EP1529035A1 - Kristallines (r) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1 (pyrrolidinocarbonyl)-ethyl]-benzimidazol sowie dessen verwendung als antithrombosemittel - Google Patents
Kristallines (r) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1 (pyrrolidinocarbonyl)-ethyl]-benzimidazol sowie dessen verwendung als antithrombosemittelInfo
- Publication number
- EP1529035A1 EP1529035A1 EP03735629A EP03735629A EP1529035A1 EP 1529035 A1 EP1529035 A1 EP 1529035A1 EP 03735629 A EP03735629 A EP 03735629A EP 03735629 A EP03735629 A EP 03735629A EP 1529035 A1 EP1529035 A1 EP 1529035A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- methyl
- pyrrolidinocarbonyl
- benzimidazole
- ethyl
- amidinophenylaminomethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/14—Radicals substituted by nitrogen atoms
-
- 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
- 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
-
- 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
Definitions
- the present invention relates to the crystalline forms of the compounds (r?) - 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - (carboxymethylamino) -l - (pyrrolidinocarbonyl) ethyl] benzimidazole and its Monohydrochloride, process for its preparation and its use as a medicament.
- an antithrombotic effect which is based, for example, on a thrombin-inhibiting or factor Xa-inhibiting effect.
- venous thrombosis in various vascular provinces, including deep and superficial leg vein thrombosis, vena cava thrombosis, thrombosis of the renal and hepatic veins including a "veno-occlusive disease", for the prevention and therapy of pulmonary embolism, for the treatment of patients with all forms of coronary artery disease, including the acute form in the sense
- Benzimidazoles mentioned can be used to treat patients undergoing renal replacement therapy.
- patients with chronic kidney failure and patients with acute kidney failure should be treated regardless of the cause of the kidney failure.
- This also includes the prevention and treatment of the closure of the dialysis shunt.
- examples of these parameters are the stability of action of the starting material under various environmental conditions, the stability during the course of the preparation of the pharmaceutical formulation and the stability in the final compositions of the drug.
- the active pharmaceutical ingredient used to produce the pharmaceutical compositions should therefore have a high level of stability, which must also be ensured under various environmental conditions. This is imperative in order to prevent pharmaceutical compositions from being used which, in addition to the actual active ingredient, contain, for example, degradation products thereof. In such a case, an active substance content found in pharmaceutical formulations could be lower than specified.
- the absorption of moisture reduces the drug content due to the weight gain caused by water absorption.
- Drugs with a tendency to moisture must be protected from moisture during storage, for example by adding suitable desiccants or by storing the medicine in an environment protected from moisture.
- the absorption of moisture can reduce the drug content during manufacture if the drug is exposed to the environment without any protection from moisture.
- a drug active ingredient should therefore preferably be only slightly hygroscopic.
- solubility of the active ingredient Another criterion, which depending on the choice of formulation or the choice of the manufacturing process of the formulation may be of outstanding importance, is the solubility of the active ingredient. If, for example, drug solutions (for example for infusions) are provided, sufficient solubility of the active ingredient in physiologically compatible solvents is indispensable. Sufficient solubility of the active ingredient is also of great importance for drugs to be administered orally.
- the object of the present invention is to provide a drug substance which is not only characterized by a high pharmacological activity, but which also meets the above-mentioned physicochemical requirements in the best possible way.
- the monohydrochloride according to the invention is characterized by a high degree of stability and is very readily soluble in physiologically compatible solvents.
- Table 1 X-ray powder reflections and intensities (normalized) of the (r?) - 2- (4-amidino-phenylaminomethyl) -1-methyl-5- [1 - (carboxymethylamino) -l - (pyrrolidinocarbonyl) -ethyl] - benzimidazole monohydrochloride.
