Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
  • C07C311/49—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom to nitrogen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
  • C07D207/48—Sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
  • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Definitions

• the invention belongs to the field of pharmaceutical industry and relates to novel azaphenylalanine derivatives, procedures for their preparation and pharmaceutical compositions containing them. These novel azaphenylalanine derivatives are useful as anticoagulants.
• Thrombin is a serine protease, which is one of the key enzymes in the processes of blood coagulation and in the development of thrombosis (Edit, J. F.; Allison, P.; Noble, S.; Ashton, J.; Golino, P.; McNard, J.; Buja, L M.; Willerson, J. T., J. Clin. Invest. 1989, 84, 18.).
• thrombin inhibitors should have a selective activity and can be used in oral administration.
• There are reversible and irreversible thrombin antagonists (Kimball, S. D., Curr. Pharm. Design 1995, 1, 441, Das, J.; Kimball, S. D., Bioorg. Med. Chem. 1995, 3, 999, Kimball, S. D., Blood Coagulation and Fibrinolysis 1995, 6, 511, Breznik, M.; Pecar, S., Farm. Vestn. 1997, 48, 545, Leung, D.; Abbenante, G.; Fairlie, D.P., J. Med. Chem. 2000, 43, 305).
• reversible thrombin antagonists derive from peptidomimetically modified structure D-Phe-Pro-Arg.
• the aim of the modification is to provide chemical stability, selectivity and activity.
• the active substance argatroban, described in EP-A-0008746 is clinical in use.
• Napsagatran is a selective reversible inhibitor of thrombin described in EP-A- 0559046.
• Meta substituted phenylalanine derivatives with amide or amidoxime structure are selective thrombin inhibitors disclosed in WO 92/08709.
• Amidinophenylalanine derivatives and aminopyridylalanine derivatives, described in WO 95/13274, have selective antithrombotic activity.
• Azapeptides are peptidomimetics in which the C ⁇ atom is replaced by nitrogen.
• the advantage of this isoelectronic substitution is the preservation of the chemical integrity of the modified amino acid and only a minor conformational modification that is important for the process of molecular identification and stabilization of the complex ligand-receptor and metabolic stabilization (Gante, J., Synthesis 1989, 405, Gante, J., Angew. Chem. 1994, 06, 1780).
• Preparation of N-naphthylsulfonyl amino acids is known (Pendleton.R.G., et al. J. Pharm. Exp. Ther. 1979, 208, 24).
• Azaphenyalanine derivatives are described in WO 02/051824 and in Zega, A.; Mlinsek, G. Sepic, P.; et al. Bioorg. Med. Chem., 2001 ; 9, 2745-2756, Zega, A.; Trampus-Bakija, A.; Fortuna, M.; Stegnar, M.; et al. Pharmazie, 2001, 56, 683-685).
• a low-molecular weight inhibitor DX-9065a exibits high thrombin selectivity and is a bis-amidino derivative (Hara, T.; Yokoyama, A.; Ishihara, H.; et al. Thromb. Haemost. 1994, 71, 314-319. Lately, compounds with only one basic group in their structure have been reported with improved bioavailability (WO 9857951, Yee, Y. K.; Tebbe, A. L; Linebarger, J. H.; J. Med. Chem. 2000, 43, 873-882.
• the object of the present invention is to provide improved new compounds with anticoagulant activity, wherein these compounds are active after oral administration, highly selective and have a low toxicity, a process for the preparation thereof as well as the use of these compounds for the preparation of a pharmaceutical composition.
• the invention relates to novel azaphenylalanine derivatives and analogs thereof of the general formula (I)
• R 1 and Z are H or a residue of the formula
• R 1 and Z are H;
• R 4 H, alkyl (C C 3 ), OH, O-alkyl (CrC 3 ), NH 2;
• R represents a residue of the formula
• R 7 H, alkyl (CrC 3 ), COOR 10 ,
• R 10 H, alkyl (C C 3 ),
• R 8 H, alkyl (C C 3 ), cycloalkyl (Cg-C ⁇ ),
• R 9 H, alkyl (C ⁇ -C 3 ), cycloalkyl (C 3 -C 6 ),
• R 11 H, alkyl (C 1 -C 3 ), benzyl,
• Y NR 12 , O, S,
• R 12 H, COCH3, alkyl (C C 3 );
• R is a residue of the formula
• the invention also relates to their pharmaceutically acceptable salts with an anticoagulant activity and to pharmaceutical compositions containing them.
