WO2001047919A9 - Substituierte oxazolidinone und ihre verwendung im gebiet der blutgerinnung - Google Patents
Substituierte oxazolidinone und ihre verwendung im gebiet der blutgerinnungInfo
- Publication number
- WO2001047919A9 WO2001047919A9 PCT/EP2000/012492 EP0012492W WO0147919A9 WO 2001047919 A9 WO2001047919 A9 WO 2001047919A9 EP 0012492 W EP0012492 W EP 0012492W WO 0147919 A9 WO0147919 A9 WO 0147919A9
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- radical
- alkyl
- phenyl
- general formula
- oxo
- 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 5
- TVQWHAIWGHYUMC-UHFFFAOYSA-N CC(C)(C)OC(C(CCC1)N1c(cc1)ccc1N(CC(CNC(c([s]1)ccc1Cl)=O)O1)C1=O)=O Chemical compound CC(C)(C)OC(C(CCC1)N1c(cc1)ccc1N(CC(CNC(c([s]1)ccc1Cl)=O)O1)C1=O)=O TVQWHAIWGHYUMC-UHFFFAOYSA-N 0.000 description 1
- SKGHRTMVDQFHIB-UHFFFAOYSA-N CC(NC(C(C=C1)N2CCCC2)C=C1N(CC(CNC(c([s]1)ccc1Cl)=O)O1)C1=O)=O Chemical compound CC(NC(C(C=C1)N2CCCC2)C=C1N(CC(CNC(c([s]1)ccc1Cl)=O)O1)C1=O)=O SKGHRTMVDQFHIB-UHFFFAOYSA-N 0.000 description 1
- VWGHMVAUEQPGJV-JTQLQIEISA-N CN(c(c(S1)c2)ccc2N(C[C@H](CNC(c([s]2)ccc2Cl)=O)O2)C2=O)C1=O Chemical compound CN(c(c(S1)c2)ccc2N(C[C@H](CNC(c([s]2)ccc2Cl)=O)O2)C2=O)C1=O VWGHMVAUEQPGJV-JTQLQIEISA-N 0.000 description 1
- VEDPEZVHGAYYBV-UHFFFAOYSA-N NC(NCc(cc1)ccc1N(CC(CNC(c([s]1)ccc1Cl)=O)O1)C1=O)=O Chemical compound NC(NCc(cc1)ccc1N(CC(CNC(c([s]1)ccc1Cl)=O)O1)C1=O)=O VEDPEZVHGAYYBV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic 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
- C07D333/26—Heterocyclic 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention relates to the field of blood coagulation.
- the present invention relates to new oxazolidinone derivatives, processes for their preparation and their use as active ingredients in pharmaceuticals.
- Blood coagulation is a protective mechanism of the organism, with the help of which defects in the vascular wall can be "sealed" quickly and reliably. In this way, blood loss can be avoided or minimized.
- Hemostasis after vascular injury occurs essentially through the coagulation system, in which an enzymatic cascade of complex reactions is triggered by plasma proteins, involving numerous blood coagulation factors, each of which, when activated, converts the next inactive precursor into its active form, and at the end of the cascade there is the conversion of soluble fibrinogen to insoluble 5 Fibrin, which leads to a blood clot.
- Fibrinogen to fibrin a fibrous-gelatinous coagulant.
- thrombin is a potent trigger for platelet aggregation, which also makes a significant contribution to hemostasis.
- Angina Angina
- reocclusions and restenosis after angioplasty or aortocoro- nare bypass stroke, transient ischemic attacks, peripheral arterial disease, pulmonary embolism or deep venous thrombosis; in the following, these diseases are also referred to collectively as thromboembolic diseases.
- hypercoagulability - systemically - can lead to disseminated intravascular coagulation in case of consumption coagulopathy.
- heparin is used for the therapy and prophylaxis of thromboembolic diseases, which is administered parenterally or subcutaneously. Because of its more favorable pharmacokinetic properties, low molecular weight heparin is increasingly preferred these days; However, the known disadvantages described below cannot be avoided in this way either
- heparin is orally ineffective and has a comparatively short half-life. Since heparin inhibits several factors in the blood coagulation cascade at the same time, it has an unselective effect. In addition, there is a high risk of bleeding, in particular bleeding from the rasp and bleeding in the gastrointestinal tract can occur, and thrombopenia,
- a second class of anticoagulants are the vitamin K antagonists.
- the compounds can be administered orally, but due to the high risk of bleeding and the narrow therapeutic index, complex individual adjustment and observation of the patient is necessary.
- other side effects such as gastrointestinal disorders, hair loss and skin necrosis are described (Pschyrembel, Klinisches Wörterbuch, 257th edition,
- thromboembolic disorders in the sense of the present invention particularly being used for serious disorders such as Heart attack, angina pectoris
- Another object of the present invention is to provide new anticoagulants which inhibit the blood clotting factor Xa with increased selectivity and which are intended to avoid, at least in part, the problems of the therapy methods known from the prior art for thromboembolic disorders.
- the present invention thus relates to substituted oxazolidinones of the general formula (I)
- R 1 represents optionally benzo-condensed thiophene (thienyl), which may optionally be substituted one or more times;
- R 2 represents any organic radical
- R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are the same or different and represent hydrogen or (C 1 -C 6 ) alkyl
- radical R 1 is an unsubstituted 2-biophene radical and at the same time the radical R 2 is a mono- or polysubstituted phenyl radical and at the same time the radicals R 3 , R 4 , R 5 , R 6 , R 7 and R 8 each represent hydrogen.
- R 2 represents one of the following groups:
- the radical "A” represents (C 6 -C 1 ) aryl, preferably (C 6 -C 1 o) aryl, in particular phenyl or naphthyl, very particularly preferably phenyl
- the radical "B” represents 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 (N-oxide) and Contains O
- 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, SO 2 , N , Contains NO (N-oxide) and O
- the radical "M” for -NH-, -CH 2 -, -CH 2 CH 2 -, -O-, -NH-CH 2 -, -CH 2
- R 27 , R 28 and R 29 are the same or different and are independently hydrogen, (-CC 4 ) alkyl, (C 3 -C 7 ) cycloalkyl, (-C 4 ) alkanoyl, carbamoyl, trifluoromethyl, phenyl or Mean pyridyl, and / or
- 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 hetero atoms from the Form group of N, O and S, and
- R 30 and R 31 are the same or different and independent of each other
- Phenyl or acetyl can be substituted, (C 6 -C 14 ) aryl, (C5-C 1 o) heteroaryl, trifluoromethyl, tetrahydrofuranyl or butyrolactone means,
- 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 is an unsubstituted 2-thiophene radical and at the same time the radical R 2 is a mono- or polysubstituted phenyl radical and at the same time the radicals R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each hydrogen.
- R 1 stands for thiophene (thienyl), in particular 2-thiophene, which can optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, amino, aminomethyl or (C Cs alkyl, preferably methyl, where the (dC ⁇ - The alkyl radical may in turn be substituted one or more times by halogen, preferably fluorine,
- R 2 represents one of the following groups:
- the radical "A” is (C 6 -C ⁇ ) -aryl, preferably (C 6 -C 1 o) aryl, in particular phenyl or naphthyl, very particularly preferably phenyl;
- the radical "B” represents 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 has up to three heteroatoms and / or hetero-chain links from the series S, SO, SO 2 , N, NO (N-oxide) and
- v means either 0 or 1
- R 27 , R 28 and R 29 are identical or different and independently of one another are hydrogen, (CC 4 ) alkyl or (C 3 -C 7 ) cycloalkyl, and / or
- 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 hetero atoms form from the group of N, O and S, and
- R 30 and R 31 are the same or different and independent of each other
- radical R 1 is an unsubstituted 2-thiophene radical and at the same time the radical R 2 is a mono- or polysubstituted phenyl radical and at the same time the radicals R 3 , R 4 , R 5 , R 6 , R 7 and R 8 each represent hydrogen.
- R 1 stands for thiophene (thienyl), in particular 2-thiophene, which can optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, or (dC 8 ) -alkyl, preferably methyl, the (dC 8 ) -
- halogen preferably chlorine or bromine
- (dC 8 ) -alkyl preferably methyl
- 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, BMA,
- the radical "A” stands for phenyl or naphthyl, in particular for phenyl
- the radical “B” stands for 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 up to two heteroatoms and / or hetero-chain links from the series S, SO, SO 2 , N, NO (N-oxide) and Contains O
- the remainder "M” for -NH-, -O-, -NH-CH 2 -, -CH 2 -NH-, -OCH 2 -, -CH 2 O-,
- v is either 0 or 1, preferably 0, and R 27 , R 28 and R 29 are the same or different and are independently hydrogen, (-CC 4 ) alkyl or cyclopropyl, cyclopentyl or cyclohexyl and / or
- 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 and R are the same or different and are independently hydrogen, (dC 4 ) alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (dC) alkylsulfonyl, (C ⁇ -C 4 ) hydroxyalkyl, (dC 4 ) - aminoalkyl, di- ( C 1 -C 4 ) alkylamino- (C 1 -C 4 ) alkyl, (dC 3 ) -
- 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
- radical R 1 is an unsubstituted 2-thiophene radical and at the same time the radical R 2 is a mono- or polysubstituted phenyl radical and at the same time the radicals R 3 , R 4 , R 5 , R 6 ,
- R 7 and R 8 each represent hydrogen.
- 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,
- R 2 represents one of the following groups:
- 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 hetero atom and / or hetero chain link from the series S, SO, SO 2 and O; or up to two Contains 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
- R, R and R are identical or different and independently of one another are hydrogen, (dC 4 ) -alkyl or else cyclopropyl, cyclopentyl or cyclohexyl and / or
- 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, (dC 4 ) alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (CC 4 ) alkylsulfonyl, (dC 4 ) hydroxyalkyl, (dC 4 ) aminoalkyl, DHd C ⁇ -alkylannno-Cd-C ⁇ -alkyl, (dC 3 ) -
- R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are the same or different and represent hydrogen or (dC 4 ) alkyl
- R is an unsubstituted 2-thiophene radical and at the same time the radical R represents an em- or multiply substituted phenyl radical and at the same time the radicals R 3 , R 4 , R 5 , R 6 ,
- R 7 o R and R each represent hydrogen.
- R 1 represents 2-thiophene which is substituted in the 5-position by a radical from the group chlorine, bromine, methyl or trifluoromethyl,
- 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;
- the previously defined group “A” in the meta position with respect to the linkage to the oxazolidinone can optionally be mono- or disubstituted with a radical from the group of fluorine, chlorine, nitro, arnino, trifluoromethyl, methyl or cyano,
- R 3 , R 4 , R 5 , R 6 , R 7 and R 8 represent hydrogen
- connection with the following is also very particularly preferred
- thienyl optionally benzo-condensed thiophene (thienyl), which may optionally be mono- or polysubstituted by a radical from the group of halogen; cyano; nitro; (dC 8 ) alkyl, which in turn can optionally be substituted one or more times by halogen; (C 3 -C 7 )
- R 1 represents thiophene (thienyl), in particular 2-thiophene, which may be mono- or polysubstituted by halogen, preferably chlorine or bromine, or (dC 8 ) -alkyl, preferably methyl, where the (dC 8 ) -
- Alkyl radical preferably the methyl radical, may in turn be substituted one or more times by halogen, preferably fluorine.
- R 3 , R 4 , R 5 , R 6 , R 7 and R 8 may be the same or different and in particular for hydrogen or for (C 1 -C 6 ) -alkyl, preferably for hydrogen or for (dC) -
- Alkyl very particularly preferably hydrogen.
