WO2004113290A1 - Alkylamides substitues - Google Patents

Alkylamides substitues Download PDF

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WO2004113290A1
WO2004113290A1 PCT/EP2004/005989 EP2004005989W WO2004113290A1 WO 2004113290 A1 WO2004113290 A1 WO 2004113290A1 EP 2004005989 W EP2004005989 W EP 2004005989W WO 2004113290 A1 WO2004113290 A1 WO 2004113290A1
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substituents
amino
alkyl
cycloalkyl
substituted
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PCT/EP2004/005989
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German (de)
English (en)
Inventor
Nina Brunner
Christoph Freiberg
Thomas Lampe
Ben Newton
Michael Otteneder
Josef Pernerstorfer
Jens Pohlmann
Guido Schiffer
Mitsuyuki Shimada
Niels Svenstrup
Rainer Endermann
Peter Nell
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Bayer Healthcare Ag
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Publication of WO2004113290A1 publication Critical patent/WO2004113290A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/50—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to compounds, processes for their preparation, pharmaceutical compositions comprising them and their use in the treatment and / or prophylaxis of diseases in humans or animals, in particular bacterial infectious diseases.
  • An object of the present invention is therefore to provide new and alternative compounds with the same or improved antibacterial activity for the treatment of bacterial diseases in humans and animals.
  • alkyl is substituted by 1, 2 or 3 substituents R 1 "1 , the substituents R 1'1 being selected independently of one another from the group consisting of halogen, nitro, amino, alkylamino, phenylamino, diphenylamino, benzylamino, cyano, trifluoromethyl, Cycloalkyl, heterocyclyl, aryl, hydroxy, alkoxy, aryloxy, benzyloxy, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonylamino, phenylcarbonylamino, alkylaminocarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino and aminosulfonyl,
  • R 1 means alkenyl
  • alkenyl is substituted with 1, 2 or 3 substituents R " , the substituents R 1" 2 being selected independently of one another from the group consisting of halogen, nitro, amino, alkylamino, phenylamino, diphenylamino, benzylamino, cyano, trifluoromethyl, cycloalkyl, Heterocyclyl, hydroxy, alkoxy, aryloxy, benzyloxy, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonylamino, alkylaminocarbonyl, alkenyloxycarbonyl, phenylaminocarbonyl, alkoxycarbonylamino and aminosulfonyl,
  • R 1 denotes alkynyl
  • alkynyl is substituted with 1, 2 or 3 substituents R 1 "3 , the substituents R 1" 3 being selected independently of one another from the group consisting of halogen, nitro, amino, alkylamino, phenylamino, diphenylamino, benzylamino, cyano, trifluoromethyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, benzyloxy, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonylamino, alkylaminocarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino and aminosulfonyl, or
  • R 1 denotes cycloalkyl or heterocyclyl
  • cycloalkyl and heterocyclyl can be substituted with 0, 1, 2 or 3 substituents R M ,
  • substituents R 1 "4 together with the carbon atoms to which they are attached form a phenyl, which phenyl can be substituted by 0, 1 or 2 substituents R 1" 4 "1 , the substituents R 1" 4 " 1 are selected independently from the group consisting of halogen, nitro, amino, alkylamino, cyano, alkyl, trifluoromethyl, hydroxy, alkoxy, alkoxycarbonyl, aminocarbonyl and alkylaminocarbonyl,
  • R 2 represents hydrogen or methyl
  • R 3 signifies hydrogen, hydroxy, amino, C 1 -C 3 alkyl, benzyl, C 3 alkoxy, benzyloxy, Cr - alkylamino, C 3 -C 3 alkylcarbonylamino, phenylcarbonylamino, benzylcarbonylamino or benzyloxycarbonylamino,
  • R 4 represents hydrogen or Cj -C 3 alkyl
  • R 5 denotes halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, alkylamino, hydroxy, alkyl, alkoxy, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, aryl or heteroaryl,
  • substituents R 5 together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl, it being possible for this cycloalkyl or heterocyclyl to be substituted by 0, 1 or 2 substituents R 5 "1 , the substituents R 5" 1 are independently selected from the group consisting of halogen, nitro, amino, trifluoromethyl, hydroxy, alkyl and alkoxy,
  • R 6 denotes alkyl, cycloalkyl, cycloalkenyl or heterocyclyl
  • R 6 can be substituted with 0, 1 or 2 substituents R 6 "1 , where the substituents R 6" 1 are selected independently of one another from the group consisting of halogen,
  • n a number 0, 1, 2 or 3
  • radicals R 5 may be the same or different
  • A means aryl or heteroaryl
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds of the formula (Ia) mentioned below and their salts, solvates and solvates of the salts as well as those of the formula (I ) and / or (la), hereinafter referred to as embodiment (e) compounds and their salts, solvates and solvates of the salts, insofar as it is not already included in the compounds mentioned below by formula (I) and / or (la) are salts, solvates and solvates of the salts.