• the pharmaceutically acceptable salts of the compounds of formula I preferably include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
• acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, hydrobromide, hydrochloride, hydroiodide, lactate, maleate, methanesulfonate,acitinate, nitrate, oxalate, pamoate, 3-phenylpropionate, picrate, pivalate, propionate, pectinate, succinate, sulfate, tartrate, thiocyan
• Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, N-methyl-D-glucamine and salts with amino acids such as arginine, lysine, and so forth.
• the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, dialkylsulfates, and diamylsulfates, long chain halides, aralkyl halides and others. The selection of the inorganic or organic acids or bases should not be restricted by these examples.
• the invention also relates to a process for the preparation of azaphenylalanine derivatives and analogs of the general formula (I).
• R 5 , R 6 and R 7 have the same meanings as in the formula (I), or with triphosgene and amine of the formula (VII or VIII),
• R 2 has the same meaning as in the formula (I).
• R 2 has the same meaning as in the formula (I).
• R 2 in R 3 have the same meanings as in the formula (I).
• the compound (XIII) is converted with an influx of gaseous hydrogen chloride in ethanolic solution, addition of ammonium acetate, followed by another influx of hydrogen chloride to the compound (XV),
• R 4 is hydrogen
• R 5 , R 6 and R 7 have the same meanings as in the formula (I), or with triphosgene and amine of the formula (VII or VIII),
• R 8 in R 9 have the same meanings as in the formula (I), or with triphosgene and amine of the formula (X),
• R has the same meaning as in the formula (I).
• the protecting BOC group in the compound (XXII) is removed with HCI (g) in AcOH at room temperature to obtain the compound (XXIII),
• R 2 has the same meaning as in the formula (I), which reacts with aromatic sulfonylchloride up to the compound (XXIV)
• R ,2 and , r R-»3 have the same meanings as in the formula (I).
• H-N are prepared in analogous way as described above with the sole exception that the starting compound is 3-cyanobenzaldehyde instead of 4-cyanobenzaldehyde.
• the starting compounds may be prepared, unless otherwise directed, according to the procedures described in the literature; e.g., the compound of the formula IV as described by A. Fassler, et. al., J. Med. Chem. 1996, 39, 3203-3215.
• the invention further relates to the use of compounds of the formula I for the production of pharmaceutical compositions used as oral and parenteral anticoagulants e.g. mostly inhibitors of thrombine and dual inhibitors of thrombine and factor Xa. They may be useful in the treatment and prevention of a variety of thrombosis forms: (i) venous thromboembolism due to formation of a thrombus within a vein ⁇ venous thrombosis) associated with acquired (prolonged bedrest, surgery, injury, malignancy, pregnancy and postpartum states) or inherited risk factors (deficiency of natural coagulation inhibitors), obstruction or occlusion of a lung artery by a detached thrombus ⁇ pulmonary embolism), (ii) cardiogenic thromboembolism due to formation of a thrombus in the heart associated with cardiac arrhythmia, heart valve defect, prosthetic heart valves or heart disease, embolism of peripheral arteries caused by a detached thrombus, most commonly in the brain
• the compounds of the formula I may be also used as an adjunct therapy in conjunction with thrombolytic therapy in recent myocardial infarction, in combination with acetylsalicylic acid in patients with unstable angina pectoris designed to undergo percutaneous transluminal angioplasty and in the treatment of patients with thrombosis and with heparin-induced thrombocytopenia.
• the anticoagulants may further be used for the prevention of blood coagulation which is in contact with nonbiological surfaces (vascular prosthesis, vascular stents, prosthetic heart valves, extracorporeal circulation systems, hemodialysis) and in vitro to prevent coagulation in biological samples for testing or storage.