- the X-ray powder diagram was recorded in the context of the present invention by means of a Bruker D8 Advanced diffractometer, equipped with a location-sensitive detector (OED) and a Cu anode as X-ray source (CuK ⁇ -
- the crystalline monohydrochloride of the compound (R) -2- (A-amidinophenylaminomethyl) -1-methyl-5- [1 - (carboxymethylamino) -l - (pyrrolidinocarbonyl) ethyl] benzimidazole according to the invention is in the form of hydrates , which contain between 3.0% and 6.5% water depending on the air humidity. Due to its structure, the compound is capable of absorbing and releasing crystal water without the crystal structure changing fundamentally.
- the monohydrochloride according to the invention forms solvates with organic solvents, for example with ethanol.
- a second subject of the present invention relates to a production process for the preparation of the crystalline salt (R) -2- (4-amidinophenylamino-D methyl) -1-methyl-5- [1 - (carboxymethylamino) -l - (pyrrolidinocarbonyl) -ethyl ] -benzimidazole monohydrochloride, comprising the following steps:
- the alkylation of the free primary amino group takes place, for example, with 1 to 1.5 equivalents, preferably with about 1.2 equivalents, of a compound of the general formula
- R is a C 3 alkyl group and X is a leaving group, for example a halogen atom such as chlorine, bromine or iodine atom, which mean p-toluenesulfonyl or methanesulfonyl group
- ethyl bromoacetate or n-propyl bromoacetic acid esters are preferably used in an organic solvent or solvent mixture in the presence of a base.
- suitable solvents are ethyl acetate, ⁇ -propyl acetate (n-propyl acetate), ⁇ / -methylpyrrolidinone, dimethylformamide, dimethylacetamide or mixtures thereof.
- a solvent mixture consisting of ⁇ / -methylpyrrolidinone and ethyl acetate or n-propyl acetate is preferably used.
- tertiary amines such as diisopropylethylamine (Hünig base) or triethylamine are used as the base in an amount of 1 to 2.5 equivalents.
- the reaction is preferably carried out at temperatures between 0 ° C. and the boiling point of the solvent mixture, approximately between 0 ° C. and 150 ° C., preferably between 10 ° C. and 30 ° C.
- the concentrated solution of the crude compound of the formula (IV) obtained in step (b) is dissolved in a C 3 -3 alcohol as solvent and by introducing hydrogen chloride gas with cooling, preferably at a temperature below about 20 ° C. as an intermediate to the imino ester implemented.
- hydrogen chloride gas preferably at a temperature below about 20 ° C.
- alcohol, methanol, ethanol or n-propanol are used as alcohol, the choice of solvent depending on the ester of formula (IV) used.
- the reaction mixture is stirred at a temperature between 0 ° C. and 30 ° C., preferably at about 20 ° C., until the reaction is complete.
- R denotes a C -3 alkyl group
- the compound (V) can be isolated as an intermediate in the form of the hydrochloride or directly as p-toluenesulfonic acid salts of the general formula (VI) (see step c).
- 5- [1- (n-C ⁇ - 3 -alkyloxycarbonylmethylamino) -1 - (pyrrolidinocarbonyl) ethyl] benzimidazole of the general formula (V) is carried out according to the invention in the form of sulfonic acid salts, for example in the form of the benzene, p-toluene, p-chlorobenzene, 1- or 2-naphthol-sulfonic acid salts, particularly preferably in the form of the p- Toluenesulfonic acid salts of the general formula (VI),
- R is a C -3 alkyl group, and allows easy isolation of the compound from aqueous media.
- the p-toluenesulfonic acid salts of the compounds of the general formula (VI) are purified further by pH-controlled dissolution and precipitation of the salt in an aqueous medium or by suspension in water.
- solvents are alcohols such as methanol, ethanol, / -propanol or polar solvents such as N- Methylpyrrolidinone or dimethylformamide, preferably methanol and ethanol, in
- sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide are considered.
- the reaction mixture can then be warmed and thus the progress of the reaction mixture
- reaction can be accelerated.
- the reaction mixture is preferably used under good conditions
- the maximum selectable temperature depends on the boiling point of the solvent used, preferably at temperatures between 30 ° C and 80 ° C.