  • the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore relates to the enantiomers or diastereomers and their respective mixtures.
  • the stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers.
  • the invention also relates to tautomers of the compounds.
  • preferred salts are physiologically acceptable salts of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds (I) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, Benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds (I) also include salts of conventional bases, such as, for example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 C - Atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydro-abietylamine, arginylendineamine and lysine, lysine.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth metal salts for example calcium and magnesium salts
  • solvates are those forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvate, in which coordination takes place with water.
  • Alkoxycarbonyl and alkoxycarbonylamino stand for a linear or branched alkyl radical with generally 1 to 8, preferably 1 to 6, particularly preferably 1 to 4, very particularly preferably 1 to 3 carbon atoms, for example and preferably for methyl, ethyl, n-propyl, isopropyl , tert-butyl, n-pentyl and n-hexyl.
  • Alkenyl stands for a linear or branched alkenyl radical with generally 2 to 8, preferably 2 to 6, particularly preferably 2 to 4 carbon atoms, by way of example and preferably vinyl, allyl, prop-1-en-1-yl, isopropenyl, but- 1-en-l-yl, but-2-en-l-yl, buta-l, 2-dien-l-yl, buta-l, 3-dien-1-yl and penta-l, 3-diene l-yl.
  • Alkynyl stands for a linear or branched alkynyl radical with generally 2 to 8, preferably 2 to 6, particularly preferably 2 to 4 carbon atoms, for example and preferably for ethynyl, propargyl (2-propynyl), 1-propynyl, but-1-in -l-yl, but-2-in-l-yl.
  • Alkoxy is exemplary and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • Alkylamino stands for an alkylamino radical with one or two (independently selected) alkyl substituents, the alkyl substituents, as a rule, independently of one another generally having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, for example and preferably for methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, Nt-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.
  • Alkylaminocarbonyl stands for an alkylaminocarbonyl radical with one or two (independently selected) alkyl substituents, the alkyl substituents usually independently of one another generally having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, for example and preferably for methylammocarbonyl, ethylaminocarbonyl , n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, NN-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminopropylyl -Nn-propylaminocarbonyl, Nt-butyl-N-methylamino-carbonyl, N-e
  • -C-C 3 alkyl aminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical each having 1 to 3 carbon atoms per alkyl substituent.
  • Alkenyloxycarbonyl is exemplary and preferably vinyloxycarbonyl, allyloxycarbonyl, prop-1-en-1-yloxycarbonyl, isopropenyloxycarbonyl, but-1-en-1-yloxycarbonyl, but-2-en-1-yloxycarbonyl, buta- 1, 2- dienyloxycarbonyl and buta- 1, 3-dienyloxycarbonyl.
  • Alkylcarbonylamino is exemplary and preferably methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino.
  • Alkoxycarbonyl is exemplified and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • Alkoxycarbonylamino is exemplary and preferably methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonylamino.
  • Cycloalkyl stands for a cycloalkyl group with generally 3 to 8, preferably 5 to 7 carbon atoms, examples and preferably for cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Cycloalkenyl stands for a cycloalkenyl group with generally 3 to 8, preferably 5 to 7 carbon atoms, examples and preferably for cycloalkenyl are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • Aryl stands for a mono- to tricyclic aromatic radical with generally 6 to 14 carbon atoms, for example and preferably for phenyl, naphthyl and phenanthrenyl.
  • Aryloxy stands for a mono- to tricyclic aromatic radical which is bonded via an oxygen atom and generally has 6 to 14 carbon atoms, for example and preferably for phenoxy, naphthyloxy and phenanthrenyloxy.
  • Heteroaryl stands for an aromatic, mono- or bicyclic radical with generally 5 to 10, preferably 5 to 6 ring atoms and up to 5, preferably up to 4 heteroatoms from the series S, O and N, by way of example and preferably for thienyl, furyl , Pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl.
  • Heterocyclyl stands for a mono- or polycyclic, preferably mono- or bicyclic, heterocyclic radical with generally 4 to 10, preferably 5 to 8 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series N, O , S, SO, SO 2 .
  • the heterocyclyl residues can be saturated or partially unsaturated.
  • Halogen represents fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
  • radicals in the compounds according to the invention are substituted, the radicals, unless otherwise specified, can be substituted one or more times in the same or different manner. A substitution with up to three identical or different substituents is preferred. Substitution with a substituent is very particularly preferred.
  • R 1 to R 6 , A and n have the same meaning as in formula (I), and their salts, their solvates and the solvates of their salts.