• nonbiological surfaces vascular prosthesis, vascular stents, prosthetic heart valves, extracorporeal circulation systems, hemodialysis
• an object of the present invention is to provide pharmaceutical compositions comprising the compounds of the formula I. They may be formulated as injectable or oral formulations. In addition to the active ingredient they may preferably contain different standard additives depending on the use.
• the pharmaceutical compositions are prepared according to the standard procedures. The preparation may be formulated in such a manner as to permit controlled and sustained release of the active ingredient. Dosage, frequency and mode of administration depend on a variety of factors, they also depend on individual active ingredient and its pharmacokinetic parameters and on patient's condition.
• Thrombin cleaves amide bonds in a synthetic chromogenic substrate wherein yellow coloured p-nitroaniline (p-NA) was released.
• the amount of p-NA produced is directly proportionate to the absorbance measured at a wavelength of 405 nm using a spectrophotometer.
• thrombin inhibitor is added, the amidolytic activity of the enzyme decreases.
• the effect of the inhibitor is expressed by the inhibition constant (Ki).
• Thrombin human thrombin, 308 NIH units, Sigma: the contents of the vial are dissolved in distilled water to give a stock solution of 20 NIH units/ml. The stock solution is pipetted into 0.5 ml aliquots and stored at -70°C. Immediately before use, a working solution of thrombin of 2 NIH units/ml activity is prepared with HBSA buffer. The final concentration of thrombin in a microtiter plate is 0.5 NIH units/ml.
• HBSA buffer, pH 7.5: 10 mM Hepes buffer (HEPES, Sigma), 150 mM NaCI and 0.1% (w/v) bovine serum albumin (98% bovine serum albumin, Sigma) are dissolved in bidistilled water. The pH is adjusted with 0.1 M NaOH solution.
• Inhibitors The inhibitors are dissolved in DMSO to give a 10 mM stock solution. Working solutions (final concentrations within the range 10 to 100 ⁇ M) are prepared with distilled water. The highest concentration of DMSO in a microtiter plate does not exceed 3%. c) Procedure
• Measurements are carried out in the microtiter plate.
• 50 ⁇ l of HBSA buffer, 50 ⁇ l of inhibitor solution of different concentrations (for control 50 ⁇ l of HBSA buffer) and 50 ⁇ l of thrombin solution are pipetted into the wells of a microtiter plate.
• the plate is incubated at a temperature of 25°C for 15 minutes.
• 50 ⁇ L of the chromogenic substrate is added and the microtiter plate is placed in the spectrophotometer (Tecan, Sunrise).
• the absorbance increase at 405 nM is measured at 10-second intervals for a period of 15 minutes at a temperature of 25° C.
• Kj inhibition constant
• Kj is determined according to the principle, described by Cheng and Prusoff (Biochem Pharmacol, 1973). Initial velocities of the reaction in the presence and absence of the inhibitor are measured. The change in the absorbance in the time unit ⁇ v) is calculated from the initial, linear part of the reaction. For competitive inhibitors it holds that v,. _ Konul +S ⁇ M + / ⁇ ,))+s and it follows that
• I inhibitor concentration
• S substrate concentration
• K m Michaelis constant
• v 0 initial velocity of the reaction in the absence of inhibitor
• Vj initial velocity of the reaction in the presence of inhibitor. Measurements are carried out with two concentrations of the inhibitor and two concentrations of the substrate. For each combination of the used concentrations of the substrate and the inhibitor, Kj is calculated and the result is their averaged value.
• the selectivity of inhibitory activity against thrombin is determined with respect to trypsin inhibition which is nonspecific serine protease.
• the inhibitory activity against thrombin is determined as described above. Trypsin inhibition is measured in the same manner as in determination of inhibitory activity for thrombin except that a different chromogenic substrate is used. For both enzymes Kj is calculated. Selectivity of the inhibitor is expressed as a ratio of Kj for trypsin to Kj for thrombin.
