CA2624310A1 - Polymorphic form of 5-chloro-n-({5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide - Google Patents

Polymorphic form of 5-chloro-n-({5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide Download PDF

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CA2624310A1
CA2624310A1 CA002624310A CA2624310A CA2624310A1 CA 2624310 A1 CA2624310 A1 CA 2624310A1 CA 002624310 A CA002624310 A CA 002624310A CA 2624310 A CA2624310 A CA 2624310A CA 2624310 A1 CA2624310 A1 CA 2624310A1
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compound
formula
modification
amorphous form
oxo
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CA2624310C (en
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Alfons Grunenberg
Jana Lenz
Gerhard Arnold Braun
Birgit Keil
Christian R. Thomas
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Bayer Intellectual Property GmbH
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or 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
    • C07D263/18Oxygen atoms
    • C07D263/20Oxygen atoms attached in position 2
    • C07D263/22Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D265/00Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/281,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/301,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or 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
    • C07D333/28Halogen atoms

Abstract

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, processes for their preparation and medicaments comprising these forms.

Description

BHC 05 1 117-Foreign countries GH/26.10.2007 Novel polymorphic form and the amorphous form of 5-chloro-N-({(5S)-2-oxo-3-14-(3-oxo-4-morpholinyl)-phenyll-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide The present invention relates to a novel polymorphic form and the amorphous form of 5-chloro-N-({ (5S)-2-oxo-3 -[4-(3 -oxo-4-morphol inyl)-phenyl]-1,3-oxazolidin-5-yl } -methyl)-2-thi ophene-carboxamide, processes for their preparation, medicaments comprising these forms, and their use in the control 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 (1):

O O

~_O H ~
0N N,N I CI (t) O

The compound of the formula (I) is a low molecular weight, orally administrable inhibitor of blood clotting factor Xa, which can be employed for the prophylaxis, secondary prophylaxis and/or treatment of various thromboembolic diseases (for this see WO 01/47919, whose disclosure is included herewith by way of reference), in particular of myocardial infarct, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep vein thromboses.

The compound of the formula (I) can be prepared as described in WO 01/47949 and WO
2004/060887. The compound of the formula (I) is obtained here in a crystal modification which is designated 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, Fig. 1-6). It has now been found that modification I has a solubility lower by the factor 4 in comparison to the modification 11.

Surprisingly, two further modifications, a hydrate, an NMP solvate and an inclusion compound with THF of the compound of the formula (I) have been found. The compound of the formula (I) in the modification II melts at approximately 203 C and has a transition point of approximately 195 C, the compound of the formula (I) in the modification III has a transition point of approximately 127 C. The hydrate contains approximately 4% of water, the NMP
solvate contains 18.5% of N-methylpyrrolidone and the inclusion compound with THF approximately 5-7% of BHC 05 1 117-Foreign countries tetrahydrofuran.

The present invention relates to the compound of the formula (I) in the modification II. By means of the use according to the invention of the compound of the formula (I) in the modification II, it is ensured that a higher solubility is achieved in comparison to the known modification.

Modification II of the compound of the formula (I), in comparison to modification 1, modification III, the hydrate form, the NMP solvate and the inclusion compound with THF, has a clearly distinguishable X-ray diffractogram, IR spectrum, NIR spectrum, FIR spectrum and Raman spectrum (Fig. 2-6). The compound of the formula (I) in the modification 11 melts at 203 C and converts at approximately 195 C and is thus clearly distinguishable from modification I (melting point 230 C) and modification III (transition point approximately 127 C). In contrast to these solvent-free forms, the hydrate of the compound of the formula (I), the NMP
solvate of the compound of the formula (I) and the inclusion compound with THF of the compound of the formula (1) show mass losses in thermogravimetric analysis (TGA) of 4%, 18.5%
and 5-7%
respectively (Fig. 1).

It is generally known that crystalline polymorphic forms have a poorer water solubility than the amorphous form. This leads to a lower bioavailability in comparison to the amorphous form.

The present invention furthermore relates to the compound of the formula (I) in amorphous form.
By means of the use according to the invention of the compound of the formula (I) in the amorphous form, it is ensured that maximum bioavailability is achieved.

The amorphous form of the compound of the formula (1) has a characteristic X-ray diffractogram, NIR spectrum, FIR spectrum and Raman spectrum (Fig. 8-12). The compound of the formula (I) in the amorphous form has a glass transition temperature of approximately 83 C
(DSC, Fig. 7).

The compound of the formula (I) according to the invention in the modification 11 or in the amorphous form is employed in high purity in pharmaceutical formulations. For reasons of stability, a pharmaceutical formulation mainly contains the compound of the formula (1) in the modification II or in the amorphous form and no relatively large proportions of another form such as, for example, of another modification or of a solvate of the compound of the formula (I).
Preferably, the medicament contains more than 90 percent by weight, particularly preferably more than 95 percent by weight of the compound of the formula (I) in the modification 11 or in the amorphous form based on the total amount of the compound of the formula (I) contained.

The present invention further relates to the use of the compound of the formula (I) in the modification 11 or in the amorphous form for the treatment and/or prophylaxis of diseases, preferably of B H C 05 1 117-Fore i gn countries thromboembolic diseases and/or thromboembolic complications.

The "thromboembolic diseases" within the meaning of the present invention in particular include diseases such as myocardial infarct with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and restenoses after coronary interventions such as angioplasty or aortocoronary bypass, peripheral arterial occlusive diseases, pulmonary embolisms, deep vein thromboses and renal vein thromboses, transitory ischemic attacks, and thrombotic and thromboembolic cerebral stroke.

The compound according to the invention is therefore also suitable for the prevention and treatment of cardiogenic thromboembolisms, such as, for example, cerebral ischemias, stroke and systemic thromboembolisms and ischemias in patients with acute, intermittent or persistent cardiac arrhythmias, such as, for example, atrial fibrillation, and those who are subject to cardioversion, furthermore in the case of patients with heart valve diseases or with artificial heart valves.
Moreover, the compound according to the invention is suitable for the treatment of disseminated intravasal clotting (DIC).
Thromboembolic complications furthermore occur in microangiopathic hemolytic anemias, extracorporeal blood circulations, such as hemodialysis, and heart valve prostheses.

