WO2003000256A1 - Kombinationstherapie substituierter oxazolidinone - Google Patents
Kombinationstherapie substituierter oxazolidinone Download PDFInfo
- Publication number
- WO2003000256A1 WO2003000256A1 PCT/EP2002/006237 EP0206237W WO03000256A1 WO 2003000256 A1 WO2003000256 A1 WO 2003000256A1 EP 0206237 W EP0206237 W EP 0206237W WO 03000256 A1 WO03000256 A1 WO 03000256A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- oxo
- chloro
- methyl
- phenyl
- oxazolidin
- Prior art date
Links
- 0 *C(*)(C(*)(C(*)(*)N1*)OC1=O)N(*)C(*)=O Chemical compound *C(*)(C(*)(C(*)(*)N1*)OC1=O)N(*)C(*)=O 0.000 description 4
- SACOFAMTBDMJNN-UHFFFAOYSA-N C=CCNC(c([s]1)ccc1Cl)=O Chemical compound C=CCNC(c([s]1)ccc1Cl)=O SACOFAMTBDMJNN-UHFFFAOYSA-N 0.000 description 1
- PLESEHHNSMOZAH-UHFFFAOYSA-N Cc1ccc(C(NCC(OC2OC)=CN2c(cc2)cc(F)c2N2CCOCC2)=O)[s]1 Chemical compound Cc1ccc(C(NCC(OC2OC)=CN2c(cc2)cc(F)c2N2CCOCC2)=O)[s]1 PLESEHHNSMOZAH-UHFFFAOYSA-N 0.000 description 1
- MHCRLDZZHOVFEE-UHFFFAOYSA-N Nc(cc1)ccc1N(CCOC1)C1=O Chemical compound Nc(cc1)ccc1N(CCOC1)C1=O MHCRLDZZHOVFEE-UHFFFAOYSA-N 0.000 description 1
- KCTMIUBEQWDLMB-CFMCSPIPSA-N O=C(CCBr)Nc(cc1)ccc1N(C[C@H](CNC(C(S1)=CCC1Cl)=O)O1)C1=O Chemical compound O=C(CCBr)Nc(cc1)ccc1N(C[C@H](CNC(C(S1)=CCC1Cl)=O)O1)C1=O KCTMIUBEQWDLMB-CFMCSPIPSA-N 0.000 description 1
- MYQOFWXLYPTHJO-UHFFFAOYSA-N [O-][N+](c(cc(cc1)N(CC(CBr)O2)C2=O)c1F)=O Chemical compound [O-][N+](c(cc(cc1)N(CC(CBr)O2)C2=O)c1F)=O MYQOFWXLYPTHJO-UHFFFAOYSA-N 0.000 description 1
- OWMGEFWSGOTGAU-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1N(CCOC1)C1=O)=O Chemical compound [O-][N+](c(cc1)ccc1N(CCOC1)C1=O)=O OWMGEFWSGOTGAU-UHFFFAOYSA-N 0.000 description 1
- CKOKGTGEVUWKTF-NSHDSACASA-N [O-][NH+](c(cc1)ccc1N(C[C@H](CNC(c([s]1)ccc1Cl)=O)O1)C1=O)[O-] Chemical compound [O-][NH+](c(cc1)ccc1N(C[C@H](CNC(c([s]1)ccc1Cl)=O)O1)C1=O)[O-] CKOKGTGEVUWKTF-NSHDSACASA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic 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
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to combinations of A) oxazolidinones of the formula (I) with B) other active substances, a process for the preparation of these combinations and their use as medicaments, in particular for the prophylaxis and / or treatment of thromboembolic disorders.
- Oxazolidinones of the formula (I) act in particular as selective inhibitors of the blood coagulation factor Xa and as anticoagulants.
- Factor Xa inhibitors can therefore preferably be used in medicaments for the prophylaxis and / or treatment of thromboembolic disorders.
- Thromboembolic vascular disease is the leading cause of morbidity and mortality in industrialized countries (Thiemes Internal Medicine, Georg Thieme Verlag Stuttgart, New York; American Heart Association, 2000 heart and stroke statistical update, Dallas, TX: American Heart Association, 2000).
- Anticoagulant therapy has been used in the treatment of vascular diseases, in order to avoid thrombotic occlusions or to reopen thrombotically occluded vessels, has proven itself and is of great importance in the prophylaxis and treatment of coronary, peripheral and cerebral vascular diseases, as well as in the prophylaxis and / or treatment of venous thrombosis and pulmonary embolism.
- Thromboembolic complications can be caused by atherosclerotic changes in the vascular wall, particularly disorders of endothelial function, which can lead to acute thrombotic occlusions.
- Atherosclerosis is a multifactorial disease that depends on a variety of cardiovascular risk factors. Clinical studies have shown that prophylaxis with anticoagulants does not have a decisive influence on the course of the arterial disease. Targeted treatment of the risk factors in conjunction with anti-thrombotic therapy is therefore advantageous.
- Risk factors for coronary, peripheral and cerebral vascular diseases are, for example: Increased serum cholesterol levels, arterial hypertension, cigarette smoking, diabetes mellitus (general and special pharmacology and toxicology, W. Forth, D. Henschler, W. Rummel, K. Starke; spectrum of academic publishing house Heidelberg Berlin Oxford; Thiemes Internal Medicine, Georg Tbieme
- Preventive medicine principles are based on the elimination of these risk factors. In addition to changing lifestyle habits, this also includes pharmacological measures such as antihypertensive therapy, lipid-lowering drugs or thrombosis prophylaxis. In addition, the combination with coronary therapeutic agents is suitable for treatment of an already existing coronary heart disease.
- B) other active substances in particular with platelet aggregation inhibitors, anticoagulants, fibrinolytics, lipid-lowering agents, coronary therapeutic agents and / or vasodilators.
- “Combinations” in the sense of the invention are not only dosage forms which contain all components (so-called fixed combinations) and combination packs which contain the components separately from one another, but also components which are applied simultaneously or at different times, provided that they are used for prophylaxis and / or It is also possible to combine two or more active substances with one another, so that these are two or more combinations.
- Suitable oxazolidinones of the combination according to the invention include, for example, compounds of the formula (I)
- R 1 represents optionally benzo-condensed thiophene (thienyl), which can optionally be mono- or polysubstituted;
- R 2 represents any organic radical;
- R, R, R, R, R and R are the same or different and represent hydrogen or (C 1 -C 6 ) alkyl
- R 2 represents one of the following groups:
- the radical "A” is (C 6 -C 14) -aryl, preferably (C 6 -C 1 o) aryl, in particular phenyl or naphthyl, very particularly preferably phenyl;
- the radical "B” for a 5- or 6-membered aromatic heterocycle which has up to 3 heteroatoms and / or hetero chain links, in particular up to 2 heteroatoms and / or hetero chain links, from the series S, N, NO
- the radical "D” stands for a saturated or partially unsaturated, mono- or bicyclic, optionally benzo-fused 4- to 9-membered heterocycle which has up to three heteroatoms and / or hetero chain links from the series S, SO, S0 2 , N Contains, NO (N-oxide) and O;
- the radical "M” for -NB-, -CH 2 -, -CH 2 CH 2 -, -O-, -NH-CH 2 -, -CH 2 -NH- , -OCH 2 -, -CH 2 O-, -CONH-, -NHCO-, -COO-, -OOC-, -S-, -SO 2 - or represents a covalent bond;
- v means either 0 or 1 and 01 AQ
- R, R and R are the same or different and are independently hydrogen, (dC 4 ) alkyl, (C 3 -C 7 ) cycloalkyl, (dC 4 ) alkanoyl, carbamoyl, trifluoromethyl, phenyl or pyridyl,
- R 27 and R 28 or R 27 and R 29 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 5- to 7-membered heterocycle with up to three, preferably up to two identical or different heteroatoms from the Group of N,
- R 30 and R 31 are the same or different and independent of each other
- R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are the same or different and are for hydrogen or for
- R 1 stands for thiophene (thienyl), in particular 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, amino, aminomethyl or (d-C8) -alkyl, preferably methyl, the ( C 1 -C 8 -alkyl radical may in turn optionally be substituted one or more times by halogen, preferably fluorine,
- R 2 represents one of the following groups:
- the radical "A” stands for (C 6 -C 14 ) aryl, preferably for (C 6 -do) aryl, in particular for phenyl or naphthyl, very particularly preferably for phenyl;
- the radical "B” for a 5- or 6-membered aromatic heterocycle which contains up to 3 heteroatoms and / or hetero chain links, in particular up to 2 heteroatoms and / or hetero chain links, from the series S, N, NO (N-oxide) and O;
- the radical “D” stands for a saturated or partially unsaturated 4- to 7-membered heterocycle which contains up to three heteroatoms and or hetero-chain links from the series S, SO, SO 2 , N, NO (N-oxide) and O;
- the remainder "M” for -NH-, -CH 2 -, -CH 2 CH 2 -, -O-, -NH-CH 2 -, -CH 2 -NH-, -OCH 2 -, -CH 2
- -C (NR 27 R 28 ) NR 29 ; -CONR 28 R 29 ; -SO 2 NR 28 R 29 ; -OR 30 ; -NR 30 R 31 , (dC 6 ) alkyl and (C 3 -C 7 ) cycloalkyl,
- v means either 0 or 1
- 77 8 77 70 R and R or R and R together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 5- to 7- membered heterocycle with up to three, preferably up to two identical or different heteroatoms from the group of N, O and S, and
- R 30 and R 31 are the same or different and independent of each other
- R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are the same or different and stand for hydrogen or for (dC 6 ) alkyl
- R 1 stands for thiophene (thienyl), in particular 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, or (d-Cg) -alkyl, preferably methyl, where the (dC 8 ) -
- the alkyl radical may in turn be substituted one or more times by halogen, preferably fluorine,
- R 2 stands for one of the following groups: A-, AM-, DMA-,
- the radical "A” represents phenyl or naphthyl, in particular phenyl
- the radical "B” represents a 5- or 6-membered aromatic heterocycle which contains up to 2 heteroatoms from the series S, N, NO (N -Oxide) and contains O
- the radical "D” represents a saturated or partially unsaturated 5- or 6-membered heterocycle which contains up to two heteroatoms and / or hetero-chain links from the series S, SO, SO 2 , N, NO (N-oxide) and O.
