DE102005047563A1 - New modification of specific substituted thiophene carboxamide, useful for prevention and treatment of thrombo-embolic disease, has higher solubility than known modifications - Google Patents

Abstract

Modification II of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (I) is new. Modification II of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide of formula (I) is new. Independent claims are included for the following: (1) method for preparing modification II by dissolving modification I in inert solvent and storing the solution at elevated temperature until all solvent has evaporated; and (2) method for preparing modification II by suspending amorphous (I) in anhydrous, inert solvent and stirring or shaking the suspension until quantitative conversion to modification II has occurred. ACTIVITY : Thrombolytic; Anticoagulant; Cardiant; Antianginal; Vasotropic; Cerebroprotective; Antiarteriosclerotic; Antiinflammatory; Antirheumatic; Nootropic; Neuroprotective; Cytostatic; Ophthalmological. No details of tests for these activities are given. MECHANISM OF ACTION : Inhibition of blood coagulation factor Xa.

Description

The The present invention relates to a novel polymorphic form of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5- yl} -methyl) -2-thiophenecarboxamide, Process for their preparation, medicines containing them and their use in combating of diseases.

The compound 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) - 2-thiophenecarboxamide is known from WO 01/47949 and WO 2004/060887 and corresponds to the formula (I):

The Compound of formula (I) is a low molecular weight, orally administered Inhibitor of the blood coagulation factor Xa, which is used for prophylaxis, secondary prophylaxis and / or treatment of various thromboembolic disorders can be used (see WO 01/47919, whose disclosure hereby incorporated by reference), in particular heart attack, Angina pectoris (including unstable angina), reocclusions and restenosis following angioplasty or aortocoronary bypass, Stroke, transient ischemic Attacks, peripheral arterial occlusive diseases, pulmonary embolism or deep venous Thromboses.

The compound of the formula (I) can be prepared as described in WO 01/47949 and WO 2004/060887. In this case, the compound of the formula (I) is obtained in a crystal modification, which is referred to below as modification I. Modification I has a melting point of 230 ° C and a characteristic X-ray diffractogram, IR spectrum, Raman spectrum, FIR spectrum and NIR spectrum (Tab. 1-6, 1 - 6 ). It has now been found that modification I has a lower solubility by a factor of 4 compared to modification II.

Surprisingly were two more modifications, a hydrate, an NMP solvate and an inclusion compound with THF of the compound of formula (I) found. The compound of formula (I) in the modification II melts at about 203 ° C or has a transformation point of about 195 ° C, the compound of formula (I) in the modification III has a transformation point of about 127 ° C. The Contains hydrate about 4% water, the NMP solvate contains 18.5% N-methylpyrrolidone and the inclusion compound with THF about 5-7% tetrahydrofuran.

object of the present invention is the compound of formula (I) in of the modification II. By the use according to the invention of the compound of the formula (I) in the modification II ensures that a higher solubility is achieved compared to the known modification.

Modification II of the compound of the formula (I) has a clearly distinguishable X-ray diffractogram, IR spectrum, NIR spectrum, FIR spectrum and Raman as compared to modification I, modification III, the hydrate form, the NMP solvate and the inclusion compound with THF. Spectrum ( 2 - 6 ). The compound of formula (I) in the modification II melts at 203 ° C or changes at about 195 ° C and is thus clearly distinguishable from modification I (melting point 230 ° C) and modification III (transformation point about 127 ° C) , In contrast to these solventless forms, the hydrate of the compound of formula (I), the NMP solvate of the compound of formula (I) and the inclusion compound with THF of the compound of formula (I) show mass losses in the thermogravimetric analysis (TGA) of FIG %, 18.5% and 5-7% respectively ( 1 ).