Moreover, the compound according to the invention is also suitable for the prophylaxis and/or treatment of atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the locomotor system, moreover also for the prophylaxis and/or treatment of Alzheimer's disease.
Moreover, the compound according to the invention can be employed for the inhibition of tumor growth and of metastasis formation, in microangiopathies, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular diseases, and for the prevention and treatment of thromboembolic complications, such as, for example, venous thromboembolisms, in tumor patients, in particular those who are subjected to relatively large surgical interventions or chemo- or radiotherapy.

The compound according to the invention can moreover be employed for the prevention of coagulation ex vivo, e.g. for the preservation of blood and plasma products, for the cleaning/pretreatinent of catheters and other medical aids and equipment, for the coating of artificial surfaces of medical aids and equipment employed in vivo or ex vivo or in biological samples which contain factor Xa.

The present invention further relates to the use of the compound according to the invention for the treatment and/or prophylaxis of diseases, in particular of the aforementioned diseases.

The present invention furthermore relates to the use of the compound according to the invention for the production of a medicament for the treatment and/or prophylaxis of diseases, in particular of the BHC 05 1 117-Foreign countries aforementioned diseases.

The present invention furthermore relates to a process for the treatment and/or prophylaxis of diseases, in particular of the aforementioned diseases, using an amount of the compound according to the invention having anticoagulatory activity.

The present invention furthermore relates to a process for the prevention of blood coagulation in vitro, in particular in blood preserves or biological samples which contain factor Xa, which is characterized in that an amount of the compound according to the invention having anticoagulatory activity is added.
The present invention furthermore relates to medicaments comprising the compound according to the invention and one or more other active substances, in particular for the treatment and/or prophylaxis of the aforementioned diseases. Suitable combination active substances which may be mentioned by way of example and preferably are:

= lipid-lowering agents, in particular HMG-CoA-(3-hydroxy-3-methylglutaryl-coenzyme A)-reductase inhibitors;

= coronary therapeutics/vasodilators, in particular ACE (angiotensin converting enzyme) inhibitors;
All (angiotensin 11) receptor antagonists; (3-adrenoceptor antagonists; alpha-l-adrenoceptor antagonists; diuretics; calcium channel blockers; substances which bring about an increase in cyclic guanosine monophosphate (cGMP), such as, for example, stimulators of soluble guanylate cyclase;

= plasminogen activators (thrombolytics/fibrinolytics) and thrombolysis/fibrinolysis-increasing compounds such as inhibitors of the plasminogen activator inhibitor (PAI
inhibitors) or inhibitors of the thrombin-activated fibrinolysis inhibitor (TAFI inhibitors);

= substances having anticoagulatory activity (anticoagulants);

= substances inhibiting platelet aggregation (platelet aggregation inhibitors, thrombocyte aggregation inhibitors);

= and fibrinogen receptor antagonists (glycoprotein Ilb/llla antagonists).

The present invention further relates to medicaments which contain the compound according to the invention, customarily together with one or more inert, nontoxic, pharmaceutically suitable excipients, and their use for the aforementioned purposes.

The compound according to the invention can act systemically and/or locally.
For this purpose, they can be administered in a suitable manner, such as, for example, orally, parenterally, pulmonarily, BHC 05 1 117-Foreign countries nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.

For these administration routes, the compound according to the invention can be administered in suitable administration forms.

For oral administration, administration forms functioning according to the prior art, releasing the compound according to the invention rapidly and/or in modified form, which contain the compound of the formula (I) in the modification 11 or in the amorphous form, such as, for example, tablets (noncoated or coated tablets, for example with enteric coatings or coatings which dissolve with a delay or are insoluble, which control the release of the compound according to the invention), tablets disintegrating rapidly in the oral cavity or films/wafers, films/lyophilizates, capsules (for example hard or soft gelatin capsules), coated tablets, granules, pellets, powders, suspensions or aerosols are suitable.
Parenteral administration can take place with circumvention of an absorption step (e.g. intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or with intervention of an absorption (e.g.
intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). For parenteral administration, suitable administration forms are, inter alia, injection and infusion preparations in the form of suspensions, lyophilizates or sterile powders.

For the other administration routes, for example, inhalation pharmaceutical forms (inter alia powder inhalers, nebulizers), tablets to be administered lingually, sublingually or buccally, films/wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, dusting powders, implants or stents are suitable.

Oral or parenteral administration is preferred, in particular oral administration.

The compound according to the invention can be converted to the administration forms mentioned.
This can take place in a manner known per se by mixing with inert, nontoxic, pharmaceutically suitable excipients. These excipients include, inter alia, vehicles (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecylsulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g.
antioxidants such as, for example, ascorbic acid), colorants (e.g. inorganic pigments such as, for example, iron oxides) and taste and/or odor corrigents.

In general, it has proven advantageous in the case of parenteral administration to administer amounts of approximately 0.001 to I mg/kg, preferably approximately 0.01 to 0.5 mg/kg of body weight to BHC 05 l 117-Foreign countries achieve effective results. In the case of oral administration, the dose is approximately 0.01 to 100 mg/kg, preferably approximately 0.01 to 20 mg/kg and very particularly preferably 0.1 to 10 mg/kg of body weight.

In spite of this, it may optionally be necessary to depart from the amounts mentioned, namely depending on body weight, route of administration, individual behavior toward the medicament, type of preparation and time or interval at which administration takes place. Thus in some cases it may be adequate to manage with less than the aforementioned minimum amount, whereas in other cases the upper limit mentioned must be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into a number of individual doses over the course of the day.

The invention further relates to a process for the preparation of the compound of the formula (I) in the modification 11, by dissolving the compound of the formula (I) in the modification I in an inert solvent and precipitating the active substance by addition of a precipitating agent at a temperature between 0 C and 80 C, preferably from 20 to 25 C. The precipitate is isolated and dried. The compound of the formula (1) is thus obtained in the modification II.