- the previously defined groups “A”, “B” and “D” can each be optionally substituted one or more times with a radical from the group consisting of halogen; trifluoromethyl; oxo; cyano; pyridyl; (dC 3 ) alkanoyl; (C 6 -C 10 ) -
- v is either 0 or 1, preferably 0, and
- R 27 , R 28 and R 29 are identical or different and independently of one another are hydrogen, (dC) -alkyl or else cyclopropyl, cyclopentyl or cyclohexyl and or
- R and R or R and R together with the nitrogen atom to which they are attached can form a saturated or partially unsaturated 5- to 7-membered heterocycle with up to two identical or different heteroatoms from the group of N, O and S. , and
- R 30 and R 31 are the same or different and are independently hydrogen, (dC) -alkyl, cyclopropyl, cyclopentyl, cyclohexyl,
- R, R, R, R, R and R are the same or different and are for hydrogen or for
- R 1 represents 2-thiophene, which may optionally be substituted in the 5-position by a radical from the group chlorine, bromine, methyl or trifluoromethyl, stands for one of the following groups: A-, AM-, DMA-,
- the radical "A” represents phenyl or naphthyl, in particular phenyl
- the radical “B” represents a 5- or 6-membered aromatic heterocycle which contains up to 2 heteroatoms from the series S, N, NO (N -Oxide) and contains O
- the radical “D” stands for a saturated or partially unsaturated 5- or 6-membered heterocycle which has a nitrogen atom and optionally a further heteroatom and or hetero chain link from the series S, SO, SO 2 and O; or up to contains two heteroatoms and / or hetero chain links from the series S, SO, SO 2 and O
- the remainder "M” for -NH-, -O-, -NH-CH 2 -, -CH 2 -NH-, - OCH 2 -, -CH 2 O-, -CONH-, -NHCO- or represents a covalent bond;
- v is either 0 or 1, preferably 0, and
- 77 7R 70 R, R and R are the same or different and are independent of each other
- R 27 and R 28 or R 27 and R 29 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 5- to 7-membered heterocycle with up to two identical or different heteroatoms from the group of N, O and S can form, and
- R 30 and R 31 are the same or different and are independently hydrogen, (-CC 4 ) -alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C 1 -C 4 ) -alkylsulfonyl, (dC 4 ) -hydroxyalkyl, (-C-C 4 ) -aminoalkyl, di- (C 1 -C 4 ) -alkylammo- (C 1 -C 4 ) -alkyl, (C 1 -C 3 ) -alkanoyl or phenylcarbonyl,
- R, R, R, R, R and R are the same or different and stand for hydrogen or for (d ⁇ -alkyl
- R 1 represents 2-thiophene which is substituted in the 5-position by a radical from the group chlorine, bromine, methyl or trifluoromethyl,
- R z stands for DA-:
- radical "A” stands for phenylene
- radical “D” stands for a saturated 5- or 6-membered heterocycle which is linked via a nitrogen atom to "A”, which has a carbonyl group in the direct vicinity of the linking nitrogen atom and in which a ring carbon member can be replaced by a hetero atom from the series S, N and O;
- R 3 , R 4 , R 5 , R 6 , R 7 and R s are hydrogen
- Substituted aryl and heteroarylphenyloxazolidinones in which a mono- or polysubstituted phenyl radical may be bonded to the N atom of the oxazolidinone ring and which may have an unsubstituted N-methyl-2-thio ⁇ hencarboxamide radical in the 5-position of the oxazolidinone ring, and also theirs Use as antibacterial substances are known from US Pat.
- benzanidine-containing oxazolidinones are known as synthetic intermediates in the synthesis of factor Xa inhibitors or fibrinogen antagonists (WO-A-99/31092, EP-A-623615).
- the compounds of the formula (I) can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers). Both the enantiomers or diastereomers and theirs are included respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
- Physiologically harmless, i.e. pharmaceutically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Salts with inorganic acids such as, for example, are preferred
- Hydrochloric acid hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as, for example, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid or toluenesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, , ,
- salts with customary bases such as alkali metal salts (e.g. sodium or potassium salts), alkaline earth salts (e.g. calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as dimethylamine, triethylamine,
- Such forms of the compounds of the above formula (I) are referred to as "hydrates" which, in the solid or liquid state, form a molecular compound (solvate) by hydration with water.
- the water molecules are secondary by intermolecular forces, in particular hydrogen.
- Solid hydrates contain water as so-called crystal water in stoichiometric proportions, the water molecules not having to be equivalent in terms of their binding state Sesquihydrates, monohydrates, dihydrates or trihydrates. Equally, the hydrates of salts of the compounds according to the invention can also be used.
- Prodrugs are those forms of the compounds of the above formula (I) which are themselves biologically active or inactive, but which can be converted into the corresponding biologically active form (for example metaboic, solvolytic or otherwise).
- Halogen stands for fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred.
- (DC 8 ) -alkyl stands for a straight-chain or branched alkyl radical having 1 to 8 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl.
- the corresponding alkyl groups with fewer carbon atoms, such as (dC 6 ) alkyl and (C 1 -C 4 ) alkyl, are derived analogously from this definition. In general, (dC 4 ) -
- Alkyl is preferred.
- Cycloalkyl stands for a cyclic alkyl radical with 3 to 7 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The corresponding cycloalkyl groups with fewer carbon atoms, such as (C 3 -C 5 ) cycloalkyl, are derived analogously from this definition. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.
- (C 2 -C 6 ) alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms.
- a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms is preferred. Examples include: vinyl, AUyl, isopropenyl and n-but-2-en-l-yl.
- (C 1 -C 8 ) alkoxy represents a straight-chain or branched alkoxy radical having 1 to 8 carbon atoms. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy, n-heptoxy and n-octoxy.
- the corresponding alkoxy groups with fewer carbon atoms, such as (dC 6 ) alkoxy and (dC 4 ) - are derived analogously from this definition.
- Mono- or di- (dC 4 ) -alkylaminocarbonyl stands for an amino group which is linked via a carbonyl group and which has a straight-chain or branched or two identical or different straight-chain or branched alkyl substituents each having 1 to 4 carbon atoms.
- Examples include: methylaminino, ethylamino, n-propylamino, isopropylamino, t-butylamino, NN-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N- Isopropyl-Nn-propylamino and Nt-butyl-N-me ylamino.
- (dC 6 ) -alkanoyl represents a straight-chain or branched alkyl radical having 1 to 6
- Carbon atoms which has a double bonded oxygen atom in the 1 position and is linked via the 1 position.
- Examples include: formyl, acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl, n-hexanoyl.
- the corresponding alkanoyl groups with fewer carbon atoms such as (d-C5) alkanoyl, (C 1 -C 4 ) alkanoyl and (C 1 -C 3 ) alkanoyl, are derived analogously from this definition. In general, (-C-C 3 ) alkanoyl is preferred.
- the meaning of the corresponding constituent of other more complex substituents such as cycloalkanoyl and alkanoylalkyl, is also derived from this definition.
- Cycloalkanoyl represents a cycloalkyl radical as defined above with 3 to 7
- Carbon atoms linked via a carbonyl group Carbon atoms linked via a carbonyl group.
- Alkanoyloxymethyloxy stands for a straight-chain or branched alkanoyloxymethyloxy radical with 1 to 6 carbon atoms. Examples include: acetoxymethyloxy, propionoxymethyloxy, n-butyroxymethyloxy, i-
- alkanoyloxymethyloxy is preferred.
- (C 6 -C 14 ) aryl represents an aromatic radical having 6 to 14 carbon atoms. Examples include: phenyl, naphthyl, phenanthrenyl and anthracenyl.
- the corresponding aryl groups with fewer carbon atoms, such as (C 6 -do) aryl, are derived analogously from this definition. In general, (C 6 -do) aryl is preferred.
- heteroatoms and / or hetero chain links from the series S, O, N and / or NO stands for a mono- or bicyclic heteroaromatic, which is linked via a ring carbon atom of the heteroaromatic, optionally also via a ring nitrogen atom of the heteroaromatic.
- N-oxide stands for a mono- or bicyclic heteroaromatic, which is linked via a ring carbon atom of the heteroaromatic, optionally also via a ring nitrogen atom of the heteroaromatic.
- Examples include: pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl,
- a 3- to 9-membered saturated or partially unsaturated, mono- or bicyclic, optionally benzo-fused heterocycle with up to 3 heteroatoms and / or hetero chain links from the series S, SO, SO, N, NO (K-oxide) and / or O represents a heterocycle which may contain one or more double bonds, which may be mono- or bicyclic, in which a benzene ring may be fused to two adjacent ring carbon atoms and which is linked via a ring carbon atom or a ring nitrogen atom.
- Examples include: tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide, thiomopholinyl, azepinyl, 1,4-diazepinyl and cyclohexyl. Piperidinyl, morpholinyl and pyrrolidinyl are preferred.
- the corresponding cycles with a smaller ring size e.g. 5- to 7-membered cycles.
- the compounds of formula (I) can be prepared by either according to a process alternative
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are those given above
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are those given above
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the meanings given above,
- Suitable solvents for the processes described above are organic solvents which are inert under the reaction conditions. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethyl methylene, alkylene glycol dimethyl ether Ethanol, n-propanol, iso-propanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine, hexa
- reagents usually used for this purpose are suitable as activation or coupling reagents for the processes described above.
- bases are suitable as bases.
- bases preferably include alkali metal hydroxides such as sodium or potassium hydroxide or alkali metal carbonates such as sodium or potassium carbonate or sodium or Potassium methoxide or sodium or potassium ethanolate or potassium tert-butoxide or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide or amines such as triethylamine, diisopropylethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine or pyridine.
- alkali metal hydroxides such as sodium or potassium hydroxide or alkali metal carbonates such as sodium or potassium carbonate or sodium or Potassium methoxide or sodium or potassium ethanolate or potassium tert-butoxide
- amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide or amines such as triethylamine, diiso
- the base can be used in an amount of 1 to 5 mol, preferably 1 to 2 mol, based on 1 mol of the compounds of the general formula (II).
- the reactions generally take place in a temperature range from -78 ° C. to the reflux temperature, preferably in the range from 0 ° C. to the reflux temperature.
- the reactions can be carried out at normal, elevated or reduced pressure (e.g. in the range from 0.5 to 5 bar). Generally one works at normal pressure.
- Suitable suitable oxidizing agents for the production of the epoxides and for the oxidation to sulfone, sulfoxide or N-oxide which may be carried out are, for example, m-chloroperbenzoic acid (MCPBA), sodium meta-periodate, N-methylmorpholine-N-oxide (NMO), monoperoxyphthalic acid or
- a preferred compound A) of the formula (I) for use in combinations is 5-chloro-N - ( ⁇ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -l , 3-oxazolidin-5- yl ⁇ methyl) -2-thiophencarboxamide, the compound from Example 44.
- the combinations according to the invention are particularly suitable for the prophylaxis and or treatment of arterial thromboses and embolisms in coronary heart diseases, cerebrovascular circulatory disorders and peripheral arterial circulatory disorders.
- the combinations of oxazolidinones of the formula (I) with platelet aggregation inhibitors, anticoagulants and / or fibrinolytics are moreover particularly suitable for the prophylaxis and / or treatment of venous thrombosis and pulmonary embolism.
- oxazolidinones of the formula (I) are known from the literature and the majority are commercially available. If appropriate, like oxazolidinones of the formula (I), they can be used in doses which have effective therapeutic effects.