• Trypsin (bovine, 6000 BAEE Units/mg protein, Sigma): A stock solution of trypsin with the activity of 300 U/ml is prepared, pipetted into 0.2 ml aliquots and stored at -70°C. Immediately before use, the stock solution is thawed and a working solution of 4 mU/ml is prepared with HBSA buffer. The final trypsin activity in a microtiter plate is 1 mU/ml.
• Chromogenic substrate for trypsin S-2222, Chromogenix, 25 mg
• HBSA buffer, pH 7.5: 10 mM Hepes buffer (HEPES, Sigma), 150 mM NaCI and 0.1% (w/v) bovine serum albumin (98% bovine serum albumin, Sigma) are dissolved in bidistilled water. The pH is adjusted with 0.1 M NaOH solution.
• Inhibitor The inhibitors are dissolved in DMSO to give a 10 mM stock solution. Working solutions (final concentrations in the range from 10 to 600 ⁇ M) are prepared with distilled water. The highest concentration of DMSO in a microtiter plate does not exceed 10%.
• Kj 100 and 50 ⁇ M substrate is used for determination of Kj 100 and 50 ⁇ M substrate. Each measurement is carried out in triplicate and the result is the averaged value of three measurements.
• Kj for thrombin and Kj for trypsin are determined.
• the selectivity is defined as the ratio:
• the selectivity of inhibitory activity against thrombin is determined with respect to inhibition of factor Xa.
• the inhibition is of FXa is measured in the same manner as in measurement of the inhibition of thrombin with chromogenic substrate S2238.
• Kj is calculated.
• Selectivity of the inhibitor is expressed as a ratio of Kj for FXa to Kj for thrombin.
• Factor Xa (Chromogenix, 71 nkat): The contents of the vial are dissolved in distilled water to give a stock solution of 10 nkat ml. The stock solution is pipetted into 0.5 ml aliquots and stored at -20°C. Immediately before use, FXa working solution having the activity of 2 nkat/ml is prepared with HBSA buffer. The final FXa activity in a microtiter plate is 0.5 nkat ml.
• HBSA buffer, pH 7.5 the same as in the method for thrombin.
• Inhibitor The inhibitors are dissolved in DMSO to give a 10 mM stock solution. Working solutions (final concentrations in the range from 5 to 300 ⁇ M) are prepared with distilled water. The highest concentration of DMSO in a microtiter plate does not exceed 3%.
• Kj for thrombin and Ki for FXa are determined.
• the selectivity is defined as a ratio:
• Clotting time of normal pooled plasma is measured by the coagulation assays (thrombin time, activated partial thromboplastin time and prothrombin time) in an coagulometer after addition of different concentrations of the inhibitor. The results are presented as the inhibitor concentration that doubled the clotting time.
• Determination of the thrombin time is used for laboratory monitoring of the treatment with nonfractionated heparin, for monitoring of thrombolytic therapy, for detecting disorders in fibrin formation and for diagnosing severe forms of fibrinogen deficiency.
• Thrombin time is prolonged due to reduced fibribogen concentration, the presence of fibrinogen degradation products or thrombin inhibitors in plasma.
• thrombin is added to plasma.
• Thrombin converts fibrinogen into fibrin and the time for the clot formation is measured.
• Thrombin (Test Thrombin Reagent, 1.5 lU/ml): lyophilised bovine thrombin is dissolved in 5 ml of HEPES buffer ( 25 nM, pH 7.4). saline to a concentration 2
• Normal pooled plasma Venous blood from at least 10 apparently healthy volunteers is collected in 0.11 M sodium citrate solution (1 part of sodium citrate and 9 parts of blood). Immediately after withdrawal the blood is centrifuged at 2000 x g for 30 minutes at 4°C. Plasma is removed, pipetted into 2-ml aliquots and stored at -70
• Inhibitors The inhibitors are dissolved in DMSO (10 mM stock solution) and diluted with distilled water to give working solutions (the highest concentration 100 ⁇ M).