The invention likewise relates to a process for the preparation of the compound of the formula (I) in the modification II, by dissolving the compound of the formula (I) in the modification I in an inert solvent and storing it, preferably at elevated temperature, in particular at a temperature of 30 C up to the reflux temperature of the solvent, until the complete evaporation of the solvent and crystallization of the active substance. The compound of the formula (I) is thus obtained in the modification 11.

The invention likewise relates to a process for the preparation of the compound of the formula (I) in the modification II, by suspending the compound of the formula (I) in the amorphous form in an anhydrous inert solvent and stirring or shaking it until achieving the desired degree of conversion, in particular until quantitative conversion, to the modification II. The crystallizate obtained is isolated and dried. The compound of the formula (I) is thus obtained in the modification 11.

Suitable inert solvents are lower alcohols such as, for example, methanol, ethanol, n-propanol, iso-propanol, n-butanol, sec-butanol, isobutanol, 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 the solvents mentioned, or mixtures of the solvents mentioned with water. Acetone, tetrahydrofuran, 1-pentanol or mixtures of the solvents mentioned are preferred. Suitable precipitating agents are inert, anhydrous solvents, in which the active substance is poorly soluble, such as, for example, n-heptane, cyclohexane or toluene. n-Heptane is preferred.

BHC 05 1 117-Foreign countries Preferably, the compound of the formula (I) is prepared in the modification II, by dissolving the compound of the formula (I) in the modification I in acetone or tetrahydrofuran and precipitating the active substance by addition of n-heptane at a temperature between 0 and 80 C, preferably at a temperature from 20 to 25 C. The precipitate is isolated and dried. The compound of the formula (I) is thus obtained in the modification II.

Likewise preferably, the compound of the formula (I) is prepared in the modification 11, by dissolving the compound of the formula (1) in the modification I in 1,4-dioxane and storing at elevated temperature, in particular at a temperature from 30 C up to the reflux temperature of the solvent, for example 50 C, until the complete evaporation of the solvent and crystallization of the active substance. The compound of the formula (I) is thus obtained in the modification 11.

Likewise preferably, the compound of the formula (I) is prepared in the modification II, by suspending the compound of the formula (I) in the amorphous form in an inert anhydrous solvent and stirring or shaking at a temperature of 20 to 25 C until achieving the desired degree of conversion to the modification lt. The crystallizate obtained is isolated and dried. The compound of the formula (1) is thus obtained in the modification 11.

The invention further relates to a process for the preparation of the compound of the formula (I) in the amorphous form, in which the compound of the formula (I) in a crystalline form is fused and subsequently rapidly cooled. The compound of the formula (1) is thus obtained in the amorphous form.

Preferably, the compound of the formula (1) is prepared in the amorphous form, by fusing the compound of the formula (I) in a crystalline form at a temperature of at least 230 C, in particular at a temperature of 240 to 250 C, and subsequently rapidly cooling it. The compound of the formula (I) is thus obtained in the amorphous form.

Of the crystalline forms modification l, ll and I11, preferably modification I
or II, are employed here, in particular modification I.

By means of rapid cooling, the temperature of the compound (1) is preferably brought to or close to room temperature, for example to a temperature of approximately 15 to 30 C, in particular of approximately 20 to 25 C. The rapid cooling is preferably carried out in the course of a few seconds, for example in the course of approximately 5 seconds. Shock cooling is preferably employed for rapid cooling.

The compound of the formula (1) in the modification III can be prepared by dissolving the compound of the formula (1) in the modification I in an inert solvent, for example acetone. The BHC 05 1 1 17-Foreign countries solution is treated with water and allowed to stand at room temperature until the solvent has completely evaporated. The compound of the formula (I) is thus obtained in the modification III.
The hydrate of the compound of the formula (I) can be prepared by dissolving the compound of the formula (1) in the modification I in ethanol:water (1:1). The solution is a stored at a temperature of approximately -20 C until the solvent has evaporated. The hydrate of the compound of the formula (I) is thus obtained.

The NMP solvate of the compound of the formula (I) can be prepared by suspending the compound of the formula (I) in the modification I in 1-methyl-2-pyrrolidone and stirring at room temperature.
After 2 days, the suspension is filtered and the product is dried. The NMP
solvate of the compound of the formula (I) with an NMP content of 18.5 percent by weight is thus obtained.

The inclusion compound with THF of the compound of the formula (I) can be prepared by dissolving the compound of the formula (I) in the modification I in tetrahydrofuran. The solution is stored at room temperature until the solvent has evaporated. The inclusion compound with THF of the compound of the formula (I) is thus obtained.

The percentages in the following tests and examples, if not stated otherwise, are percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid/liquid solutions in each case relate to the volume.

BHC 05 1 117-Foreign countries Workin$! examples The thermograms were obtained using a DSC 7 or Pyris-1 differential scanning calorimeter and TGA 7 thermogravimetric analyzer from Perkin-Elmer. The X-ray diffractograms were recorded in a Stoe transmission diffractometer. The IR, FIR, NIR and Raman spectra were recorded using IFS
66v Fourier IR (IR, FIR), IFS 28/N (NIR) and RFS 100 (Raman) spectrometers from Bruker.

Example 1: 5-Chloro-N-({(5S)-2-oxo-3-I4-(3-oxo-4-morpholinyl)-phenyll-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide in the modification I

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

Example 2: Preparation of 5-chloro-N-({(5S)-2-oxo-3-14-(3-oxo-4-morpholinyl)-phenyll-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide in the modification II

Example 2.1 208 g of chlorothiophenecarboxylic acid were suspended in 1100 ml of toluene and heated to 75 to 80 C. 112 ml of thionyl chloride were added dropwise at this temperature in the course of 2 h. The resulting reaction solution was stirred for a further 2 h until the end of evolution of gas. In the course of this, the internal temperature was increased to 100-110 C in 5 steps. The mixture was cooled and the solution of the acid chloride was concentrated on a rotary evaporator.