- a combination therapy of oxazolidinones of the formula (I) with lipid-lowering agents, in particular with HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reduction inhibitors such as, for example, cerivastatin (rivastatin, Baycol; US 5,177,080), Lovastatin (Mevacor; US 4,231,938), Simvastatin (Zocor; US 4,444,784), Pravastatin
- ACE angiotensm converting enzyme
- Embusartan (US 5,863,930), losartan, valsartan, irbesartan, candesartan, eprosartan, temisartan; ⁇ -adrenoceptor antagonists such as, for example, Carvedilol, Alprenolol, Bisoprolol, Acebutolol, Atenolol, Betaxolol, Carteolol, Metoprolol, Nadolol, Penbutolol, Pindolol, Propanolol, Timolol; alpha-1 adrenoceptor antagonists such as prazosin, bunazosin, doxazosin, terazosin;
- Diuretics such as hydrochlorothiazide, furosemide, bumetanide, piretanide, torasemide, amiloride; hydralazine; Calcium channel blockers such as verapamil, diltiazem or dihydropyridine derivatives such as nifedipine (Adalat) or nitrendipine (bayotensin); Substances which increase cyclic guanosine monophosphate (cGMP), such as, for example, stimulators of soluble guanylate cyclase (WO 98/16223, WO 98/16507, WO 98/23619, WO 00/06567, WO 00/06568, WO 00/06569 , WO 00/21954, WO 00/66582, WO 01/17998, WO 01/19776, WO 01/19355, WO 01/19780, WO 01/19778), are suitable.
- cGMP cycl
- the pharmacotherapeutic aim of treating an already existing coronary heart disease is to eliminate the mismatch between oxygen supply and oxygen demand in the myocardial areas affected by ischemia.
- a combination therapy of an oxazolidinone of the formula (I) with coronary therapeutic agents, in particular with ⁇ -adrenoceptor antagonists, is therefore particularly suitable for treatment of an already existing coronary heart disease;
- ACE angiotensin converting enzyme
- A-II- angiotensin Ifj receptor antagonists; itro-preparations such as isosorbide-5-mononitrate, isosorbide dinitrate, glycerol trinitrate; Substances that cause an increase in cyclic guanosine monophosphate (cGMP); Calcium channel blockers suitable. The majority of these compounds are also used to treat high pressure.
- thrombolytic therapy with plasminogen activators (thrombolytics / fibrinolytics) such as tissue plasminogen activator (t-PA), streptokinase, reteplase or urokinase has proven effective.
- plasminogen activators such as tissue plasminogen activator (t-PA), streptokinase, reteplase or urokinase has proven effective.
- t-PA tissue plasminogen activator
- streptokinase streptokinase
- reteplase reteplase
- urokinase urokinase
- Plasminogen activators can also mean an increased risk of bleeding.
- the combined administration of a thrombolytic agent with an oxazolidinone of the formula (I) for opening thrombotic occluded vessels in coronary heart disease, transient ischemic attacks, stroke, peripheral arterial occlusive diseases and pulmonary embolism prevents further growth of the
- Thrombus by inhibiting thrombin formation and thus reducing the risk of re-occlusion.
- the therapeutically required dose of the thrombolytic agent can be reduced, which leads to a reduction in the bleeding complications and thus a considerable one
- Oxazolidinones of the formula (I) can also be used in combination with other anticoagulant substances (anticoagulants) for the prophylaxis and / or treatment of arterial, intracardiac and venous thromboembolic
- oxazolidinones of the formula (I) in particular with heparin (UFH), low molecular weight heparins (NMH) such as, for example, tinzaparin, certoparin, pamaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin or direct thrombin inhibitors such as, for example, hirudin, leads to an increased antithrombotic effect.
- UHF heparin
- NMH low molecular weight heparins
- Oxazolidinones of the formula (I) can also be given in combination with platelet aggregation-inhibiting substances (platelet aggregation inhibitors, platelet aggregation inhibitors) for the prophylaxis and or treatment of arterial, intracardiac and venous thromboembolic disorders. Endothelial lesion leads to the lifting and activation of
- Combinations of an oxazolidinone of the formula (I) with platelet aggregation inhibitors such as, for example, aspirin, ticlopidine (ticlid), clopidogrel (Plavix) are particularly suitable for the combination therapy; Fibrinogen receptor antagonists; (Glycoprotein ilb / ITIa antagonists) such as, for example, abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban.
- the application is preferably oral, lingual, sublingual, buccal, rectal, topical or parenteral (i.e. bypassing the intestinal tract, i.e. intravenously, intraarterially, intracardially, intracutaneously, subcutaneously, transdermally, intraperitoneally or intramuscularly).
- the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable auxiliaries and / or carriers, contain one or more combinations according to the invention or which consist of a combination according to the invention, and processes for the preparation of these preparations.
- the combinations according to the invention should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.
- the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.
- the pharmaceutical preparations listed above can be prepared in a customary manner by known methods, e.g. by mixing the active ingredient or ingredients with the carrier or carriers.
- the combinations according to the invention in total amounts of about 0.001 to 100 mg / kg, preferably about 0.01 to 100 mg / kg, in particular about 0.1 to 10 mg / kg body weight per 24 hours, if appropriate in the form of several single doses to achieve the desired results.
- the invention therefore also relates to the combinations defined above for the prophylaxis and / or treatment of diseases.
- the invention further relates to medicaments containing at least one of the combinations defined above and optionally further pharmaceutical active ingredients.
- Another object of the invention is the use of the combinations defined above for the production of medicaments for the prophylaxis and / or treatment of the diseases described above, preferably thromboembolic diseases, in particular of heart attack, angina pectoris (including unstable angina), sudden cardiac death, reocclusions and restenoses after an angioplasty or aortocoronary bypass, stroke, transient ischemic
- the compounds of the formula (I) act, in particular, as selective inhibitors of the blood coagulation factor Xa and do not inhibit, or only at significantly higher concentrations, other serine proteases such as thrombin, plasmin or trypsin.
- Inhibitors of the blood coagulation factor Xa are termed "selective" in which the IC5 0 values for factor Xa inhibition compared to the IC 50 values for inhibition of other serine proteases, in particular thrombin, plasmin and trypsin, by 100 times, are preferably 500 times, in particular 1,000 times, smaller, with respect to the test methods for selectivity
- the enzymatic activity of human factor Xa was measured via the conversion of a chromogenic substrate specific for the FXa.
- the factor Xa cleaves p-nitroaniline from the chromogenic substrate.
- the chromogenic substrate 150 ⁇ mol / 1 Pefachrome® FXa from Pentapharm
- the absorbance at 405 nm was determined.
- the extinctions of the test batches with test substance were compared with the control batches without test substance and the IC50 values were calculated therefrom.
- test substances were examined for their inhibition of other human serine proteases such as thrombin, trypsin, plasmin.
- thrombin 75 mU / ml
- Chromozym Plasmin® from Boehringer Mannheim
- the anticoagulant effect of the test substances was determined in vitro in human plasma.
- human blood was used using a 0.11 molar sodium citrate solution as a template in a mixing ratio of sodium citrate / blood 1/9 decreased.
- the blood was mixed well immediately after collection and centrifuged at about 2000 g for 10 minutes. The supernatant was pipetted off.
- the prothrombin time (PT, synonyms: thromboplastin time, quick test) was measured in the presence of varying concentrations of test substance or the corresponding solvent using a commercially available test kit (Neoplastin® from the company
- test compounds were incubated with the plasma at 37 ° C. for 10 minutes.
- the coagulation was then triggered by adding thromboplastin and the time at which the coagulation started was determined.
- concentration of test substance which doubled the prothrombin time was determined.
- Fasted male rats (strain: HSD CPB: WU) weighing 200-250 g were anesthetized with a Rompun / Ketavet solution (12 mg / kg / 50 mg / kg). Thrombus formation was carried out in an arteriovenous shunt based on the method described by Christopher N. Berry et al., Br. J. Pharmacol. (1994), 113, 1209-1214 triggered the method described. To this end, the left jugular vein and the right carotid artery were dissected. An extracorporeal shunt was placed between the two vessels using a 10 cm long polyethylene tube (PE 60). The middle of this polyethylene tube was bound in a further 3 cm long polyethylene tube (PE 160), which contained a roughened nylon thread and a loop to create a thrombogenic surface. The extracorporeal
- mice Male fasting rats (strain: HSD CPB: WU) were anesthetized as described above. The rats weighed approximately 200 g on average. The left carotid artery was dissected (approx. 2 cm). The formation of an arterial thrombus was caused by a mechanical vascular injury based on that of K. Meng et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. For this purpose, the freely prepared carotid artery was disconnected from the blood flow, cooled to -12 ° C. in a metal channel for 2 minutes and compressed to a weight of 200 g to standardize the thrombus size.
- the blood flow was then additionally reduced by a clip placed around the carotid artery distally from the injured vessel section.
- the proximal clamp was removed, the wound was closed and opened again after 4 hours to remove the injured section of the vessel.
- the vascular section was opened longitudinally and the thrombus removed from the injured vascular section.
- the wet weight of the thrombi was determined immediately.
- the test substances became too
- the start of the experiment was administered either intravenously via the tail vein or orally to animals awake using a pharynx.
- mice Male fasting rats (strain: HSD CPB: WU) were anesthetized as described above. The rats weighed approximately 200 g on average. The left jugular vein was dissected (approx. 2 cm). The formation of a venous thrombus was caused by mechanical vascular injury based on that of K. Meng et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. For this purpose, the jugular vein was disconnected from the blood flow, cooled in a metal channel to - 12 ° C for 2 minutes and simultaneously compressed with a weight of 200 g to standardize the thrombus size. The blood flow was reopened and the wound closed. After 4 hours the wound was opened again to remove the thrombi from the injured vascular sections.
- the wet weight of the thrombi was determined immediately.
- the test substances were either administered intravenously via the tail vein or orally by means of a pharyngeal tube to awake animals.
- the carotid artery was dissected under anesthesia in rats (HSD CPB: WU, Harlan Winkelmann).
- a piece of filter paper impregnated with an aqueous 10% FeCl 3 solution (dissolved in IN aqueous hydrochloric acid) was carefully pushed under the prepared container, in accordance with the method described by Kurz et al. (Rat Model of Arterial Thrombosis Induced by Ferne Chloride, Thrombosis Research 60, 269-280, 1990). After 3 minutes the piece of filter paper was removed.
- the carotid artery was removed after 15 minutes, the thrombus detached and weighed immediately.
- the animals (10 rats per group) were pretreated with 1 mg kg each of the individual active substances (oxazolidinone of the formula (I) or combination active substance) or with the combination of 1 mg / kg oxazolidinone of the formula (I) and 1 mg / kg combination active substance Service.
- the animals in the control group were treated with the appropriate solvent.
- Statistical significance was calculated using Student's t test. Values with p ⁇ 0.05 are regarded as statistically significant effects (Medical Statistics, MJ Campbell, D.Machin, Second Edition, John Wiley & Sons). The results are shown in Table 2:
- Table 2 Synergistic antithrombotic effect of the combination of a Qxazolidinone of formula (I) with a platelet aggregation inhibitor
- N- (2,3-epoxypropyl) phthaline is in J.-W. Chern et al. Tetrahedron Lett. 1998.5P, 8483.
- the substituted anilines can be obtained by reacting, for example, 4-fluoronitrobenzene, 2,4-difluoronitrobenzene or 4-chloronitrobenzene with the corresponding amines or amides in the presence of a base.