- Acid preferably p-toluenesulfonic acid, added.
- the desired product of the formula (VII) is obtained directly on crystallization. If potassium hydroxide is used as the base, the potassium salt of p-toluenesulfonic acid first crystallizes. The desired product of formula (VII) can then be crystallized.
- the base (VII) obtained in step (d) is suspended or dissolved in a suitable organic solvent or solvent mixture.
- suitable organic solvent or solvent mixture particularly preferred solvents are methanol, ethanol, n-propanol, / -propanol, acetone, dimethylformamide or ⁇ / -methylpyrrolidinone.
- a certain amount of water can be added as a cosolvent.
- the reaction mixture is heated to a temperature between 20 ° C and the reflux temperature of the solvent, preferably between 30 ° C and 80 ° C.
- hydrogen chloride dissolved in an organic solvent or hydrochloric acid is added to the solution or suspension.
- a third object of the present invention relates to crystalline (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - (carboxymethylamino) -l - (pyrrolidinocarbonyl) ethyl] -benzimidazole monohydrochloride, obtainable according to method described above.
- a fourth object of the present invention is due to the pharmaceutical activity of the crystalline monohydrochloride according to the invention of the compound (A?) - 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - (carboxymethylamino) -l - (pyrrolidinocarbonyl) -ethyl] -benzimidazole its use as a medicine.
- a fifth object of the present invention is thus the p-toluenesulfonic acid salts of the general formula (VI):
- the crystalline form of the free base (r?) - 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole is the direct precursor for the preparation of the monohydrochloride of formula (I) and also has the pharmacological activity described above.
- the X-ray powder diagram was recorded in the context of the present invention by means of a Bruker D8 Advanced diffractometer, equipped with a location-sensitive detector (OED) and a Cu anode as X-ray source (CuK ⁇ -
- Another object of the invention is due to the pharmaceutical activity of the crystalline base according to the invention (r?) - 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - (carboxymethylamino) -1 - (pyrrolidinocarbonyl) ethyl] benzimidazole their use as medicines.
- aqueous phase is separated off.
- the aqueous phase is separated off.
- 3.5 L of water and 105 g of sodium chloride are added to the organic phase with stirring.
- the aqueous phase is separated off.
- the organic phase is evaporated under reduced pressure on a rotary evaporator. 0.9 L of n-propyl acetate and 3.5 L of n-propanol are added to the oil obtained. 3 L of solvent are distilled off under reduced pressure.
- the pressure filter is washed with 3.5 L hot n-propanol. 8.8 L of solvent are distilled off from the filtrate in a rotary evaporator under reduced pressure. The remaining residue is suspended with 7 L acetone while heating to reflux. The suspension is cooled to 0 ° C. and stirred at this temperature for one hour. The suspension is filtered off and washed with 2.8 L acetone. The filter cake is dried in a forced-air drying cabinet at 50 ° C.
- Example 2 Instructions for the preparation of the free base by ester cleavage with sodium hydroxide starting from the p-toluenesulfonic acid salt of the n-propyl ester
- Example 3 Instructions for the preparation of the free base by ester cleavage with sodium hydroxide starting from the hydrochloride salt of the n-propyl ester
- the product obtained in this way can be crystallized from methanol.
- Example 6 Instructions for the preparation of the free base by ester cleavage with 5 potassium hydroxide starting from the p-toluenesulfonic acid salt of
- the precipitated product is suctioned off under argon, washed with 3.7 L of methanol and returned to the reactor in a moist state. 18.5 L of methanol are added and the suspension is refluxed for one hour and cooled to 22 ° C.
- the product is suctioned off under argon, washed with 3.7 L of methanol and dried at 30 ° C. in a forced-air drying cabinet.
- Example 7 Instructions for the precipitation of the monohydrochloride from ethanol
- the filtrate is heated to 70 ° C. A solution of 0.802 mL conc. Hydrochloric acid in 25 mL ethanol and then another 25 mL ethanol. The mixture is cooled to 25 ° C. and stirred at this temperature for one hour. The product is filtered off, washed with 15 mL ethanol and dried in a forced-air drying cabinet.
