WO2000005207A1 - Substituierte phenylamidine mit antithrombotischer wirkung - Google Patents
Substituierte phenylamidine mit antithrombotischer wirkung Download PDFInfo
- Publication number
- WO2000005207A1 WO2000005207A1 PCT/EP1999/005161 EP9905161W WO0005207A1 WO 2000005207 A1 WO2000005207 A1 WO 2000005207A1 EP 9905161 W EP9905161 W EP 9905161W WO 0005207 A1 WO0005207 A1 WO 0005207A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenyl
- salts
- general formula
- ethyl
- methyl
- Prior art date
Links
Classifications
-
- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
- 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
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/49—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton
- C07C211/50—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton with at least two amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
Definitions
- Phenylamidines of the general formula fall within the scope of protection of WO 96/33970
- R 1 is a C 1 . 4 alkyloxycarbonyl group, an aryl C 1 . 3- alkyloxycarbonyl group or a group of the formula
- R a is a hydrogen atom or an alkyl group
- ⁇ Ü ° represent an alkyl group or a 3- to 7-membered cycloalkyl group, means, with no such compound expressis verbis described in this published application.
- R 6 is a C 1-6 alkyloxycarbonyl or phenyl C 1-4 alkyloxycarbonyl group
- R 7 is a hydrogen atom, a C 4 _ 7 cycloalkyl, phenyl-C- 4 alkyl or R 8 -CO-OCHR 9 group in which
- R e a C-. 4 -alkyl-, C 1 . 4 -alkoxy-, C 3 . 7- cycloalkyl or C 4 _ 7 -cycloalkoxy group and
- R 9 represents a hydrogen atom or a C 1 _ i alkyl group
- the present invention relates to the compounds of the general formula I above, their tautomers, their stereoisomers and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, medicaments containing these compounds, their use and process for their preparation.
- the substituted amidino group is in the 4-position, in particular those compounds in which R 6 -alkyloxycar- bonylrios a C "18 alkyloxycarbonyl or phenyl-C 1 _ 4, and
- R 7 is a hydrogen atom, a C ⁇ -Alky! -, C 5 . 7 denotes cycloalkyl or phenyl-C 1-4 alkyl group,
- R 6 is a C 1 . 12 alkyloxycarbonyl or phenyl-C-. 2 -alkyloxycarbonyl group and
- R 7 is a C- B alkyl or C 5 . 7 -cycloalkyl group
- R 6 is a C 5 . 12 alkyloxycarbonyl or benzyloxycarbonyl group and
- R 7 is a C 1-4 alkyl or C 5 . 6 -cycloalkyl group
- the new compounds of the general formula I are obtained, for example, by the following process:
- R 6 is as defined in the introduction, with a compound of the general formula
- R 7 is as defined in the introduction, or its reactive
- Reactive derivatives of a compound of general formula III include, for example, their acid chlorides, acid azides, mixed anhydrides with aliphatic or aromatic carboxylic acids or carbonic acid monoesters, their imidazolides and their esters such as their alkyl, aryl and aralkyl esters such as the methyl, ethyl, isopropyl, pentyl, phenyl, nitrophenyl or benzyl ester.
- the reaction is advantageously carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, dimethylsulfoxide, benzene, toluene, chlorobenzene, tetrahydrofuran, pyridine, pyridine / methylene chloride, pyridine / dimethylformamide, benzene / tetrahydrofuran or dioxane, if appropriate in the presence of a dehydrating agent
- a solvent or solvent mixture such as methylene chloride, dimethylformamide, dimethylsulfoxide, benzene, toluene, chlorobenzene, tetrahydrofuran, pyridine, pyridine / methylene chloride, pyridine / dimethylformamide, benzene / tetrahydrofuran or dioxane, if appropriate in the presence of a dehydrating agent
- a dehydrating agent By means of, for example, in the presence of isobut
- the subsequent conversion of the radical R 7 into a hydrogen atom is advantageously carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof, or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable Solvents such as water, water / methanol, water / ethanol, water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane at temperatures between -10 and 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture.
- an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof
- a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable Solvent
- the compounds of general formula I obtained can optionally be in their enantiomers and / or diastereomers are separated.