350 g of oxamine hydrochloride were suspended in 2450 ml of NMP, treated with 385 ml of triethylamine and stirred for 15 min. The mixture was cooled to 10 C, treated with the solution of the acid chloride and 70 ml of toluene and stirred. 350 ml of tap water were added to the suspension and it was heated to 82 C. After filtration, the active substance was precipitated using 3.5 1 of water and the mixture was subsequently stirred for 2 h. Drying at 70 C in vacuo.

Example 2.2 About 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 80 ml of tetrahydrofuran. The solution was filtered and divided in half. One half was treated at room temperature with n-heptane until the active substance precipitated. The residue was filtered off and dried at room temperature. It was investigated by X-ray diffractometry and corresponded to the title compound in the modification 11.

BHC 05 l 117-Foreign countries Example 2.3 About 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-pentanol. The solution was filtered and divided in half. One half was treated with n-heptane until the active substance precipitated. The residue was filtered off and dried at room temperature. It was investigated by X-ray diffractometry and corresponded to the title compound in the modification 11.
Example 2.4 About 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 divided in half. One half was stored at 50 C in a drying oven until the solvent had evaporated. The residue was investigated by X-ray diffractometry and corresponded to the title compound in the modification M.

Example 2.5 About 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, prepared by fusing on a Kofler heating bench at about 240 C and subsequent shock cooling to room temperature, were suspended in about 2 ml of ethanol and stirred at 25 C for 0.5 h. The crystallizate was isolated and dried. The residue was investigated by X-ray diffractometry and corresponded to the title compound in the modification II.

Example 2.6 About 100 mg of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-I,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 with n-heptane in an ice bath until the active substance precipitated. The residue was filtered off and dried at room temperature. It was investigated by X-ray diffractometry and corresponded to the title compound in the modification 11.
Example 3: Preparation of 5-chloro-N-({(5S)-2-oxo-3-14-(3-oxo-4-morpholinyl)-phenvll-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide in the modification III

About 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 allowed to stand at room temperature until the solvent had evaporated. The residue was investigated thermoanalytically and BHC 05 1 117-Foreign countries corresponded to the title compound in the modification 111.

Example 4: Preparation of the hydrate of 5-chloro-N-({(5S)-2-oxo-3-f4-(3-oxo-4-morpholinyl)-phenyll-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide About 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 hot in about 60 ml of ethanol:water (1:1) and filtered. A part of the solution was stored in a freezer at a temperature of approximately -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-3-14-(3-oxo-4-morpholinyl)-phenyll-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide About 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 the 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 additionally added. After two days, the suspension was filtered off with suction and the residue was dried at room temperature. The residue was investigated thermoanalytically and corresponded to the NMP solvate of the title compound having an NMP content of 18.5 percent by weight.

Example 6: Preparation of the inclusion compound with THF of 5-chtoro-N-({(5S)-2-oxo-3-14-(3-oxo-4-morpholinyl)-phenyll-l ,3-oxazolidin-5-yl}-methyl)-2-thiopheneca rboxamide About 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 hot in about 50 ml of tetrahydrofuran and filtered. A part of the solution was stored at room temperature until the solvent had evaporated. The residue was investigated thermoanalytically and corresponded to the inclusion compound with THF of the title compound.

Tab. 1: Differential scanning calorimetry and thermogravimetry Modifi- Modifi- Modifi- Hydratc NMP ESV cation I cation IIeation III
solvatetoluene Melting point [ C] 230 203 - - - -Transition point [ C:] - ca. 192 ca. 127 - -Mass loss [% by wt.] 0.1 0.1 <0.5 ca. 4 18.5 5-7 = BHC 05 1 1 17-Foreign countries Tab. 2: X-ray diffractometry - - -- _ 1 Reflectionsdifi- Modifi- Modifi- Hydrate NMP ESV with 4M) cation I cation ll cation Ill [2 theta] solvate THF
[2 theta] [2 theta] [2 theta] [2 theta] [2 theta]
8.9 12.8 11.7 3.6 4.8 9.0 12.0 17.7 16.5 14.3 5.8 12.0 14.3 18.1 17.5 16.4 7.3 14.3 16.5 18.4 19.1 16.6 10.9 14.7 17.4 19.0 19.6 17.5 14.5 16.5 18.1 19.9 19.8 19.3 15.2 16.8 19.5 20.8 23.1 19.6 15.7 17.5 19.9 21.6 23.2 19.9 16.0 19.6 21.7 22.1 23.8 20.2 17.6 19.9 22.5 22.9 24.3 21.7 17.9 21.7 23.4 24.1 28.1 22.5 20.0 22.5 24.1 26.1 28.2 24.2 20.6 23.4 24.5 26.4 31.2 25.6 21.3 24.5 24.7 26.6 25.8 21.8 24.7 25.6 27.2 28.8 22.3 25.2 26.4 27.5 29.5 22.7 25.6 26.7 28.8 31.8 23.1 26.4 30.0 29.8 32.7 23.3 26.7 30.1 31.0 23.5 28.7 31.8 31.6 24.0 30.1 32.9 24.7 31.0 24.9 31.8 25.2 26.0 26.5 26.9 28.0 28.8 29.2 29.5 29.8 = BHC 05 1 117-Foreign countries Tab. 3: IR spectroscop -y Peak maxima Modification Modification Moditication Hydrate NMP
11 11 lll [cm-'] solvate [em-i] [cm_,] [cm-1] [cm-i]

BHC 05 1 117-Foreig n countries Peak snaxima Modificatiori Modification Modification Hydrate NMP
11 ll 111 [cm-'] solvate [cm.11 [cln.-'1 [cm-'] [cm-']

Tab. 4: Raman spectroscopy Peak maxima Modift* Moditi- Modifi- Hydrate NMP
cation1 cation II cation IIII [crri'] solvate [em-r] [cm-11 [cm-1 I[cm r]

11] 184 112 111 105 BHC 05 1 117-Foreign countries Peak niaxima Modifi- Modifi- Modifi- Hydrate NMP cation I cation 11 cationIII [cm-']
solvate [cm-'] [cirn-'] [cm-'] [cm-']

BHC 05 1 117-Foreign countries Tab. 5: FIR spectroscopy Peak maxima Modifi- Modifi- Hydrate NMP solvate cation I cation II [cm '] [cul-i]
[cm'] [cm']

BHC 05 1 117-Foreign countries Tab. 6: NIR spectroscopy pPeak maxima Modifi- Modifi- Modifi- Hydrate NMP
cation I cation I cation 1[cm'] solvate [cm-'] [cm-'][cm-i] [cm ']

Example 7: Preparation of 5-chloro-N-({(5S)-2-oxo-3-14-(3-oxo-4-morpholinyl)-phenyll-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide in amorphous form Example 7.1 About 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 modification I were fused on a Kofler heating bench at about 240 C and subsequently brought to room temperature by shock cooling. The active substance was investigated by X-ray diffractometry and was present in the amorphous form.