- the radical R 2 ie the organic radical, can in particular be selected from the substituent groups listed below:
- R 2 in particular represents a group of the following formula:
- n denotes an integer between 0 and 6, preferably between 1 and 3,
- n means either 0 or 1
- p is an integer between 0 and 3, preferably either 0 or 1
- ⁇ j represents an integer 0 or 1
- o 2 means an integer 0 or 1
- R 9 and R 10 are the same or different and are hydrogen; (dC 4 ) alkyl, preferably methyl; (dC) alkoxy, preferably methoxy; (C 3 -C 7 ) cycloalkyl; Are hydroxy or fluorine,
- X and X ' are the same or different and are for O; NR 11 or a covalent bond,
- R 11 is H; (dC 4 ) alkyl, preferably methyl, or (C 3 -C) cycloalkyl,
- Y represents a 3- to 7-membered saturated or partially unsaturated cyclic hydrocarbon radical which optionally contains 1 to 3 identical or different heteroatoms and / or hetero chain links from the group consisting of N, O, S, SO and SO 2 ,
- this radical Y can be optionally substituted by a 5- or 6-membered aromatic or a 3- to 7-membered saturated or partially unsaturated cyclic hydrocarbon radical which may optionally contain up to 3 identical or different heteroatoms from the group of N, O and S contains and
- R »1 1 2 Z is hydrogen, (dC 4 ) alkyl or (C 3 -C 7 ) cycloalkyl;
- R 13 and R 13 are identical or different and independently of one another are hydrogen, (dC) -alkyl or (C 3 -C) -cycloalkyl
- R 13 and R 13 ' together with the N atom to which they are attached form a 5- to 7-membered heterocycle which can optionally contain up to 2 further heteroatoms from the series N, O and / or S;
- R 14 and R 15 are the same or different and independent of each other
- R 16 and R 17 are the same or different and independently of one another are hydrogen, (-CC) alkyl, (C 3 -C 7 ) cycloalkyl or (dC 3 ) alkanoyl;
- R 18 represents hydrogen, (dC 4 ) alkyl or (C 3 -C 7 ) cycloalkyl
- R 19 and R 19 are the same or different and are independently hydrogen, (-CC 4 ) alkyl or (C 3 -C 7 ) - cycloalkyl and / or R 19 and R 19 ' together with the N atom that they are bonded, form a 5- to 7-membered heterocycle which can optionally contain up to 2 further heteroatoms from the series N, O and / or S.
- R 2 represents a group of the following formula:
- n an integer between 0 and 3
- n an integer 0 or 1
- p represents an integer 0 or 1
- ⁇ j represents an integer 0 or 1
- o 2 means an integer 0 or 1
- R 9 and R 10 are the same or different and are hydrogen; Methyl; methoxy; Are hydroxy or fluorine,
- X and X ' are the same or different and are for O; NR 11 or a covalent bond,
- R 11 is H or methyl
- Y represents a 5- to 7-membered saturated cyclic hydrocarbon radical which optionally contains 1 or 2 identical or different heteroatoms and / or hetero chain links from the group of N, O, S,
- this radical Y can optionally be substituted by a 5- or 6-membered aromatic or a 5- to 7-membered saturated or partially unsaturated cyclic hydrocarbon radical which optionally contains up to 2 identical or different heteroatoms from the group of N, O and S. and
- R 12 represents hydrogen, methyl, ethyl, cyclopropyl, cyclopentyl or cyclohexyl;
- R and R are the same or different and are independently hydrogen, methyl, ethyl, cyclopropyl, cyclopentyl or cyclohexyl and / or
- R 13 and R 13 together with the N atom to which they are attached form a 5- to 7-membered heterocycle which can optionally contain up to 2 further heteroatoms from the series N, O and / or S, in particular piperidinyl , Piperazinyl, morpholinyl and thiomorpholinyl;
- R 14 and R 15 are the same or different and independently of one another are hydrogen, methyl, ethyl, cyclopropyl, cyclopentyl or cyclohexyl or else acetyl;
- R 16 and R 17 are the same or different and are independently hydrogen, methyl, (C 3 -C 7 ) cycloalkyl or acetyl;
- R 18 represents hydrogen, methyl or (C 3 -C 7 ) cycloalkyl
- R 19 and R 19 are identical or different and independently of one another are hydrogen, methyl or (C 3 -C 7 ) cycloalkyl and / or
- R 19 and R 19 ' together with the N atom to which they are attached form a 5- to 7-membered heterocycle which may optionally contain up to 2 further heteroatoms from the
- Row can contain N, O and / or S, in particular piperidinyl, piperazinyl, morpholinyl and thimorpholinyl.
- R 2 represents a group of the following formula:
- R 20 and R 21 are the same or different and represent hydrogen, (dC 4 ) alkyl, (dC) alkoxy, (C 3 -C 7 ) cycloalkyl, hydroxy or fluorine,
- Z represents a radical selected from the group of cyano
- -C (NR 22 R 23 ) NR 24 ; -CO (NH) u NR 22 R 23 ; and -NR 25 R 26 ,
- u is either 0 or 1, preferably 0, and
- R 22 , R 23 and R 24 are the same or different and independently of one another are hydrogen, (dC 4 ) -alkyl or (C 3 -C 7 ) -cycloalkyl, preferably hydrogen or methyl, and / or
- R 22 and R 23 together with the N atom to which they are attached form a 5- to 7-membered heterocycle which may optionally contain up to 2 further heteroatoms and / or hetero-chain links from the series N, O, S, May contain SO and / or SO 2 ;
- R 25 and R 26 are the same or different and are independently hydrogen, (-CC 4 ) -alkyl or (C 3 -C 7 ) -cycloalkyl, preferably hydrogen, methyl or ethyl, where (dC) -alkyl and ( C 3 -C) cycloalkyl may in turn optionally be substituted by hydroxy or (dC 6 ) alkoxy.
- R 2 represents one of the following groups: A, AM, DMA, BMA, B,
- the radical "A” stands for (C 6 -C 1 ) aryl, preferably for (C 6 -C 1 o) aryl, in particular for phenyl or naphthyl, very particularly preferably for phenyl;
- the radical "B” for one 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 has up to three heteroatoms and / or hetero chain links from the series S, SO, SO 2 , N, NO (N-oxide) and Contains O;
- the radical "M” for -NH-, -CH 2 -, -CH 2 CH 2 -, -O-, -NH-CH 2 -, -CH 2 -NH-, -OCH 2 -, -CH 2 O-, -CONH-, -NHCO-, -COO-, -OOC-, -S- or stands for a covalent bond;
- v means either 0 or 1
- R 27 , R 28 and R 29 are identical or different and independently of one another are hydrogen, (dC 4 ) -alkyl or (C 3 -C 7 ) -cycloalkyl and / or
- 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, Form O and S, and
- R 30 and R 31 are the same or different and independent of each other
- radical "A” stands for phenyl or naphthyl, in particular for phenyl
- radical “B” stands for a 5- or 6-membered aromatic heterocycle which contains up to 2 heteroatoms from the series S, N, NO (N -Oxide) and contains O
- 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.
- NR 27 R 28 NR 29 ; -CONR 28 R 29 ; -SO 2 NR 28 R 29 ; -OH; -NR 30 R 31 ; (CC 4 ) alkyl; and cyclopropyl, cyclopentyl or cyclohexyl,
- v is either 0 or 1, preferably 0, and
- R 27 , R 28 and R 29 are the same or different and are independently hydrogen, (-CC 4 ) alkyl or cyclopropyl, cyclopentyl or cyclohexyl and / or
- 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) alkyl, cyclopropyl, cyclopentyl, cyclohexyl,
- R represents a group of the following formula: in which
- R 32 for hydrogen or (dC) alkyl, preferably for hydrogen or methyl
- W stands for S, NH or O, preferably for S.
- R 2 is a group of the following formula
- R 2 is a group of the following formula
- benzamidine-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 general formula (I) according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
- the invention relates both to the enantiomers or diastereomers and to their respective mixtures.
- the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
- Shapes are available. This is known to those skilled in the art and such compounds are also within the scope of the invention.
- Physiologically acceptable, ie 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, for example, alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, dimethylamine, triemylamine,
- hydrates are those forms of the compounds of the above general formula (I) which are in the solid or liquid state
- Hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Equally, the hydrates of salts of the compounds according to the invention can also be used.
- prodrugs refer to those forms of the compounds of the general formula (I) above which can themselves be biologically active or inactive, but which can be converted into the corresponding biologically active form (for example metabolically, solvolytically or in some other way).
- Halogen stands for fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred.
- (C -C 8 ) alkyl represents 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 (dC) 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 -Cs) 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, allyl, isopropenyl and n-but-2-en-l -yl.
- (d-CgVAlkoxy stands for a straight-chain or branched alkoxy radical with 1 to
- Examples include: methoxy, ethoxy, n-propoxy,
- ⁇ represents 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: methylamino, ethylamino, n-propylamino, isopropylamino, t-butylamino, A N-dimethyl-arnino, N, N-diemylamino, N-emyl-N-methylamino, N-methyl-Nn-propylamino, N - Isopropyl-Nn-propylamino and Nt-butyl-N-memylamino.
- (C 1 -C 6 ) - Alkanoyl stands for a straight-chain or branched alkyl radical with 1 to 6 carbon atoms, which carries 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 (dC 5 ) alkanoyl, (dC) alkanoyl and (dC 3 ) alkanoyl, are derived analogously from this definition. In general, (dC 3 ) alkanoyl is preferred.
- Cycloalkanoyl stands for a cycloalkyl radical as defined above with 3 to 7 carbon atoms, which is linked via a carbonyl group.
- Alkanoyloxymethyloxy radical with 1 to 6 carbon atoms For example called: acetoxymethyloxy, propionoxymethyloxy, n-butyroxymethyloxy, i-butyroxymethyloxy, pivaloyloxymethyloxy, n-hexanoyloxymethyloxy.
- the corresponding alkanoyloxymethyloxy groups with fewer carbon atoms such as (dC 3 ) alkanoyloxymethyloxy, are derived analogously from this definition. In general, (C 1 -C 3 ) alkanoyloxymethyloxy is preferred.
- (C 6 -C 1 ) aryl represents an aromatic radical having 6 to 14 carbon atoms. Examples include: phenyl, naphthyl, phenanthrenyl and anthracenyl. From this definition, are derived analogously the corresponding aryl groups with fewer carbon atoms, such as (C 6 -C 1 o) aryl from. In general, (C 6 -do) -
- Aryl is preferred.
- (C 5 -C 1 o) heteroaryl or a 5- to 10-membered aromatic heterocycle having up to 3 heteroatoms and / or hetero chain members from the series S, O, N and / or NO (N-oxide) represents a mono- - Or bicyclic heteroaromatics, which is linked via a ring carbon atom of the heteroaromatic, optionally also via a ring nitrogen atom of the heteroaromatic.
- Examples include: pyridyl,
- 5- or 6-membered aromatic heterocycles such as e.g. Pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, furyl and thienyl are preferred.
- 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 2 , N, NO (N-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, thiomorpholinyl, azepinyl,
- the corresponding cycles with a smaller ring size e.g. 5- to 7-membered cycles.
- the present invention also relates to a process for the preparation of the compounds of the general formula (I) according to the invention, wherein 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
- 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 methanol, 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 methods described above, for example N-
- 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 ethoxide or potassium tert-butoxide or amides such as sodium amide, LitMum-bis- (trimethylsilyl) amide or lithium diisopropylamide or amines such as triethylamine, diisopropylethylamine, diisopropylamine, 4- ⁇ 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 ethoxide or potassium tert-butoxide
- amides such as sodium amide, LitMum-bis- (trimethylsilyl) amide or lithium diisopropylamide or amines such as triethylamine
- 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 selective 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) and monoperoxyphthalic acid or osmium tetroxide.
- MCPBA m-chloroperbenzoic acid
- NMO N-methylmorpholine-N-oxide
- monoperoxyphthalic acid or osmium tetroxide monoperoxyphthalic acid or osmium tetroxide.
- the compounds of the general formula (I) according to the invention have an unforeseeable, valuable pharmacological activity spectrum and are therefore particularly suitable for the prophylaxis and / or treatment of diseases.
- thromboembolic diseases in the sense of the present invention include in particular serious diseases such as heart attack, angina pectoris (including unstable angina), reocclusions and restenosis after angioplasty or aortocoronary bypass, stroke, transient ischemic attacks, peripheral arterial occlusive diseases or deep venous embolism thromboses.
- the compounds of the general formula (I) according to the invention - including also the compounds excluded from chemical protection by disclaimer - are equally suitable for the treatment of disseminated intravascular coagulation (DIC).