• Activated partial thromboplastin time a) Principle aPTT is used as a screening test for coagulation disorders of the intrinsic coagulation pathway. The method is sensitive to deficit of coagulation factors VIII and IX and contact factors. The aPTT is prolonged due to the deficit of the factors or due to the presence of inhibitors (e.g., lupus anticoagulants, heparin). Incubation of plasma with the optimal quantity of phospholipids and a contact activator leads to activation of the factors of the intrinsic coagulation pathway. The addition of calcium ions triggers the coagulation process. The time of fibrin clot formation is measured.
• inhibitors e.g., lupus anticoagulants, heparin
• Phospholipids with an activator silicon dioxide particles, vegetable phospholipids, sodium chloride (2.4 g/l), HEPES (14.3 g/l), pH 7.6 and sodium azide ( ⁇ 1 g/l). Before use, the reagent must have room temperature and be well agitated. Calcium chloride solution: 0.025 mol/l Normal pooled plasma: in the same as for thrombin time. Inhibitors: in the same as for thrombin time.
• Prothrombin time is a rapid, sensitive screening test for determination of coagulation disorders of the intrinsic pathway (factors II, V, VII, and X). Owing to high sensitivity to these coagulation factors, the test is well suited for monitoring of oral anticoagulant therapy, for diagnosing genetic and acquired deficiencies in coagulation factors and checking the liver for its synthesis performance. Prothrombin time is prolonged due to the coagulation factors deficit or due to the presence of inhibitors. For the procedure, optimal amount of thromboplastin and calcium are added to plasma and the time of clot formation is measured.
• Thromboplastin human placental thromboplastin with calcium chloride and stabilising agents; dissolve in 4 ml of distilled water. Before use, warm the reagent to 37°C at least for 30 minutes. Normal pooled plasma: in the same as for thrombin time. Inhibitors: in the same as for thrombin time. c) Procedure
• the reaction mixture was stirred at room temperature for 1 hour, followed by the addition of powdered 2-(1-azepanylcarbonyl)-2-(4-cyanobenzyl)hydrazine chloride (2.00 g, 6.48 mmol). After the addition, it was further stirred at room temperature for 3 days. The solvent was removed on a rotavapor and the residue was dissolved in 50 ml of ethylacetate, followed by washing with 10% citric acid, 5% NaHC0 3 solution and distilled water. The organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo. The crude product was re-precipitated from acetone.
• N-(4- ⁇ [1 -[(4-methyl-1 -piperidinyl)carbonyl]-2-(1 -naphthylsulfonyl)hydrazino] methyl ⁇ benzyl)acetamide 1.98 g (5.59 mmol) of 2- ⁇ 4-[(acetylamino)methyl]benzyl ⁇ -2-[(4-methyl-1- piperidinyl)carbonyl]hydrazine chloride and 1.39 g (6.13 mmol) of naphthalen-2- sulfonylchloride were dissolved in dichloromethane (25 ml), 2.16 g (16.7 mmol) of N- diisopropyl-N-ethylamine was added and stirred at room temperature for 3 days.
• the mixture was stirred for additional half an hour at room temperature. 2.23 ml (25.60 mmol) of morpholine was added and stirred for another hour at room temperature.
• the reaction mixture was then extracted with 4 x 25 ml of 10% citric acid solution, 30 ml of saturated NaHC0 3 solution, followed by washing with 30 ml of purified water and 20 ml of saturated brine.
• the organic phase was dried over Na 2 S0 4 .
• the solvent was evaporated in vacuo, and the residue was dissolved in 10 ml of diethylether. A white precipitate was formed which was filtered off by suction.
• EXAMPLE 22 /V-(3-Cyanobenzyl)-/V-(2-naphthoyl)-1-azepanecarbohydrazide 2-(1-azepanylcarbonyl)-2-(3-cyanobenzyl)hydrazinium chloride (312 mg, 1.03 mmol), N-diisopropyl-N-ethylamine (2 ml) and benzoylchloride (210 mg, 1.11 mmol) were dissolved in dichloromethane (30 ml). The reaction mixture was stirred at room temperature for 2 days.

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• 2002
  • 2002-01-24 SI SI200200013A patent/SI21137A/sl not_active IP Right Cessation
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  • 2003-01-27 DE DE10392134T patent/DE10392134T5/de not_active Withdrawn
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