BHC 05 1 117-Foreign countries Example 7.2 About 3 g 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 fused in a drying oven at about 250 C
and subsequently brought to room temperature by shock cooling. The active compound was investigated by X-ray diffractometry and was present in the amorphous form.

Tab. 7: Differential scanning calorimetry and thermogravimetry (amorphous form) Glass transition temperature: about 83 C

Tab. 8: Spectroscopy (amorphous form) F Peak maxima [-IR Raman FIR NIR
[cm'i][cm-' ] [cm ' ] [cm ' ] 467 486 91 4006 BHC 05 1 117-Foreign countries CA 02624310 2008-04-01 Peak maxima IRRarnan FIR NIR [cm"] [cn-'] [cm'] [cm 1288 3090

Claims (14)

  1. claims I. A compound of the formula (I) in the modification II or in the amorphous form.
  2. 2. A 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 is dissolved in an inert solvent and the compound is precipitated by addition of a precipitating agent.
  3. 3. A process for the preparation of the compound of the formula (I) in the modification 11, characterized in that the compound of the formula (I) in the modification I is dissolved in an inert solvent and the solution is stored at elevated temperature until the complete evaporation of the solvent.
  4. 4. A 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 is suspended in an anhydrous inert solvent and the suspension is stirred or shaken until quantitative conversion to the modification II.
  5. 5. A process for the preparation of the compound of the formula (I) in the amorphous form, characterized in that the compound of the formula (I) in a crystalline form is completely fused and subsequently rapidly cooled.
  6. 6. A compound of the formula (I) obtainable in the amorphous form by completely fusing the compound of the formula (I) in a crystalline form and rapidly cooling it.
  7. 7. A compound of the formula (I) in the modification II or in the amorphous form for the treatment and/or prophylaxis of diseases.
  8. 8. The use of the compound of the formula (I) in the modification II or in the amorphous form for the production of a medicament for the treatment and/or prophylaxis of thromboembolic diseases.
  9. 9. The use of the compound of the formula (I) in the modification II or in the amorphous form for the prevention of blood coagulation in vitro.
  10. 10. A medicament comprising the compound of the formula (I) in the modification II or in the amorphous form in combination with an inert, nontoxic, pharmaceutically suitable excipient.
  11. 11. A medicament comprising the compound of the formula (I) in the modification II or in the amorphous form in combination with a further active substance.
  12. 12. The medicament as claimed in claim 10 or 11 for the treatment and/or prophylaxis of thromboembolic diseases.
  13. 13. A process for the treatment and/or prophylaxis of thromboembolic diseases in humans and animals using an amount of the compound of the formula (I) having anticoagulatory activity in the modification II or in the amorphous form or of a medicament as defined in one of claims to 12.
  14. 14. A process for the prevention of blood coagulation in vitro, characterized in that an amount of the compound of the formula (I) having anticoagulatory activity in the modification II or in the amorphous form is added.
CA2624310A 2005-10-04 2006-09-22 Polymorphic form of 5-chloro-n-({5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide Active CA2624310C (en)

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DE102005047563A DE102005047563A1 (en) 2005-10-04 2005-10-04 New modification of specific substituted thiophene carboxamide, useful for prevention and treatment of thrombo-embolic disease, has higher solubility than known modifications
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DE102005047564A DE102005047564A1 (en) 2005-10-04 2005-10-04 New forms of specific substituted thiophene carboxamide (rivaroxaban), useful for prevention and treatment of thromboembolic disease, have higher solubility than known modifications
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PCT/EP2006/009202 WO2007039132A1 (en) 2005-10-04 2006-09-22 Novel polymorphous form and the amorphous form of 5-chloro-n-({ (5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidine-5-yl}-methyl)-2-thiophene carboxamide

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010075631A1 (en) * 2008-12-31 2010-07-08 Apotex Pharmachem Inc Polymorphic form of 5-chloro-n-{[(5s)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxa-zolidin-5-yl]-methyl}thiophene-2-carboxamide
US7816355B1 (en) 2009-04-28 2010-10-19 Apotex Pharmachem Inc Processes for the preparation of rivaroxaban and intermediates thereof
US8741890B2 (en) 2007-11-15 2014-06-03 Boehringer Ingelheim International Gmbh Substituted amides, manufacturing and use thereof as medicaments