- Pd catalysts such as Pd (OAc) 2 / DPPF / NaOt-Bu (Tetrahedron Lett. 1999, 40, 2035) or copper (Renger, Synthesis 1985, 856; Aebischer et al, Heterocycles 1998, 5.2225) happen.
- halogen aromatics without a nitro group can first be converted into the corresponding amides in order to then nitrate them in the 4-position (US3279880).
- NMP N-methylpyrrolidone
- MS (rI%) 222 (74, M 4 ), 193 (100), 164 (28), 150 (21), 136 (61), 117 (22), 106 (24), 90 (37), 76 (38), 63 (32), 50 (25)
- the purification can also be carried out by chromatography on silica gel with hexane / ethyl acetate.
- 1 H NMR 300 MHz, CDC1 3 ): 3.67 (m, 2 H, CH 2 CH 2 ), 3.99 (m, 2 H, CH 2 CH 2 ), 4.27
- MS (rI%) 192 (100, M + ), 163 (48), 133 (26), 119 (76), 106 (49), 92 (38), 67 (27), 65 (45), 52 (22), 28 (22)
- the nitro compound is dissolved in methanol, ethanol or ethanol / dichloromethane mixtures (0.01 M to 0.5 M solution), palladium on carbon (10%) is added and the mixture is stirred overnight under hydrogen pressure.
- the crude product can be purified by chromatography on silica gel (dichloromethane / ethanol mixtures) or preparative reversed-phase HPLC (acetonitrile / water mixtures).
- iron powder can also be used as the reducing agent.
- the nitro compound is dissolved in acetic acid (0.1 M to 0.5 M solution) and at 90 ° C six equivalents of iron powder and water (0.3 to 0.5 times the volume of acetic acid) are added in portions within 10-15 min. After a further 30 min at 90 ° C., the mixture is filtered and the filtrate is concentrated. The residue is worked up extractively with ethyl acetate and 2N sodium hydroxide solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product can be purified by chromatography on silica gel (dichloromethane / ethanol mixtures) or preparative reversed-phase HPLC (acetonitrile / water mixtures).
- the amide is dissolved in DMF and 1.5 equivalents of potassium tert-butoxide are added. The mixture is stirred at RT for 1 h, then 1.2 equivalents of 1-fluoro-4-nitrobenzene are added in portions. The reaction mixture is stirred at RT overnight, diluted with ether or ethyl acetate and washed with sat. aq. Washed sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product can be purified by chromatography on silica gel (dichloromethane / ethanol mixtures).
- the nitro compound is dissolved in ethanol (0.01 M to 0.5 M solution), palladium-on-carbon (10%) is added and the mixture is left overnight
- iron powder can also be used as the reducing agent.
- the nitro compound is dissolved in acetic acid (0.1 M to 0.5 M solution) and at 90 ° C six equivalents of iron powder and water (0.3 to 0.5 times the volume of acetic acid) are added in portions within 10-15 min. After a further 30 min at 90 ° C., the mixture is filtered and the filtrate is concentrated. The residue is worked up extractively with ethyl acetate and 2N sodium hydroxide solution. The organic phase is dried over magnesium sulfate, filtered and concentrated.
- the raw product can by chromatography on silica gel (dichloromethane / ethanol mixtures) or preparative reversed-phase HPLC (acetonitrile / water mixtures).
- Example 12 is obtained by reacting Example 12 with trifluoroacetic acid in methylene chloride.
- IC 50 value 140 nM;
- Example 17 1H-NMR (d 6 -DMSO, 300 MHz): 2.05 (m, 2H), 2.45 (m, 2H), 3.6 (t, 2H), 3.77-3.85 (m, 3H), 4.15 (t, lH), 4.75-4.85 (m, lH), 7.2 (d, lH), 7.5 (d, 2H), 7.65 (d, 2H), 7.69 (d, lH), 8.96 (t, lH).
- the individual stages of the previously described synthesis of Example 17 with the respective precursors are as follows:
- reaction mixture is washed with water and the aqueous phase is extracted again with methylene chloride.
- the combined organic extracts are dried with MgSO 4 and evaporated.
- the residue (1.67 g) is then dissolved in 70 ml of acetonitrile, mixed with 2.62 g (14.16 mmol) of phthalimide potassium and stirred in a closed vessel in a microwave oven at 180 ° C. for 45 minutes.
- the suspension is stirred gently for 2 h, filtered after dilution with dichloromethane / DMF (3: 1) (the resin is washed with dichloromethane / DMF) and the filtrate is concentrated.
- the product obtained is optionally purified by preparative RP-HPLC.
- Methylamine 50% in water, 10.2 ml, 0.142 mol is added dropwise to a suspension of the oxazolidinone (4.45 g, 10.6 mmol) in ethanol (102 ml) at room temperature. The reaction mixture is refluxed for 1 h and concentrated in vacuo. The crude product is used in the next reaction without further purification.
- 5-chlorothiophene-2-carboxylic acid chloride (7.61 g, 42 mmol) is added dropwise to an ice-cooled solution of 2.63 ml (35 mmol) allylamine in 14.2 ml absolute pyridine and 14.2 ml absolute THF. The ice cooling is removed and the mixture is stirred at room temperature for 3 h before being concentrated in vacuo. Water is added to the residue and the solid is filtered off. The crude product is purified by flash chromatography on silica gel (dichloromethane).
- the reaction mixture the product can be isolated by chromatography on silica gel (cyclohexane / ethyl acetate mixtures, dichloromethane / methanol mixtures or dichloromethane / methanol / triethylamine mixtures).
- silica gel cyclohexane / ethyl acetate mixtures, dichloromethane / methanol mixtures or dichloromethane / methanol / triethylamine mixtures.
- the mixture is poured into 50 ml of water and extracted three times with ethyl acetate. 23 mg are obtained from the organic phase after drying and evaporation and 19 mg (in total from the aqueous phase after the insoluble solid has been filtered off with suction).
- Examples 31 to 35 and 140 to 147 relate to the optional, i.e. any amidimerization process step that takes place.
- the crude product is dissolved in acetone (0.01-0.1 mol / 1) and methyl iodide (40 eq.) Is added.
- the reaction mixture is stirred for 2 to 5 h at room temperature (RT) and then concentrated in vacuo.
- Aqueous trifluoroacetic acid (TFA, approx. 90%) is added dropwise to an ice-cooled solution of a compound protected from tert-butyloxycarbonyl (Boc) in chloroform or dichloromethane (approx. 0.1 to 0.3 nmol / 1). After about 15 minutes, the ice cooling is removed and the mixture is stirred at room temperature for about 2-3 hours before the solution is concentrated and dried in a high vacuum. The residue is taken up in dichloromethane or dichloromethane / methanol and washed with saturated sodium hydrogen carbonate or IN sodium hydroxide solution. The organic phase is washed with saturated sodium chloride solution, over a little magnesium sulfate dried and concentrated. If necessary, cleaning is carried out by crystallization from ether or ether / dichloromethane mixtures.
- Example 149 is obtained in an analogous manner from Example 149.
- the resin was then suspended in DMF / water (v / v 9: 2, 80 ml), mixed with SnCl 2 * 2H 2 O (5 eq) and reacted for 18 h at room temperature.
- the resin was again washed repeatedly with MeOH, DMF, water, MeOH, DCM and diethyl ether and dried.
- This resin was suspended in DCM, DIEA (10 eq) and an acid chloride (5 eq acid derivative 1) were added at 0 ° C. and the mixture was reacted at room temperature overnight.
- carboxylic acids were converted into the corresponding acid chlorides by reaction with 1-dimethylamino-1-chloro-2-methylpropene (1 eq, based on the carboxylic acid) in DCM at room temperature for 15 min.
- the resin was washed repeatedly with DMF, water, DMF, MeOH, DCM and diethyl ether and dried.
- Fmoc-protected amino acids as acid derivative 1, the Fmoc protective group was cleaved in the last reaction step by reaction with piperidine / DMF (v / v, 1/4) at room temperature for 15 minutes and the resin with DMF, MeOH, DCM and washed and dried diethyl ether.
- This crude product was purified by reversed phase HPLC with a water / TFA / acetonitrile gradient.