- cis / trans mixtures can be separated into their eis and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.
- the cis / trans mixtures obtained can be chromatographed into their eis and trans isomers, the compounds of general formula I obtained which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)) in their optical antipodes and compounds of the general formula I with at least 2 asymmetric carbon atoms due to their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.
- the enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols, and Separation of the diastereomeric salt mixture or derivative obtained in this way, for example on the basis of different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
- an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols
- optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
- (+) - or (-) -Menthol comes as optically active alcohol and as optically active Acyl radical in amides, for example, (+) or (-) menthyloxycarbonyl into consideration.
- the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
- suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
- the new compounds of formula I obtained in this way contain a carboxyl group, they can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
- Suitable bases are, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
- the new phenylamidines of the general formula I and their salts in particular their physiologically tolerable salts with inorganic or organic acids or bases, have valuable properties.
- the new compounds of the general formula I achieve high and long-lasting plasma levels compared to the aggregation-inhibiting compound 4- [2- [(4-amidinophenyl) aminocarbonyl] ethyl] -1-carb- described in WO 96/33970 oxymethyl-piperidine (Compound A) achieved.
- the new phenylamidines of the general formula I and their salts have valuable pharmacological properties, in addition to an anti-inflammatory and bone-depleting effect. special antithrombotic, antiaggregatory and anti-tumor or metastatic effects.
- the concentration of Compound A after oral administration of the compounds of Examples 1 (Compound B) and 1 (1) (Compound C) of the present invention in plasma was determined and compared to the plasma concentration of Compound A after oral administration of Compound A.
- the concentration of compound A in the plasma is measured 4, 8, 12 and 24 hours after substance administration.
- the rhesus plasma is incubated with a suspension of human platelets in plasma and 3 H-BIBU 52 (see DE-A-4, 21, 245) as ligand.
- the free and bound ligand is separated by centrifugation and quantified by scintillation counting.
- the concentration of compound A is calculated from the amount of bound ligand using a calibration curve.
- donor blood is drawn from an anti-cubital vein and anticoagulated with trisodium citrate (final concentration: 13 mmol / 1).
- the blood is centrifuged at 170 x g for 10 minutes and the supernatant platelet-rich plasma (PRP) is removed.
- PRP supernatant platelet-rich plasma
- the residual blood is sharply centrifuged again at 3200 x g and the excess platelet-poor plasma (PPP) is removed.
- the new compounds of general formula I according to the invention and their physiologically tolerable salts are suitable for combating or preventing diseases in which smaller or larger cell aggregates occur or cell matrix interactions play a role, for example in combating or prevention of venous and arterial thrombosis, of cerebrovascular diseases, pulmonary embolism, heart attack, arteriosclerosis, osteoporosis and the metastasis of tumors and the therapy of genetic or acquired disorders of the interactions of cells with one another or with solid structures.
- These are also suitable for Accompanying therapy for thrombolysis with fibrinolytics or vascular interventions such as transluminal angioplasty or also for the therapy of shock conditions, psoriasis, diabetes and inflammation.
- the dose is between 0.1 ⁇ g and 30 mg / kg body weight, preferably 1 ⁇ g to 15 mg / kg body weight, with up to 4 doses per day.
- the compounds of formula I prepared according to the invention optionally in combination with other active substances such as thromboxane receptor antagonists and thromboxane synthesis inhibitors or their combinations, ADP receptor antagonists, clopidogrel, ticopidines, serotonin antagonists, ⁇ receptor antagonists, alkyl nitrates such as glycerol trinitrate, phosphodiesterase inhibitors, prostacyclin and their analogs, fibrinolytics such as tPA, prourokinase, urokinase, streptokinase, or anticoagulants such as heparin, dermatan sulfate, activated protein C, vitamin K antagonists, hirudin, inhibitors of activated clotting factors or other thro
- carboxylic acid chloride instead of the carboxylic acid chloride, the corresponding carboxylic acid is used in the presence of N-methyl-morpholine and 2-chloro-1-methylpyridinium iodide in dimethyl formamide.