Families Citing this family (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19962924A1 (en) 1999-12-24 2001-07-05 Bayer Ag Substituted oxazolidinones and their use
DE10129725A1 (en) 2001-06-20 2003-01-02 Bayer Ag Combination therapy of substituted oxazolidinones
DE10300111A1 (en) 2003-01-07 2004-07-15 Bayer Healthcare Ag Process for the preparation of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5-yl} methyl ) -2-thiophenecarboxamide
DE10355461A1 (en) 2003-11-27 2005-06-23 Bayer Healthcare Ag Solid, high bioavailabilty oral formulations of N-substituted 5-chloro-2-thiophene-carboxamide derivative in hydrophilized form, useful for combating thrombo-embolic diseases
EP1685841A1 (en) 2005-01-31 2006-08-02 Bayer Health Care Aktiengesellschaft Prevention and treatment of thromboembolic disorders
DE102005045518A1 (en) 2005-09-23 2007-03-29 Bayer Healthcare Ag New 5-thienylaminocarbonylmethyl-oxazolidin-2-one derivatives, useful for treating and preventing thromboembolic disease, are selective inhibitors of coagulation factor Xa
DE502006009169D1 (en) 2005-10-04 2011-05-05 Bayer Schering Pharma Ag NEUE POLYMORPHE FORM VON 5-CHLOR-N-(ä ( 5S )-2-0X0-3-Ä4-( 3-OXO-4-MORPHOLINYL)-PHENYLÜ-1,3-OXAZOLIDIN-5-YLü -METHYL)-2-THIOPHENCARBOXAMID
DE102005047561A1 (en) 2005-10-04 2007-04-05 Bayer Healthcare Ag Drug delivery system, useful to treat and/or prevent e.g. thromboembolic disease, comprises 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxo-4-morpholinyl)-phenyl)-1,3-oxazolidine-5-yl)-methyl)-2-thiophene carboxamide with fast release active substance
DE102007028318A1 (en) * 2007-06-20 2008-12-24 Bayer Healthcare Ag Oxazolidinone for the treatment and prophylaxis of sepsis
US7985750B2 (en) * 2007-08-14 2011-07-26 Concert Pharmaceuticals, Inc. Substituted oxazolidinone derivatives
DE102008028071A1 (en) * 2008-06-12 2009-12-17 Bayer Schering Pharma Aktiengesellschaft New cocrystal compound of rivaroxaban and malonic acid
MX2011000277A (en) 2008-07-08 2011-06-22 Ratiopharm Gmbh Pharmaceutical compositions comprising 5-chloro-n-({(5s)-2 -oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-met hyl)-2-thiophencarboxamid.
EP2266541A1 (en) 2009-06-18 2010-12-29 Krka Tovarna Zdravil, D.D., Novo Mesto Solid pharmaceutical composition comprising rivaroxaban
HUE031177T2 (en) 2009-06-18 2017-07-28 Krka Tovarna Zdravil D D Novo Mesto Solid pharmaceutical composition comprising rivaroxaban
PL2459555T3 (en) 2009-07-31 2022-03-28 Krka, D.D., Novo Mesto Processes for crystallization of rivaroxaban
EP2308472A1 (en) 2009-10-06 2011-04-13 ratiopharm GmbH Pharmaceutical compositions comprising rivaroxaban
WO2011042156A1 (en) 2009-10-06 2011-04-14 Ratiopharm Gmbh Pharmaceutical compositions comprising rivaroxaban
EP2404920A1 (en) 2010-07-06 2012-01-11 Sandoz AG Crystalline form of Rivaroxaban dihydrate
US20130253187A1 (en) 2010-09-14 2013-09-26 Medichem, S.A. Process for Determining the Suitability for Distribution of a Batch of Thiophene-2-Carboxamide Derivative
AT511045A1 (en) 2011-01-28 2012-08-15 Blum Gmbh Julius FURNITURE WITH A TORQUE TRANSMISSION
WO2013098833A2 (en) 2011-09-08 2013-07-04 Cadila Healthcare Limited Processes and intermediates for preparing rivaroxaban
EP2573084A1 (en) 2011-09-22 2013-03-27 Enantia, S.L. Novel crystalline forms of rivaroxaban and processes for their preparation
HU230734B1 (en) 2011-10-10 2017-12-28 EGIS Gyógyszergyár Nyrt Cocrystals of rivaroxaban for producing pharmaceutical compositions
WO2014016842A1 (en) * 2012-07-23 2014-01-30 Symed Labs Limited Amorphous coprecipitates of rivaroxaban
ES2647607T3 (en) * 2012-12-21 2017-12-22 Farma Grs, D.O.O. Procedure for the preparation of rivaroxaban
US9359341B2 (en) 2012-12-26 2016-06-07 Wanbury Ltd. Aldehyde derivative of substitute oxazolidinones
PT2895176T (en) 2012-12-26 2017-01-27 Wanbury Ltd Rivaroxaban intermediate and preparation thereof
IN2014CH00290A (en) 2014-01-23 2015-08-14 Symed Labs Ltd
WO2015176677A1 (en) * 2014-05-22 2015-11-26 Sunshine Lake Pharma Co., Ltd. Crystalline forms and amorphism of oxazolidinone compound
EA034656B1 (en) * 2014-10-22 2020-03-03 Закляды Фармацеутычне Польфарма С.А Process for preparing a polymorph of rivaroxaban
RU2020103395A (en) * 2020-01-28 2021-07-28 Закрытое Акционерное Общество "Алмаз Фарм" L-, U-modification of 5-chloro-N - ({5S) -2-oxo-3- [4-3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl} -methyl ) -2-thiophenecarboxamide, solvate with dimethyl sulfoxide, methods for their preparation, pharmaceutical compositions based on them, inhibiting factor Xa
GB202102575D0 (en) 2021-02-23 2021-04-07 Teva Pharmaceutical Industries Ltd Fixed-dose pharmaceutical compositions
GR1010231B (en) 2021-03-24 2022-05-10 Φαρματεν Α.Β.Ε.Ε., Pharmaceutical composition comprising rivaroxaban and method of preparation thereof
EP4201933A1 (en) 2021-12-23 2023-06-28 Zaklady Farmaceutyczne Polpharma S.A. Crystallisation process for rivaroxaban