The compound of the formula (I) according to the invention in the modification II is used in high purity in pharmaceutical formulations. For stability reasons, a pharmaceutical formulation mainly contains the compound of the formula (I) in the modification II and no major parts of another Form such as another modification or a solvate of the compound of formula (I). The medicament preferably contains more than 90 percent by weight, particularly preferably more than 95 percent by weight, of the compound of the formula (I) in modification II, based on the total amount of the compound of the formula (I).

Another The present invention is the use of the compound of the formula (I) in the modification II for the treatment and / or prophylaxis of diseases, preferably thromboembolic diseases and / or thromboembolic complications.

To the "thromboembolic Diseases "im Senses of the present invention include in particular diseases such as heart attack with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and restenosis following coronary interventions such as angioplasty or aortocoronary bypass, peripheral arterial occlusive diseases, pulmonary embolism, deep venous Thromboses and renal vein thrombosis, transient ischemic attacks as well as thrombotic and thromboembolic stroke.

The inventive compound is therefore also suitable for prevention and treatment of cardiogenic thromboembolism, such as Brain ischemia, Stroke and systemic thromboembolism and ischaemia, at Patients with acute, intermittent or persistent cardiac arrhythmias, such as atrial fibrillation, and those undergoing cardioversion in patients with valvular heart disease or with artificial Heart valves. About that In addition, the compound of the invention suitable for the treatment of disseminated intravascular coagulation (DIC).

thromboembolic Complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits, like hemodialysis, and heart valve prostheses.

Besides that comes the compound of the invention also for the prophylaxis and / or treatment of atherosclerotic vascular disease and inflammatory Diseases such as rheumatic diseases of the musculoskeletal system into consideration, about it also for the prophylaxis and / or treatment of Alzheimer's disease. In addition, the compound of the invention to inhibit tumor growth and metastasis Microangiopathies, age-related macular degeneration, diabetic Retinopathy, diabetic nephropathy and other microvascular diseases as well as for prevention and treatment of thromboembolic complications, such as venous Thromboembolism, in tumor patients, especially those who are larger surgical Have surgery or undergo chemo- or radiotherapy become.

The inventive compound can over it also used to prevent coagulation ex vivo be, e.g. for the preservation of blood and plasma products, for Cleaning / pretreatment of catheters and other medical Aids and devices, for coating artificial Surfaces of in vivo or ex vivo used medical aids and devices or in biological samples containing factor Xa.

Another The present invention is the use of the compound of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another The present invention is the use of the compound of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another The subject of the present invention is a method of treatment and / or prophylaxis of diseases, in particular those mentioned above Diseases using an anticoagulant Amount of the compound of the invention.

Another The present invention is a method for preventing the blood coagulation in vitro, especially in blood or biological samples containing factor Xa characterized is that an anticoagulatory effective amount of the compound of the invention is added.

• • Lipidsenker, insbesondere HMG-CoA-(3-Hydroxy-3-methylglutaryl-Coenzym A)-Reduktase-Inhibitoren;
• • Koronartherapeutika/Vasodilatatoren, insbesondere ACE-(Angiotensin-Converting-Enzyme)-Inhibitoren; AII-(Angiotensin II)-Rezeptor-Antagonisten; β-Adrenozeptor-Antagonisten; alpha-1-Adrenozeptor-Antagonisten; Diuretika; Calciumkanal-Blocker; Substanzen, die eine Erhöhung von cyclischem Guanosinmonophosphat (cGMP) bewirken, wie beispielsweise Stimulatoren der löslichen Guanylatcyclase;
• • Plasminogen-Aktivatoren (Thrombolytika/Fibrinolytika) und die Thrombolyse/Fibrinolyse steigernde Verbindungen wie Inhibitoren des Plasminogen-Aktivator-Inhibitors (PAI-Inhibitoren) oder Inhibitoren des Thrombin-aktivierten Fibrinolyse-Inhibitors (TAFI-Inhibitoren);
• • antikoagulatorisch wirksame Substanzen (Antikoagulantien);
• • plättchenaggregationshemmende Substanzen (Plättchenaggregationshemmer, Thrombozytenaggregationshemmer);
• • sowie Fibrinogen-Rezeptor-Antagonisten (Glycoprotein-IIb/IIIa-Antagonisten).