- (1), (2) and (3) are mixed and granulated with an aqueous solution of (4).
- (5) is added to the dried granulate mixes. Tablets are pressed from this mixture, biplan with a facet on both sides and a partial notch on one side. Tablet diameter: 12 mm.
- (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
- This powder mixture is filled into size 3 hard gelatin capsules on a capsule filling machine.
- (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
- This powder mixture is filled in a size 0 hard gelatin capsule on a capsule filling machine.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Heart & Thoracic Surgery (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Oncology (AREA)
- Dermatology (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SK105-2001A SK1052001A3 (en) | 1998-07-23 | 1999-07-20 | Substituted phenylamidines with antithrombotic action |
BR9912321-5A BR9912321A (pt) | 1998-07-23 | 1999-07-20 | Fenilamidinas substituìdas, composições farmacêuticas que contém esses compostos e processos para a preparação dos mesmos |
CA002337413A CA2337413A1 (en) | 1998-07-23 | 1999-07-20 | Substituted phenylamidines,pharmaceutical compositions containing these compounds and processes for preparing them |
EEP200100048A EE200100048A (et) | 1998-07-23 | 1999-07-20 | Antitrombootilise toimega asendatud fenüülamidiinid |
EA200100106A EA200100106A1 (ru) | 1998-07-23 | 1999-07-20 | Замещенные фениламидины с антитромботическим действием |
AU52853/99A AU5285399A (en) | 1998-07-23 | 1999-07-20 | Substituted phenylamidines with antithrombotic action |
EP99938296A EP1102746B1 (de) | 1998-07-23 | 1999-07-20 | Substituierte phenylamidine mit antithrombotischer wirkung |
AT99938296T ATE240297T1 (de) | 1998-07-23 | 1999-07-20 | Substituierte phenylamidine mit antithrombotischer wirkung |
DE59905568T DE59905568D1 (de) | 1998-07-23 | 1999-07-20 | Substituierte phenylamidine mit antithrombotischer wirkung |
JP2000561164A JP3629208B2 (ja) | 1998-07-23 | 1999-07-20 | 置換フェニルアミジン、これらの化合物を含む医薬組成物及びそれらの調製方法 |
DK99938296T DK1102746T3 (da) | 1998-07-23 | 1999-07-20 | Substituerede phenylamidiner med antitrombotisk virkning |
PL99345624A PL345624A1 (en) | 1998-07-23 | 1999-07-20 | Substituted phenylamidines with antithrombotic action |
IL14077499A IL140774A0 (en) | 1998-07-23 | 1999-07-20 | Substituted phenylamidines with antithrombotic action |
HU0103327A HUP0103327A3 (en) | 1998-07-23 | 1999-07-20 | Substituted phenylamidines with antithrombotic action |
KR1020017001005A KR20010072046A (ko) | 1998-07-23 | 1999-07-20 | 항혈전 작용을 갖는 치환된 페닐아미딘 |
BG105159A BG105159A (bg) | 1998-07-23 | 2001-01-16 | Заместени фениламидини с антитромботично действие |
NO20010354A NO20010354D0 (no) | 1998-07-23 | 2001-01-22 | Substituerte fenylamidiner med antitrombosevirkning |
HK02100364.6A HK1038750A1 (zh) | 1998-07-23 | 2002-01-17 | 具有抗血栓形成作用的取代的苯基脒 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19833105A DE19833105A1 (de) | 1998-07-23 | 1998-07-23 | Substituierte Phenylamidine, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
DE19833105.3 | 1998-07-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000005207A1 true WO2000005207A1 (de) | 2000-02-03 |
Family
ID=7875009
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1999/005161 WO2000005207A1 (de) | 1998-07-23 | 1999-07-20 | Substituierte phenylamidine mit antithrombotischer wirkung |