- FIG. 1 shows the X-ray powder diffractogram of the crystalline monohydrochloride of the compound (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - (carboxymethylamino) - 1 - (pyrrolidinocarbonyl) -ethyl] -benzimidazole.
- FIG. 2 shows the X-ray powder diffractogram of the crystalline compound (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1 - (carboxymethylamino) -l - (pyrrolidinocarbonyl) ethyl] benzimidazole.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10227666A DE10227666A1 (de) | 2002-06-20 | 2002-06-20 | (R)-2-(4-Amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)- ethyl]-benzimidazol, dessen Monohydrochlorid, Verfahren zu deren Herstellung sowie Verwendung als Arzneimittel |
DE10227666 | 2002-06-20 | ||
PCT/EP2003/006317 WO2004000818A1 (de) | 2002-06-20 | 2003-06-16 | Kristallines (r)-2-(4-amidinophenylaminomethyl)-1-methyl-5-(1-(carboxymethylamino)-1(pyrrolidinocarbonyl)-ethyl)-benzimidazol sowie dessen verwendung als antithrombosemittel |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1529035A1 true EP1529035A1 (de) | 2005-05-11 |
Family
ID=29719306
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP03735629A Withdrawn EP1529035A1 (de) | 2002-06-20 | 2003-06-16 | Kristallines (r) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1 (pyrrolidinocarbonyl)-ethyl]-benzimidazol sowie dessen verwendung als antithrombosemittel |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP1529035A1 (ja) |
JP (1) | JP2006508037A (ja) |
AR (1) | AR040445A1 (ja) |
AU (1) | AU2003237945A1 (ja) |
CA (1) | CA2485545A1 (ja) |
DE (1) | DE10227666A1 (ja) |
TW (1) | TW200413329A (ja) |
UY (1) | UY27856A1 (ja) |
WO (1) | WO2004000818A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2822350A1 (en) | 2010-12-21 | 2012-06-28 | The Medicines Company (Leipzig) Gmbh | Trypsin-like serine protease inhibitors, their preparation and use as selective inhibitors of the clotting factors iia and xa |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI248435B (en) * | 1998-07-04 | 2006-02-01 | Boehringer Ingelheim Pharma | Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions |
DE19962329A1 (de) * | 1999-12-23 | 2001-06-28 | Boehringer Ingelheim Pharma | Benzimidazole, deren Herstellung und deren Verwendung als Arzneimittel |
-
2002
- 2002-06-20 DE DE10227666A patent/DE10227666A1/de not_active Withdrawn
-
2003
- 2003-06-16 CA CA002485545A patent/CA2485545A1/en not_active Abandoned
- 2003-06-16 EP EP03735629A patent/EP1529035A1/de not_active Withdrawn
- 2003-06-16 JP JP2004514726A patent/JP2006508037A/ja active Pending
- 2003-06-16 WO PCT/EP2003/006317 patent/WO2004000818A1/de active Application Filing
- 2003-06-16 AU AU2003237945A patent/AU2003237945A1/en not_active Abandoned
- 2003-06-18 UY UY27856A patent/UY27856A1/es not_active Application Discontinuation
- 2003-06-19 TW TW092116667A patent/TW200413329A/zh unknown
- 2003-06-20 AR AR20030102210A patent/AR040445A1/es not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO2004000818A1 * |
Also Published As
Publication number | Publication date |
---|---|
TW200413329A (en) | 2004-08-01 |
AR040445A1 (es) | 2005-04-06 |
JP2006508037A (ja) | 2006-03-09 |
DE10227666A1 (de) | 2004-01-08 |
WO2004000818A1 (de) | 2003-12-31 |
AU2003237945A1 (en) | 2004-01-06 |
CA2485545A1 (en) | 2003-12-31 |
UY27856A1 (es) | 2003-12-31 |
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