- the compounds of the general formula (I) according to the invention - including also the compounds excluded from chemical protection by disclaimer - are also suitable for the prophylaxis and / or treatment of atherosclerosis and arthritis, and also for the prophylaxis and / or
- selective means inhibitors of the blood coagulation factor Xa in which the IC 50 values for the factor Xa
- Inhibition against the IC 50 values for the inhibition of other serine proteases, in particular thrombin, plasmin and trypsin, are 100 times, preferably 500 times, in particular 1,000 times smaller, with regard to the test methods for selectivity Reference is made to the test methods of Examples A1) a.1) and a.2) described below.
- the compounds of the general formula (I) according to the invention - including the compounds excluded from chemical protection by disclaimer - can also be used to prevent coagulation ex vivo, e.g. for preserved blood or biological samples containing factor Xa.
- the present invention thus relates to oxazolidinones of the formula (I) which, in particular, bring about an unexpected, strong and selective inhibition of factor Xa, which also applies to the compounds excluded from chemical protection by disclaimer.
- the present invention thus furthermore also relates to pharmaceuticals and pharmaceutical compositions which contain at least one compound of the general formula (I) according to the invention together with one or more pharmaceutically acceptable auxiliaries or excipients and can be used for the aforementioned indications.
- the present invention relates to a method for the prophylaxis and / or treatment of diseases of the human or animal body, in particular the aforementioned diseases, using the compounds of the general formula (I) according to the invention - including also the compounds excluded from substance protection by disclaimer.
- the present invention also includes a method for preventing blood coagulation in vitro, in particular in the case of preserved blood or biological samples which contain factor Xa, which is characterized in that compounds of the general formula (I) - including also those compounds which are excluded from the protection of substances by disclaimer - be added.
- the application is preferably oral, lingual, sublingual, buccal, rectal or parenteral (i.e. bypassing the intestinal tract, i.e. intravenously, mtraarterially, intracardially, intracutaneously, subcutaneously, transdermally, intraperitoneally or intramuscularly).
- Oral and intravenous administration are particularly suitable.
- Oral application is very particularly preferred, in which there is a further advantage over the therapy of thromboembolic disorders known from the prior art.
- the new active compounds of the general formula (I) can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable Carriers or solvents.
- the therapeutically active compound should in each case be present in a concentration of about 0.1 to 95% by weight, preferably in 0.5 to 90% by weight, in particular 1 to 85% by weight, of the total mixture, ie in amounts sufficient to achieve the dosage range indicated.
- the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. in the case of the use of water as a diluent, organic solvents can optionally be used as auxiliary solvents.
- the compounds of the general formula (I) according to the invention - including also the compounds excluded from chemical protection by disclaimer - are distinguished from conventional preparations for the treatment of thromboembolic disorders in particular by the fact that the selective inhibition of
- Factor Xa a greater therapeutic breadth is achieved. This means a lower risk of bleeding for the patient and better adjustability of the patient for the attending physician. In addition - due to the mechanism - there is a quick onset of action. Above all, however, the compounds according to the invention allow oral administration, which is a further advantage of therapy with the compounds according to the invention.
- the particularly advantageous biological properties of the compounds according to the invention can be determined by the following methods.
- the enzymatic activity of human factor Xa was measured using a chromogenic substrate specific for the FXa.
- the factor Xa cleaves p-nitroaniline from the chromogenic substrate. The determinations were carried out in microtiter plates as follows.
- test substances were dissolved in different concentrations in DMSO and for 10 minutes with human FXa (0.5 nmol / 1 dissolved in 50 mmol / 1 Tris buffer
- the chromogenic substrate 150 ⁇ mol 1 Pefachrome® FXa from Pentapharm
- the absorbance at 405 nm was determined. The extinctions of the test approaches with
- test substances were examined for their inhibition of other human serine proteases such as thrombin, trypsin, plasmin.
- thrombin 75 U / ml
- Chromozym Plasmin® from Boehringer Mannheim
- the anticoagulant effect of the test substances was determined in vitro in human plasma.
- Human blood was drawn using a 0.11 molar sodium citrate solution as a template in a sodium citrate / blood mixing ratio of 1/9.
- 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 determined in the presence of varying concentrations of test substance or the corresponding solvent using a commercially available test kit (Neoplastin® from Boehringer Mannheim).
- the test compounds were incubated with the plasma at 37 ° C. for 10 minutes.
- 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
- test substances were either administered intravenously via the tail vein or orally by means of a pharyngeal tube to awake animals.
- 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 free carotid artery was disconnected from the blood flow, cooled to -12 ° C in a metal channel for 2 minutes and used to standardize the
- the proximal clamp was removed, the wound was closed and opened again after 4 hours to remove the injured section of the vessel.
- the wet weight of the thrombi was determined immediately.
- the test substances became too 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.
- test substances were either administered intravenously via the tail vein or orally by means of a pharyngeal tube to awake animals.
- N- (2,3-epoxypropyl) phthalimide is described in J.-W. Chem et al. Tetrahedron Lett. 1998.3 °, 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 , 45,2225) 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).
- MS (rI%) 222 (74, M + ), 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.
- 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 at normal pressure. Then it is 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).
- 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 arrears with
- 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 stirred overnight under hydrogen pressure. Then it is 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).
- 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 following starting compounds were prepared in an analogous manner:
- Example 12 is obtained by reacting Example 12 with trifluoroacetic acid in methylene chloride.
- IC 50 value 140 nM; 1H-NMR [d ⁇ -DMSO]: 3.01-3.25 (m, 8H), 3.5-3.65 (m, 2H), 3.7-3.9 (m, IH), 4.05-4.2 (m, IH), 4.75-4.9 (m , IH), 7.05-7.25 (m, 3H), 7.5 (dd, IH), 7.7 (d, IH), 8.4 (broad s, IH), 9.0 (t, IH).
- chlorothiophene-2-carboxylic acid is 5-chloro-N - ( ⁇ (5S) - 2-oxo-3- [4- (2-oxo-l-pyrrolidmyl) phenyl] -l, 3-oxazolidin-5-yl ⁇ methyl) -2-thiophene-carboxamide.
- Example 17 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 batch is filtered off from insoluble residue, the filtrate is evaporated in vacuo, the residue (1.9 g) is dissolved in methanol and 0.47 g (9.37 mmol) of hydrazine hydrate are added. It is boiled for 2 hours, cooled, mixed with saturated sodium bicarbonate solution and extracted six times with a total of 2 l of methylene chloride.
- the 5-chloro-N - ( ⁇ (5S) -2-oxo-3- [4- (2-oxo-l- ⁇ yrrolidinyl) phenyl] -l, 3-oxazolidin-5-yl ⁇ methyl) - 2-thiophene carboxarnide is prepared by 0.32 g (1.16 mmol) of the (5S) -5- (aminomethyl) -3- [4- (2-oxo-l-pyrrolidinyl) phenyl] -l, 3- shown above oxazolidin-2-ones, 5-chlorothiophene-2-carboxylic acid (0.19 g; 1.16 mmol) and 1-hydroxy-IH-benzotriazole hydrate (HOBT) (0.23 g, 1.51 mmol) can be dissolved in 7.6 ml DMF. 0.29 g (1.51 mmol) of N , - (3-dimethylamino-propyl)
- DIEA diisopropylethylamine
- IC 50 90 nM
- 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.
- the product can be isolated from the reaction mixture 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.
- a solution of substituted N- (3-amino-2-hydroxypropyl) -5-chloro-2-thiophenecarboxamide derivative (1.0 eq.) In absolute THF (approx. 0.1 mol / 1) is carbodiimidazole (1.2 up to 1.8 eq.) or a comparable phosgene equivalent.
- the mixture is at room temperature or optionally at elevated temperature (up to 70 ° C) for 2 to 18 h before being concentrated in vacuo.
- the product can be purified by chromatography on silica gel (dichloromethane / methanol mixtures or cyclohexane / ethyl acetate mixtures).
- the following compounds were also prepared via the route of epoxy opening with an amine and subsequent cyclization to the corresponding oxazolidinone:
- the following examples 14 to 16 are exemplary embodiments of the optional, ie optionally occurring, oxidation process step.
- NMO N-methylnholine-N-oxide
- IC 50 value 210 nM
- Examples 31 to 35 and 140 to 147 relate to the optional, i.e. any amidination 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 against tert-butyloxycarbonyl (Boc) in chloroform or dichloromethane (approx. 0.1 to 0.3 mol / 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.
Abstract
Description
Claims
Priority Applications (41)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MXPA02006241A MXPA02006241A (es) | 1999-12-24 | 2000-12-11 | Oxazolidinonas sustituidas y su uso en el campo de la coagulacion sanguinea. |
NZ519730A NZ519730A (en) | 1999-12-24 | 2000-12-11 | Substituted oxazolidinones and their use in the field of blood coagulation and preparation process thereof |