Country Status (30)
Country | Link |
---|---|
EP (1) | EP1102746B1 (de) |
JP (1) | JP3629208B2 (de) |
KR (1) | KR20010072046A (de) |
CN (1) | CN1310708A (de) |
AR (1) | AR019462A1 (de) |
AT (1) | ATE240297T1 (de) |
AU (1) | AU5285399A (de) |
BG (1) | BG105159A (de) |
BR (1) | BR9912321A (de) |
CA (1) | CA2337413A1 (de) |
CO (1) | CO5080745A1 (de) |
DE (2) | DE19833105A1 (de) |
DK (1) | DK1102746T3 (de) |
EA (1) | EA200100106A1 (de) |
EE (1) | EE200100048A (de) |
ES (1) | ES2199587T3 (de) |
HK (1) | HK1038750A1 (de) |
HU (1) | HUP0103327A3 (de) |
ID (1) | ID27205A (de) |
IL (1) | IL140774A0 (de) |
NO (1) | NO20010354D0 (de) |
PL (1) | PL345624A1 (de) |
PT (1) | PT1102746E (de) |
SK (1) | SK1052001A3 (de) |
TR (1) | TR200100182T2 (de) |
TW (1) | TW460461B (de) |
UY (1) | UY25621A1 (de) |
WO (1) | WO2000005207A1 (de) |
YU (1) | YU3701A (de) |
ZA (1) | ZA200100363B (de) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001053280A1 (de) * | 2000-01-21 | 2001-07-26 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Substituierte phenylamidine, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
EP2522662A1 (de) * | 2011-05-11 | 2012-11-14 | Medichem, S.A. | Dabigatranetexilat und zugehörige Substanzen, Verfahren und Zusammensetzungen sowie Verwendung der Substanzen als Referenzstandards und Marker |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8399678B2 (en) * | 2009-11-18 | 2013-03-19 | Boehringer Ingelheim International Gmbh | Process for the manufacture of dabigatran etexilate |
CN105330568B (zh) * | 2015-11-27 | 2017-05-10 | 山东省医学科学院药物研究所 | 一种对氨基苯甲脒盐酸盐的制备方法 |
CN105732433A (zh) * | 2016-04-13 | 2016-07-06 | 山东新华制药股份有限公司 | 达比加群酯中间体缩合物的精制方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996033970A1 (de) * | 1995-04-27 | 1996-10-31 | Dr. Karl Thomae Gmbh | Substituierte phenylamidine, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
EP0805149A1 (de) * | 1994-12-01 | 1997-11-05 | Toyama Chemical Co., Ltd. | Neues 2,3-diketopiperazinderivat oder sein salz |
-
1998
- 1998-07-23 DE DE19833105A patent/DE19833105A1/de not_active Withdrawn
-
1999
- 1999-07-19 CO CO99045660A patent/CO5080745A1/es unknown
- 1999-07-20 DK DK99938296T patent/DK1102746T3/da active
- 1999-07-20 ID IDW20010171A patent/ID27205A/id unknown
- 1999-07-20 EP EP99938296A patent/EP1102746B1/de not_active Expired - Lifetime
- 1999-07-20 BR BR9912321-5A patent/BR9912321A/pt not_active IP Right Cessation
- 1999-07-20 SK SK105-2001A patent/SK1052001A3/sk unknown
- 1999-07-20 CN CN99808971A patent/CN1310708A/zh active Pending
- 1999-07-20 PT PT99938296T patent/PT1102746E/pt unknown
- 1999-07-20 TR TR2001/00182T patent/TR200100182T2/xx unknown
- 1999-07-20 KR KR1020017001005A patent/KR20010072046A/ko not_active Application Discontinuation
- 1999-07-20 WO PCT/EP1999/005161 patent/WO2000005207A1/de not_active Application Discontinuation
- 1999-07-20 EE EEP200100048A patent/EE200100048A/xx unknown
- 1999-07-20 AU AU52853/99A patent/AU5285399A/en not_active Abandoned
- 1999-07-20 DE DE59905568T patent/DE59905568D1/de not_active Expired - Fee Related
- 1999-07-20 YU YU3701A patent/YU3701A/sh unknown
- 1999-07-20 HU HU0103327A patent/HUP0103327A3/hu unknown
- 1999-07-20 AT AT99938296T patent/ATE240297T1/de not_active IP Right Cessation