  • R 1 denotes alkyl
  • alkyl is substituted by 1, 2 or 3 substituents R 1 "1 , the substituents R 1" 1 being selected independently of one another from the group consisting of halogen, amino, alkylamino, phenylamino, diphenylamino, benzylamino, cyano, trifluoromethyl, cycloalkyl, Heterocyclyl, phenyl, naphthyl, hydroxy, alkoxy, phenoxy, benzyloxy,
  • R 1 means alkenyl
  • alkenyl is substituted with 1, 2 or 3 substituents R 1 "2 , where the substituents
  • R 1 "2 are independently selected from the group consisting of halogen, amino, alkylamino, phenylamino, diphenylamino, benzylamino, cyano, trifluoromethyl, cycloalkyl, heterocyclyl, hydroxy, alkoxy, phenoxy, benzyloxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkenyloxycarbonyl, phenylaminocarbonyl and alkoxycarbonylamino,
  • R l denotes alkynyl
  • alkynyl is substituted with 1, 2 or 3 substituents R 1 "3 , where the substituents
  • R 1 "3 are selected independently of one another from the group consisting of halogen, amino, alkylamino, phenylamino, diphenylamino, benzylamino, cyano, trifluoromethyl,
  • Cycloalkyl heterocyclyl, phenyl, naphthyl, 5- or 6-membered heteroaryl, hydroxy, Alkoxy, phenoxy, benzyloxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkenyloxycarbonyl and alkoxycarbonylamino,
  • R 1 denotes cycloalkyl or heterocyclyl
  • cycloalkyl or heterocyclyl can be substituted by 0, 1, 2 or 3
  • substituents R 1 "4 are independently selected from the group consisting of halogen, amino, alkylamino, phenylamino, diphenylamino, benzylamino, cyano, alkyl, trifluoromethyl, heterocyclyl, phenyl, 5- or 6-membered heteroaryl, hydroxy, alkoxy, Phenoxy, benzyloxy, alkoxycarbonyl,
  • substituents R 1 "4-1 where the substituents R 1" 4 "1 are selected independently of one another from the group consisting of halogen, amino, alkylamino, cyano, alkyl, trifluoromethyl, hydroxy, alkoxy, alkoxycarbonyl, aminocarbonyl and alkylaminocarbonyl .
  • R 2 represents hydrogen
  • R 3 signifies hydrogen, hydroxy, amino, methyl, C 1 -C 3 -alkoxy or C 1 -C 4 -alkylamino
  • R 4 means methyl
  • R 5 is fluorine, chlorine, trifluoromethyl, trifluoromethoxy, nitro, amino, alkylamino, hydroxy, alkyl, alkoxy, alkoxycarbonyl, aminocarbonyl, alkylamino-carbonyl, phenyl or 5- or 6-membered heteroaryl,
  • R 5 is C 2 -C 7 alkyl or C 3 -C 7 cycloalkyl
  • R 6 can be substituted with 0, 1 or 2 substituents R 6 "1 , the substituents R 6" 1 being selected independently of one another from the group consisting of halogen, trifluoromethyl, alkyl and alkoxy,
  • n a number 0, 1 or 2
  • radicals R 5 may be the same or different
  • A is phenyl, naphthyl or 5-, 6-, 9- or 10-membered heteroaryl.
  • R 1 denotes Ci-Cj-alkyl
  • alkyl is substituted with 1 or 2 substituents R 1'1 , the substituents R 1 "1 being selected independently of one another from the group consisting of fluorine, chlorine, amino, -C - alkylamino, phenylamino, cyano, trifluoromethyl, C 3 - C 6 cycloalkyl, 5- or 6-membered heterocyclyl, phenyl, naphthyl, hydroxy, C 1 -C 3 alkoxy, aminocarbonyl and C 1 -C 4 alkylaminocarbonyl,
  • R 1 is C 2 -C 5 alkenyl
  • alkenyl is substituted with 1 or 2 substituents R 1 "2 , the substituents R 1" 2 being selected independently of one another from the group consisting of fluorine, chlorine,
  • R 1 is C 2 -C 5 alkynyl
  • alkynyl is substituted with 1 or 2 substituents R 1 "3 , the substituents R 1" 3 being selected independently of one another from the group consisting of fluorine, chlorine, amino, CC - alkylamino, phenylamino, cyano, trifluoromethyl, C 3 -C 6- cycloalkyl, 5- or 6-membered heterocyclyl, phenyl, 5- or 6-membered heteroaryl, hydroxy, C 1 -C 3 alkoxy, aminocarbonyl and C 1 -C 4 alkylaminocarbonyl,
  • R 1 is C 3 -C 6 cycloalkyl or 5- or 6-membered heterocyclyl
  • cycloalkyl or heterocyclyl can be substituted with 0, 1 or 2 substituents
  • substituents R 1 "4 are independently selected from the group consisting of fluorine, chlorine, amino, C 1 -C 4 alkylamino, cyano, C 1 -C 3 alkyl, trifluoromethyl, phenyl, 5- or 6-membered heteroaryl, Hydroxy, -C 3 - alkoxy, aminocarbonyl and -CC 4 -alkylaminocarbonyl,
  • R 2 represents hydrogen
  • R 3 denotes hydrogen, hydroxy, amino, methyl, methoxy, ethoxy, methylamino or dimethylamino
  • R 4 means methyl
  • R 5 is fluorine, chlorine, trifluoromethyl, trifluoromethoxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, phenyl or pyridyl,
  • R 6 is C 3 -C 6 alkyl or C 3 -C 6 cycloalkyl
  • n a number 0, 1 or 2
  • radicals R 5 may be the same or different
  • A is phenyl, naphthyl, pyridyl, thienyl, furanyl, quinolinyl or isoquinolinyl.