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
Claims
Priority Applications (25)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IL15925702A IL159257A0 (en) | 2001-06-20 | 2002-06-07 | Substituted oxazolidinones for combinational therapy |
EEP200400020A EE05419B1 (et) | 2001-06-20 | 2002-06-07 | Asendatud oksasolidinoonid kombineeritud raviks |
SK1530-2003A SK287904B6 (sk) | 2001-06-20 | 2002-06-07 | Substituted oxazolidinones for combinational therapy |
DK02738154.0T DK1411932T3 (da) | 2001-06-20 | 2002-06-07 | Kombinationsterapi med substituerede oxazolidinoner |
US10/481,297 US7767702B2 (en) | 2001-06-20 | 2002-06-07 | Substituted oxazolidinones for combinational therapy |
AU2002312982A AU2002312982B2 (en) | 2001-06-20 | 2002-06-07 | Substituted oxazolidinones for combinational therapy |
PL368079A PL206803B1 (pl) | 2001-06-20 | 2002-06-07 | Kombinacja zawierająca 5-chloro-N({(5S)-2-okso-3-[4-(3-okso-4-morfolinylo)fenylo]-1,3-oksazolidyn-5-ylo}-metylo)- 2-tiofenokarboksyamid i klopidogrel lub aspirynę oraz jej zastosowanie do wytwarzania leku do stosowania w profilaktyce i/lub leczeniu chorób |
DE50214206T DE50214206D1 (de) | 2001-06-20 | 2002-06-07 | Kombinationstherapie substituierter oxazolidinone |
CA2451258A CA2451258C (en) | 2001-06-20 | 2002-06-07 | Combination therapy of substituted oxazolidinones |
BRPI0210941A BRPI0210941B8 (pt) | 2001-06-20 | 2002-06-07 | produto farmacêutico contendo combinações de oxazolidinonas substituídas, seu uso, seu processo de produção, e medicamento |
HU0400240A HU230120B1 (hu) | 2001-06-20 | 2002-06-07 | Szubsztituált oxazolidinon-származékok kombinációs terápiához |
JP2003506901A JP4667744B2 (ja) | 2001-06-20 | 2002-06-07 | 置換オキサゾリジノン類の組合せ治療 |
AT02738154T ATE457171T1 (de) | 2001-06-20 | 2002-06-07 | Kombinationstherapie substituierter oxazolidinone |
SI200230892T SI1411932T1 (sl) | 2001-06-20 | 2002-06-07 | Kombinirana terapija substituiranih oksazolidinonov |
EP02738154A EP1411932B1 (de) | 2001-06-20 | 2002-06-07 | Kombinationstherapie substituierter oxazolidinone |
KR1020037016596A KR100904138B1 (ko) | 2001-06-20 | 2002-06-07 | 복합 요법을 위한 치환된 옥사졸리디논 |
NZ530223A NZ530223A (en) | 2001-06-20 | 2002-06-07 | Substituted oxazolidinones for combinational therapy |
MXPA03011519A MXPA03011519A (es) | 2001-06-20 | 2002-06-07 | Oxazolidinonas substituidas para terapia de combinacion. |
IL159257A IL159257A (en) | 2001-06-20 | 2003-12-09 | Substituted oxazolidinones for combinational therapy, their preparation and pharmaceutical compositions comprising them |
BG108443A BG66354B1 (bg) | 2001-06-20 | 2003-12-12 | Заместени оксазолидинони за комбинирана терапия |
ZA2003/09799A ZA200309799B (en) | 2001-06-20 | 2003-12-18 | Substituted oxazolidinones for combinational therapy |
NO20035743A NO334821B1 (no) | 2001-06-20 | 2003-12-19 | Substituerte oksazolindinoner for kombinasjonsterapi |
HRP20040042AA HRP20040042B1 (hr) | 2001-06-20 | 2004-01-19 | Supstituirani oksazolidinoni za kombinacijsku terapiju |
HK05101508.8A HK1068811A1 (en) | 2001-06-20 | 2005-02-23 | Substituted oxazolidinones for combinational therapy |
US12/766,365 US20100267685A1 (en) | 2001-06-20 | 2010-04-23 | Methods For The Prophylaxis And/or Treatment Of Thromboembolic Disorders By Combination Therapy With Substituted Oxazolidinones |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10129725A DE10129725A1 (de) | 2001-06-20 | 2001-06-20 | Kombinationstherapie substituierter Oxazolidinone |
DE10129725.4 | 2001-06-20 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/766,365 Division US20100267685A1 (en) | 2001-06-20 | 2010-04-23 | Methods For The Prophylaxis And/or Treatment Of Thromboembolic Disorders By Combination Therapy With Substituted Oxazolidinones |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2003000256A1 true WO2003000256A1 (de) | 2003-01-03 |
WO2003000256A9 WO2003000256A9 (de) | 2003-02-06 |
Family
ID=7688824
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2002/006237 WO2003000256A1 (de) | 2001-06-20 | 2002-06-07 | Kombinationstherapie substituierter oxazolidinone |
Country Status (33)
Country | Link |
---|---|
US (2) | US7767702B2 (de) |
EP (1) | EP1411932B1 (de) |
JP (1) | JP4667744B2 (de) |
KR (1) | KR100904138B1 (de) |
CN (1) | CN100577162C (de) |
AT (1) | ATE457171T1 (de) |
AU (1) | AU2002312982B2 (de) |
BG (1) | BG66354B1 (de) |
BR (1) | BRPI0210941B8 (de) |
CA (1) | CA2451258C (de) |
CO (1) | CO5550434A2 (de) |
CU (1) | CU23366B7 (de) |
CY (1) | CY1110019T1 (de) |
CZ (1) | CZ303715B6 (de) |
DE (2) | DE10129725A1 (de) |
DK (1) | DK1411932T3 (de) |
EC (1) | ECSP034916A (de) |
EE (1) | EE05419B1 (de) |
ES (1) | ES2338997T3 (de) |
HK (1) | HK1068811A1 (de) |
HR (1) | HRP20040042B1 (de) |
HU (1) | HU230120B1 (de) |
IL (2) | IL159257A0 (de) |
MX (1) | MXPA03011519A (de) |
NO (1) | NO334821B1 (de) |
NZ (1) | NZ530223A (de) |
PL (1) | PL206803B1 (de) |
PT (1) | PT1411932E (de) |
RU (1) | RU2321407C9 (de) |
SI (1) | SI1411932T1 (de) |
SK (1) | SK287904B6 (de) |
UA (1) | UA82986C2 (de) |
WO (1) | WO2003000256A1 (de) |
Cited By (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004060887A1 (de) * | 2003-01-07 | 2004-07-22 | Bayer Healthcare Ag | Verfahren zur herstellung von 5-chlor-n-({5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid |
WO2004101552A1 (en) * | 2003-05-14 | 2004-11-25 | Orchid Chemicals & Pharmaceuticals Ltd | Oxazolidinone derivatives as antibacterial agents |
WO2005026135A1 (de) * | 2003-09-15 | 2005-03-24 | Bayer Healthcare Ag | Verfahren zur herstellung von 4-(4-aminophenyl)-3-morpholinon |
WO2005027896A1 (ja) * | 2003-09-19 | 2005-03-31 | Kissei Pharmaceutical Co., Ltd. | 併用医薬 |
WO2005054234A2 (en) * | 2003-09-08 | 2005-06-16 | Wockhardt Limited | Substituted piperidino phenyloxazolidinones having antimicriobial activity with improved in vivo efficacy |
JP2006347980A (ja) * | 2005-06-17 | 2006-12-28 | Fujifilm Finechemicals Co Ltd | 新規なビピリジン誘導体 |
US7157456B2 (en) | 1999-12-24 | 2007-01-02 | Bayer Healthcare Ag | Substituted oxazolidinones and their use in the field of blood coagulation |
JP2007501818A (ja) * | 2003-08-11 | 2007-02-01 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | N−アリ−ルモルホリノンの製造方法 |
WO2007051532A1 (de) | 2005-11-02 | 2007-05-10 | Bayer Healthcare Ag | Phenylen-bis-oxazolidin-derivate und ihre verwendung als antikoagulantien |
JP2007517816A (ja) * | 2004-01-15 | 2007-07-05 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | 製造方法 |
WO2007092961A2 (en) * | 2006-02-09 | 2007-08-16 | University Of New Orleans Research & Technologies Foundation | Antibacterial agents |
JP2007525460A (ja) * | 2003-04-25 | 2007-09-06 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | c−fmsキナーゼ阻害剤 |
US7371743B2 (en) | 2004-02-28 | 2008-05-13 | Boehringer Ingelheim International Gmbh | Carboxylic acid amides, the preparation thereof and their use as medicaments |
WO2008120655A1 (ja) | 2007-03-30 | 2008-10-09 | Institute Of Medicinal Molecular Design, Inc. | I型11βヒドロキシステロイド脱水素酵素阻害活性を有するオキサゾリジノン誘導体 |
JP2009526788A (ja) * | 2006-02-16 | 2009-07-23 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | 血栓塞栓性障害の処置用のアミノアシルプロドラッグ誘導体および医薬 |
JP2010501504A (ja) * | 2006-08-24 | 2010-01-21 | バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト | アミノアシルプロドラッグ誘導体および血栓塞栓性障害の処置用の医薬 |
US20100184767A1 (en) * | 2007-06-20 | 2010-07-22 | Susanne Rohrig | Substituted oxazolidinones and use thereof |
CN102311400A (zh) * | 2010-06-29 | 2012-01-11 | 翔真生物科技股份有限公司 | 制备5-左旋-氨甲基-3-芳基-2-恶唑烷酮类的方法 |
US8153670B2 (en) | 2004-06-18 | 2012-04-10 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
US8198267B2 (en) * | 2007-06-20 | 2012-06-12 | Bayer Intellectual Property Gmbh | Substituted oxazolidinones and their use |
AU2006299126B2 (en) * | 2005-10-04 | 2012-06-28 | Bayer Intellectual Property Gmbh | 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 |
WO2012153155A1 (en) * | 2011-05-06 | 2012-11-15 | Egis Gyógyszergyár Nyilvãnosan Müködö Részvény-Társaság | Process for the preparation of a rivaroxaban and intermediates formed in said process |
US8530501B2 (en) | 2009-12-17 | 2013-09-10 | Millennium Pharmaceuticals, Inc. | Salts and crystalline forms of a factor Xa inhibitor |
US8742120B2 (en) | 2009-12-17 | 2014-06-03 | Millennium Pharmaceuticals, Inc. | Methods of preparing factor xa inhibitors and salts thereof |
CN104447728A (zh) * | 2014-12-05 | 2015-03-25 | 广东东阳光药业有限公司 | 噁唑烷酮类化合物及其在药物中的应用 |
CN104478866A (zh) * | 2014-12-05 | 2015-04-01 | 广东东阳光药业有限公司 | 噁唑烷酮类化合物及其在药物中的应用 |
US9402851B2 (en) | 2003-11-27 | 2016-08-02 | Bayer Intellectual Property Gmbh | Process for the preparation of a solid, orally administrable pharmaceutical composition |
US9539218B2 (en) | 2005-01-31 | 2017-01-10 | Bayer Intellectual Property Gmbh | Prevention and treatment of thromboembolic disorders |
EP2099453B1 (de) | 2006-11-02 | 2017-09-06 | Bayer Intellectual Property GmbH | Kombinationstherapie substituierter Oxazolidinone |
US10231951B2 (en) | 2015-03-03 | 2019-03-19 | Saniona A/S | Tesofensine, beta blocker combination formulation |
US10828310B2 (en) | 2018-02-02 | 2020-11-10 | Bayer Pharma Aktiengesellschaft | Reducing the risk of cardiovascular events |
Families Citing this family (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10129725A1 (de) | 2001-06-20 | 2003-01-02 | Bayer Ag | Kombinationstherapie substituierter Oxazolidinone |