- 1999-07-20 ES ES99938296T patent/ES2199587T3/es not_active Expired - Lifetime
- 1999-07-20 PL PL99345624A patent/PL345624A1/xx not_active Application Discontinuation
- 1999-07-20 JP JP2000561164A patent/JP3629208B2/ja not_active Expired - Fee Related
- 1999-07-20 CA CA002337413A patent/CA2337413A1/en not_active Abandoned
- 1999-07-20 IL IL14077499A patent/IL140774A0/xx unknown
- 1999-07-20 EA EA200100106A patent/EA200100106A1/ru unknown
- 1999-07-21 TW TW088112395A patent/TW460461B/zh not_active IP Right Cessation
- 1999-07-22 UY UY25621A patent/UY25621A1/es not_active Application Discontinuation
- 1999-07-23 AR ARP990103627A patent/AR019462A1/es not_active Withdrawn
-
2001
- 2001-01-12 ZA ZA200100363A patent/ZA200100363B/en unknown
- 2001-01-16 BG BG105159A patent/BG105159A/bg active Pending
- 2001-01-22 NO NO20010354A patent/NO20010354D0/no unknown
-
2002
- 2002-01-17 HK HK02100364.6A patent/HK1038750A1/zh unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0805149A1 (de) * | 1994-12-01 | 1997-11-05 | Toyama Chemical Co., Ltd. | Neues 2,3-diketopiperazinderivat oder sein salz |
WO1996033970A1 (de) * | 1995-04-27 | 1996-10-31 | Dr. Karl Thomae Gmbh | Substituierte phenylamidine, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001053280A1 (de) * | 2000-01-21 | 2001-07-26 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Substituierte phenylamidine, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
US6838460B2 (en) | 2000-01-21 | 2005-01-04 | Boehringer Ingelheim Pharma Kg | Substituted phenylamidines medicaments containing said compounds and method for production thereof |
EP2522662A1 (de) * | 2011-05-11 | 2012-11-14 | Medichem, S.A. | Dabigatranetexilat und zugehörige Substanzen, Verfahren und Zusammensetzungen sowie Verwendung der Substanzen als Referenzstandards und Marker |
WO2012152855A1 (en) * | 2011-05-11 | 2012-11-15 | Medichem S.A. | Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers |
US9086390B2 (en) | 2011-05-11 | 2015-07-21 | Medichem, S.A. | Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers |
Also Published As
Publication number | Publication date |
---|---|
IL140774A0 (en) | 2002-02-10 |
DE59905568D1 (de) | 2003-06-18 |
DK1102746T3 (da) | 2003-09-08 |
PL345624A1 (en) | 2002-01-02 |
ZA200100363B (en) | 2001-07-18 |
CO5080745A1 (es) | 2001-09-25 |
CA2337413A1 (en) | 2000-02-03 |
ATE240297T1 (de) | 2003-05-15 |
ES2199587T3 (es) | 2004-02-16 |
BG105159A (bg) | 2001-07-31 |
AU5285399A (en) | 2000-02-14 |
BR9912321A (pt) | 2001-04-24 |
JP3629208B2 (ja) | 2005-03-16 |
JP2002521363A (ja) | 2002-07-16 |
CN1310708A (zh) | 2001-08-29 |
EP1102746A1 (de) | 2001-05-30 |
AR019462A1 (es) | 2002-02-20 |
EP1102746B1 (de) | 2003-05-14 |
TR200100182T2 (tr) | 2001-07-23 |
SK1052001A3 (en) | 2001-08-06 |
EE200100048A (et) | 2002-06-17 |
NO20010354L (no) | 2001-01-22 |
YU3701A (sh) | 2003-01-31 |
HUP0103327A2 (hu) | 2002-01-28 |
ID27205A (id) | 2001-03-08 |
HUP0103327A3 (en) | 2003-11-28 |
KR20010072046A (ko) | 2001-07-31 |
NO20010354D0 (no) | 2001-01-22 |
DE19833105A1 (de) | 2000-01-27 |
HK1038750A1 (zh) | 2002-03-28 |
UY25621A1 (es) | 2001-12-28 |
TW460461B (en) | 2001-10-21 |
PT1102746E (pt) | 2003-10-31 |
EA200100106A1 (ru) | 2001-08-27 |
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