  • R 1 is CC 4 alkyl
  • alkyl is substituted with 1 or 2 substituents R 1 "1 , the substituents R 1" 1 being selected independently of one another from the group consisting of fluorine, chlorine, amino, methylamino, dimethylamino, phenylamino, cyano, trifluoromethyl, C 3 -C 6- cycloalkyl, 5- or 6-membered heterocyclyl, phenyl, naphthyl, hydroxy, C 1 -C 3 -alkoxy, aminocarbonyl and C 1 -C 4 -alkylaminocarbonyl,
  • R 1 is C 2 -C 5 alkenyl
  • alkenyl is substituted with 1 or 2 substituents R 1 "2 , the substituents R 1" 2 being selected independently of one another from the group consisting of fluorine, chlorine, amino, C 1 -C 4 -alkylamino, phenylamino, cyano, trifluoromethyl, C 3 -C 6 -cycloalkyl, 5- or 6-membered heterocyclyl, hydroxy, -C-C 3 alkoxy, aminocarbonyl and -GrAlkyl- aminocarbonyl,
  • R 1 represents ethynyl
  • R 1 is C 3 -C 6 cycloalkyl or 5- or 6-membered heterocyclyl
  • heterocyclyl can be substituted by 2 substituents which, together with the carbon atoms to which they are attached, form a phenyl
  • R 2 represents hydrogen
  • R 3 denotes hydrogen, amino, methyl, methylamino or dimethylamino
  • R 4 means methyl
  • R 5 is fluorine, chlorine, trifluoromethyl, trifluoromethoxy, C 1 -C 4 -alkyl, C 1 -C 3 -alkoxy, phenyl or pyridyl,
  • R 6 denotes isopropyl, isobutyl, isopentyl, tert-butyl or cyclopentyl
  • n a number 0 or 1
  • A means phenyl
  • R 1 is methyl, ethyl or propyl, where methyl, ethyl and propyl are substituted by 1 or 2 substituents R 1 "1 , the substituents R 1'1 being selected independently of one another are selected from the group consisting of amino, phenylamino, phenyl, naphthyl, cyclopentyl, cyclohexyl and tetrahydrofuranyl, a preferred tetrahydrofuranyl being tetrahydrofuran- 2-yl.
  • R 1 is ethenyl, buta-l, 3-dien-l-yl or penta-l, 3-dien-l-yl are also preferred in the context of the present invention, ethenyl, buta-1,3 - Dien-1-yl and penta-l, 3-dien-l-yl are substituted with a substituent R 1 "2 , the substituent R 1" 2 being selected from the group consisting of aminocarbonyl, C 1 -C 4 alkyl - Aminocarbonyl, -CC 3 alkoxycarbonyl, phenylamino-carbonyl and cyano.
  • R 1 denotes cyclopropyl, cyclopentyl or cyclohexyl
  • R 1 denotes cyclopropyl, cyclopentyl or cyclohexyl
  • R 1 is 1,2,3,4-tetrahydroisoquinolinyl or indolinyl are also preferred in the context of the present invention.
  • n denotes the number zero are also preferred in the context of the present invention.
  • R 6 is C 3 -C 6 alkyl or C 3 -C 6 cycloalkyl
  • R 6 is C 3 -C 6 alkyl or C 3 -C 6 cycloalkyl
  • the invention further relates to a process for the preparation of the compounds of the formula (I), wherein
  • R 2 to R 6 , A and n have the meaning given above,
  • R 1 has the meaning given above, which may optionally be present in activated form
  • R 1 , R 2 , R 5 , A and n have the meaning given above, where these can optionally be present in activated form.
  • carbodiimides such as, for example, N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N - (3-Dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N-cyclohexylcarbodiimide-N '- propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium per
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • alkali carbonates e.g. Sodium or potassium carbonate
  • hydrogen carbonate or organic bases
  • organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • HATU diisopropylethylamine
  • EDC HOBt and triethylamine
  • Inert organic solvents which do not change under the reaction conditions are suitable as solvents. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide or acetonitrile or ethers such as diethyl ether, tetrahydrofuran or dioxane. It is also possible to use mixtures of the solvents. Dichloromethane or a mixture of dichloromethane and dimethylformamide are particularly preferred.