DE102004062475A1 (de) * | 2004-12-24 | 2006-07-06 | Bayer Healthcare Ag | Feste, oral applizierbare pharmazeutische Darreichungsformen mit modifizierter Freisetzung |
DE102005018690A1 (de) * | 2005-04-22 | 2006-10-26 | Bayer Healthcare Ag | Imino-oxazolidine und ihre Verwendung |
DE102005045518A1 (de) | 2005-09-23 | 2007-03-29 | Bayer Healthcare Ag | 2-Aminoethoxyessigsäure-Derivate und ihre Verwendung |
DE102005047564A1 (de) * | 2005-10-04 | 2007-05-31 | Bayer Healthcare Ag | Amorphe Form von 5-Chlor-N-({(5S)2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl)-methyl)-2-thiophencarboxamid |
DE102005047558A1 (de) * | 2005-10-04 | 2008-02-07 | Bayer Healthcare Ag | Kombinationstherapie substituierter Oxazolidinone zur Prophylaxe und Behandlung von cerebralen Durchblutungsstörungen |
DE102005047561A1 (de) | 2005-10-04 | 2007-04-05 | Bayer Healthcare Ag | Feste, oral applizierbare pharmazeutische Darreichungsformen mit schneller Wirkstofffreisetzung |
NZ572418A (en) * | 2006-05-05 | 2011-08-26 | Millennium Pharm Inc | Factor xa inhibitors |
WO2008140220A1 (en) * | 2007-05-09 | 2008-11-20 | Legochem Bioscience Ltd. | Fxa inhibitors with cyclic amidines as p4 subunit, processes for their preparations, and pharmaceutical compositions and derivatives thereof |
KR101009594B1 (ko) * | 2007-05-09 | 2011-01-20 | 주식회사 레고켐 바이오사이언스 | P4 위치에 사이클릭 아미딘을 가지는 FXa 저해제, 이의유도체, 제조방법 및 이를 함유하는 의약 조성물 |
DE102007028319A1 (de) * | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituierte Oxazolidinone und ihre Verwendung |
DE102007028407A1 (de) * | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituierte Oxazolidinone und ihre Verwendung |
ES2425183T3 (es) | 2007-08-14 | 2013-10-11 | Concert Pharmaceuticals Inc. | Derivados de oxazolidinonas sustituidas |
CA2708418C (en) * | 2007-12-11 | 2013-11-12 | Bayer Schering Pharma Aktiengesellschaft | Oxazolidinones for the treatment and/or prophylaxis of heart failure |
KR100898361B1 (ko) * | 2008-07-03 | 2009-05-20 | 주식회사 레고켐 바이오사이언스 | P4 위치에 사이클릭 아미독심 또는 사이클릭 아미드라존기를 가지는 FXa 저해제, 이의 유도체, 제조방법 및이를 함유하는 의약 조성물 |
EA031064B2 (ru) | 2009-07-31 | 2020-07-01 | КРКА, д.д., НОВО МЕСТО | Способы кристаллизации ривароксабана |
CN102050819B (zh) * | 2009-11-10 | 2012-05-23 | 天津药物研究院 | 噁唑烷酮衍生物及其制备方法和用途 |
DE102010028362A1 (de) | 2010-04-29 | 2011-11-03 | Bayer Schering Pharma Aktiengesellschaft | Herstellverfahren |
AU2011300365A1 (en) * | 2010-09-07 | 2013-05-02 | Symed Labs Limited | Processes for the preparation of 4-{4-[5(S)-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} morpholin-3-one |
CN104693139B (zh) * | 2011-01-07 | 2017-04-19 | 浙江九洲药业股份有限公司 | 一种合成利伐沙班中间体的新工艺 |
EP2753619A2 (de) * | 2011-09-08 | 2014-07-16 | Cadila Healthcare Limited | Verfahren und zwischenprodukte zur herstellung von rivaroxaban |
JP6162704B2 (ja) * | 2011-10-11 | 2017-07-12 | カウンシル オブ サイエンティフィク アンド インダストリアル リサーチ | オキサゾリジノン誘導体のシラアナログ及びその合成 |
EP3309158B1 (de) | 2012-12-21 | 2022-03-16 | Krka, tovarna zdravil, d.d. | Kristalline form k von rivaroxaban and verfahren zur herstellung |
EP2897619A4 (de) * | 2012-12-26 | 2016-08-17 | Wanbury Ltd | Aldehydderivat aus substituierten oxazolidinonen |
CN103936763B (zh) * | 2013-01-18 | 2017-10-31 | 中国科学院上海药物研究所 | 噁唑烷酮类化合物及其制备方法和用途 |
WO2015124995A1 (en) | 2014-02-19 | 2015-08-27 | Aurobindo Pharma Ltd | Solid dosage forms of rivaroxaban |
WO2016066128A1 (zh) * | 2014-10-30 | 2016-05-06 | 成都百裕科技制药有限公司 | 一种含有银杏内酯B和Xa因子抑制剂的药物组合物及其制备方法和用途 |
CN104356124A (zh) * | 2014-10-30 | 2015-02-18 | 广东东阳光药业有限公司 | 噁唑烷酮类化合物及其组合物和用途 |
CN104402876A (zh) * | 2014-11-25 | 2015-03-11 | 沈阳药科大学 | 噁唑烷酮类化合物及其应用 |
CN104447729A (zh) * | 2014-12-05 | 2015-03-25 | 广东东阳光药业有限公司 | 噁唑烷酮类化合物及其在药物中的应用 |
CN104497008B (zh) * | 2014-12-09 | 2016-11-16 | 广东东阳光药业有限公司 | 取代噁唑烷酮类化合物及其使用方法和用途 |
EP3750885A4 (de) * | 2018-02-06 | 2021-10-27 | Shanghai Haihe Pharmaceutical Co., Ltd. | Verbindung mit bet-hemmender wirkung und herstellungsverfahren und verwendung dafür |
US11608320B2 (en) | 2020-02-02 | 2023-03-21 | Kuwait University | Oxazolidinone hydroxamic acid derivatives |
CN111253383A (zh) * | 2020-03-27 | 2020-06-09 | 南京国星生物技术研究院有限公司 | 一种利伐沙班的合成方法 |
CN112159402B (zh) * | 2020-10-28 | 2022-04-05 | 南京法恩化学有限公司 | 一种利伐沙班的制备方法 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5532255A (en) * | 1993-05-01 | 1996-07-02 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Adhesion receptor antagonists |
WO1999031092A1 (de) * | 1997-12-12 | 1999-06-24 | Merck Patent Gmbh | Benzamidinderivate als koagulationsfaktor-xa-hemmer |
EP0930076A1 (de) * | 1996-07-15 | 1999-07-21 | Sankyo Company Limited | Pharmazeutische zusammensetzungen |
US6159997A (en) * | 1995-07-03 | 2000-12-12 | Sankyo Company, Limited | Treatment of arteriosclerosis and xanthoma |
WO2001047919A1 (de) * | 1999-12-24 | 2001-07-05 | Bayer Aktiengesellschaft | Substituierte oxazolidinone und ihre verwendung im gebiet der blutgerinnung |
DE10105989A1 (de) * | 2001-02-09 | 2002-08-14 | Bayer Ag | Substituierte Oxazolidinone und ihre Verwendung |
Family Cites Families (72)
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 (fr) * | 1977-08-26 | 1979-05-15 | Delalande Sa | Nouvelles hydroxymethyl-5 oxazolidinones-2,leur procede de preparation et leur application therapeutique |
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 |
US4765989A (en) * | 1983-05-11 | 1988-08-23 | Alza Corporation | Osmotic device for administering certain drugs |
NZ206600A (en) | 1983-05-11 | 1987-01-23 | Alza Corp | Osmotic drug delivery device |
ES533097A0 (es) | 1983-06-07 | 1985-08-01 | Du Pont | Un procedimiento para la preparacion de nuevos derivados del amino-metil-oxooxazolidinil-benzeno. |
DE3884563T2 (de) | 1987-10-21 | 1994-02-17 | Du Pont Merck Pharma | Aminomethyl-oxo-oxazolidinyl-ethenylbenzen-Derivate, nützlich als antibakterielles Mittel. |
DE3822650A1 (de) | 1988-07-05 | 1990-02-01 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
US5254577A (en) * | 1988-07-29 | 1993-10-19 | The Du Pont Merck Pharmaceutical Company | Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents |
US4948801A (en) | 1988-07-29 | 1990-08-14 | E. I. Du Pont De Nemours And Company | Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents |
US5654285A (en) * | 1991-04-06 | 1997-08-05 | Astra Pharmaceuticals Limited | ADP and ATP analogues, process for making and administration to inhibit ADP-induced platelet aggregation |
DK0610265T3 (da) | 1991-11-01 | 1997-06-09 | Upjohn Co | Substituerede aryl- og heteroarylphenyloxazolidioner, som kan anvendes som antibakterielle midler |
SK283420B6 (sk) | 1992-05-08 | 2003-07-01 | Pharmacia & Upjohn Company | Antimikrobiálne oxazolidinóny obsahujúce substituované diazínové skupiny |
US5349045A (en) * | 1993-01-26 | 1994-09-20 | United States Surgical Corporation | Polymer derived from cyclic amide and medical devices manufactured therefrom |
US5688792A (en) * | 1994-08-16 | 1997-11-18 | Pharmacia & Upjohn Company | Substituted oxazine and thiazine oxazolidinone antimicrobials |
DE4332384A1 (de) * | 1993-09-23 | 1995-03-30 | Merck Patent Gmbh | Adhäsionsrezeptor-Antagonisten III |
PL185872B1 (pl) * | 1995-02-03 | 2003-08-29 | Upjohn Co | Nowe podstawione fenylooksazolidynonyNowe podstawione fenylooksazolidynony |
HRP960159A2 (en) * | 1995-04-21 | 1997-08-31 | Bayer Ag | Benzocyclopentane oxazolidinones containing heteroatoms |
JP3651816B2 (ja) * | 1995-07-03 | 2005-05-25 | 三共株式会社 | 動脈硬化症予防および治療剤 |
DE19524765A1 (de) | 1995-07-07 | 1997-01-09 | Boehringer Mannheim Gmbh | Neue Oxazolidinonderivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
US5968962A (en) | 1995-09-01 | 1999-10-19 | Pharmacia & Upjohn Company | Phenyloxazolidinones having a C-C bond to 4-8 membered heterocyclic rings |
US6277985B1 (en) | 1995-09-15 | 2001-08-21 | Pharmacia & Upjohn Company | Aminoaryl oxazolidinone N-oxides |
JP2001502655A (ja) | 1995-12-21 | 2001-02-27 | デュポン ファーマシューティカルズ カンパニー | Xa因子阻害薬であるイソオキサゾリン、イソチアゾリンおよびピラゾリン |
DE19601264A1 (de) * | 1996-01-16 | 1997-07-17 | Bayer Ag | Pyrido-annellierte Thienyl- und Furanyl-Oxazolidinone |
HRP970049A2 (en) * | 1996-02-06 | 1998-04-30 | Bayer Ag | New heteroaryl oxazolidinones |
DE19604223A1 (de) * | 1996-02-06 | 1997-08-07 | Bayer Ag | Neue substituierte Oxazolidinone |
GB9614238D0 (en) | 1996-07-06 | 1996-09-04 | Zeneca Ltd | Chemical compounds |
JPH1081632A (ja) * | 1996-07-15 | 1998-03-31 | Sankyo Co Ltd | 医 薬 |
AU723315B2 (en) * | 1996-09-18 | 2000-08-24 | Merck & Co., Inc. | Combination therapy for reducing the risks associated with cardiovascular disease |
US6273913B1 (en) | 1997-04-18 | 2001-08-14 | Cordis Corporation | Modified stent useful for delivery of drugs along stent strut |
CN1138765C (zh) | 1997-05-30 | 2004-02-18 | 法玛西雅厄普约翰美国公司 | 带有硫代羰基功能基的噁唑烷酮抗菌剂 |
WO1999002525A1 (en) | 1997-07-11 | 1999-01-21 | Pharmacia & Upjohn Company | Thiadiazolyl and oxadiazolyl phenyl oxazolidinone antibacterial agents |
DE19730847A1 (de) | 1997-07-18 | 1999-01-28 | Bayer Ag | Tricyclisch substituierte Oxazolidinone |
GB9715894D0 (en) | 1997-07-29 | 1997-10-01 | Zeneca Ltd | Heterocyclic derivatives |
DE19747261A1 (de) | 1997-10-25 | 1999-04-29 | Bayer Ag | Osmotisches Arzneimittelfreisetzungssystem |
TR200001330T2 (tr) | 1997-11-12 | 2000-11-21 | Pharmacia & Upjohn Company | Oksazolidinon türevleri ve farmasötik terkipler |