JP2001549389A JP4143297B2 (ja) | 1999-12-24 | 2000-12-11 | 置換オキサゾリジノン及び血液凝固の分野におけるそれらの使用 |
DE50009607T DE50009607D1 (de) | 1999-12-24 | 2000-12-11 | Substituierte oxazolidinone und ihre verwendung im gebiet der blutgerinnung |
CA002396561A CA2396561C (en) | 1999-12-24 | 2000-12-11 | Substituted oxazolidinones and their use in the field of blood coagulation |
HU0203902A HU226522B1 (en) | 1999-12-24 | 2000-12-11 | Substituted oxazolidinones, process for their preparation and pharmaceutical compositions containing them their use |
EEP200200341A EE05169B1 (et) | 1999-12-24 | 2000-12-11 | Asendatud oksasolidinoonid ja nende kasutamine |
SK908-2002A SK287272B6 (sk) | 1999-12-24 | 2000-12-11 | Substituované oxazolidinóny, spôsob ich výroby, lieky tieto látky obsahujúce a ich použitie |
IL14989600A IL149896A0 (en) | 1999-12-24 | 2000-12-11 | Substituted oxazolidinones and their use in the field of blood coagulation |
DK00993610T DK1261606T3 (da) | 1999-12-24 | 2000-12-11 | Substituerede oxazolidinoner og deres anvendelse inden for blodkoagulationsområdet |
US10/181,051 US7157456B2 (en) | 1999-12-24 | 2000-12-11 | Substituted oxazolidinones and their use in the field of blood coagulation |
DE122009000014C DE122009000014I1 (de) | 1999-12-24 | 2000-12-11 | Substituierte oxazolidinone und ihre verwendung im gebiet der blutgerinnung |
EP00993610A EP1261606B1 (de) | 1999-12-24 | 2000-12-11 | Substituierte oxazolidinone und ihre verwendung im gebiet der blutgerinnung |
AT00993610T ATE289605T1 (de) | 1999-12-24 | 2000-12-11 | Substituierte oxazolidinone und ihre verwendung im gebiet der blutgerinnung |
AU28414/01A AU775126C (en) | 1999-12-24 | 2000-12-11 | Substituted oxazolidinones and their use in the field of blood coagulation |
SI200030679T SI1261606T1 (de) | 1999-12-24 | 2000-12-11 | |
UA2002076161A UA73339C2 (en) | 1999-12-24 | 2000-12-11 | Substituted oxazolidinones and use thereof for the prevention of blood coagulation |
BRPI0017050-0A BR0017050B1 (pt) | 1999-12-24 | 2000-12-11 | oxazolidinonas substituÍdas, processo para sua produÇço, uso das mesmas e processo para impedir a coagulaÇço de sangue in vitro. |
PL355665A PL200413B1 (pl) | 1999-12-24 | 2000-12-11 | Podstawione oksazolidynony, sposób ich wytwarzania, środki lecznicze je zawierające oraz ich zastosowanie do wytwarzania środków leczniczych i do zapobiegania krzepnięciu krwi ex vivo |
NO20023043A NO323699B1 (no) | 1999-12-24 | 2002-06-21 | Substituerte oksazolidinoner, fremgangsmate for fremstilling derav og deres anvendelse innenfor feltet blodkoagulasjon |
HR20020617A HRP20020617B1 (en) | 1999-12-24 | 2002-07-23 | Substituted oxazolidinones and ther use in the field of blood coagulation |
HK04100440A HK1057556A1 (en) | 1999-12-24 | 2004-01-20 | Substituted oxazolidinones and their use in the field of blood coagulation |
AU2004218729A AU2004218729A1 (en) | 1999-12-24 | 2004-10-13 | Substituted oxazolidinones and their use in the field of blood coagulation |
HRP20060251AA HRP20060251B1 (hr) | 1999-12-24 | 2006-07-18 | Supstituirani oksazolidinoni i njihova uporaba |
US11/460,529 US7592339B2 (en) | 1999-12-24 | 2006-07-27 | Substituted oxazolidinones and their use in the field of blood coagulation |
NO20070981A NO20070981L (no) | 1999-12-24 | 2007-02-20 | Substituerte oksazolidinoner og deres anvendelse innenfor feltet blodkoagulasjon. |
US11/932,082 US7576111B2 (en) | 1999-12-24 | 2007-10-31 | Substituted oxazolidinones and their use in the field of blood coagulation |
US12/027,553 US7585860B2 (en) | 1999-12-24 | 2008-02-07 | Substituted oxazolidinones and their use in the field of blood coagulation |
LU91497C LU91497I2 (fr) | 1999-12-24 | 2008-11-19 | Rivaroxaban et ses sels pharmaceutiquement acceptables,hydrates,hydrates de ces sels et promédicaments |
NL300370C NL300370I2 (nl) | 1999-12-24 | 2008-11-25 | Gesubstitueerde oxazolidinonen en toepassing daarvan op het terrein van Rivaroxaban, desgewenst in de vorm van een farmaceutisch aanvaardbaar zout, hydraat of hydraat van het zout |
CY200800019C CY2008019I2 (el) | 1999-12-24 | 2008-12-02 | Υποκατεστημενες οξαζολιδινονες και η χρηση των στο πεδιο της πηξης αιματος |
LTPA2008018C LTC1261606I2 (lt) | 1999-12-24 | 2008-12-04 | Pakeisti oksazolidinonai ir jų panaudojimas kraujo krešėjimo srityje |
BE2008C046C BE2008C046I2 (de) | 1999-12-24 | 2008-12-10 | |
FR08C0051C FR08C0051I2 (fr) | 1999-12-24 | 2008-12-11 | Oxazolidinones substituees et leur utilisation dans le domaine de la coagulation sanguine |
NO2009001C NO2009001I1 (no) | 1999-12-24 | 2009-01-08 | Rivaroksaban |
US12/494,879 US8129378B2 (en) | 1999-12-24 | 2009-06-30 | Substituted oxazolidinones and their use in the field of blood coagulation |
IL205242A IL205242A (en) | 1999-12-24 | 2010-04-22 | Transduced oxazolidinones and their use in the field of blood clotting |
US13/360,107 US8530505B2 (en) | 1999-12-24 | 2012-01-27 | Substituted oxazolidinones and their use in the field of blood coagulation |
US13/961,264 US8822458B2 (en) | 1999-12-24 | 2013-08-07 | Substituted oxazolidinones and their use in the field of blood coagulation |
US14/336,379 US20150166568A1 (en) | 1999-12-24 | 2014-07-21 | Substituted oxazolidinones and their use in the field of blood coagulation |
NO2021009C NO2021009I1 (no) | 1999-12-24 | 2021-02-25 | XARELTO - forlenget SPC |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19962924A DE19962924A1 (de) | 1999-12-24 | 1999-12-24 | Substituierte Oxazolidinone und ihre Verwendung |
DE19962924.2 | 1999-12-24 |
Related Child Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10181051 A-371-Of-International | 2000-12-11 | ||
US10/181,051 A-371-Of-International US7157456B2 (en) | 1999-12-24 | 2000-12-11 | Substituted oxazolidinones and their use in the field of blood coagulation |
US11/460,529 Division US7592339B2 (en) | 1999-12-24 | 2006-07-27 | Substituted oxazolidinones and their use in the field of blood coagulation |
US11/460,529 Continuation US7592339B2 (en) | 1999-12-24 | 2006-07-27 | Substituted oxazolidinones and their use in the field of blood coagulation |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2001047919A1 WO2001047919A1 (de) | 2001-07-05 |
WO2001047919A9 true WO2001047919A9 (de) | 2002-12-19 |
Family
ID=7934434
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2000/012492 WO2001047919A1 (de) | 1999-12-24 | 2000-12-11 | Substituierte oxazolidinone und ihre verwendung im gebiet der blutgerinnung |
Country Status (50)
Families Citing this family (246)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19962924A1 (de) | 1999-12-24 | 2001-07-05 | Bayer Ag | Substituierte Oxazolidinone und ihre Verwendung |
US6710058B2 (en) | 2000-11-06 | 2004-03-23 | Bristol-Myers Squibb Pharma Company | Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors |
DE10105989A1 (de) | 2001-02-09 | 2002-08-14 | Bayer Ag | Substituierte Oxazolidinone und ihre Verwendung |
DE10129725A1 (de) * | 2001-06-20 | 2003-01-02 | Bayer Ag | Kombinationstherapie substituierter Oxazolidinone |
AU2002367959A1 (en) * | 2001-10-18 | 2003-12-31 | Michigan State University | Process for the preparation of oxazolidinones and method of use thereof |
DE10152460A1 (de) * | 2001-10-24 | 2003-05-08 | Bayer Ag | Stents |
JP2005512975A (ja) | 2001-10-25 | 2005-05-12 | アストラゼネカ アクチボラグ | 抗菌薬として有用なイソキサゾリン誘導体 |
WO2003078448A1 (en) | 2002-03-13 | 2003-09-25 | Signum Biosciences, Inc. | Modulation of protein methylation and phosphoprotein phosphate |
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 |
US7012088B2 (en) | 2003-02-24 | 2006-03-14 | Pharmacia & Upjohn Company | Indolone oxazolidinones and derivatives thereof |
DE10322469A1 (de) * | 2003-05-19 | 2004-12-16 | Bayer Healthcare Ag | Heterocyclische Verbindungen |
DE10336716A1 (de) * | 2003-08-11 | 2005-03-10 | Merck Patent Gmbh | Verfahren zur Herstellung von N-Aryl-morpholinonen |
DE10342570A1 (de) * | 2003-09-15 | 2005-04-14 | Bayer Healthcare Ag | Verfahren zur Herstellung von 4-(4-Aminophenyl)-3-morpholinon |
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 |
US7371743B2 (en) | 2004-02-28 | 2008-05-13 | Boehringer Ingelheim International Gmbh | Carboxylic acid amides, the preparation thereof and their use as medicaments |
EP1571154A1 (de) * | 2004-03-03 | 2005-09-07 | Aventis Pharma Deutschland GmbH | Derivate des Beta-Alanins als Hemmer des Faktors Xa |
US7550499B2 (en) | 2004-05-12 | 2009-06-23 | Bristol-Myers Squibb Company | Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions |
CA2562714A1 (en) * | 2004-05-13 | 2005-11-24 | Boehringer Ingelheim International Gmbh | Substituted thiophene-2-carboxylic acid amides, the production thereof and the use thereof as drugs |
AU2005243535A1 (en) * | 2004-05-13 | 2005-11-24 | Boehringer Ingelheim International Gmbh | Novel substituted thiophenecarboxamides, their production and their use as medicaments |
US7696352B2 (en) | 2004-06-18 | 2010-04-13 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
AU2005257999B2 (en) * | 2004-06-18 | 2011-12-08 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
US7429661B2 (en) * | 2004-07-20 | 2008-09-30 | Symed Labs Limited | Intermediates for linezolid and related compounds |
TW200612923A (en) | 2004-07-29 | 2006-05-01 | Ferrer Int | Oxazolidinone compounds and compositions and methods related thereto |
DE102004047840A1 (de) * | 2004-09-29 | 2006-03-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue substituierte Thiophencarbonsäureamide, deren Herstellung und deren Verwendung als Arzneimittel |
DE102004050283A1 (de) * | 2004-10-15 | 2006-04-27 | Lanxess Deutschland Gmbh | 4-Aminophenyl-morpholinon-Derivate und deren Herstellung |
US7645755B2 (en) * | 2004-10-22 | 2010-01-12 | Janssen Pharmaceutical N.V. | Inhibitors of c-fms kinase |
US7662837B2 (en) | 2004-10-22 | 2010-02-16 | Janssen Pharmaceutica N.V. | Inhibitors of c-fms kinase |
DE102004062475A1 (de) * | 2004-12-24 | 2006-07-06 | Bayer Healthcare Ag | Feste, oral applizierbare pharmazeutische Darreichungsformen mit modifizierter Freisetzung |