  • R 2 to R 6 , A and n have the meaning given above,
  • the compounds of the formula (II) are obtained in the form of the corresponding salts, for example in the form of their hydrochlorides, and can be used further in this form or converted to their salt-free form by chromatographic purification.
  • Inert organic solvents which do not change under the reaction conditions are suitable as solvents.
  • halogenated hydrocarbons such as dichloromethane or trichloromethane
  • hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide or acetonitrile or ethers such as diethyl ether, tetrahydrofuran or dioxane. It is also possible to use mixtures of the solvents.
  • hydrochloric acid in dioxane or trifluoroacetic acid in dichloromethane is particularly preferred.
  • the compounds of formula (VI) are known or can be prepared by combining compounds of formula (IV) with compounds of the formula
  • R 2 , R 5 , A and n have the meaning given above, which may optionally be present in activated form.
  • carbodiimides such as e.g. N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC ) (optionally in the presence of pentafluorophene (PFP)), N-cyclohexylcarbodiimide-N '-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l , 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or
  • Bases are, for example, alkali carbonates, such as sodium or potassium carbonate, or hydrogen carbonate, or organic bases, such as trialkylamines, for example triethylamine, N-methylmo ⁇ holin, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine. It is preferred to use HATU with diisopropylethylamine and EDC with HOBt and triethylamine.
  • Inert organic solvents which do not change under the reaction conditions are suitable as solvents. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide or acetonitrile or ethers such as diethyl ether, tetrahydrofuran or dioxane. It is also possible to use mixtures of the solvents. Dichloromethane or a mixture of dichloromethane and dimethylformamide are particularly preferred.
  • acid especially with hydrochloric acid or trifluoroacetic acid.
  • Inert organic solvents which do not change under the reaction conditions are suitable as solvents. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide or acetonitrile or ethers such as diethyl ether, tetrahydrofuran or dioxane. It is also possible to use mixtures of the solvents. The use of hydrochloric acid in dioxane or trifluoroacetic acid in dichloromethane is particularly preferred.
  • the compounds of formula (VII) are known or can be prepared according to instructions known from the literature. (Regarding the representation of aromatic beta amino acids see, for example, S. Rault, P. Dallemagne, M. Robba, Bull. Soc. Chim. Fr., 1987, 1079-1083; SG Davies et al., J. Chem. Soc, Chem. Commun., 1993, 1153-1155; VA Soloshonok et al., Tetrahedron Asymmetry, 1995, 1601-1610; regarding the conversion to the tert-butoxycarbonyl-protected compounds, see TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, 3rd Edt. 1999, J. Wiley & Sons, Inc.).
  • VJJI The compounds of the formula (VJJI) are known or can be prepared by processes known from the literature. (See e.g. SG Davies, DJ Dixon, J. Chem. Soc, Perkin Trans. 1, 1998, 17, 2635-2643; AV Rama Rao, AK Singh, Ch. VNS Varaprasad, Tetrahedron Letters, 1991, 32, 4393- 4396).
  • R 1 , R 2 , R 5 , A and n have the meaning given above, and
  • R 7 represents an alkyl radical, are saponified.
  • the saponification can be carried out according to standard methods, e.g. at room temperature in a mixture of ethanol and water with 40% sodium hydroxide solution or with 10% methanolic potassium hydroxide solution in a mixture of dioxane and water.
  • R, R, R, A and n have the meaning given above, with compounds of the formula (HI), where these can optionally be present in activated form.
  • carbodiimides such as, for example, N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N - (3-Dimethylaminoisopropyl) -N , -ethylcarbodiimide hydrochloride
  • EDC pentafluorophene
  • PFP pentafluorophene
  • PS-carbodiimide N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene
  • carbonyl compounds such as carbonyldimidazole
  • 1,2-oxazolium compounds such as 2-ethyl-5-phenyl -l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate
  • acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate , or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotria
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmo ⁇ holin, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • alkali carbonates e.g. Sodium or potassium carbonate
  • hydrogen carbonate e.g. Sodium or potassium carbonate
  • organic bases such as trialkylamines e.g. Triethylamine, N-methylmo ⁇ holin, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • HATU diisopropylethylamine
  • EDC HOBt and triethylamine
  • Inert organic solvents which do not change under the reaction conditions are suitable as solvents. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide or acetonitrile or ethers such as diethyl ether, tetrahydrofuran or dioxane. It is also possible to use mixtures of the solvents. Dichloromethane or a mixture of dichloromethane and dimethylformamide are particularly preferred.
  • the compounds of the formula (X) are known or can be prepared by processes known from the literature (with regard to the preparation of aromatic beta-amino acids and their conversion into the corresponding alkyl esters, see, for example, S. Rault, P. Dallemagne, M. Robba, Bull. Soc. Chim. Fr., 1987, 1079-1083; SG Davies et al., J. Chem. Soc, Chem. Commun., 1993, 1153-1155; VA Soloshonok et al., Tetrahedron Asymmetry, 1995, 1601-1610; SJ Faulconbridge et al., Tetrahedron Letters, 2000, 41, 2679-2682).