Family Cites Families (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2811555A (en) 1955-05-02 1957-10-29 Eastman Kodak Co Reduction of 2-nitroso-5-diethylaminotoluene
US3279880A (en) 1965-07-12 1966-10-18 Eastman Kodak Co Polyester textile material dyed with 1-hydroxy-4-n-p-(2'-pyrrolidonyl-1-) phenyl-amino anthraquinones
LU80081A1 (en) 1977-08-26 1979-05-15 Delalande Sa NEW HYDROXYMETHYL-5 OXAZOLIDINONES-2, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION
US4128654A (en) 1978-02-10 1978-12-05 E. I. Du Pont De Nemours And Company 5-Halomethyl-3-phenyl-2-oxazolidinones
US4500519A (en) 1978-11-06 1985-02-19 Choay S.A. Mucopolysaccharides having biological properties, preparation and method of use
US4327725A (en) 1980-11-25 1982-05-04 Alza Corporation Osmotic device with hydrogel driving member
HU190072B (en) 1983-03-11 1986-08-28 Biogal Gyogyszergyar,Hu Process for production of medical preparatives with sinergetic influence
NZ206600A (en) 1983-05-11 1987-01-23 Alza Corp Osmotic drug delivery device
US4765989A (en) 1983-05-11 1988-08-23 Alza Corporation Osmotic device for administering certain drugs
ES8506659A1 (en) 1983-06-07 1985-08-01 Du Pont Aminomethyl oxooxazolidinyl benzene derivatives useful as antibacterial agents.
US4977173A (en) 1987-10-21 1990-12-11 E. I. Du Pont De Nemours And Company Aminomethyl oxooxazolidinyl ethenylbenzene derivatives useful as antibacterial agents
CA1317594C (en) 1987-10-21 1993-05-11 Chung-Ho Park Aminomethyloxooxazolidinyl ethenylbenzene derivatives useful as antibacterial agents
DE3822650A1 (en) 1988-07-05 1990-02-01 Boehringer Mannheim Gmbh NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
US4948801A (en) 1988-07-29 1990-08-14 E. I. Du Pont De Nemours And Company Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents
US5254577A (en) 1988-07-29 1993-10-19 The Du Pont Merck Pharmaceutical Company Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents
JP3176626B2 (en) 1991-11-01 2001-06-18 ファルマシア・アンド・アップジョン・カンパニー Substituted aryl- and heteroarylphenyloxazolidinones useful as antimicrobial agents
SK283420B6 (en) 1992-05-08 2003-07-01 Pharmacia & Upjohn Company Oxazolidinones containing a substituted diazine moiety and their use as antimicrobials
US5349045A (en) 1993-01-26 1994-09-20 United States Surgical Corporation Polymer derived from cyclic amide and medical devices manufactured therefrom
DK0623615T3 (en) 1993-05-01 1999-12-13 Merck Patent Gmbh Adhesion receptor antagonists
US5688792A (en) 1994-08-16 1997-11-18 Pharmacia & Upjohn Company Substituted oxazine and thiazine oxazolidinone antimicrobials
DE4332384A1 (en) 1993-09-23 1995-03-30 Merck Patent Gmbh Adhesion receptor antagonists III
DK0807112T3 (en) 1995-02-03 2001-12-17 Upjohn Co Antimicrobial heteroaromatic ring-substituted phenyloxazolidinone
HRP960159A2 (en) 1995-04-21 1997-08-31 Bayer Ag Benzocyclopentane oxazolidinones containing heteroatoms
DE19524765A1 (en) 1995-07-07 1997-01-09 Boehringer Mannheim Gmbh New oxazolidinone derivatives, processes for their preparation and medicaments containing these compounds
HUP9901979A3 (en) 1995-09-01 2000-03-28 Upjohn Co Phenyloxazolidinones having a c-c bond to 4-8 membered heterocyclic rings and pharmaceutical compositions containing the same
WO1997010223A1 (en) 1995-09-15 1997-03-20 Pharmacia & Upjohn Company Aminoaryl oxazolidinone n-oxides
DE19601264A1 (en) 1996-01-16 1997-07-17 Bayer Ag Pyrido-annellated thienyl and furanyl oxazolidinones
DE19604223A1 (en) 1996-02-06 1997-08-07 Bayer Ag New substituted oxazolidinones
HRP970049A2 (en) 1996-02-06 1998-04-30 Bayer Ag New heteroaryl oxazolidinones
GB9614238D0 (en) 1996-07-06 1996-09-04 Zeneca Ltd Chemical compounds
CZ299162B6 (en) 1996-07-15 2008-05-07 Sankyo Company, Limited Pharmaceutical composition and kit
US5935724A (en) 1997-04-04 1999-08-10 Wilson Greatbatch Ltd. Electrochemical cell having multiplate electrodes with differing discharge rate regions
US6273913B1 (en) 1997-04-18 2001-08-14 Cordis Corporation Modified stent useful for delivery of drugs along stent strut
NZ501412A (en) 1997-05-30 2001-11-30 Upjohn Co Oxazolidinone antibacterial agents having a thiocarbonyl functionality
EP0994874A1 (en) 1997-07-11 2000-04-26 PHARMACIA &amp; UPJOHN COMPANY Thiadiazolyl and oxadiazolyl phenyl oxazolidinone antibacterial agents
DE19730847A1 (en) 1997-07-18 1999-01-28 Bayer Ag Tricyclically substituted oxazolidinones
GB9715894D0 (en) 1997-07-29 1997-10-01 Zeneca Ltd Heterocyclic derivatives
DE19747261A1 (en) 1997-10-25 1999-04-29 Bayer Ag Single-chamber osmotic pharmaceutical release system
CA2303959A1 (en) 1997-11-12 1999-05-20 Pharmacia & Upjohn Company Oxazolidinone derivatives and pharmaceutical compositions
US6083967A (en) 1997-12-05 2000-07-04 Pharmacia & Upjohn Company S-oxide and S,S-dioxide tetrahydrothiopyran phenyloxazolidinones
DE19755268A1 (en) 1997-12-12 1999-06-17 Merck Patent Gmbh Benzamidine derivatives
AU764184B2 (en) 1998-01-23 2003-08-14 Pharmacia & Upjohn Company Oxazolidinone combinatorial libraries, compositions and methods of preparation
ZA99607B (en) 1998-01-27 1999-07-27 Rhone Poulenc Rorer Pharma Substituted oxoazaheterocyclyl factor xa inhibitors.
US20010029351A1 (en) 1998-04-16 2001-10-11 Robert Falotico Drug combinations and delivery devices for the prevention and treatment of vascular disease