ATE499370T1 (de) | 2005-01-19 | 2011-03-15 | Bristol Myers Squibb Co | 2-phenoxy-n-(1,3,4-thiadizol-2-yl)pyridin-3- aminderivate und verwandte verbindungen als p2y1- rezeptor-hemmer zur behandlung thromboembolischer erkrankungen |
EP1685841A1 (de) | 2005-01-31 | 2006-08-02 | Bayer Health Care Aktiengesellschaft | Prophylaxe und Behandlung von thrombolischen Erkrankungen |
US7923041B2 (en) | 2005-02-03 | 2011-04-12 | Signum Biosciences, Inc. | Compositions and methods for enhancing cognitive function |
US8221804B2 (en) * | 2005-02-03 | 2012-07-17 | Signum Biosciences, Inc. | Compositions and methods for enhancing cognitive function |
DE102005018690A1 (de) * | 2005-04-22 | 2006-10-26 | Bayer Healthcare Ag | Imino-oxazolidine und ihre Verwendung |
US20060281788A1 (en) * | 2005-06-10 | 2006-12-14 | Baumann Christian A | Synergistic modulation of flt3 kinase using a flt3 inhibitor and a farnesyl transferase inhibitor |
US7714002B2 (en) | 2005-06-27 | 2010-05-11 | Bristol-Myers Squibb Company | Carbocycle and heterocycle antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions |
EP1896417B1 (de) | 2005-06-27 | 2011-03-23 | Bristol-Myers Squibb Company | Lineare harnstoffmimetika-antagonisten des p2y1-rezeptors zur behandlung von thromboseleiden |
US7700620B2 (en) | 2005-06-27 | 2010-04-20 | Bristol-Myers Squibb Company | C-linked cyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions |
EP1896466B1 (de) | 2005-06-27 | 2011-04-13 | Bristol-Myers Squibb Company | N-gebundene heterocyclische antagonisten des p2y1-rezeptors zur behandlung von thromboseleiden |
PE20070171A1 (es) | 2005-06-30 | 2007-03-08 | Boehringer Ingelheim Int | GLICINAMIDAS SUSTITUIDAS CON EFECTO ANTITROMBOTICO E INHIBIDOR DEL FACTOR Xa |
WO2007007588A1 (ja) * | 2005-07-08 | 2007-01-18 | Ono Pharmaceutical Co., Ltd. | 平面性を有する環状基を母核とする化合物 |
US20070032473A1 (en) * | 2005-07-19 | 2007-02-08 | Kai Gerlach | Substituted amides and their use as medicaments |
AR057976A1 (es) * | 2005-08-29 | 2008-01-09 | Boehringer Ingelheim Int | Biarilos sustituidos y su uso como medicamentos. |
DE102005045518A1 (de) * | 2005-09-23 | 2007-03-29 | Bayer Healthcare Ag | 2-Aminoethoxyessigsäure-Derivate und ihre Verwendung |
DE102005047558A1 (de) * | 2005-10-04 | 2008-02-07 | Bayer Healthcare Ag | Kombinationstherapie substituierter Oxazolidinone zur Prophylaxe und Behandlung von cerebralen Durchblutungsstörungen |
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 |
DE102005047561A1 (de) | 2005-10-04 | 2007-04-05 | Bayer Healthcare Ag | Feste, oral applizierbare pharmazeutische Darreichungsformen mit schneller Wirkstofffreisetzung |
US8188270B2 (en) * | 2005-10-04 | 2012-05-29 | Bayer Schering Pharma Aktiengesellschaft | Polymorphous form of 5-chloro-N-({(5S)-2-oxo-3[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidine-5-yl}-methyl)-2-thiophene carboxamide |
DE102005048824A1 (de) * | 2005-10-10 | 2007-04-12 | Bayer Healthcare Ag | Behandlung und Prophylaxe von Mikroangiopathien |
CN101340909B (zh) | 2005-10-18 | 2012-01-11 | 詹森药业有限公司 | 抑制flt3激酶的方法 |
US7962847B2 (en) * | 2005-10-20 | 2011-06-14 | International Business Machines Corporation | Method for providing dynamic process step annotations |
DE102005052174A1 (de) * | 2005-11-02 | 2007-06-06 | Bayer Healthcare Ag | Phenylen-bis-oxazolidin-Derivate und ihre Verwendung |
JP2007154330A (ja) * | 2005-12-01 | 2007-06-21 | Nippon Paper Industries Co Ltd | 印刷用塗工紙 |
JP5040036B2 (ja) * | 2005-12-30 | 2012-10-03 | メルク・シャープ・エンド・ドーム・コーポレイション | Cetp阻害剤として有用な1,3−オキサゾリジン−2−オン誘導体 |
DE102006007146A1 (de) | 2006-02-16 | 2007-08-23 | Bayer Healthcare Ag | Aminoacyl-Prodrugs |
CN103497173A (zh) | 2006-03-31 | 2014-01-08 | 财团法人乙卯研究所 | 具有杂环的新化合物 |
ES2389678T3 (es) | 2006-04-20 | 2012-10-30 | Janssen Pharmaceutica Nv | Un inhibidor de la quinasa C-Kit para su uso en el tratamiento de tumores del estroma gastrointestinal o mastocitosis |
DK2021335T3 (da) * | 2006-04-20 | 2011-09-05 | Janssen Pharmaceutica Nv | Heterocykliske forbindelser som C-FMS-kinasehæmmere |
US8697716B2 (en) | 2006-04-20 | 2014-04-15 | Janssen Pharmaceutica Nv | Method of inhibiting C-KIT kinase |
NZ572201A (en) | 2006-04-20 | 2011-09-30 | Janssen Pharmaceutica Nv | Inhibitors of c-fms kinase |
MX2008013530A (es) | 2006-04-20 | 2009-01-14 | Janssen Pharmaceutica Nv | Inhibidores de c-fms cinasa. |
US7763608B2 (en) * | 2006-05-05 | 2010-07-27 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
DE102006025314A1 (de) * | 2006-05-31 | 2007-12-06 | Bayer Healthcare Ag | Arylsubstituierte Heterozyklen und ihre Verwendung |
DE102006025319A1 (de) * | 2006-05-31 | 2007-12-06 | Bayer Healthcare Aktiengesellschaft | Substituierte Heterozyklen und ihre Verwendung |
DE102006034916A1 (de) * | 2006-07-28 | 2008-01-31 | Bayer Healthcare Ag | Beschichtung künstlicher Oberflächen von medizinischen Hilfsmitteln und Geräten sowie Reinigung und/oder Vorbehandlung von Kathetern und anderen medizinischen Hilfsmitteln und Geräten |
DE102006039589A1 (de) * | 2006-08-24 | 2008-03-06 | Bayer Healthcare Ag | Aminoacyl-Prodrugs II |
US7960569B2 (en) | 2006-10-17 | 2011-06-14 | Bristol-Myers Squibb Company | Indole antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions |
DE102006051625A1 (de) * | 2006-11-02 | 2008-05-08 | Bayer Materialscience Ag | Kombinationstherapie substituierter Oxazolidinone |
JP5342450B2 (ja) | 2006-12-15 | 2013-11-13 | ブリストル−マイヤーズ スクイブ カンパニー | 第XIa因子インヒビターとしてのアリールプロピオンアミド、アリールアクリルアミド、アリールプロピンアミド、またはアリールメチルウレアアナログ |
PE20081775A1 (es) | 2006-12-20 | 2008-12-18 | Bristol Myers Squibb Co | Compuestos macrociclicos como inhibidores del factor viia |
AU2008205093A1 (en) * | 2007-01-05 | 2008-07-17 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
EP2141154A4 (de) | 2007-03-30 | 2011-06-01 | Inst Med Molecular Design Inc | Oxazolidinonderivat mit hemmender wirkung auf die 11-hydroxysteroiddehydrogenase vom typ i |
DE102007018662A1 (de) * | 2007-04-20 | 2008-10-23 | Bayer Healthcare Ag | Oxazolidinone zur Behandlung und Prophylaxe von pulmonaler Hypertonie |
BRPI0810462A2 (pt) | 2007-04-23 | 2014-10-14 | Sanofi Aventis | Derivados de quinolina-carboxamida como antagonistas de p2y12 |
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 |
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 |
DE102007028318A1 (de) * | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Oxazolidinone zur Behandlung und Prophylaxe von Sepsis |
DE102007028407A1 (de) | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituierte Oxazolidinone und ihre Verwendung |
DE102007028319A1 (de) | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituierte Oxazolidinone und ihre Verwendung |
DE102007028320A1 (de) * | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituierte Oxazolidinone und ihre Verwendung |
DE102007028406A1 (de) * | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituierte Oxazolidinone und ihre Verwendung |
DE102007037373A1 (de) | 2007-08-06 | 2009-02-19 | Schebo Biotech Ag | Neue Pharmazeutika, Verfahren zu ihrer Herstellung und ihre Verwendung in der Therapie |
WO2009018807A1 (de) * | 2007-08-06 | 2009-02-12 | Schebo Biotech Ag | Oxazolidinone als faktor xa- inhibitoren, verfahren zu ihrer herstellung und ihre verwendung in der therapie |
US20090076264A1 (en) * | 2007-09-15 | 2009-03-19 | Protia, Llc | Deuterium-enriched rivaroxaban |
EP2669283A1 (de) | 2007-10-02 | 2013-12-04 | Shionogi&Co., Ltd. | Oxazolidinonderivat mit 7-gliedrigem Heteroring |
JO3240B1 (ar) | 2007-10-17 | 2018-03-08 | Janssen Pharmaceutica Nv | c-fms مثبطات كيناز |
JP5524852B2 (ja) * | 2007-11-15 | 2014-06-18 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 置換アミド、それらの製造及び医薬品としての使用 |
NZ586002A (en) * | 2007-12-11 | 2012-06-29 | Bayer Schering Pharma Ag | Oxazolidinones for the treatment and/or prophylaxis of heart failure |
JP5504171B2 (ja) | 2007-12-26 | 2014-05-28 | サノフイ | P2y12アンタゴニストとしてのヘテロサイクリックピラゾール−カルボキサミド |
CN102014897B (zh) | 2008-04-21 | 2015-08-05 | 西格纳姆生物科学公司 | 化合物、组合物和其制备方法 |
DE102008028071A1 (de) | 2008-06-12 | 2009-12-17 | Bayer Schering Pharma Aktiengesellschaft | Neue Cokristall-Verbindung von Rivaroxaban und Malonsäure |
EP2138178A1 (de) * | 2008-06-28 | 2009-12-30 | Bayer Schering Pharma Aktiengesellschaft | Oxazolidninone zur Behandlung der chronisch obstruktiven Lungenerkrankung (COPD) und/oder Asthma |
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 |
EP2140866A1 (de) * | 2008-07-04 | 2010-01-06 | Bayer Schering Pharma Aktiengesellschaft | Oxazolidinone zur Behandlung von Entzündungserkrankungen des Magen-Darm-Trakts |
WO2010003641A1 (en) | 2008-07-08 | 2010-01-14 | Ratiopharm Gmbh | Pharmaceutical compositions comprising 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid |
KR101023174B1 (ko) * | 2008-09-24 | 2011-03-18 | 주식회사 레고켐 바이오사이언스 | 사이클릭 아미독심 또는 사이클릭 아미드라존 기를 가지는 신규한 옥사졸리디논 유도체 및 이를 함유하는 의약 조성물 |
US20100168111A1 (en) * | 2008-12-31 | 2010-07-01 | 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 |
NZ594064A (en) * | 2009-01-30 | 2012-08-31 | Glaxosmithkline Llc | Crystalline n-{ (1s)-2-amino-1-[(3-fluorophenyl)methyl]ethyl} -5-chloro-4-(4-chloro-1-methyl-1h-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride |
US7816355B1 (en) | 2009-04-28 | 2010-10-19 | Apotex Pharmachem Inc | Processes for the preparation of rivaroxaban and intermediates thereof |
EP2266541A1 (de) | 2009-06-18 | 2010-12-29 | Krka Tovarna Zdravil, D.D., Novo Mesto | Feste pharmazeutische Zusammensetzung mit Rivaroxaban |
WO2010146179A2 (en) | 2009-06-18 | 2010-12-23 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Solid pharmaceutical composition comprising rivaroxaban |
KR101037051B1 (ko) | 2009-07-08 | 2011-05-26 | 주식회사 레고켐 바이오사이언스 | (s)-5-클로로-n-((3-(4-(5,6-다이하이드로-4h-1,2,4-옥사다이아진-3-일)페닐)-2-옥소옥사졸리딘-5-일)메틸)싸이오펜-2-카르복사미드 유도체의 제조방법 |
KR101037052B1 (ko) * | 2009-07-08 | 2011-05-26 | 주식회사 레고켐 바이오사이언스 | 5-클로로-n-(((5s)-2-옥소-3-(4-(5,6-디하이드로-1,2,4-트리아진-1(4h)-일)페닐)-1,3-옥사졸리딘-5-일)메틸)티오펜-2-카르복사미드 유도체의 제조방법 및 그 제조중간체 |
ES2905760T3 (es) | 2009-07-31 | 2022-04-12 | Krka D D Novo Mesto | Procedimientos para la cristalización del rivaroxabán |
WO2011042156A1 (en) | 2009-10-06 | 2011-04-14 | Ratiopharm Gmbh | Pharmaceutical compositions comprising rivaroxaban |