  • the present invention further relates to compounds of the formula (I) for combating diseases, in particular bacterial diseases, and to medicaments comprising compounds of the formula (I) and auxiliaries and also to the use of compounds of the formula (I) for the preparation of a medicament for the treatment of bacterial diseases.
  • the preparations 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 these pathogens.
  • local and / or systemic diseases that are caused by the following pathogens or by mixtures of the following pathogens can be treated and / or prevented:
  • Gram-positive cocci e.g. Staphylococci (Staph. Aureus, Staph. Epidermidis), enterococci (E. faecalis, E. faecius) and streptococci (Strept. Agalactiae, Strept. Pneumoniae); gram-negative cocci (Neisseria gonorrhoeae) and gram-negative rods such as enterobacteriaceae, e.g. Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob. Freundii, Citrob. Divernis), Salmonella and Shigella; also Klebsielles (Klebs. pneumoniae, Klebs.
  • the antibacterial spectrum includes strictly anaerobic bacteria such as Bacteroides fragilis, representatives of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; also mycoplasma (M. pneumoniae, M. hominis, M. urealyticum) and mycobacteria, e.g. Mycobacterium tuberculosis.
  • pathogens are only an example and is in no way to be interpreted as limiting.
  • diseases which can be caused by the pathogens mentioned or mixed infections and which can be prevented, improved or cured by the preparations according to the invention are:
  • Infectious diseases in humans such as septic infections, bone and joint infections, skin infections, postoperative wound infections, abscesses, phlegmon, wound infections, infected burns, burns, infections in the mouth area, infections after dental operations, septic arthritis, mastitis, tonsillitis, genital infections and eye infections.
  • bacterial infections can also be treated in other species. Examples include: Pig: coli diarrhea, enterotoxemia, sepsis, dysentery, salmonellosis, metritis-mastitis-agalaktiae syndrome, mastitis;
  • Ruminants (cattle, sheep, goats): diarrhea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections;
  • Horse bronchopneumonia, foal paralysis, pue ⁇ erale and postpue ⁇ erale infections, salmonellosis;
  • Dog and cat bronchopneumonia, diarrhea, dermatitis, otitis, urinary tract infections, prostatitis;
  • Poultry (chicken, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, E. coli infections, chronic respiratory diseases, salmonellosis, pasteurellosis, psittacosis.
  • Bacterial diseases in the rearing and keeping of farmed and ornamental fish can also be treated, the antibacterial spectrum extending beyond the previously mentioned pathogens to other pathogens such as e.g. Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothris, Corynebacteria, Borellia, Treponema, Nocardia, Rikettsie, Yersinia.
  • Pasteurella Brucella, Campylobacter, Listeria, Erysipelothris, Corynebacteria, Borellia, Treponema, Nocardia, Rikettsie, Yersinia.
  • the active substance can act systemically and / or locally.
  • it can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic or as an implant.
  • the active ingredient can be administered in suitable administration forms for these administration routes.
  • Known application forms which deliver the active ingredient quickly and / or modified such as e.g. Tablets (non-coated and coated tablets, e.g. tablets or film-coated tablets provided with enteric coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions and solutions.
  • Tablets non-coated and coated tablets, e.g. tablets or film-coated tablets provided with enteric coatings
  • capsules dragees, granules, pellets, powders, emulsions, suspensions and solutions.
  • Parenteral administration can be done by bypassing a resorption step (intravenously, intraarterially, intracardially, intraspinally or intralumbally) or by switching on a resection (intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • Suitable forms of application for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.
  • parenteral, in particular intravenous, administration is preferred.
  • inhalation pharmaceutical forms including powder inhalers, nebulizers
  • nasal drops / solutions, sprays are suitable;
  • the active compounds can be converted into the administration forms mentioned in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable excipients.
  • Carriers e.g. microcrystalline cellulose
  • solvents e.g. liquid polyethylene glycols
  • emulsifiers e.g. sodium dodecyl sulfate
  • dispersants e.g. polyvinylpyrrolidone
  • synthetic and natural biopolymers e.g. albumin
  • stabilizers e.g. antioxidants such as ascorbic acid
  • dyes e.g. inorganic pigments such as iron oxides
  • taste and / or smell e.g. inert, non-toxic, pharmaceutically suitable excipients.
  • Carriers e.g. microcrystalline cellulose
  • solvents e.g. liquid polyethylene glycols
  • emulsifiers e.g. sodium dodecyl sulfate
  • dispersants e.g.
  • Method 10 Instrument: Waters Alliance 2790 LC; Column: Symmetry C18, 50 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 5% B * - 5.0 min 10% B -> 6.0 min 10% B; Temperature: 50 ° C, flow: 1.0 ml / min, UV detection: 210 nm.