US6083967A (en) | 1997-12-05 | 2000-07-04 | Pharmacia & Upjohn Company | S-oxide and S,S-dioxide tetrahydrothiopyran phenyloxazolidinones |
DE19802239A1 (de) | 1998-01-22 | 1999-07-29 | Bayer Ag | Neue mit Bicyclen substituierte Oxazolidinone |
AU764184B2 (en) | 1998-01-23 | 2003-08-14 | Pharmacia & Upjohn Company | Oxazolidinone combinatorial libraries, compositions and methods of preparation |
CN1291892A (zh) | 1998-01-27 | 2001-04-18 | 阿温蒂斯药物制品公司 | 取代的氧代氮杂杂环基因子Xa抑制剂 |
DE19805117A1 (de) | 1998-02-09 | 1999-08-12 | Bayer Ag | Neue Oxazolidinone mit azolhaltigen Tricyclen |
US20010029351A1 (en) * | 1998-04-16 | 2001-10-11 | Robert Falotico | Drug combinations and delivery devices for the prevention and treatment of vascular disease |
PL344049A1 (en) | 1998-05-18 | 2001-09-24 | Upjohn Co | Enhancement of oxazolidinone antibacterial agents activity by using arginine derivatives |
DE19842753A1 (de) | 1998-09-18 | 2000-03-23 | Bayer Ag | Agitationsunabhängige pharmazeutische Retardzubereitungen und Verfahren zu ihrer Herstellung |
AU766089B2 (en) * | 1999-03-11 | 2003-10-09 | Du Pont Pharmaceuticals Company | Treatment of thrombosis by combined use of a factor Xa inhibitor and aspirin, tissue plasminogen activator (TPA), a GPIIb/IIIa antagonist, low molecular weight heparin or heparin |
US6413981B1 (en) | 1999-08-12 | 2002-07-02 | Ortho-Mcneil Pharamceutical, Inc. | Bicyclic heterocyclic substituted phenyl oxazolidinone antibacterials, and related compositions and methods |
PE20010851A1 (es) | 1999-12-14 | 2001-08-17 | Upjohn Co | Esteres del acido benzoico de oxazolidinonas que tienen un substituyente hidroxiacetilpiperazina |
MXPA02006233A (es) | 1999-12-21 | 2002-12-05 | Upjohn Co | Oxazolidinonas que tienen un grupo funcional sulfoximina y su uso como agentes antimicrobianos. |
CA2395948A1 (en) * | 1999-12-28 | 2001-07-05 | Ajinomoto Co., Inc. | Crystal of aspartame derivative |
DE10110438A1 (de) * | 2001-03-05 | 2002-09-19 | Bayer Ag | Substituierte 2-Oxy-3,5-dicyano-4-aryl-6-aminopyridine und ihre Verwendung |
DE10110747A1 (de) * | 2001-03-07 | 2002-09-12 | Bayer Ag | Substituierte 2,6-Diamino-3,5-dicyano-4-aryl-pyridine und ihre Verwendung |
DE10110754A1 (de) * | 2001-03-07 | 2002-09-19 | Bayer Ag | Substituierte 2-Thio-3,5-dicyano-4-aryl-6-aminopyridine und ihre Verwendung |
DE10115922A1 (de) * | 2001-03-30 | 2002-10-10 | Bayer Ag | Cyclisch substituierte 2-Thio-3,5-dicyano-4-aryl-6-aminopyridine und ihre Verwendung |
DE10115945A1 (de) * | 2001-03-30 | 2002-10-02 | Bayer Ag | Substituierte 2-Carba-3,5-dicyano-4-aryl-6-aminopyridine und ihre Verwendung |
DE10129725A1 (de) | 2001-06-20 | 2003-01-02 | Bayer Ag | Kombinationstherapie substituierter Oxazolidinone |
DE10152460A1 (de) | 2001-10-24 | 2003-05-08 | Bayer Ag | Stents |
DE10238113A1 (de) * | 2001-12-11 | 2003-06-18 | Bayer Ag | Substituierte 2-Thio-3,5-dicyano-4-phenyl-6-aminopyridine und ihre Verwendung |
US20030161882A1 (en) * | 2002-02-01 | 2003-08-28 | Waterman Kenneth C. | Osmotic delivery system |
DE10300111A1 (de) | 2003-01-07 | 2004-07-15 | Bayer Healthcare Ag | Verfahren zur Herstellung von 5-Chlor-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid |
DE10355461A1 (de) * | 2003-11-27 | 2005-06-23 | Bayer Healthcare Ag | Verfahren zur Herstellung einer festen, oral applizierbaren pharmazeutischen Zusammensetzung |
DE102004002044A1 (de) * | 2004-01-15 | 2005-08-04 | Bayer Healthcare Ag | Herstellverfahren |
DE102004062475A1 (de) * | 2004-12-24 | 2006-07-06 | Bayer Healthcare Ag | Feste, oral applizierbare pharmazeutische Darreichungsformen mit modifizierter Freisetzung |
EP1685841A1 (de) | 2005-01-31 | 2006-08-02 | Bayer Health Care Aktiengesellschaft | Prophylaxe und Behandlung von thrombolischen Erkrankungen |
DE102005045518A1 (de) | 2005-09-23 | 2007-03-29 | Bayer Healthcare Ag | 2-Aminoethoxyessigsäure-Derivate und ihre Verwendung |
DE102005047561A1 (de) * | 2005-10-04 | 2007-04-05 | Bayer Healthcare Ag | Feste, oral applizierbare pharmazeutische Darreichungsformen mit schneller Wirkstofffreisetzung |
RU2429236C2 (ru) | 2005-10-04 | 2011-09-20 | Байер Шеринг Фарма Акциенгезельшафт | Новая полиморфная форма и аморфная форма 5-хлор-n-({(5s)-2-оксо-3-[4-(3-оксо-4-морфолинил)-фенил]-1, 3-оксазолидин-5-ил}-метил)-2-тиофенкарбоксамида |
DE102005048824A1 (de) | 2005-10-10 | 2007-04-12 | Bayer Healthcare Ag | Behandlung und Prophylaxe von Mikroangiopathien |
DE102008028071A1 (de) * | 2008-06-12 | 2009-12-17 | Bayer Schering Pharma Aktiengesellschaft | Neue Cokristall-Verbindung von Rivaroxaban und Malonsäure |
-
2001
- 2001-06-20 DE DE10129725A patent/DE10129725A1/de not_active Withdrawn
-
2002
- 2002-06-07 EE EEP200400020A patent/EE05419B1/xx unknown
- 2002-06-07 PT PT02738154T patent/PT1411932E/pt unknown
- 2002-06-07 RU RU2004101404/15A patent/RU2321407C9/ru active
- 2002-06-07 JP JP2003506901A patent/JP4667744B2/ja not_active Expired - Lifetime
- 2002-06-07 BR BRPI0210941A patent/BRPI0210941B8/pt not_active IP Right Cessation
- 2002-06-07 EP EP02738154A patent/EP1411932B1/de not_active Expired - Lifetime
- 2002-06-07 KR KR1020037016596A patent/KR100904138B1/ko active IP Right Grant
- 2002-06-07 SK SK1530-2003A patent/SK287904B6/sk unknown
- 2002-06-07 HU HU0400240A patent/HU230120B1/hu unknown
- 2002-06-07 DE DE50214206T patent/DE50214206D1/de not_active Expired - Lifetime
- 2002-06-07 ES ES02738154T patent/ES2338997T3/es not_active Expired - Lifetime
- 2002-06-07 IL IL15925702A patent/IL159257A0/xx unknown
- 2002-06-07 NZ NZ530223A patent/NZ530223A/en not_active IP Right Cessation
- 2002-06-07 US US10/481,297 patent/US7767702B2/en not_active Expired - Fee Related
- 2002-06-07 DK DK02738154.0T patent/DK1411932T3/da active
- 2002-06-07 MX MXPA03011519A patent/MXPA03011519A/es active IP Right Grant
- 2002-06-07 SI SI200230892T patent/SI1411932T1/sl unknown
- 2002-06-07 WO PCT/EP2002/006237 patent/WO2003000256A1/de active IP Right Grant
- 2002-06-07 AU AU2002312982A patent/AU2002312982B2/en not_active Expired
- 2002-06-07 CZ CZ20033451A patent/CZ303715B6/cs not_active IP Right Cessation
- 2002-06-07 AT AT02738154T patent/ATE457171T1/de active
- 2002-06-07 CN CN02812411A patent/CN100577162C/zh not_active Expired - Lifetime
- 2002-06-07 PL PL368079A patent/PL206803B1/pl unknown
- 2002-06-07 CA CA2451258A patent/CA2451258C/en not_active Expired - Lifetime
- 2002-07-06 UA UA2004010387A patent/UA82986C2/uk unknown
-
2003
- 2003-11-26 CU CU20030276A patent/CU23366B7/es unknown
- 2003-12-09 IL IL159257A patent/IL159257A/en active IP Right Grant
- 2003-12-12 BG BG108443A patent/BG66354B1/bg unknown
- 2003-12-18 EC EC2003004916A patent/ECSP034916A/es unknown
- 2003-12-19 NO NO20035743A patent/NO334821B1/no not_active IP Right Cessation
-
2004
- 2004-01-19 CO CO04003298A patent/CO5550434A2/es not_active Application Discontinuation
- 2004-01-19 HR HRP20040042AA patent/HRP20040042B1/hr not_active IP Right Cessation
-
2005
- 2005-02-23 HK HK05101508.8A patent/HK1068811A1/xx not_active IP Right Cessation
-
2010
- 2010-04-16 CY CY20101100348T patent/CY1110019T1/el unknown
- 2010-04-23 US US12/766,365 patent/US20100267685A1/en not_active Abandoned
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5532255A (en) * | 1993-05-01 | 1996-07-02 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Adhesion receptor antagonists |
US6159997A (en) * | 1995-07-03 | 2000-12-12 | Sankyo Company, Limited | Treatment of arteriosclerosis and xanthoma |
EP0930076A1 (de) * | 1996-07-15 | 1999-07-21 | Sankyo Company Limited | Pharmazeutische zusammensetzungen |
WO1999031092A1 (de) * | 1997-12-12 | 1999-06-24 | Merck Patent Gmbh | Benzamidinderivate als koagulationsfaktor-xa-hemmer |
WO2001047919A1 (de) * | 1999-12-24 | 2001-07-05 | Bayer Aktiengesellschaft | Substituierte oxazolidinone und ihre verwendung im gebiet der blutgerinnung |
DE10105989A1 (de) * | 2001-02-09 | 2002-08-14 | Bayer Ag | Substituierte Oxazolidinone und ihre Verwendung |
Cited By (58)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7157456B2 (en) | 1999-12-24 | 2007-01-02 | Bayer Healthcare Ag | Substituted oxazolidinones and their use in the field of blood coagulation |
JP4667044B2 (ja) * | 2003-01-07 | 2011-04-06 | バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト | 5−クロロ−n−({(5s)−2−オキソ−3−[4−(3−オキソ−4−モルホリニル)−フェニル]−1,3−オキサゾリジン−5−イル}−メチル)−2−チオフェンカルボキサミドの製造方法 |
WO2004060887A1 (de) * | 2003-01-07 | 2004-07-22 | Bayer Healthcare Ag | Verfahren zur herstellung von 5-chlor-n-({5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid |
JP2006513227A (ja) * | 2003-01-07 | 2006-04-20 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | 5−クロロ−n−({(5s)−2−オキソ−3−[4−(3−オキソ−4−モルホリニル)−フェニル]−1,3−オキサゾリジン−5−イル}−メチル)−2−チオフェンカルボキサミドの製造方法 |
JP2007525460A (ja) * | 2003-04-25 | 2007-09-06 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | c−fmsキナーゼ阻害剤 |
WO2004101552A1 (en) * | 2003-05-14 | 2004-11-25 | Orchid Chemicals & Pharmaceuticals Ltd | Oxazolidinone derivatives as antibacterial agents |
JP4668903B2 (ja) * | 2003-08-11 | 2011-04-13 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | N−アリ−ルモルホリノンの製造方法 |
JP2007501818A (ja) * | 2003-08-11 | 2007-02-01 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | N−アリ−ルモルホリノンの製造方法 |
KR101119940B1 (ko) | 2003-08-11 | 2012-03-19 | 메르크 파텐트 게엠베하 | N-아릴 모르폴리논의 제조 방법 |
