05 | 2011-12-06 | Gurbel Paul A | Detection of restenosis risk in patients receiving a stent by measuring the characteristics of blood clotting including the measurement of maximum thrombin-induced clot strength |
TW200827336A (en) | 2006-12-06 | 2008-07-01 | Astrazeneca Ab | New crystalline forms |
CN102924567B (zh) * | 2008-10-28 | 2014-06-04 | 上海医药工业研究院 | 一类肽化合物、其制备方法及用途 |
CN102464701B (zh) | 2010-11-08 | 2015-10-21 | 上海医药工业研究院 | 一类新型化合物、其制备方法及用途 |
WO2012171984A1 (fr) * | 2011-06-16 | 2012-12-20 | Lonza Ltd | Procédé pour l'extraction de peptides et son application en synthèse peptidique en phase liquide |
US9737454B2 (en) | 2012-03-02 | 2017-08-22 | Hill-Rom Services, Inc. | Sequential compression therapy compliance monitoring systems and methods |
EP3207911B1 (fr) | 2016-02-18 | 2019-04-03 | Hill-Rom Services, Inc. | Dispositif de support pour patient doté d'un dispositif de compression de membre intégré |
RU2712194C1 (ru) * | 2019-10-02 | 2020-01-27 | Федеральное государственное бюджетное учреждение "Государственный научно-исследовательский институт генетики и селекции промышленных микроорганизмов Национального исследовательского центра "Курчатовский институт" (НИЦ "Курчатовский институт" - ГосНИИгенетика) | Антикоагулянтное лекарственное средство, представляющее собой синтетический дипептид Ac-Trp-Arg-Pip ⋅HCl, фармацевтическая композиция, включающая это антикоагулянтное лекарственное средство |
Family Cites Families (15)
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 |
US4568636A (en) * | 1981-03-25 | 1986-02-04 | Pentapharm Ag | Tripeptide derivatives |
US4395401A (en) * | 1981-09-09 | 1983-07-26 | Smithkline Beckman Corporation | Renally active dipeptides |
DE3505555A1 (de) * | 1985-02-18 | 1986-09-11 | Behringwerke Ag, 3550 Marburg | Neue oligopeptidylargininolderivate und deren homologe, verfahren zu deren herstellung, deren verwendung und diese enthaltende mittel |
US4906659A (en) * | 1985-06-18 | 1990-03-06 | Takeda Chemical Industries, Ltd. | Antibiotic tan-749, its derivatives, production and use thereof |
DE3606480A1 (de) * | 1986-02-28 | 1987-09-03 | Behringwerke Ag | Oligopeptidylnitrilderivate, diese enthaltende mittel, verfahren zu ihrer herstellung und ihre verwendung |
US5187157A (en) * | 1987-06-05 | 1993-02-16 | Du Pont Merck Pharmaceutical Company | Peptide boronic acid inhibitors of trypsin-like proteases |
US5037819A (en) * | 1990-06-04 | 1991-08-06 | Bristol-Myers Squibb Company | Azetidin-2-one derivatives as serine protease inhibitors |
US5110812A (en) * | 1990-06-04 | 1992-05-05 | Bristol-Myers Squibb Co. | Azetidin-2-one derivatives as serine protease inhibitors |
TW201303B (fr) * | 1990-07-05 | 1993-03-01 | Hoffmann La Roche | |
GB9019558D0 (en) * | 1990-09-07 | 1990-10-24 | Szelke Michael | Enzyme inhibitors |
GB9024129D0 (en) * | 1990-11-06 | 1990-12-19 | Thrombosis Research Trust | Inhibitors and substrates of thrombin |
EP0503203A1 (fr) * | 1991-03-15 | 1992-09-16 | Merrell Dow Pharmaceuticals Inc. | Nouveaux inhibiteurs de la thrombine |
SE9102462D0 (sv) * | 1991-08-28 | 1991-08-28 | Astra Ab | New isosteric peptides |
ZA928581B (en) * | 1991-11-12 | 1994-05-06 | Lilly Co Eli | Antithrombotic agents |
-
1991
- 1991-12-04 SE SE9103612A patent/SE9103612D0/xx unknown
-
1992
- 1992-11-24 TW TW081109412A patent/TW223078B/zh active
- 1992-11-24 ZA ZA929099A patent/ZA929099B/xx unknown
- 1992-11-27 IL IL103910A patent/IL103910A0/xx unknown
- 1992-12-01 CZ CZ953338A patent/CZ333895A3/cs unknown
- 1992-12-01 SK SK631-94A patent/SK63194A3/sk unknown
- 1992-12-01 AT AT92924993T patent/ATE190066T1/de not_active IP Right Cessation
- 1992-12-01 EP EP92924993A patent/EP0618926B1/fr not_active Expired - Lifetime
- 1992-12-01 DE DE69230727T patent/DE69230727T2/de not_active Expired - Lifetime
- 1992-12-01 NZ NZ280762A patent/NZ280762A/en not_active IP Right Cessation
- 1992-12-01 CZ CZ941296A patent/CZ129694A3/cs unknown
- 1992-12-01 JP JP51005393A patent/JP3306826B2/ja not_active Expired - Fee Related
- 1992-12-01 HU HU9401474A patent/HUT70431A/hu unknown
- 1992-12-01 WO PCT/SE1992/000832 patent/WO1993011152A1/fr active IP Right Grant
- 1992-12-01 AU AU31209/93A patent/AU670052B2/en not_active Ceased
- 1992-12-01 NZ NZ246106A patent/NZ246106A/en not_active IP Right Cessation
- 1992-12-01 CA CA002125175A patent/CA2125175C/fr not_active Expired - Fee Related
- 1992-12-02 MX MX9206938A patent/MX9206938A/es unknown
- 1992-12-02 MA MA23019A patent/MA22729A1/fr unknown
- 1992-12-02 US US07/984,884 patent/US5614499A/en not_active Expired - Lifetime
- 1992-12-03 IS IS3954A patent/IS3954A/is unknown
- 1992-12-03 TN TNTNSN92109A patent/TNSN92109A1/fr unknown
- 1992-12-04 AP APAP/P/1992/000457A patent/AP353A/en active
- 1992-12-04 CN CN92115304A patent/CN1076199A/zh active Pending
- 1992-12-04 SI SI19929200363A patent/SI9200363A/sl unknown
- 1992-12-04 YU YU104592A patent/YU104592A/sh unknown
-
1994
- 1994-06-03 FI FI942645A patent/FI115770B/fi not_active IP Right Cessation
- 1994-06-03 NO NO19942066A patent/NO311361B1/no not_active IP Right Cessation
- 1994-11-23 EE EE9400455A patent/EE9400455A/xx unknown
-
1995
- 1995-06-07 US US08/484,426 patent/US5747460A/en not_active Expired - Lifetime
- 1995-06-07 US US08/480,818 patent/US5955433A/en not_active Expired - Fee Related
- 1995-06-07 US US08/481,810 patent/US5736521A/en not_active Expired - Lifetime
-
1996
- 1996-04-12 AU AU50616/96A patent/AU683793B2/en not_active Ceased
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