HUP0101958A3 (en) 1998-05-18 2003-07-28 Upjohn Co Enhancement oxazolidinone antibacterial agents activity by using arginine derivatives
DE19842753A1 (en) 1998-09-18 2000-03-23 Bayer Ag Multiple-unit retard oral dosage formulation having controlled release independent of agitation and food effect, containing particles of combination of drug and hydroxypropyl cellulose
US6413981B1 (en) 1999-08-12 2002-07-02 Ortho-Mcneil Pharamceutical, Inc. Bicyclic heterocyclic substituted phenyl oxazolidinone antibacterials, and related compositions and methods
PE20010851A1 (en) 1999-12-14 2001-08-17 Upjohn Co BENZOIC ACID ESTERS OF OXAZOLIDINONES HAVING A HYDROXYACETILPIPERAZINE SUBSTITUENT
AU782078B2 (en) 1999-12-21 2005-06-30 Pharmacia & Upjohn Company Oxazolidinones having a sulfoximine functionality and their use as antimicrobial agents
DE19962924A1 (en) 1999-12-24 2001-07-05 Bayer Ag Substituted oxazolidinones and their use
AU2225901A (en) 1999-12-28 2001-07-09 Ajinomoto Co., Inc. Aspartame derivative crystals
DE10105989A1 (en) 2001-02-09 2002-08-14 Bayer Ag Substituted oxazolidinones and their use
DE10110438A1 (en) 2001-03-05 2002-09-19 Bayer Ag Substituted 2-oxy-3,5-dicyano-4-aryl-6-aminopyridines and their use
DE10110747A1 (en) 2001-03-07 2002-09-12 Bayer Ag Substituted 2,6-diamino-3,5-dicyano-4-aryl-pyridines and their use
DE10110754A1 (en) 2001-03-07 2002-09-19 Bayer Ag Substituted 2-thio-3,5-dicyano-4-aryl-6-aminopyridines and their use
DE10115922A1 (en) 2001-03-30 2002-10-10 Bayer Ag Cyclically substituted 2-thio-3,5-dicyano-4-aryl-6-aminopyridines and their use
DE10115945A1 (en) 2001-03-30 2002-10-02 Bayer Ag Substituted 2-carba-3,5-dicyano-4-aryl-6-aminopyridines and their use
DE10129725A1 (en) * 2001-06-20 2003-01-02 Bayer Ag Combination therapy of substituted oxazolidinones
DE10134481A1 (en) 2001-07-16 2003-01-30 Bayer Ag Substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines and their use
DE10152460A1 (en) 2001-10-24 2003-05-08 Bayer Ag stents
DE10238113A1 (en) 2001-12-11 2003-06-18 Bayer Ag New 2-substituted methylthio-dicyanopyridine derivatives, useful for treating or preventing e.g. cardiovascular disease and inflammation, are adenosine A1 receptor agonists
US20030161882A1 (en) 2002-02-01 2003-08-28 Waterman Kenneth C. Osmotic delivery system
US20040024660A1 (en) 2002-08-05 2004-02-05 General Electric Company System and method for providing asset management and tracking capabilities
DE10300111A1 (en) * 2003-01-07 2004-07-15 Bayer Healthcare Ag Process for the preparation of 5-chloro-N - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5-yl} methyl ) -2-thiophenecarboxamide
DE10355461A1 (en) 2003-11-27 2005-06-23 Bayer Healthcare Ag Solid, high bioavailabilty oral formulations of N-substituted 5-chloro-2-thiophene-carboxamide derivative in hydrophilized form, useful for combating thrombo-embolic diseases
DE102004002044A1 (en) * 2004-01-15 2005-08-04 Bayer Healthcare Ag manufacturing
DE102004062475A1 (en) 2004-12-24 2006-07-06 Bayer Healthcare Ag Solid, orally administrable, modified release pharmaceutical dosage forms
EP1685841A1 (en) 2005-01-31 2006-08-02 Bayer Health Care Aktiengesellschaft Prevention and treatment of thromboembolic disorders
DE102005045518A1 (en) 2005-09-23 2007-03-29 Bayer Healthcare Ag New 5-thienylaminocarbonylmethyl-oxazolidin-2-one derivatives, useful for treating and preventing thromboembolic disease, are selective inhibitors of coagulation factor Xa
DE102005047558A1 (en) 2005-10-04 2008-02-07 Bayer Healthcare Ag Combination therapy of substituted oxazolidinones for the prophylaxis and treatment of cerebral circulatory disorders
DE502006009169D1 (en) 2005-10-04 2011-05-05 Bayer Schering Pharma Ag NEUE POLYMORPHE FORM VON 5-CHLOR-N-(ä ( 5S )-2-0X0-3-Ä4-( 3-OXO-4-MORPHOLINYL)-PHENYLÜ-1,3-OXAZOLIDIN-5-YLü -METHYL)-2-THIOPHENCARBOXAMID
DE102005047561A1 (en) 2005-10-04 2007-04-05 Bayer Healthcare Ag Drug delivery system, useful to treat and/or prevent e.g. thromboembolic disease, comprises 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxo-4-morpholinyl)-phenyl)-1,3-oxazolidine-5-yl)-methyl)-2-thiophene carboxamide with fast release active substance
DE102005048824A1 (en) 2005-10-10 2007-04-12 Bayer Healthcare Ag Treatment and prophylaxis of microangiopathies

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8741890B2 (en) 2007-11-15 2014-06-03 Boehringer Ingelheim International Gmbh Substituted amides, manufacturing and use thereof as medicaments
WO2010075631A1 (en) * 2008-12-31 2010-07-08 Apotex Pharmachem Inc Polymorphic form of 5-chloro-n-{[(5s)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxa-zolidin-5-yl]-methyl}thiophene-2-carboxamide
US7816355B1 (en) 2009-04-28 2010-10-19 Apotex Pharmachem Inc Processes for the preparation of rivaroxaban and intermediates thereof
WO2010124385A1 (en) * 2009-04-28 2010-11-04 Apotex Pharmachem Inc. Processes for the preparation of rivaroxaban and intermediates thereof
US8101609B2 (en) 2009-04-28 2012-01-24 Apotex Pharmachem Inc. Processes for the preparation of rivaroxaban and intermediates thereof
AU2010242496B2 (en) * 2009-04-28 2015-08-27 Apotex Pharmachem Inc. Processes for the preparation of Rivaroxaban and intermediates thereof

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