WO2005054234A3 (en) * | 2003-09-08 | 2005-09-29 | Prasad Keshav Deshpande | Substituted piperidino phenyloxazolidinones having antimicriobial activity with improved in vivo efficacy |
JP2007505102A (ja) * | 2003-09-08 | 2007-03-08 | ウォックハート・リミテッド | インビボ効力が改良された抗菌活性を有する置換ピペリジノフェニルオキサゾリジノン化合物 |
WO2005054234A2 (en) * | 2003-09-08 | 2005-06-16 | Wockhardt Limited | Substituted piperidino phenyloxazolidinones having antimicriobial activity with improved in vivo efficacy |
JP2007505821A (ja) * | 2003-09-15 | 2007-03-15 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | 4−(4−アミノフェニル)−3−モルホリノンの製造方法 |
US7598378B2 (en) | 2003-09-15 | 2009-10-06 | Bayer Schering Pharma Ag | Method for the production of 4-(4-aminophenyl)-3-morpholinone |
WO2005026135A1 (de) * | 2003-09-15 | 2005-03-24 | Bayer Healthcare Ag | Verfahren zur herstellung von 4-(4-aminophenyl)-3-morpholinon |
CN100430384C (zh) * | 2003-09-15 | 2008-11-05 | 拜耳医药保健股份公司 | 制备4-(4-氨基苯基)-3-吗啉酮的方法 |
JP4852419B2 (ja) * | 2003-09-15 | 2012-01-11 | バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト | 4−(4−アミノフェニル)−3−モルホリノンの製造方法 |
JPWO2005027896A1 (ja) * | 2003-09-19 | 2006-11-24 | キッセイ薬品工業株式会社 | 併用医薬 |
JP4855073B2 (ja) * | 2003-09-19 | 2012-01-18 | キッセイ薬品工業株式会社 | 併用医薬 |
WO2005027896A1 (ja) * | 2003-09-19 | 2005-03-31 | Kissei Pharmaceutical Co., Ltd. | 併用医薬 |
US9415053B2 (en) | 2003-11-27 | 2016-08-16 | Bayer Intellectual Property Gmbh | Solid, orally administrable pharmaceutical composition |
US9402851B2 (en) | 2003-11-27 | 2016-08-02 | Bayer Intellectual Property Gmbh | Process for the preparation of a solid, orally administrable pharmaceutical composition |
JP2007517816A (ja) * | 2004-01-15 | 2007-07-05 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | 製造方法 |
JP2012097106A (ja) * | 2004-01-15 | 2012-05-24 | Bayer Pharma AG | 製造方法 |
US8445525B2 (en) | 2004-02-28 | 2013-05-21 | Boehringer Ingelheim International Gmbh | Carboxylic acid amides, the preparation thereof and their use as medicaments |
US8791103B2 (en) | 2004-02-28 | 2014-07-29 | Boehringer Ingelheim International Gmbh | Carboxylic acid amides, the preparation thereof and their use as medicaments |
US7371743B2 (en) | 2004-02-28 | 2008-05-13 | Boehringer Ingelheim International Gmbh | Carboxylic acid amides, the preparation thereof and their use as medicaments |
US7947700B2 (en) | 2004-02-28 | 2011-05-24 | Boehringer Ingelheim International Gmbh | Carboxylic acid amides, the preparation thereof and their use as medicaments |
US8377974B2 (en) | 2004-06-18 | 2013-02-19 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
US8153670B2 (en) | 2004-06-18 | 2012-04-10 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
US9539218B2 (en) | 2005-01-31 | 2017-01-10 | Bayer Intellectual Property Gmbh | Prevention and treatment of thromboembolic disorders |
JP2006347980A (ja) * | 2005-06-17 | 2006-12-28 | Fujifilm Finechemicals Co Ltd | 新規なビピリジン誘導体 |
AU2006299126B2 (en) * | 2005-10-04 | 2012-06-28 | Bayer Intellectual Property Gmbh | 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 |
WO2007051532A1 (de) | 2005-11-02 | 2007-05-10 | Bayer Healthcare Ag | Phenylen-bis-oxazolidin-derivate und ihre verwendung als antikoagulantien |
US7700590B2 (en) | 2006-02-09 | 2010-04-20 | University Of New Orleans Research And Technology Foundation, Inc. | Antibacterial agents |
WO2007092961A2 (en) * | 2006-02-09 | 2007-08-16 | University Of New Orleans Research & Technologies Foundation | Antibacterial agents |
WO2007092961A3 (en) * | 2006-02-09 | 2008-07-17 | Univ New Orleans Res & Technol | Antibacterial agents |
JP2009526788A (ja) * | 2006-02-16 | 2009-07-23 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | 血栓塞栓性障害の処置用のアミノアシルプロドラッグ誘導体および医薬 |
JP2010501504A (ja) * | 2006-08-24 | 2010-01-21 | バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト | アミノアシルプロドラッグ誘導体および血栓塞栓性障害の処置用の医薬 |
EP2099453B1 (de) | 2006-11-02 | 2017-09-06 | Bayer Intellectual Property GmbH | Kombinationstherapie substituierter Oxazolidinone |
WO2008120655A1 (ja) | 2007-03-30 | 2008-10-09 | Institute Of Medicinal Molecular Design, Inc. | I型11βヒドロキシステロイド脱水素酵素阻害活性を有するオキサゾリジノン誘導体 |
US8198267B2 (en) * | 2007-06-20 | 2012-06-12 | Bayer Intellectual Property Gmbh | Substituted oxazolidinones and their use |
US20100184767A1 (en) * | 2007-06-20 | 2010-07-22 | Susanne Rohrig | Substituted oxazolidinones and use thereof |
US8530501B2 (en) | 2009-12-17 | 2013-09-10 | Millennium Pharmaceuticals, Inc. | Salts and crystalline forms of a factor Xa inhibitor |
US8742120B2 (en) | 2009-12-17 | 2014-06-03 | Millennium Pharmaceuticals, Inc. | Methods of preparing factor xa inhibitors and salts thereof |
CN102311400A (zh) * | 2010-06-29 | 2012-01-11 | 翔真生物科技股份有限公司 | 制备5-左旋-氨甲基-3-芳基-2-恶唑烷酮类的方法 |
WO2012153155A1 (en) * | 2011-05-06 | 2012-11-15 | Egis Gyógyszergyár Nyilvãnosan Müködö Részvény-Társaság | Process for the preparation of a rivaroxaban and intermediates formed in said process |
EA024685B1 (ru) * | 2011-05-06 | 2016-10-31 | Эгиш Дьёдьсердьяр Ньильваношан Мюкёдё Ресвеньтаршашаг | Способ получения ривароксабана и промежуточные соединения, получаемые в указанном способе |
US9556163B2 (en) | 2011-05-06 | 2017-01-31 | Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag | Process for the preparation of a rivaroxaban and intermediates formed in said process |
MD4557B1 (ro) * | 2011-05-06 | 2018-03-31 | Egis Gyogysszegyar Nyilvanosan Mukodo Reszvenytarsasag | Procedeu de obţinere a rivaroxabanului şi un compus intermediar utilizat în acest procedeu |
CN104447728A (zh) * | 2014-12-05 | 2015-03-25 | 广东东阳光药业有限公司 | 噁唑烷酮类化合物及其在药物中的应用 |
CN104478866A (zh) * | 2014-12-05 | 2015-04-01 | 广东东阳光药业有限公司 | 噁唑烷酮类化合物及其在药物中的应用 |
US10231951B2 (en) | 2015-03-03 | 2019-03-19 | Saniona A/S | Tesofensine, beta blocker combination formulation |
US10537551B2 (en) | 2015-03-03 | 2020-01-21 | Saniona A/S | Tesofensine and beta blocker combination formulations |
US10828278B2 (en) | 2015-03-03 | 2020-11-10 | Saniona A/S | Tesofensine and beta blocker combination formulations |
US11426383B2 (en) | 2015-03-03 | 2022-08-30 | Saniona A/S | Tesofensine and beta blocker combination formulations |
US12016840B2 (en) | 2015-03-03 | 2024-06-25 | Saniona A/S | Tesofensine and beta blocker combination formulations |
US10828310B2 (en) | 2018-02-02 | 2020-11-10 | Bayer Pharma Aktiengesellschaft | Reducing the risk of cardiovascular events |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1411932B1 (de) | Kombinationstherapie substituierter oxazolidinone | |
EP1261606B1 (de) | Substituierte oxazolidinone und ihre verwendung im gebiet der blutgerinnung | |
DE102005047558A1 (de) | Kombinationstherapie substituierter Oxazolidinone zur Prophylaxe und Behandlung von cerebralen Durchblutungsstörungen | |
JP5379012B2 (ja) | 置換オキサゾリジノン類の併用療法 | |
EP1937271A1 (de) | Behandlung und prophylaxe von mikroangiopathien | |
STRAUB et al. | Patent 2451258 Summary |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG UZ VN YU ZA ZM ZW GH GM KE LS MW Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
AK | Designated states |
Kind code of ref document: C2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: C2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
COP | Corrected version of pamphlet |
Free format text: PUBLISHED INTERNATIONAL SEARCH REPORT (10 PAGES) REPLACED BY CORRECT INTERNATIONAL SEARCH REPORT (12 PAGES) |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2002738154 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2042/DELNP/2003 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 159257 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002312982 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2003/011519 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 10844302 Country of ref document: BG Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15302003 Country of ref document: SK |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2451258 Country of ref document: CA Ref document number: 530223 Country of ref document: NZ Ref document number: PV2003-3451 Country of ref document: CZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2003/09799 Country of ref document: ZA Ref document number: 200309799 Country of ref document: ZA Ref document number: 1-2003-501327 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 028124111 Country of ref document: CN Ref document number: 1020037016596 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2003506901 Country of ref document: JP |
|
ENP | Entry into the national phase |
Ref document number: 20031091 Country of ref document: UZ Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: P20040042A Country of ref document: HR |
|
ENP | Entry into the national phase |
Ref document number: 20040020 Country of ref document: UZ Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: PV2003-3451 Country of ref document: CZ |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 2002738154 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10481297 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 530223 Country of ref document: NZ |
|
WWG | Wipo information: grant in national office |
Ref document number: 530223 Country of ref document: NZ |
|
ENP | Entry into the national phase |
Ref document number: 2002312982 Country of ref document: AU Date of ref document: 20020607 Kind code of ref document: B |