EP2308472A1 (de) | 2009-10-06 | 2011-04-13 | ratiopharm GmbH | Pharmazeutische Zusammensetzungen, die Rivaroxaban umfassen |
WO2011061760A1 (en) * | 2009-11-18 | 2011-05-26 | Cadila Healthcare Limited | Novel antithrombotic agents |
US8742120B2 (en) | 2009-12-17 | 2014-06-03 | Millennium Pharmaceuticals, Inc. | Methods of preparing factor xa inhibitors and salts thereof |
US8530501B2 (en) * | 2009-12-17 | 2013-09-10 | Millennium Pharmaceuticals, Inc. | Salts and crystalline forms of a factor Xa inhibitor |
CN102822167A (zh) * | 2010-01-04 | 2012-12-12 | 埃南蒂亚有限公司 | 用于制备利伐沙班的方法及其中间体 |
EA015918B1 (ru) | 2010-03-03 | 2011-12-30 | Дмитрий Геннадьевич ТОВБИН | УРЕТАНЫ, МОЧЕВИНЫ, АМИДЫ И РОДСТВЕННЫЕ ИНГИБИТОРЫ ФАКТОРА Xa |
EP2354128A1 (de) * | 2010-02-10 | 2011-08-10 | Sandoz Ag | Verfahren zur Herstellung von Rivaroxaban |
ES2674745T3 (es) | 2010-02-11 | 2018-07-03 | Bristol-Myers Squibb Company | Macrociclos como inhibidores del factor XIa |
DE102010018299A1 (de) | 2010-04-23 | 2011-10-27 | Archimica Gmbh | Verfahren zur Herstellung von 4-(4-Aminophenyl)-morpholin-3-on |
DE102010028362A1 (de) | 2010-04-29 | 2011-11-03 | Bayer Schering Pharma Aktiengesellschaft | Herstellverfahren |
KR101799429B1 (ko) * | 2010-05-03 | 2017-11-21 | 에스케이바이오팜 주식회사 | 신경 세포 사멸 또는 신경 퇴화를 억제하기 위한 약학적 조성물 |
EP2388260A1 (de) | 2010-05-21 | 2011-11-23 | Archimica GmbH | Herstellungsverfahren für einen Inhibitor eines Blutgerinnungsfaktors |
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 |
EP2404920A1 (de) | 2010-07-06 | 2012-01-11 | Sandoz AG | Kristalline Form von Rivaroxaban-Dihydrat |
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 |
CZ2010714A3 (cs) | 2010-09-30 | 2012-04-11 | Farmak, A. S. | Zpusob výroby 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morfolinyl)fenyl]-1,3oxazolidin-5-yl}methyl)-1H-isoindol-1,3(2H)-dionu ve vysoké optické cistote |
AU2010362639B2 (en) * | 2010-10-18 | 2016-10-27 | Apotex Pharmachem Inc. | Processes for the preparation of Rivaroxaban and intermediates thereof |
CN102464658B (zh) * | 2010-11-03 | 2014-04-16 | 天津药物研究院 | 噁唑烷酮衍生物及其制备方法和用途 |
DE102010063127A1 (de) | 2010-12-15 | 2012-06-21 | Bayer Schering Pharma Aktiengesellschaft | Flüssige, oral applizierbare pharmazeutische Zusammensetzungen enthaltend 5-Chlor-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid |
EP2665751A1 (de) | 2011-01-19 | 2013-11-27 | Bayer Intellectual Property GmbH | Bindung von proteinen an hemmer von gerinnungsfaktoren |
CN102199150A (zh) * | 2011-04-01 | 2011-09-28 | 中国药科大学 | 光学活性噁唑烷酮类衍生物及其制备方法与在制药中的用途 |
US9221771B2 (en) | 2011-04-11 | 2015-12-29 | Sandoz Ag | Method for the preparation of substituted oxazolidinones |
GEP20156397B (en) * | 2011-05-06 | 2015-11-10 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | Process for the preparation of a rivaroxaban and intermediates formed in said process |
WO2012156983A1 (en) * | 2011-05-16 | 2012-11-22 | Symed Labs Limited | Processes 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 |
ES2395304B1 (es) * | 2011-05-20 | 2014-01-16 | Interquim, S.A. | Procedimiento de obtención de una tiofen-2-carboxamida. |
CN102796092B (zh) * | 2011-05-24 | 2015-04-08 | 北大方正集团有限公司 | 噁唑烷酮衍生物及其制备方法和应用 |
CN102796091A (zh) * | 2011-05-24 | 2012-11-28 | 北大方正集团有限公司 | 取代的噁唑烷酮化合物及其制备方法和应用 |
CN102320988B (zh) * | 2011-06-03 | 2014-04-09 | 中国科学院上海有机化学研究所 | 4-(4-氨基苯基)-3-吗啉酮中间体酰胺、合成方法和用途 |
CN102827154B (zh) | 2011-06-14 | 2015-04-22 | 上海科胜药物研发有限公司 | 一种合成利伐沙班中间体4-{4-[(5s)-5-(氨基甲基)-2-氧代-1,3-恶唑烷-3-基]苯基}吗啉-3-酮的方法 |
TW201319068A (zh) | 2011-08-05 | 2013-05-16 | 必治妥美雅史谷比公司 | 作為xia因子抑制劑之環狀p1接合劑 |
TW201311689A (zh) | 2011-08-05 | 2013-03-16 | 必治妥美雅史谷比公司 | 作為因子xia抑制劑之新穎巨環化合物 |
US20140378682A1 (en) | 2011-09-08 | 2014-12-25 | Cadila Healthcare Limited | Processes and intermediates for preparing rivaroxaban |
EP2573084A1 (de) | 2011-09-22 | 2013-03-27 | Enantia, S.L. | Neue kristalline Formen von Rivaroxaban und Verfahren zur deren Herstellung |
WO2013046211A1 (en) * | 2011-09-27 | 2013-04-04 | Symed Labs Limited | Processes for the preparation of 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide and intermediates thereof |
WO2013053739A1 (en) | 2011-10-10 | 2013-04-18 | Laboratorios Lesvi, S. L. | Process for preparing factor xa inhibitors |
HU230734B1 (hu) | 2011-10-10 | 2017-12-28 | EGIS Gyógyszergyár Nyrt | Gyógyászati készítmény előállítására alkalmazható rivaroxaban kokristályok |
WO2013054275A1 (en) * | 2011-10-11 | 2013-04-18 | Council Of Scientific & Industrial Research | Sila analogs of oxazolidinone derivatives and synthesis thereof |
PT2766346T (pt) | 2011-10-14 | 2017-05-26 | Bristol Myers Squibb Co | Compostos de tetrahidroisoquinolina substituídos como inibidores do fator xia |
IN2014CN02805A (de) | 2011-10-14 | 2015-07-03 | Bristol Myers Squibb Co | |
CN103987697B (zh) | 2011-10-14 | 2017-04-26 | 百时美施贵宝公司 | 作为因子xia抑制剂的取代的四氢异喹啉化合物 |
CN102408420B (zh) * | 2011-10-19 | 2014-10-22 | 汕头经济特区鮀滨制药厂 | 一种利伐沙班及其中间体的制备方法以及中间体化合物 |
WO2013121436A2 (en) | 2012-02-06 | 2013-08-22 | Megafine Pharma (P) Ltd | A process for preparation of rivaroxaban and intermediates thereof |
CZ2012111A3 (cs) | 2012-02-16 | 2013-08-28 | Zentiva, K.S. | Zpusob prípravy rivaroxabanu zalozený na vyuzití (S)-epichlorhydrinu |
CZ2012114A3 (cs) | 2012-02-17 | 2013-02-20 | Zentiva, K.S. | Zpusob prípravy rivaroxabanu zalozený na úspore 1,1´ -karbonyldiimidazolu |
CN103288814B (zh) | 2012-02-24 | 2016-07-06 | 国药集团国瑞药业有限公司 | 一种利伐沙班中间体的制备方法 |
WO2013151719A2 (en) * | 2012-04-05 | 2013-10-10 | Scifluor Life Sciences, Llc | Fluorinated oxazolidinone derivatives |
WO2013152168A1 (en) | 2012-04-06 | 2013-10-10 | Indiana University Research And Technology Corporation | Processes for preparing rivaroxaban |
WO2013156936A1 (en) | 2012-04-16 | 2013-10-24 | Ranbaxy Laboratories Limited | Process for the preparation of rivaroxaban and intermediates thereof |
EP2844654B1 (de) * | 2012-05-02 | 2021-03-10 | Symed Labs Limited | Verbessertes verfahren zur herstellung von rivaroxaban unter verwendung neuartiger zwischenprodukte |
IN2014DN10209A (de) * | 2012-05-24 | 2015-08-07 | Ranbaxy Lab Ltd | |
CN102746287B (zh) * | 2012-06-21 | 2014-05-28 | 成都苑东药业有限公司 | 一种恶唑烷酮化合物及其制备方法 |
UY34856A (es) | 2012-07-03 | 2013-12-31 | Bayer Pharma AG | Formas de presentación farmacéuticas que contienen 5-cloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4- morfolinil)-fenil]-1,3-oxazolidin-5-il}-metil)-2-tiofencarboxamida |
CN102757424B (zh) * | 2012-07-09 | 2014-10-15 | 云南大学 | 2-苄基取代苯并呋喃—咪唑盐类化合物及其制备方法 |
CN102746288B (zh) * | 2012-07-24 | 2015-04-08 | 常州制药厂有限公司 | 一种抗凝血药及其关键中间体的制备方法 |
CA2880898A1 (en) | 2012-08-03 | 2014-02-06 | Bristol-Myers Squibb Company | Dihydropyridone p1 as factor xia inhibitors |
CA2880866A1 (en) | 2012-08-03 | 2014-02-06 | Bristol-Myers Squibb Company | Dihydropyridone p1 as factor xia inhibitors |
JOP20180012A1 (ar) | 2012-08-07 | 2019-01-30 | Janssen Pharmaceutica Nv | عملية السلفنة باستخدام نونافلوروبوتانيسولفونيل فلوريد |
EP2882757B1 (de) | 2012-08-07 | 2016-10-05 | Janssen Pharmaceutica, N.V. | Verfahren zur herstellung heterocyclischer esterderivate |
CN103626749A (zh) * | 2012-08-21 | 2014-03-12 | 苏州泽璟生物制药有限公司 | 取代的噁唑烷酮化合物和包含该化合物的药物组合物及其用途 |
EP2900663A2 (de) | 2012-09-26 | 2015-08-05 | Ranbaxy Laboratories Limited | Verfahren zur herstellung von rivaroxaban |
CN103864773B (zh) * | 2012-12-13 | 2017-03-15 | 北京藏卫信康医药研发有限公司 | 利伐沙班及其中间体的制备方法 |
SI2935255T1 (en) * | 2012-12-21 | 2018-01-31 | Farma Grs, D. O. O. | PROCEDURE FOR PREPARATION OF RIVAROKSABAN |
US9394292B2 (en) | 2012-12-26 | 2016-07-19 | Wanbury Ltd. | Rivaroxaban intermediate and preparation thereof |
AU2013368847B2 (en) * | 2012-12-26 | 2017-03-16 | Wanbury Ltd. | Aldehyde derivative of substitute oxazolidinones |
US9663505B2 (en) | 2013-03-25 | 2017-05-30 | Glenmark Pharmaceuticals Limited | Process for the preparation of rivaroxaban |
ES2712699T3 (es) | 2013-03-25 | 2019-05-14 | Bristol Myers Squibb Co | Tetrahidroisoquinolinas que contienen azoles sustituidos como inhibidores del factor XIa |
CN104098556B (zh) * | 2013-04-09 | 2019-01-08 | 浙江九洲药物科技有限公司 | 一种利伐沙班的合成工艺 |
CN103242307B (zh) * | 2013-05-17 | 2015-08-12 | 天津药物研究院有限公司 | 一种噁唑烷酮类衍生物晶型ⅰ及其制备方法和用途 |
WO2014183667A1 (zh) * | 2013-05-17 | 2014-11-20 | 天津药物研究院 | 一种噁唑烷酮衍生物的乙酸溶剂化物及其制备方法和用途 |
WO2014195244A1 (de) * | 2013-06-03 | 2014-12-11 | Bayer Pharma Aktiengesellschaft | Triazolopyridine als thrombininhibitoren zur behandlung von thromboembolischen erkrankungen |
UY35592A (es) | 2013-06-03 | 2014-12-31 | Bayer Pharma AG | Benzoxazoles sustituidos |
JP2016520110A (ja) * | 2013-06-03 | 2016-07-11 | バイエル ファーマ アクチエンゲゼルシャフト | 置換ベンゾキサゾール |
WO2015011617A1 (en) | 2013-07-23 | 2015-01-29 | Ranbaxy Laboratories Limited | Process for the preparation of rivaroxaban |
IN2013MU02699A (de) | 2013-08-19 | 2015-06-19 | Amneal Pharmaceuticals Llc | |
IN2014MU00072A (de) | 2014-01-08 | 2015-08-21 | Wockhardt Ltd | |
WO2015111076A2 (en) * | 2014-01-23 | 2015-07-30 | Symed Labs Limited | Improved processes for the preparation of highly pure rivaroxaban crystal modification i |
NO2760821T3 (de) | 2014-01-31 | 2018-03-10 | ||
KR20240017118A (ko) | 2014-01-31 | 2024-02-06 | 브리스톨-마이어스 스큅 컴퍼니 | 인자 XIa 억제제로서의 헤테로시클릭 P2' 기를 갖는 마크로사이클 |
WO2015124995A1 (en) | 2014-02-19 | 2015-08-27 | Aurobindo Pharma Ltd | Solid dosage forms of rivaroxaban |
EP2929885A1 (de) | 2014-04-11 | 2015-10-14 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmazeutische kombinationen von rivaroxaban und protonenpumpenhemmern |
CN104974149B (zh) * | 2014-04-14 | 2018-05-01 | 北大方正集团有限公司 | 一种利伐沙班的制备方法 |
KR101499867B1 (ko) * | 2014-04-22 | 2015-03-06 | 에스케이케미칼주식회사 | 활성 성분 (i) 함유 조성물 및 이의 제조 방법 |
CN105085371B (zh) * | 2014-04-22 | 2017-06-16 | 北大方正集团有限公司 | (s)‑{1‑(氯甲酸酯基)‑2‑[2‑(1,3‑二氧异吲哚)基]乙基}卤化盐及其制备方法 |
CN105085370B (zh) * | 2014-04-22 | 2017-04-12 | 北大方正集团有限公司 | (s)‑1‑卤代‑2‑[2‑(1,3‑二氧异吲哚)基]乙基氯甲酸酯及其制备方法 |
EP2942058A1 (de) | 2014-05-09 | 2015-11-11 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmazeutische Kombinationen aus Rivaroxaban und Histamin-H2-Rezeptorantagonisten |
CN104031036A (zh) * | 2014-05-16 | 2014-09-10 | 南通常佑药业科技有限公司 | 一种利伐沙班的制备方法 |
JP2017516845A (ja) | 2014-05-22 | 2017-06-22 | ノース チャイナ ファーマシューティカル カンパニー リミテッド | 血液凝固因子Xa阻害剤としてのヒドラジド化合物 |
CN103980221B (zh) * | 2014-05-26 | 2016-03-23 | 山东康美乐医药科技有限公司 | 4-(硝基苯基)-3-吗啉酮的制备方法及利用其制备利伐沙班的方法 |
DE102014108210A1 (de) | 2014-06-11 | 2015-12-17 | Dietrich Gulba | Rodentizid |
WO2015198259A1 (en) | 2014-06-26 | 2015-12-30 | Erregierre S.P.A. | Process for the synthesis of rivaroxaban and intermediate for the production thereof |
TW201607923A (zh) | 2014-07-15 | 2016-03-01 | 歌林達有限公司 | 被取代之氮螺環(4.5)癸烷衍生物 |
WO2016008582A1 (en) | 2014-07-15 | 2016-01-21 | Grünenthal GmbH | Substituted azaspiro(4.5)decane derivatives |
CN104086539A (zh) * | 2014-07-17 | 2014-10-08 | 天津炜捷制药有限公司 | 一种利伐沙班的制备方法 |
WO2016030669A1 (en) | 2014-08-25 | 2016-03-03 | Cipla Limited | Process for the preparation of rivaroxaban |
NO2721243T3 (de) | 2014-10-01 | 2018-10-20 | ||
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 |
CN104478866B (zh) * | 2014-12-05 | 2017-07-07 | 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 |
CN104478869B (zh) * | 2014-12-05 | 2017-04-12 | 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 |
CN104447728B (zh) * | 2014-12-05 | 2017-01-04 | 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 |
CN104530029B (zh) * | 2014-12-09 | 2017-04-12 | 广东东阳光药业有限公司 | 作为Xa因子抑制剂的杂环化合物及其使用方法和用途 |
CN104496978A (zh) * | 2014-12-09 | 2015-04-08 | 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 |
CN104530030A (zh) * | 2014-12-10 | 2015-04-22 | 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 |
CN104530031A (zh) * | 2014-12-10 | 2015-04-22 | 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 |
CN104530080B (zh) * | 2014-12-10 | 2017-01-11 | 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 |
CN105777734A (zh) * | 2014-12-22 | 2016-07-20 | 常州方楠医药技术有限公司 | 一种利伐沙班中间体的合成方法 |
CN104557900A (zh) * | 2014-12-23 | 2015-04-29 | 中国药科大学 | 噁唑烷酮类化合物及其制备方法与医药用途 |
CN105820161A (zh) * | 2015-01-08 | 2016-08-03 | 常州方楠医药技术有限公司 | 一种利伐沙班中间体5-羟基甲基噁唑烷酮衍生物的合成方法 |
TR201501970A2 (en) | 2015-02-19 | 2016-09-21 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Pharmaceutical combinations of dronedarone. |
MX2017012188A (es) | 2015-03-20 | 2017-12-15 | Hoffmann La Roche | Inhibidores de beta-secretasa 1 (bace1). |
WO2016150937A1 (en) | 2015-03-25 | 2016-09-29 | Lonza Ltd | Method for preparation of thiophenecarbonyl chlorides |
CN104926807B (zh) * | 2015-06-04 | 2017-10-31 | 沈阳药科大学 | 一种利伐沙班相关物质“二胺”及其合成方法 |
JP6742348B2 (ja) | 2015-06-19 | 2020-08-19 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 第xia因子阻害剤としてのジアミド大員環 |
ES2937156T3 (es) | 2015-07-29 | 2023-03-24 | Bristol Myers Squibb Co | Inhibidores macrocíclicos del factor XIa que llevan un grupo P2' no aromático |
WO2017023992A1 (en) | 2015-08-05 | 2017-02-09 | Bristol-Myers Squibb Company | Novel substituted glycine derived fxia inhibitors |
JP6410989B2 (ja) * | 2015-11-04 | 2018-10-24 | ロンザ・リミテッド | 塩化オキサリルを用いたチオフェン−2−カルボニルクロリド類の調製方法 |
HRP20211946T1 (hr) | 2016-02-23 | 2022-03-18 | Morgandane Scientific, LLC | Postupak liječenja bolesnika s istodobnom primjenom rivaroksabana i verapamila |
CN109195973A (zh) | 2016-03-02 | 2019-01-11 | 百时美施贵宝公司 | 具有因子xia抑制活性的二酰胺大环类化合物 |
EP3263096A1 (de) | 2016-06-28 | 2018-01-03 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmazeutische kapselformulierung von rivaroxaban |
CN106588905A (zh) * | 2016-12-13 | 2017-04-26 | 重庆英斯凯化工有限公司 | 一种利伐沙班中间体的制备方法 |
WO2018127762A1 (en) * | 2017-01-04 | 2018-07-12 | Unichem Laboratories Ltd | An improved process for the preparation of rivaroxaban involving novel intermediate |
CN107586291B (zh) * | 2017-11-03 | 2019-08-20 | 梯尔希(南京)药物研发有限公司 | 一种利伐沙班代谢物5的合成方法 |
CN107857761A (zh) * | 2017-11-14 | 2018-03-30 | 安徽华胜医药科技有限公司 | 一种氘代利伐沙班及其制备方法 |
CN107857739A (zh) * | 2017-11-14 | 2018-03-30 | 安徽华胜医药科技有限公司 | 一种氘代利伐沙班关键中间体及其制备方法 |
CN108164519A (zh) * | 2017-12-28 | 2018-06-15 | 江苏悦兴医药技术有限公司 | 利伐沙班工艺杂质的合成方法 |
EP4257136A3 (de) | 2017-12-31 | 2023-11-29 | Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. | Herstellung einer festen pharmazeutischen zusammensetzung mit rivaroxaban und herstellung davon |
HU231119B1 (hu) | 2018-01-12 | 2020-11-30 | Richter Gedeon Nyrt. | Eljárás 4-(4-aminofenil)morfolin-3-on előállítására |
US10828310B2 (en) | 2018-02-02 | 2020-11-10 | Bayer Pharma Aktiengesellschaft | Reducing the risk of cardiovascular events |
GB201807014D0 (en) | 2018-04-30 | 2018-06-13 | Univ Leeds Innovations Ltd | Factor xlla inhibitors |
CN108546265A (zh) * | 2018-06-22 | 2018-09-18 | 苏州中联化学制药有限公司 | 一种利伐沙班中间体的合成方法 |
US10722486B2 (en) | 2018-08-13 | 2020-07-28 | Morgandane Scientific, LLC | Method of treating patients with a factor Xa inhibitor, aspirin, and verapamil |
CN110054621A (zh) * | 2019-03-12 | 2019-07-26 | 浙江天宇药业股份有限公司 | 一种利伐沙班中间体的制备方法 |
CN110615756A (zh) * | 2019-06-28 | 2019-12-27 | 南京红杉生物科技有限公司 | 1-(4-硝基苯基)哌啶-2-酮及其合成方法和应用 |
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 |
GB202102575D0 (en) | 2021-02-23 | 2021-04-07 | Teva Pharmaceutical Industries Ltd | Fixed-dose pharmaceutical compositions |
EP4070658A1 (de) | 2021-04-06 | 2022-10-12 | BIORoxx GmbH | Verwendung von blutgerinnungshemmenden verbindungen als rodentizide |
GB202107722D0 (en) | 2021-05-28 | 2021-07-14 | Lunac Therapeutics Ltd | Factor XIIA Inhibitors |
Family Cites Families (75)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1035546B (de) | 1955-02-16 | 1958-07-31 | Max Ruf | Torbegrenzung fuer Ballspiele |
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. |
EP0316594B1 (de) | 1987-10-21 | 1993-09-29 | The Du Pont Merck Pharmaceutical Company | 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 |
AU667198B2 (en) | 1991-11-01 | 1996-03-14 | Pharmacia & Upjohn Company | Substituted aryl- and heteroarylphenyloxazolidinones useful as antibacterial agents |
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 |
ATE181735T1 (de) | 1993-05-01 | 1999-07-15 | Merck Patent Gmbh | Substituierte 1-phenyl-oxazolidin-2-on derivate, deren herstellung und deren verwendung als adhäsionsrezeptor-antagonisten |
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 |
US5910504A (en) | 1995-02-03 | 1999-06-08 | Pharmacia & Upjohn | Hetero-aromatic ring substituted phenyloxazolidinone antimicrobials |
HRP960159A2 (en) | 1995-04-21 | 1997-08-31 | Bayer Ag | Benzocyclopentane oxazolidinones containing heteroatoms |
DE19524765A1 (de) | 1995-07-07 | 1997-01-09 | Boehringer Mannheim Gmbh | Neue Oxazolidinonderivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
AU716493B2 (en) | 1995-09-01 | 2000-02-24 | Pharmacia & Upjohn Company | Phenyloxazolidinones having a C-C bond to 4-8 membered heterocyclic rings |
EP1019385B1 (de) | 1995-09-15 | 2004-01-14 | PHARMACIA & UPJOHN COMPANY | Aminoaryl oxazolidinone n-oxide |
DE19601264A1 (de) | 1996-01-16 | 1997-07-17 | Bayer Ag | Pyrido-annellierte Thienyl- und Furanyl-Oxazolidinone |
DE19604223A1 (de) | 1996-02-06 | 1997-08-07 | Bayer Ag | Neue substituierte Oxazolidinone |
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 |
DK1175902T3 (da) | 1996-07-15 | 2005-12-19 | Sankyo Co | Anvendelse CS-866 (olmesartan) til fremstillingen af et medikament til behandling af arteriosclerose |
US6273913B1 (en) | 1997-04-18 | 2001-08-14 | Cordis Corporation | Modified stent useful for delivery of drugs along stent strut |
JP2002501530A (ja) | 1997-05-30 | 2002-01-15 | ファルマシア・アンド・アップジョン・カンパニー | チオカルボニル官能基を有するオキサゾリジノン抗菌剤 |
NZ502253A (en) | 1997-07-11 | 2001-06-29 | Upjohn Co | Thiadiazolyl and oxadiazolyl phenyl oxazolidinone derivatives which are 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 |
US5998406A (en) | 1997-11-12 | 1999-12-07 | 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 (de) | 1997-12-12 | 1999-06-17 | Merck Patent Gmbh | Benzamidinderivate |
DE19802239A1 (de) | 1998-01-22 | 1999-07-29 | Bayer Ag | Neue mit Bicyclen substituierte Oxazolidinone |
BR9907183A (pt) | 1998-01-23 | 2003-06-10 | Versicor Inc | Colet neas combinatórias de oxazolidinona, composições e processos de preparação |
DE69934093T2 (de) | 1998-01-27 | 2007-06-21 | Aventis Pharmaceuticals Inc. | SUBSTITUIERTE OXOAZAHETEROCYCLYL FAKTOR Xa HEMMER |
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 |
ATE222115T1 (de) | 1998-05-18 | 2002-08-15 | Upjohn Co | Verbesserung der antibakteriellen wirkung von oxazolidinon durch arginin derivate |
DE19842753A1 (de) | 1998-09-18 | 2000-03-23 | Bayer Ag | Agitationsunabhängige pharmazeutische Retardzubereitungen und Verfahren zu ihrer Herstellung |
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 |
SK7572002A3 (en) | 1999-12-21 | 2002-12-03 | Upjohn Co | Oxazolidinones having a sulfoximine functionality and their use as antimicrobial agents |
DE19962924A1 (de) | 1999-12-24 | 2001-07-05 | Bayer Ag | Substituierte Oxazolidinone und ihre Verwendung |
KR20020063609A (ko) | 1999-12-28 | 2002-08-03 | 아지노모토 가부시키가이샤 | 아스파탐 유도체 결정 |
DE10105989A1 (de) | 2001-02-09 | 2002-08-14 | Bayer Ag | Substituierte Oxazolidinone und ihre Verwendung |
DE10110438A1 (de) | 2001-03-05 | 2002-09-19 | Bayer Ag | Substituierte 2-Oxy-3,5-dicyano-4-aryl-6-aminopyridine 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 |
DE10110747A1 (de) | 2001-03-07 | 2002-09-12 | Bayer Ag | Substituierte 2,6-Diamino-3,5-dicyano-4-aryl-pyridine 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 |
DE10134481A1 (de) | 2001-07-16 | 2003-01-30 | Bayer Ag | Substituierte 2-Thio-3,5-dicyano-4-phenyl-6-aminopyridine und ihre Verwendung |
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 |
NZ589238A (en) | 2005-02-14 | 2012-02-24 | Epitopix Llc | Polypeptides from staphylococcus aureus and methods of use |
DE102005045518A1 (de) | 2005-09-23 | 2007-03-29 | Bayer Healthcare Ag | 2-Aminoethoxyessigsäure-Derivate und ihre Verwendung |
US8188270B2 (en) | 2005-10-04 | 2012-05-29 | Bayer Schering Pharma Aktiengesellschaft | Polymorphous form of 5-chloro-N-({(5S)-2-oxo-3[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidine-5-yl}-methyl)-2-thiophene carboxamide |
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 |
DE102005048824A1 (de) | 2005-10-10 | 2007-04-12 | Bayer Healthcare Ag | Behandlung und Prophylaxe von Mikroangiopathien |
KR101378695B1 (ko) * | 2007-04-18 | 2014-03-31 | 삼성전자주식회사 | 통신 시스템에서의 훈련 시퀀스 코드 생성 방법 및 장치 |
-
1999
- 1999-12-24 DE DE19962924A patent/DE19962924A1/de not_active Withdrawn
-
2000
- 2000-11-29 HN HN2000000267A patent/HN2000000267A/es unknown
- 2000-12-11 CN CN2006100819193A patent/CN1900074B/zh not_active Expired - Lifetime
- 2000-12-11 KR KR1020077008192A patent/KR20070044075A/ko not_active Application Discontinuation
- 2000-12-11 CZ CZ20022202A patent/CZ301432B6/cs not_active IP Right Cessation
- 2000-12-11 IL IL14989600A patent/IL149896A0/xx active Protection Beyond IP Right Term
- 2000-12-11 AU AU28414/01A patent/AU775126C/en not_active Expired
- 2000-12-11 HU HU0203902A patent/HU226522B1/hu active Protection Beyond IP Right Term
- 2000-12-11 EP EP00993610A patent/EP1261606B1/de not_active Expired - Lifetime
- 2000-12-11 SG SG200403830-3A patent/SG130939A1/en unknown
- 2000-12-11 CA CA002396561A patent/CA2396561C/en not_active Expired - Lifetime
- 2000-12-11 KR KR1020077020537A patent/KR20070094672A/ko not_active Application Discontinuation
- 2000-12-11 DK DK00993610T patent/DK1261606T3/da active
- 2000-12-11 PL PL382243A patent/PL201121B1/pl unknown
- 2000-12-11 SI SI200031079T patent/SI1526132T1/sl unknown
- 2000-12-11 TR TR2002/01636T patent/TR200201636T2/xx unknown
- 2000-12-11 ES ES04027037.3T patent/ES2457021T3/es not_active Expired - Lifetime
- 2000-12-11 MX MXPA02006241A patent/MXPA02006241A/es active IP Right Grant
- 2000-12-11 TR TR2004/01314T patent/TR200401314T2/xx unknown
- 2000-12-11 CN CNB008189668A patent/CN1262551C/zh not_active Expired - Lifetime
- 2000-12-11 US US10/181,051 patent/US7157456B2/en active Active
- 2000-12-11 NZ NZ519730A patent/NZ519730A/en not_active IP Right Cessation
- 2000-12-11 ES ES00993610T patent/ES2237497T3/es not_active Expired - Lifetime
- 2000-12-11 RU RU2002120456/04A patent/RU2297415C2/ru active Protection Beyond IP Right Term
- 2000-12-11 DE DE50009607T patent/DE50009607D1/de not_active Expired - Lifetime
- 2000-12-11 SK SK908-2002A patent/SK287272B6/sk not_active IP Right Cessation
- 2000-12-11 AT AT00993610T patent/ATE289605T1/de active
- 2000-12-11 PL PL355665A patent/PL200413B1/pl unknown
- 2000-12-11 BR BRPI0017050-0A patent/BR0017050B1/pt active IP Right Grant
- 2000-12-11 EE EEP200200341A patent/EE05169B1/xx active Protection Beyond IP Right Term
- 2000-12-11 DK DK04027037.3T patent/DK1526132T3/da active
- 2000-12-11 JP JP2001549389A patent/JP4143297B2/ja not_active Expired - Lifetime
- 2000-12-11 WO PCT/EP2000/012492 patent/WO2001047919A1/de active Application Filing
- 2000-12-11 NZ NZ537058A patent/NZ537058A/en not_active IP Right Cessation
- 2000-12-11 CN CNB2005101271139A patent/CN100549008C/zh not_active Expired - Lifetime
- 2000-12-11 PT PT00993610T patent/PT1261606E/pt unknown
- 2000-12-11 KR KR1020027008172A patent/KR100804932B1/ko active IP Right Review Request
- 2000-12-11 PT PT40270373T patent/PT1526132E/pt unknown
- 2000-12-11 SI SI200030679T patent/SI1261606T1/xx unknown
- 2000-12-11 DE DE122009000014C patent/DE122009000014I1/de active Pending
- 2000-12-11 EP EP04027037.3A patent/EP1526132B1/de not_active Expired - Lifetime
- 2000-12-11 UA UA2002076161A patent/UA73339C2/uk unknown
- 2000-12-18 AR ARP000106733A patent/AR032436A1/es active IP Right Grant
- 2000-12-19 GT GT200000216A patent/GT200000216A/es unknown
- 2000-12-20 TW TW089127307A patent/TWI226330B/zh active
- 2000-12-20 TW TW083120747A patent/TWI277615B/de not_active IP Right Cessation
- 2000-12-20 DO DO2000000114A patent/DOP2000000114A/es unknown
- 2000-12-21 SV SV2000000245A patent/SV2002000245A/es active IP Right Grant
- 2000-12-22 MY MYPI20006170A patent/MY140488A/en unknown
- 2000-12-22 PE PE2000001388A patent/PE20010963A1/es not_active IP Right Cessation
- 2000-12-22 CO CO00097415A patent/CO5251440A1/es active IP Right Grant
-
2002
- 2002-05-27 ZA ZA200204188A patent/ZA200204188B/en unknown
- 2002-06-07 CU CU20020114A patent/CU23208A3/es unknown
- 2002-06-14 BG BG106825A patent/BG65683B1/bg unknown
- 2002-06-21 MA MA26708A patent/MA25646A1/fr unknown
- 2002-06-21 NO NO20023043A patent/NO323699B1/no not_active IP Right Cessation
- 2002-07-23 HR HR20020617A patent/HRP20020617B1/xx not_active IP Right Cessation
-
2004
- 2004-01-20 HK HK06112529.9A patent/HK1092140A1/xx not_active IP Right Cessation
- 2004-01-20 HK HK04100440A patent/HK1057556A1/xx not_active IP Right Cessation
- 2004-10-13 CU CU20040221A patent/CU23423B7/es unknown
- 2004-10-13 AU AU2004218729A patent/AU2004218729A1/en not_active Withdrawn
- 2004-12-10 JP JP2004358908A patent/JP5190173B2/ja not_active Expired - Lifetime
-
2006
- 2006-07-18 HR HRP20060251AA patent/HRP20060251B1/hr not_active IP Right Cessation
- 2006-07-27 US US11/460,529 patent/US7592339B2/en not_active Expired - Fee Related
-
2007
- 2007-02-20 NO NO20070981A patent/NO20070981L/no not_active Application Discontinuation
- 2007-07-17 HK HK07107638.6A patent/HK1103235A1/xx not_active IP Right Cessation
- 2007-10-31 US US11/932,082 patent/US7576111B2/en not_active Expired - Fee Related
-
2008
- 2008-01-11 DO DO2008000001A patent/DOP2008000001A/es unknown
- 2008-02-07 US US12/027,553 patent/US7585860B2/en not_active Expired - Fee Related
- 2008-11-19 LU LU91497C patent/LU91497I2/xx unknown
- 2008-11-25 NL NL300370C patent/NL300370I2/nl unknown
- 2008-12-02 CY CY200800019C patent/CY2008019I2/el unknown
- 2008-12-04 LT LTPA2008018C patent/LTC1261606I2/lt unknown
- 2008-12-10 BE BE2008C046C patent/BE2008C046I2/fr unknown
- 2008-12-11 FR FR08C0051C patent/FR08C0051I2/fr active Active
-
2009
- 2009-01-08 NO NO2009001C patent/NO2009001I1/no not_active IP Right Cessation
- 2009-06-30 US US12/494,879 patent/US8129378B2/en not_active Expired - Fee Related
-
2010
- 2010-04-22 IL IL205242A patent/IL205242A/en unknown
-
2012
- 2012-01-27 US US13/360,107 patent/US8530505B2/en not_active Expired - Fee Related
- 2012-06-22 UY UY0001034152A patent/UY34152A/es not_active Application Discontinuation
-
2013
- 2013-08-07 US US13/961,264 patent/US8822458B2/en not_active Expired - Fee Related
-
2014
- 2014-05-29 CY CY20141100383T patent/CY1115117T1/el unknown
- 2014-07-21 US US14/336,379 patent/US20150166568A1/en not_active Abandoned
-
2021
- 2021-02-25 NO NO2021009C patent/NO2021009I1/no unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1526132B1 (de) | Substituierte Oxazolidinone und ihre Verwendung als Faktor Xa Hemmer | |
EP1411932B1 (de) | Kombinationstherapie substituierter oxazolidinone | |
WO2007039134A1 (de) | Kombinationstherapie mit substituierten oxazolidinonen zur prophylaxe und behandlung von cerebralen durchblutungsstörungen | |
EP1937271A1 (de) | Behandlung und prophylaxe von mikroangiopathien | |
EP2099453A2 (de) | Kombinationstherapie substituierter oxazolidinone | |
AU2004202422A1 (en) | Substituted oxazolidinones and their use in the field of blood coagulation |
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 CR CU CZ DE DK DM DZ 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 PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA 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 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 GW ML MR NE SN TD TG |
|
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: 2000993610 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002/04188 Country of ref document: ZA Ref document number: 200204188 Country of ref document: ZA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 149896 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: IN/PCT/2002/00763/MU Country of ref document: IN |
|
ENP | Entry into the national phase |
Ref document number: 2000 106825 Country of ref document: BG Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 28414/01 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 9082002 Country of ref document: SK Ref document number: PA/a/2002/006241 Country of ref document: MX Ref document number: PV2002-2202 Country of ref document: CZ Ref document number: 519730 Country of ref document: NZ Ref document number: 2396561 Country of ref document: CA Ref document number: 2002/01636 Country of ref document: TR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020027008172 Country of ref document: KR |
|
ENP | Entry into the national phase |
Ref document number: 2001 549389 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10181051 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: P20020617A Country of ref document: HR |
|
ENP | Entry into the national phase |
Ref document number: 2002 2002120456 Country of ref document: RU Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 008189668 Country of ref document: CN |
|
WWP | Wipo information: published in national office |
Ref document number: 1020027008172 Country of ref document: KR |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: PV2002-2202 Country of ref document: CZ |
|
WWP | Wipo information: published in national office |
Ref document number: 2000993610 Country of ref document: EP |
|
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 CR CU CZ DE DK DM DZ 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 PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA 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 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 GW ML MR NE SN TD TG |
|
COP | Corrected version of pamphlet |
Free format text: PAGE 103, DESCRIPTION, ADDED |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004/01314 Country of ref document: TR |
|
WWG | Wipo information: grant in national office |
Ref document number: 28414/01 Country of ref document: AU |
|
WWG | Wipo information: grant in national office |
Ref document number: 2000993610 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 519730 Country of ref document: NZ |
|
WWG | Wipo information: grant in national office |
Ref document number: 519730 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: P20060251A Country of ref document: HR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 205242 Country of ref document: IL |