  • Method 11 MS device type: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Column: Symmetry C 18, 50 mm x 2.1 mm, 3.5 ⁇ m; Eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; Gradient: 0.0 min 10% B - 3.5 min 90% B - 5.5 min 90% B; Oven: 50 ° C, flow: 0.8 ml / min, UV detection: 210 nm.
  • Method 12 Instrument: Waters Alliance 2790 LC; Column: Symmetry C18, 50 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 min 5% B - 4.5 min 10% B - 5.5 min 10% B; Temperature: 50 ° C, flow: 1.0 ml / min, UV detection: 210 nm.
  • Method 13 Instrument: Micromass Quattro LCZ, HP1100; Column: Symmetry C18, 50 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 min 90% A - 4.0 min 10% A -> 6.0min 10% A; Oven: 40 ° C, flow: 0.5 ml / min, UV detection: 208-400 nm.
  • Method 14 Instrument: Micromass Platform LCZ, HP1100; Column: Symmetry C18, 50 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 min 90% A - 4.0 min 10% A - 6.0 min 10% A; Oven: 40 ° C, flow: 0.5 ml / min, UV detection: 208-400 nm.
  • Method 15 Instrument: Waters Alliance 2790 LC; Column: Symmetry C18, 50 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 min 10% B - * »4.0 min 90% B - 6.0 min 90% B; Temperature: 50 ° C, flow: 0.0 min 0.5 ml / min * - 4.0 min 0.8 ml / min, UV detection: 210 nm.
  • Method 16 Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Column: Symmetry C 18, 50 mm x 2.1 mm, 3.5 ⁇ m; Eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; Gradient: 0.0min 5% B 4.5min 90% B 5.5min 90% B; Oven: 50 ° C, flow: 1.0ml /, UV detection: 210 nm.
  • Method 17 MS device type: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Column: Uptisphere C 18, 50 mm x 2.0 mm, 3.0 ⁇ m; Eluent B: acetonitrile + 0.05% formic acid, eluent
  • Method 18 Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Grom- SIL120 ODS-4 HE, 50 mm x 2.0 mm, 3 ⁇ m; Eluent A: 11 water + 1ml 50% formic acid, eluent B: 11 acetonitrile + 1ml 50% formic acid; Gradient: 0.0min 100% A - 0.2min 100% A - 2.9min 30% A - 3.1min 10% A - »4.5min 10% A; Oven: 55 ° C, flow: 0.8ml / min, UV detection: 208-400 nm.
  • Method 19 Instrument: Micromass Quattro LCZ, with HPLC Agilent Series 1100; Column: Grom- SIL120 ODS-4 HE, 50 mm x 2.0 mm, 3 ⁇ m; Eluent A: 11 water + 1ml 50% formic acid, eluent B: 11 acetonitrile + 1ml 50% formic acid; Gradient: 0.0min 100% A - 0.2min 100% A - »2.9min 30% A - 3.1min 10% A - * 4.5min 10% A; Oven: 55 ° C, flow: 0.8ml / min, UV detection: 208-400 nm.
  • Method 20 Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Column: Grom-Sil 120 ODS ⁇ l HE 50 x 2 mm, 3.0 ⁇ m; Eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; Gradient: 0.0min 5% B - »2.0min 40% B -> 4.5min 90% B- 5.5min 90% B; Oven: 45 ° C; Flow: 0.0min 0.75ml min - 4.5min 0.75ml / min-> 5.5min 1.25ml / min; UV detection: 210 nm.
  • Method 21 Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Column: Grom-Sil 120 ODS-4 HE 50x2 mm, 3.0 ⁇ m; Eluent B: acetonitrile + 500 ⁇ l 50% formic acid / 1; Eluent A: water + 500 ⁇ l 50% formic acid / 1; Gradient: 0.0min 0% B - 0.2min 0% B - 2.9min 70% B- 3.1min 90% B - * 4.5min 90% B, oven: 50 ° C, flow: 0.8 ml / min; UV detection: 210 nm.
  • Method 22 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: UPTISPHERE HDO, 50 mm x 2.0 mm, 3 ⁇ m; Eluent A: 11 water + 1ml 50% formic acid, eluent B: 11 acetonitrile + 1ml 50% formic acid; Gradient: 0.0min 100% A - 0.2min 100% A - 2.9min 30% A - »3.1min 10% A - * 4.5min 10% A; Oven: 55 ° C, flow: 0.8ml / min, UV detection: 208-400 nm.
  • Example 1A Analogously to Example 1A, the following compounds are obtained by reacting (35) -3-methyl-dihydro-2,5-furanedione with the corresponding primary amines, hydroxylamine or hydrazine derivatives.
  • the raw products can be purified by RP-HPLC (eluent: water-acetonitrile, gradient).
  • N-tert-butoxycarbonyl-protected amino acid (1 eq.) And N, N-carbonyldiimidazole (1.1 eq.) are stirred in tetrahydrofuran (approx. 0.1 - 1 mol / 1) for 2 hours at room temperature.
  • the 2,5-pyrrolidinedione (1 eq.) Is then added to this mixture and the entire mixture is added dropwise within 30 min to a 1 molar solution of lithium hexamethyldisilazide (2 eq.) In THF cooled to -65 ° C. When the addition is complete, the mixture is stirred at -65 ° C. for a further 15 min before saturated aqueous ammonium chloride solution is added.
  • the l-benzyloxy-2,5-pyrrolidinedione (1 eq) is dissolved in methanol (approx. 0.02 mol / 1), a catalytic amount of palladium-carbon (10%) is added and the mixture is stirred for 1 h under a hydrogen atmosphere (Normal pressure) stirred. Then the reaction mixture is filtered and concentrated. The residue is dissolved in acetonitrile (approx. 0.05 mol 1) and added dropwise to a solution of 2-bromoacetophenone (1 eq) in acetonitrile (approx. 0.03 mol / 1) at room temperature.
  • the tert-butyloxycarbonyl (BOC) protected amine derivative (optionally as a solution in dioxane) is mixed with 4N hydrochloric acid solution in 1,4-dioxane (approx. 0.1 mol / 1) and stirred for 2 to 24 hours at room temperature before in vacuo is concentrated.
  • the residue can be reacted further without further purification or is optionally treated with dichloromethane and diethyl ether.
  • the precipitated crystals are suctioned off and dried in a high vacuum. The product is obtained as the hydrochloride.
  • the beta-amino acid [synthesis according to regulations known from the literature (e.g. S. Rault, P. Dallemagne, M. Robba, Bull. Soc. Chim. Fr., 1987, 1079-1083; L. Läzär, T. Martinek, G. Bernäth, F. Fülöp, Synth. Comm., 1998, 28, 219-224)] is placed in methanol (approx. 0.5 to 1.0 mol / 1) and 1.2 eq of thionyl chloride are added dropwise at 0 ° C. When the addition is complete, the reaction mixture is stirred at room temperature overnight and then concentrated. The residue is dissolved in a little methanol and the product is precipitated with diethyl ether. The solid is filtered off, washed several times with diethyl ether and dried in vacuo.
  • the work-up can also be carried out as follows: after evaporation to dryness, the residue is taken up in water and washed twice with ethyl acetate. The organic phase is discarded, the aqueous phase is saturated with saturated sodium hydrogen Neutralized carbonate solution and extracted again three times with ethyl acetate. The organic phases of the last extraction are dried over sodium sulfate or magnesium sulfate, decanted and evaporated to dryness.
  • the carboxylic acid (1.3 - 1.5 eq) is placed in dichloromethane (approx. 0.1 mol / 1) at 0 ° C and mixed with 1.3 - 1.5 eq HATU.
  • the implementation can also be carried out according to the following procedure:
  • the residue is taken up in ethyl acetate or dichloromethane and the organic phase is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated.
  • the product can be purified by chromatography on silica gel (eluents: mixtures of cyclohexane / ethyl acetate or mixtures of dichloromethane and ethanol) or by RP-HPLC (eluents: variable gradients of water and acetonitrile), alternatively by a combination of the two methods. According to the general regulation E the following connection can be obtained:
  • the alkyl propionate is placed in a 3: 1 mixture of ethanol and water (approx. 0.1-0.15 mol / 1) and 5 eq of 40% sodium hydroxide solution are added.
  • the reaction mixture is stirred for 24 h at room temperature, acidified with dilute hydrochloric acid (approx. PH 3) and concentrated.
  • the residue is taken up in ethyl acetate and washed with saturated aqueous sodium chloride solution.
  • the organic phase is dried over magnesium sulfate, filtered and concentrated. The product obtained can be used in the next step without further purification.
  • the alkyl propionate is placed in a 1: 1 mixture of dioxane and water (about 0.1-0.15 mol 1) and 3 eq of a solution of potassium hydroxide in methanol (100 mg / ml) are added.
  • the reaction mixture is stirred at room temperature for 2 h and then concentrated.
  • the residue is taken up in water and acidified with dilute hydrochloric acid.
  • the aqueous phase is extracted three times with a 1: 1 mixture of dichloromethane and ethyl acetate.
  • the combined organic phases are dried over sodium sulfate, filtered and concentrated.
  • the product obtained can be used in the next step without further purification.
  • the general regulation F the following connection can be obtained:
  • the propionic acid derivatives thus obtained can be reacted according to the procedure described below (acylation of 3- [2-aminoalkanoyl] -2,5-pyrrolidinedione hydrochloride derivatives with carboxylic acid derivatives).
  • the beta-amino acid (1 eq.) [Synthesis according to regulations known from the literature (e.g. S. Rault, P. Dallemagne, M. Robba, Bull. Soc. Chim. Fr., 1987, 1079-1083; L. Läzär, T. Martinek , G. Bernäth, F. Fülöp, