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WO1999037652A1 - Oxazolidinones substituees avec des indoles tricycliques - Google Patents

Oxazolidinones substituees avec des indoles tricycliques Download PDF

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Publication number
WO1999037652A1
WO1999037652A1 PCT/EP1999/000097 EP9900097W WO9937652A1 WO 1999037652 A1 WO1999037652 A1 WO 1999037652A1 EP 9900097 W EP9900097 W EP 9900097W WO 9937652 A1 WO9937652 A1 WO 9937652A1
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carbon atoms
chain
straight
hydrogen
formula
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German (de)
English (en)
Inventor
Martin Ruppelt
Stephan Bartel
Walter Guarnieri
Siegfried Raddatz
Ulrich Rosentreter
Hanno Wild
Rainer Endermann
Hein-Peter Kroll
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Bayer AG
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Bayer AG
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Priority to AU24206/99A priority Critical patent/AU2420699A/en
Priority to EP99903616A priority patent/EP1049701A1/fr
Priority to JP2000528573A priority patent/JP2002501073A/ja
Publication of WO1999037652A1 publication Critical patent/WO1999037652A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to new oxazolidinones substituted with tricyclic indoles, processes for their preparation and their use as medicaments, in particular as antibacterial medicaments.
  • EP 609 441 and EP 657 440 oxazolidinone derivatives with a monoamine oxidase inhibitory effect and in EP 645 376 with an effect as adhesion receptor antagonists.
  • the present invention relates to new oxazolidinones of the general formula (I) substituted with tricyclic indoles
  • L and L ' are identical or different and represent an oxygen atom or a radical of the formula -NR 13 ,
  • R 13 is hydrogen, carboxyl, cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or straight-chain or branched acyl having up to 6 carbon atoms, which may be by halogen, hydroxyl, straight-chain or branched alkoxy having up to 5 carbon atoms or substituted by a group of the formula -NR 14 R 15 ,
  • R 14 and R 15 are the same or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,
  • R 14 and R 15 have the meaning of R 14 and R 15 given above and are the same or different with this,
  • alkyl or alkenyl are optionally substituted by aryl having 6 to 14 carbon atoms, which in turn can be substituted by halogen or by straight-chain or branched alkyl, alkoxy or acyl each having up to 6 carbon atoms,
  • R 4 , R 5 and R 6 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by halogen,
  • R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are the same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which may optionally be substituted by hydroxy, halogen, straight-chain or branched alkoxy or alkoxycarbonyl up to 6 carbon atoms, aryl with 6 to 10 carbon atoms or substituted by a group of the formula -NR 16 R 17 ,
  • R 16 and R 17 have the meaning of R 14 and R 15 given above and are the same or different with this,
  • R 10 and R 11 together form an endocyclic double bond
  • R 1 represents azido or a radical of the formula -OR ' 8 , -O-SO 2 -R 19 or -NR 20 R 21 ,
  • R 18 denotes hydrogen or straight-chain or branched acyl having up to 6 carbon atoms
  • R 19 denotes straight-chain or branched alkyl having up to 6 carbon atoms or phenyl
  • R 20 and R 21 are hydrogen
  • R 2Ü means hydrogen
  • Q represents an oxygen or sulfur atom
  • R 22 denotes straight-chain or branched alkoxy having up to 8 carbon atoms or trifluoromethyl, or
  • R 22 denotes cycloalkyl having 3 to 6 carbon atoms, which is optionally substituted by halogen or aryl having 6 to 10 carbon atoms, or
  • Heteroatoms from the series S, N and / or O means, the ring systems listed under R 22 optionally being substituted up to 2 times identically or differently by halogen, cyano, nitro, hydroxy or phenyl,
  • R 22 denotes straight-chain or branched alkyl having up to 6 carbon atoms, which may be by phenoxy, benzyloxy, carboxyl, halogen or straight-chain or branched alkoxycarbonyl or acyl each having up to 6 carbon atoms or by a 5- to 6-membered heterocycle from Row S, N and / or O is substituted,
  • R 22 represents a radical of the formula -NR 25 R 26 ,
  • R 25 and R 26 are the same or different and are hydrogen
  • R 23 and R 24 are identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
  • R represents hydrogen, halogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • E represents hydrogen or halogen
  • the compounds 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 to both
  • Enantiomers or diastereomers or their respective mixtures can be separated into the stereoisomerically uniform constituents in a known manner.
  • Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids.
  • Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Salts which may furthermore be mentioned are salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine , Dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1 - ephenamine or methyl-piperidine.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example calcium or magnesium salts
  • ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine , Dibenzylamine, N-methylmorpholine, dihydroabietylamine,
  • the oxazolidinone skeleton is preferably attached in positions 5 and 6.
  • the oxazolidinone skeleton is particularly preferably attached in position 5.
  • Cycloalkyl generally represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl,
  • Cyclohexyl, Cycloheptyl and Cyclooctyl called.
  • the cyclopropyl, cyclopentyl and cyclohexyl rings are preferred.
  • Aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • acyl stands for a straight-chain or branched acyl radical having 1 to 6 carbon atoms.
  • a straight-chain or branched lower acyl radical having 1 to 4 carbon atoms is preferred.
  • Preferred acyl radicals are acetyl and propionyl.
  • alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms.
  • a straight-chain or branched lower alkoxy radical having 1 to 4 carbon atoms is preferred. Examples include: methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-
  • alkoxycarbonyl represents a straight-chain or branched alkoxycarbonyl radical having 1 to 6 carbon atoms.
  • a straight-chain or branched lower alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred. Examples include: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • a and D together with the nitrogen atom form a heterocyclic radical of the formula
  • L and L ' are identical or different and represent an oxygen atom or a radical of the formula -NR 13 ,
  • R 13 denotes hydrogen, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, or straight-chain or branched acyl having up to 4 carbon atoms, which is optionally by fluorine, chlorine, bromine, hydroxyl, straight-chain or branched Alkoxy with up to 4 carbon atoms or through a group of the formula
  • R 14 and R 15 are the same or different and are hydrogen
  • straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms which are optionally substituted by fluorine, chlorine, bromine, cyano, methoxycarbonyl, ethoxycarbonyl, amino, N, N-dimethylamino or phenyl, which in turn is substituted by fluorine, chlorine, bromine or can be substituted by straight-chain or branched alkyl, alkoxy or acyl each having up to 4 carbon atoms,
  • R 3 , R 4 , R 5 and R 6 are the same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by fluorine, chlorine or bromine,
  • R 7 , R 8 , R 9 , R 10 , R u and R 12 are the same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, optionally by hydroxy, fluorine, chlorine, bromine, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, phenyl or by a group of
  • R 16 and R 17 have the meaning of R 14 and R 15 given above and are the same or different with this, or
  • R 10 and R 11 together form an endocyclic double bond
  • R 18 denotes hydrogen or straight-chain or branched acyl having up to 4 carbon atoms
  • R 19 denotes straight-chain or branched alkyl having up to 4 carbon atoms or phenyl
  • R 20 and R 21 are hydrogen
  • R 20 means hydrogen
  • R 21 is a radical of the formula Q is -C - R 22 or -P (O) (OR 23 ) (OR 24 ),
  • Q represents an oxygen or sulfur atom
  • R 22 denotes straight-chain or branched alkoxy having up to 6 carbon atoms or trifluoromethyl, or
  • R 22 cyclopropyl, cyclopentyl, cycloheptyl, cyclobutyl or
  • Cyclohexyl means, which are optionally substituted by fluorine, chlorine or phenyl, or
  • Phenyl, naphthyl, pyridyl, thienyl, oxazolyl, furyl, imidazolyl, pyridazolyl or pyrimidyl means, the ring systems listed under R 22 optionally being substituted up to 2 times identically or differently by fluorine, chlorine, bromine, cyano, nitro, hydroxy or phenyl are,
  • R 22 denotes straight-chain or branched alkyl having up to 4 carbon atoms, optionally by phenoxy, benzyloxy, carboxyl, fluorine, chlorine, bromine or straight-chain or branched alkoxycarbonyl or acyl each having up to 4 carbon atoms or by pyridyl, thienyl, furyl or
  • R 22 represents a radical of the formula -NR 25 R 26 , wherein
  • R 25 and R 26 are the same or different and are hydrogen, phenyl, pyridyl or straight or branched
  • R 23 and R 24 are identical or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
  • R 2 represents hydrogen, fluorine, chlorine, bromine or straight-chain or branched alkyl having up to 3 carbon atoms
  • E represents hydrogen or fluorine, chlorine or bromine
  • a and D together with the nitrogen atom form a heterocyclic radical of the formula
  • R 22 denotes straight-chain or branched alkyl having up to 3 carbon atoms, optionally by phenoxy, benzyloxy, carboxyl, fluorine, chlorine, bromine or straight-chain or branched alkoxycarbonyl or acyl each having up to 3 carbon atoms or by pyridyl, thienyl, furyl or Pyrimidyl is substituted,
  • R 22 represents a radical of the formula -NR 5 R 6 ,
  • R 25 and R 26 are the same or different and are hydrogen
  • R 2 represents hydrogen, fluorine or straight-chain or branched alkyl having up to 3 carbon atoms
  • E represents hydrogen or fluorine
  • the particularly preferred oxazolidones of the general formula (I) include those in which - 14 -
  • L and L ' are identical or different and represent an oxygen atom or a radical of the formula -NR 13 ,
  • R 13 denotes hydrogen, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, or straight-chain or branched acyl having up to 3 carbon atoms, which may be replaced by fluorine, chlorine, bromine, hydroxyl, amino or N, N -Dimethylamino straight-chain or branched alkoxy with up to 3 carbon atoms is substituted
  • straight-chain or branched alkyl with up to 3 carbon atoms means that optionally by fluorine, chlorine, bromine,
  • Cyano, methoxycarbonyl, ethoxycarbonyl, amino, N, N-dimethylamino or phenyl is substituted, which in turn can be substituted by fluorine, chlorine, bromine or by straight-chain or branched alkyl, alkoxy or acyl each having up to 3 carbon atoms,
  • R 3 , R 4 , R 5 and R 6 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by fluorine, chlorine or bromine, - 15 -
  • R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are the same or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, optionally by hydroxy, fluorine, chlorine, straight-chain or branched alkoxy or alkoxycarbonyl is substituted with up to 3 carbon atoms, phenyl
  • R 18 denotes hydrogen or straight-chain or branched acyl having up to 3 carbon atoms
  • R 19 denotes straight-chain or branched alkyl having up to 3 carbon atoms or phenyl, - 16 -
  • R 20 and R 21 are hydrogen
  • R 20 means hydrogen
  • R 21 is a radical of the formula
  • Q represents an oxygen or sulfur atom
  • R 22 denotes straight-chain or branched alkoxy having up to 4 carbon atoms or trifluoromethyl, or
  • R 22 means cyclopropyl, cyclopentyl, cycloheptyl, cyclobutyl or cyclohexyl, which are optionally substituted by fluorine, chlorine or phenyl, or
  • R 13 denotes straight-chain or branched alkyl having 1 to 3 carbon atoms or cyclopropyl
  • R 9 , R 10 , R 1 1 and R 12 are hydrogen
  • R 2 represents hydrogen
  • R 1 -NR 20 R 21 means
  • R 20 is hydrogen and Q
  • R 2 * - CR 22 means
  • Q represents an oxygen or sulfur atom
  • R 21 is selected from
  • R l 3 is straight-chain or branched alkyl having 1 to 3 carbon atoms or cyclopropyl.
  • the very particularly preferred compounds also include compounds of the general formula (I)
  • R 13 is hydrogen, straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by cyano, methoxycarbonyl, ethoxycarbonyl, amino, N, N-dimethylamino or by phenyl, or straight-chain or branched acyl having up to 3 carbon atoms, that is is optionally substituted by hydroxy, amino or N, N-dimethylamino, or is methoxycarbonyl, represents hydrogen or fluorine,
  • R 1 represents hydroxy or a radical of the formula -OSO, -CH "-NH-CO-R 22 or -NH-CS-R 22
  • R 22 straight-chain or branched alkyl or alkoxy, each with up to 3
  • R 2 represents hydrogen, fluorine
  • R 1 particularly preferably represents a radical of the formula -NH-CO-R 22 , in which R 22 can have the meanings given above.
  • Y represents halogen, preferably chlorine or the radical -OCOR.
  • R 27 represents radicals of the formulas NH-CO-R 22 , O-CO-R 28 or NH-R 29 ,
  • R 28 denotes straight-chain or branched alkyl having up to 6 carbon atoms
  • R 29 denotes an amino protective group, preferably tert-butyloxycarbonyl
  • Amino protecting groups in the context of the invention are the usual amino protecting groups used in peptide chemistry. These preferably include: benzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert.butoxycarbonyl, allyloxycarbonyl, phthaloyl, 2,2,2-trichloro- ethoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, acetyl, 2-chloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxymethylene, 4-nitrobenzyl, 2,4-dinitrobenzyl, 4- Nitrophenyl, 4-methoxyphenyl or triphenylmethyl.
  • the reductions can generally by hydrogen in water or in inert organic solvents such as alcohols, ethers or halogenated hydrocarbons or mixtures thereof with catalysts such as Raney nickel, palladium, palladium on animal charcoal or platinum or with hydrides or boranes in inert solvents, optionally in the presence of a Catalyst, are carried out.
  • inert organic solvents such as alcohols, ethers or halogenated hydrocarbons or mixtures thereof with catalysts such as Raney nickel, palladium, palladium on animal charcoal or platinum or with hydrides or boranes in inert solvents, optionally in the presence of a Catalyst, are carried out.
  • the reductions are preferably carried out using hydrides such as complex borohydrides or aluminum hydrides and boranes.
  • hydrides such as complex borohydrides or aluminum hydrides and boranes.
  • Sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) or borane are particularly preferred.
  • the reduction is generally carried out in a temperature range from -50 ° C to the respective boiling point of the solvent, preferably from -20 ° C to + 90 ° C.
  • solvents which do not change under the reaction conditions are suitable as solvents.
  • solvents preferably include alcohols such as methanol, ethanol, propanol or isopropanol or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether or amides such as hexamethylphosphoric triamide or dimethylformamide or acetic acid. It is also possible to use mixtures of the solvents mentioned. Methanol is particularly preferred.
  • the reaction with benzyl chloroformate is carried out in one of the ethers listed above, preferably with tetrahydrofuran.
  • Bases which are generally suitable are sodium hydrogen carbonate, sodium methanolate, hydrazine hydrate, potassium carbonate or cesium carbonate. Sodium bicarbonate is preferred.
  • the base is used in an amount of 1 mol to 10 mol, preferably 1 mol to 3 mol, based on 1 mol of the compounds of the general formula (III).
  • the reaction is generally carried out in a temperature range from -30 ° C to + 30 ° C, preferably at 0 ° C.
  • the cyclization to give compounds of the general formula (Ia) is generally carried out in one of the ethers listed above, preferably in tetrahydrofuran.
  • Bases suitable for this step are generally lithium alkyl compounds or lithium N-silylamides, such as, for example, n-butyllithium, lithium diisopropyl amide or lithium bistrimethylsilylamide, preferably lithium bistrimethylsilyl amide or n-butyllithium.
  • the base is used in an amount of 1 mol to 10 mol, preferably 1 mol to 3 mol, based on 1 mol of the compounds of the general formula (IV).
  • a temperature range from -78 ° C to -50 ° C, preferably at -78 ° C.
  • the acylation step in process [B] is generally carried out in one of the ethers or halogenated hydrocarbons listed above, preferably tetrahydrofuran or methylene chloride, in a temperature range from -30 ° C to 50 ° C, preferably from -10 ° C to room temperature.
  • the reductions in process [B] are generally carried out using hydrides in inert solvents or using boranes, diboranes or their complex compounds.
  • the reductions can generally be carried out by hydrogen in water or in inert organic solvents such as alcohols, ones or halogenated hydrocarbons, or mixtures thereof, with catalysts such as Raney nickel, palladium, palladium on animal charcoal or platinum, or with hydrides or boranes in inert solvents, if appropriate be carried out in the presence of a catalyst.
  • inert organic solvents such as alcohols, ones or halogenated hydrocarbons, or mixtures thereof
  • catalysts such as Raney nickel, palladium, palladium on animal charcoal or platinum, or with hydrides or boranes in inert solvents, if appropriate be carried out in the presence of a catalyst.
  • the reductions are preferably carried out using hydrides, such as complex borohydrides or aluminum hydrides and boranes.
  • hydrides such as complex borohydrides or aluminum hydrides and boranes.
  • Sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride or borane tetrahydrofuran are particularly preferably used here.
  • the reduction is generally carried out in a temperature range from -50 ° C to the respective boiling point of the solvent, preferably from -20 ° C to + 90 ° C.
  • solvents which do not change under the reaction conditions are suitable as solvents. These preferably include alcohols such as
  • the usual solvents are suitable as solvents for process [C]. Dichloromethane and chloroform are preferred for the reaction with the epoxy and THF for the ring closure with carbonyldiimidazole (CDI).
  • a temperature range from -78 ° C to + 50 ° C, preferably at room temperature.
  • the reaction temperature is between room temperature and the boiling point of tetrahydrofuran.
  • silica gel is suitable as a catalyst for process [C].
  • organic solvents which do not change under the reaction conditions are suitable as solvents for the alkylation.
  • solvents for the alkylation preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichlorethylene, trichlorethylene or dimethylchloride or dimethylbenzene or chlorobenzene or chlorobenzene , Dimethylformamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dichloromethane, dimethyl sulfoxide and dimethylformamide are preferred.
  • the alkylation is carried out in the solvents listed above at temperatures from 0 ° C. to + 150 ° C., preferably at room temperature to + 100 ° C., under normal pressure.
  • the amino protective group is generally split off, likewise by customary methods, preferably Boc with hydrochloric acid in dioxane, Fmoc with piperidine and Z with HBr / HOAc or by hydrogenolysis.
  • the MIC values were determined using the microdilution method in BH medium. Each test substance was dissolved in the nutrient medium. A series of concentrations of the test substances was created in the microtiter plate by serial dilution. Overnight cultures of the pathogens were used for inoculation, which were previously diluted 1: 250 in the nutrient medium. 100 ⁇ l of inoculation solution were added to 100 ⁇ l of the diluted nutrient solution containing the active substance.
  • the microtiter plates were incubated at 37 ° C and read after about 20 hours or after 3 to 5 days.
  • the MIC value ( ⁇ g / ml) indicates the lowest active substance concentration at which no growth was discernible.
  • the compounds of the general formulas (I), (la), (Ib), (Ic), (Id) (Ie) and (If) according to the invention have a broad antibacterial spectrum with low toxicity, especially against gram-positive germs and some gram -negative bacteria as well as mycobacteria, corynebacteria, Haemophilus influenzae and anaerobic germs. These properties enable their use as chemotherapeutic agents in human and veterinary medicine.
  • the compounds according to the invention are active against a broad spectrum of microorganisms. With their help gram-positive germs, gram-negative Bacteria and bacteria-like microorganisms such as mycoplasmas are combated and the diseases caused by these pathogens are prevented, improved and / or cured.
  • the compounds according to the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly well suited for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine which are caused by such exciters.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert, pharmaceutically suitable excipients, contain one or more compounds according to the invention or which consist of one or more active compounds according to the invention, and processes for the preparation of these preparations.
  • the active ingredient (s) can optionally also be in microencapsulated form in one or more of the above-mentioned carriers.
  • the therapeutically active compounds should be present in the pharmaceutical preparations listed above preferably in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.
  • the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.
  • the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight per 24 hours, if appropriate in Form of multiple doses to be administered to achieve the desired results.
  • a single dose contains the Active substances according to the invention preferably in amounts of about 1 to about 80, in particular 3 to 30 mg / kg, body weight.
  • the compounds according to the invention can also be used with others for the purpose of expanding the spectrum of action and to achieve an increase in activity
  • Antibiotics can be combined.
  • the target product is obtained as a racemate from 10 g (49 mmol) of the compound from Example IX and 4.8 g (42 mmol) of (2S, R) -2,3-epoxy-propyl-acetamide. Yield: 4.06 g (24%) MS (ESI) 320 (M + H) +
  • Example XIII Analogously to the procedure of Example XIII, 359 mg of the target product are obtained from 240 mg of the compound of Example XII and 173 mg of (2S) -2,3-epoxypropylcarbamic acid methyl ester.
  • R j 0.23 (100/5 CH 2 Cl 2 / CH 3 OH)
  • Example XIII Analogously to the procedure of Example XIII, 182 mg of the target product are obtained from 240 mg of the compound of Example XII and 204 mg (2S) -2,3-epoxypropylpropionamide. R f -. 0.18 (100/5 CH 2 Cl 2 / CH 3 OH) MS (DCI) 332 (M + H) +
  • Cooling is mixed with 230 ml of 6 M HCl, heated to 80 ° C. for 2 h, cooled, made alkaline with 500 ml of 3N NaOH, extracted 5 times with EA, the combined organic phases with sat. Washed NaHCO 3 solution, dried (MgSO 4 ), filtered and evaporated.
  • the crude product is chromatographed on silica gel (dichloromethane / methanol 50: 1). 1.3 g of the title compound are obtained as a light yellow
  • the catalyst is suctioned off through Celite and the solvents are spun in.
  • the crude product is chromatographed on silica gel (mobile phase: dichloromethane / methanol 100: 4).
  • Epoxypropyl-1-acetamide is boiled under reflux in 100 ml of chloroform with 12.5 g of silica gel for two days. The solvent is evaporated and the product through Chromatography on silica gel (mobile phase: dichloromethane / methanol 100: 4) purified.
  • the target product is obtained analogously to the regulation of Example XIII.
  • Example XXXV Analogously to the procedure of Example XXI, the title compound is obtained in the reaction of compound XXXIII. Yield: 55% of theory Mp: 259 ° CR f (I, 10: 1): 0.35 Example XXXV
  • Example XXIII Analogously to Example XXIII, the title compound is obtained in the reaction of the compound from Example XXXIV. Yield: 67% of theory R f (1.5: 1): 0.3
  • Example XXXVII Analogously to Example XXIII, the title compound is obtained in the reaction of the compound from Example XXV. Yield: 31% of theory R f (I, 10: 1): 0.23 Example XXXVII
  • Example XXIII Analogously to Example XXIII, the title compound is obtained in the reaction of the compound from Example XXVIII. Yield: 6% of theory R f (I, 10: 1): 0.33
  • the target product is obtained in the same way as in Example 1.

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Abstract

L'invention concerne de nouvelles oxazolidinones, substituées avec des indoles tricycliques, de la formule générale (I) dans laquelle A, D, E, R1 et R2 ont les significations indiquées, ainsi que leur procédé de préparation et leur utilisation comme médicaments, notamment comme médicaments antibactériens.
PCT/EP1999/000097 1998-01-22 1999-01-09 Oxazolidinones substituees avec des indoles tricycliques Ceased WO1999037652A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU24206/99A AU2420699A (en) 1998-01-22 1999-01-09 Tricyclic indolene substituted oxazolidinones
EP99903616A EP1049701A1 (fr) 1998-01-22 1999-01-09 Oxazolidinones substituees avec des indoles tricycliques
JP2000528573A JP2002501073A (ja) 1998-01-22 1999-01-09 三環式インドレン置換オキサゾリジノン

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19802235A DE19802235A1 (de) 1998-01-22 1998-01-22 Mit tricyclischen Indolen substituierte Oxazolidinone
DE19802235.2 1998-01-22

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WO1999037652A1 true WO1999037652A1 (fr) 1999-07-29

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PCT/EP1999/000097 Ceased WO1999037652A1 (fr) 1998-01-22 1999-01-09 Oxazolidinones substituees avec des indoles tricycliques

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AU (1) AU2420699A (fr)
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001009107A1 (fr) * 1999-07-28 2001-02-08 Pharmacia & Upjohn Company Oxazolidinones et leur utilisation comme anti-infectieux
US6617339B1 (en) 1998-06-05 2003-09-09 Syngenta Limited Oxazolidinone derivatives, process for their preparation and pharmaceutical compositions containing them
WO2002014545A3 (fr) * 2000-08-15 2003-10-09 Ribotargets Ltd Essai
US6919329B2 (en) 2002-02-25 2005-07-19 Pharmacia & Upjohn Company N-Aryl-2-oxazolidinone-5-carboxamides and their derivatives
US7081538B1 (en) 1999-12-03 2006-07-25 Astrazeneca Ab Substituted isoxazolines and their use as antibacterial agents
US7094900B2 (en) 2002-08-12 2006-08-22 Pharmacia & Upjohn Company Llc N-Aryl-2-oxazolidinones and their derivatives
US7141570B2 (en) 2002-11-21 2006-11-28 Pharmacia & Upjohn Company N-aryl-2-oxazolidinone-5-carboxamides and their derivatives
US7141588B2 (en) 2002-02-25 2006-11-28 Pfizer, Inc. N-aryl-2-oxazolidinone-5-carboxamides and their derivatives
US7141583B2 (en) 2000-04-25 2006-11-28 Astrazeneca Ab Oxazolidinone derivatives with antibiotic activity
US7304050B2 (en) 2003-09-16 2007-12-04 Pfizer Inc. Antibacterial agents

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EP2254886B1 (fr) * 2008-03-28 2016-05-25 Nerviano Medical Sciences S.r.l. Dérivés actifs de 3,4-dihydro-2h-pyrazino[1,2-a]indol-1-one en tant qu'inhibiteurs de kinase, procédé pour leur préparation et compositions pharmaceutiques les contenant
ES2607113T3 (es) 2012-03-16 2017-03-29 Vitae Pharmaceuticals, Inc. Moduladores de los receptores X del hígado
PT2825541T (pt) 2012-03-16 2016-09-28 Vitae Pharmaceuticals Inc Moduladores de recetor de fígado x

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EP0311090A1 (fr) * 1987-10-09 1989-04-12 The Du Pont Merck Pharmaceutical Company Dérivés d'aminométhyl-oxo-oxazolidinyl-cycloalkylbenzène comme agents antibactériens
WO1997019089A1 (fr) * 1995-11-17 1997-05-29 Pharmacia & Upjohn Company Agent anti-bacterien a base d'oxazolidinone a substituants tricycliques

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EP0311090A1 (fr) * 1987-10-09 1989-04-12 The Du Pont Merck Pharmaceutical Company Dérivés d'aminométhyl-oxo-oxazolidinyl-cycloalkylbenzène comme agents antibactériens
WO1997019089A1 (fr) * 1995-11-17 1997-05-29 Pharmacia & Upjohn Company Agent anti-bacterien a base d'oxazolidinone a substituants tricycliques

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6617339B1 (en) 1998-06-05 2003-09-09 Syngenta Limited Oxazolidinone derivatives, process for their preparation and pharmaceutical compositions containing them
US6441005B1 (en) 1999-07-28 2002-08-27 Pharmacia & Upjohn Company Oxazolidinone compounds and compositions, and methods of using the same
WO2001009107A1 (fr) * 1999-07-28 2001-02-08 Pharmacia & Upjohn Company Oxazolidinones et leur utilisation comme anti-infectieux
US6743811B2 (en) 1999-07-28 2004-06-01 Pharmacia & Upjohn Company Oxazalidinone compounds and methods of preparation and use thereof
US7081538B1 (en) 1999-12-03 2006-07-25 Astrazeneca Ab Substituted isoxazolines and their use as antibacterial agents
US7141583B2 (en) 2000-04-25 2006-11-28 Astrazeneca Ab Oxazolidinone derivatives with antibiotic activity
WO2002014545A3 (fr) * 2000-08-15 2003-10-09 Ribotargets Ltd Essai
US7141588B2 (en) 2002-02-25 2006-11-28 Pfizer, Inc. N-aryl-2-oxazolidinone-5-carboxamides and their derivatives
US6919329B2 (en) 2002-02-25 2005-07-19 Pharmacia & Upjohn Company N-Aryl-2-oxazolidinone-5-carboxamides and their derivatives
US7645781B2 (en) 2002-02-25 2010-01-12 Pfizer Inc N-aryl-2-oxazolidinone-5-carboxamides and their derivatives
US7094900B2 (en) 2002-08-12 2006-08-22 Pharmacia & Upjohn Company Llc N-Aryl-2-oxazolidinones and their derivatives
US7141570B2 (en) 2002-11-21 2006-11-28 Pharmacia & Upjohn Company N-aryl-2-oxazolidinone-5-carboxamides and their derivatives
US7304050B2 (en) 2003-09-16 2007-12-04 Pfizer Inc. Antibacterial agents

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EP1049701A1 (fr) 2000-11-08
DE19802235A1 (de) 1999-07-29
JP2002501073A (ja) 2002-01-15
AU2420699A (en) 1999-08-09

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