Another object of the present invention are pharmaceutical compositions containing the inventive Compound and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases. As suitable combination active ingredients may be mentioned by way of example and preferably:

• • lipid-lowering drugs, in particular HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors;
• Coronary / vasodilators, especially angiotensin converting enzyme (ACE) inhibitors; AII (angiotensin II) receptor antagonists; β-adrenoceptor antagonists; alpha-1-adrenoceptor antagonists; diuretics; Calcium channel blockers; Substances that cause an increase in cyclic guanosine monophosphate (cGMP), such as soluble guanylate cyclase stimulators;
• Plasminogen activators (thrombolytics / fibrinolytics) and thrombolysis / fibrinolysis-enhancing compounds such as inhibitors of plasminogen activator inhibitor (PAI inhibitors) or inhibitors of thrombin-activated fibrinolysis inhibitor (TAFI inhibitors);
• • anticoagulant substances (anticoagulants);
• • platelet aggregation inhibiting substances (platelet aggregation inhibitors, antiplatelet agents);
• • as well as fibrinogen receptor antagonists (glycoprotein IIb / IIIa antagonists).

Another The present invention relates to medicaments containing the Compound of the invention, usually together with one or more inert, non-toxic, pharmaceutical contain suitable excipients, as well as their use to the previously mentioned purposes.

The inventive compound can be systemic and / or local. For this purpose they can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For this Application routes, the compound of the invention in suitable Administration forms are administered.

For the oral Applicable to the state of the art working, the invention compound rapidly and / or modified donating application forms that the Compound of formula (I) in the modification II, as e.g. Tablets (non-coated or coated Tablets, for example, with enteric or delayed dissolving or insoluble coatings that control the release of the compound of the invention), in the oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, Capsules (for example hard or Soft gelatin capsules), dragees, granules, pellets, powders, suspensions or aerosols.

The Parenteral administration can bypass a resorption step happen (e.g., intravenously, intraarterial, intracardiac, intraspinal or intralumbar) or involving absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of suspensions, lyophilisates or sterile powders.

For the others Application routes are suitable, e.g. Inhalation medicines (i.a. Powder inhalers, nebulizers), lingual, sublingual or buccal applying tablets, films / wafers or capsules, suppositories, Ear or eye preparations, Vaginal capsules, watery Suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic Systems (e.g., plasters), milk, pastes, foams, powdered powders, implants or stents.

Prefers are the oral or parenteral administration, especially oral Application.

The inventive compound can in the cited Application forms are transferred. This can in a conventional manner by mixing with inert, non-toxic, done pharmaceutically suitable excipients. To these excipients counting et al excipients (for example, microcrystalline cellulose, lactose, mannitol), solvent (e.g., liquid Polyethylene glycols), emulsifiers and dispersing or wetting agents (For example, sodium dodecyl sulfate, Polyoxysorbitanoleat), binder (For example, polyvinylpyrrolidone), synthetic and natural polymers (for example, albumin), stabilizers (e.g., antioxidants such as for example ascorbic acid), Dyes (e.g., inorganic pigments such as iron oxides) and Flavor and / or odor remedies.

In general, it has proven to be advantageous for parenteral administration amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight to achieve effective results to administer. When administered orally, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.

Nevertheless it may be necessary, if necessary, of the quantities mentioned to deviate, depending on of body weight, Route of administration, individual behavior towards the active substance, type of Preparation and time or interval to which the application he follows. So it can in some cases be sufficient, with less than the aforementioned minimum quantity to get along while in other cases exceeded the mentioned upper limit must become. In case of application of larger quantities it may be recommended be to distribute these in several single doses throughout the day.

Another The invention relates to a process for the preparation of the compound of the formula (I) in the modification II, by the compound of Formula (I) in the modification I dissolved in an inert solvent and the Active ingredient by adding a precipitant at a temperature between 0 ° C and 80 ° C, preferably from 20 to 25 ° C, like becomes. The precipitate is isolated and dried. You get that way Compound of the formula (I) in the modification II.

Also The invention relates to a process for the preparation of the compound of the formula (I) in the modification II, by the compound of Formula (I) in the modification I dissolved in an inert solvent and, preferably at elevated Temperature, in particular at a temperature of 30 ° C to Reflux the solvent, until the complete Evaporation of the solvent and crystallizing the drug is stored. You get that way Compound of the formula (I) in the modification II.

Also The invention relates to a process for the preparation of the compound of the formula (I) in the modification II, by the compound of Formula (I) in the amorphous form in an anhydrous inert solvent suspended and until the desired degree of conversion, in particular until the quantitative conversion, stirred in the modification II or shaken becomes. The resulting crystals are isolated and dried. you receives so the compound of formula (I) in the modification II.

When inert solvent are lower alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, sec-butanol, iso-butanol, 1-pentanol, or ketones such as Acetone, or alkanes such as n-pentane, cyclopentane, n-hexane, cyclohexane, or tetrahydrofuran, or acetonitrile, or toluene, or ethyl acetate, or 1,4-dioxane, or mixtures of said solvents, or mixtures the said solvent with water. Preference is given to acetone, tetrahydrofuran, 1-pentanol or Mixtures of the solvents mentioned. As precipitant are inert, anhydrous solvents in which the active ingredient poorly soluble is, such. As n-heptane, cyclohexane or toluene. Preference is given to n-heptane.

Prefers the compound of the formula (I) is prepared in the modification II, by the compound of the formula (I) in the modification I in acetone or tetrahydrofuran dissolved and the active ingredient by adding n-heptane at a temperature between 0 and 80 ° C, preferably at a temperature of 20 to 25 ° C, is precipitated. The rainfall is isolated and dried. This gives the compound of the formula (I) in the modification II.

Also preferred is the compound of formula (I) in the modification II prepared by the compound of formula (I) in the modification I dissolved in 1,4-dioxane is and at elevated Temperature, in particular at a temperature of 30 ° C to Reflux the solvent, for example 50 ° C, until the complete Evaporation of the solvent and crystallizing the drug is stored. You get that way Compound of the formula (I) in the modification II.

Also preferred is the compound of formula (I) in the modification II prepared by the compound of formula (I) in the amorphous Mold suspended in an inert anhydrous solvent and until reaching the desired Degree of conversion to the modification II at a temperature of 20 to 25 ° C touched or shaken becomes. The resulting crystals are isolated and dried. Man receives so the compound of formula (I) in the modification II.

The compound of formula (I) in the amorphous form can be prepared by melt-blowing the compound of formula (I) in a crystalline form followed by rapid cooling. Preferably, the compound of formula (I) is prepared in the amorphous form by the compound of formula (I) in a crystalline form at a temperature of at least 230 ° C, in particular at a temperature of 240 to 250 ° C, melted and then is cooled quickly. Of the crystalline forms Modification I, II and III, preference is given to using modification I or II, in particular modification I. By the rapid cooling, the temperature of the compound (I) is preferably brought to or near the room temperature, for example to a temperature of about 15 to 30 ° C, in particular from about 20 to 25 ° C. The rapid cooling preferably takes place within a few seconds, for example within about 5 seconds. For rapid cooling, shock cooling is preferably used.

The Compound of formula (I) in the modification III can be prepared be prepared by the compound of formula (I) in the modification I in an inert solvent, for example, acetone, dissolved becomes. The solution is added with water and allowed to stand at room temperature, until the solvent Completely has evaporated. You get so the compound of formula (I) in the modification III.

The Hydrate of the compound of formula (I) can be prepared by the compound of formula (I) in the modification I in ethanol: water (1: 1) solved becomes. The solution is stored at a temperature of about -20 ° C until the solvent has evaporated. You get so the hydrate of the compound of formula (I).

The NMP solvate of the compound of formula (I) can be prepared by the compound of formula (I) in the modification I in 1-methyl-2-pyrrolidone is suspended and stirred at room temperature. After 2 days will be filtered and the product dried. This gives the NMP solvate of the compound of the formula (I) with an NMP content of 18.5 percent by weight.

The Inclusion compound with THF of the compound of formula (I) can be prepared by the compound of formula (I) in the modification I dissolved in tetrahydrofuran becomes. The solution is stored at room temperature until the solvent has evaporated. You get so the inclusion compound with THF of the compound of formula (I).

The Percentages in the following tests and examples are provided not stated otherwise, weight percentages; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions each on the volume.

The Thermograms were determined using differential scanning Calorimeters DSC 7 resp. Pyris-1 and Thermogravimetric Analyzer TGA 7 of Fa. Perkin Elmer received. The X-ray diffractograms were registered in a Stoe transmission diffractometer. The IR, FIR, NIR and Raman spectra were performed with Fourier IR spectrometers IFS 66v (IR, FIR), IFS 28 / N (NIR) and RFS 100 (Raman) from Bruker added.

Example 1: 5-Chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide in the modification I

The Preparation of modification I of the title compound is in WO 01/47949 and WO 2004/060887.

Example 2: Preparation of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) -2 -thiophencarboxamid in modification II

Example 2.1

208 g chlorothiophenecarboxylic acid were suspended in 1100 ml of toluene and heated to 75 to 80 ° C. At this temperature 112 ml of thionyl chloride were obtained within 2 h dropwise. The resulting reaction solution was until the end of the Gas evolution stirred for a further 2 h. The internal temperature became in 5 ° steps at 100-110 ° C elevated. The mixture was cooled and the solution of the acid chloride concentrated on a rotary evaporator.

350 g of oxamine hydrochloride were suspended in 2450 ml of NMP, with 385 ml of triethylamine and stirred for 15 min. The mixture was on Cooled to 10 ° C, with the solution from the acid chloride and 70 ml of toluene and stirred. To the suspension were 350 ml tap water and heated to 82 ° C. After filtration was the active ingredient is precipitated with 3.5 l of water and stirred for 2 h. desiccation at 70 ° C in a vacuum.

Example 2.2

Approximately 200 mg of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) - 2-thiophenecarboxamide in the modification I were dissolved in about 80 ml of tetrahydrofuran hot. The Solution became filtered and halved. A half was at room temperature with n-heptane added until the drug failed. The residue was filtered off and dried at room temperature. He was examined by X-ray diffractometry and corresponded to the title compound in the modification II.

Example 2.3

Approximately 200 mg of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) - 2-thiophenecarboxamide in the modification I were dissolved in about 40 ml of 1-pentanol hot. The solution was filtered and halved. One half was mixed with n-heptane until the drug failed. The residue was filtered off and dried at room temperature. He was X-ray diffractometric examined and corresponded to the title compound in the modification II.

Example 2.4

Approximately 200 mg of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) - 2-thiophenecarboxamide in the modification I were dissolved hot in about 40 ml of 1,4-dioxane. The solution was filtered and halved. One half was at 50 ° C in a drying oven stored until the solvent had evaporated. The residue was X-ray diffractometric examined and corresponded to the title compound in the modification II.

Example 2.5

Approximately 50 mg of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) - 2-thiophenecarboxamide in the amorphous form produced by melting on the Kofler heating bench about 240 ° C and subsequent chilling to room temperature, were suspended in about 2 ml of ethanol and 0.5 h at 25 ° C touched. The crystals were isolated and dried. The residue was X-ray diffractometric examined and corresponded to the title compound in the modification II.

Example 2.6

Approximately 100 mg 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) - 2-thiophenecarboxamide in the modification I were dissolved hot in about 50 ml of acetone. The solution was filtered and treated in an ice bath with n-heptane until the active ingredient failed. The residue was filtered off and dried at room temperature. He was X-ray diffractometric examined and corresponded to the title compound in the modification II.

Example 3: Production of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) -2 -thiophencarboxamid in modification III

Approximately 120 mg of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) - 2-thiophenecarboxamide in the modification I were dissolved hot in about 50 ml of acetone. The solution was filtered, treated with about 50 ml of water and at room temperature let stand until the solvent had evaporated. The residue was examined thermoanalytically and corresponded to the title compound in modification III.

Example 4: Preparation the hydrate of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-S-yl} -methyl) -2-thiophenecarboxamide

Approximately 400 mg of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) - 2-thiophenecarboxamide in the modification I were dissolved in about 60 ml of ethanol: water (1: 1) hot and filtered. Part of the solution was stored in the freezer at a temperature of about -20 ° C, until the solvent had evaporated. The residue corresponded to the hydrate of the title compound.

Example 5: Preparation of the NMP solvate of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} - methyl) -2-thiophenecarboxamide

Approximately 3.5 g of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} - methyl) -2-thiophenecarboxamide in modification I were suspended in 10 ml of 1-methyl-2-pyrrolidone and stirred at room temperature. After a few hours, about 20 ml of NMP were added. After two Days, the suspension was filtered with suction and the residue at room temperature dried. The residue was thermoanalytically investigated and corresponded to the NMP solvate of Title compound with an NMP content of 18.5% by weight.

Example 6: Preparation the inclusion compound with THF of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} - methyl) -2-thiophenecarboxamide

Approximately 400 mg of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl) - 2-thiophenecarboxamide in the modification I were dissolved in about 50 ml of hot tetrahydrofuran and filtered. One Part of the solution was stored at room temperature until the solvent had evaporated. The residue became investigated thermoanalytically and corresponded to the inclusion compound with THF of the title compound.

Tab. 1: Differential scanning calorimetry and thermogravimetry

Tab. 2: X-ray diffractometry

Tab. 3: IR spectroscopy

Tab. 4: Raman spectroscopy

Tab. 5: FIR spectroscopy

Tab. 6: NIR spectroscopy

Claims (12)

Compound of the formula (I)

in modification II. Process for the preparation of the compound of the formula (I) in the modification II, characterized in that the compound of the formula (I) in the modification I in an inert solvent solved and the compound is precipitated by adding a precipitant. Process for the preparation of the compound of the formula (I) in the modification II, characterized in that the compound of the formula (I) in the modification I in an inert solvent solved and the solution increased Temperature until complete Evaporation of the solvent is stored. Process for the preparation of the compound of the formula (I) in the modification II, characterized in that the compound of the formula (I) in the amorphous form in an anhydrous inert solvent suspended and the suspension until quantitative conversion stirred in the modification II or shaken. Compound of the formula (I) in the modification II for the treatment and / or prophylaxis of diseases. Use of the compound of formula (I) in the modification II for the manufacture of a medicament for the treatment and / or prophylaxis of thromboembolic disorders. Use of the compound of formula (I) in the modification II for the prevention of blood coagulation in vitro. Medicaments containing the compound of the formula (I) in the modification II in combination with an inert, non-toxic, pharmaceutically suitable excipient Medicaments containing the compound of the formula (I) in the modification II in combination with another active ingredient. Medicament according to claim 8 or 9 for the treatment and / or prophylaxis of thromboembolic disorders. Method for the treatment and / or prophylaxis of using thromboembolic diseases in humans and animals an anticoagulatory effective amount of the compound of the formula (I) in the modification II or a medicine as in a the claims 8 to 10 defined. Method for preventing blood coagulation in in vitro, characterized in that an anticoagulatory effective Amount of the compound of formula (I) added in the modification II becomes.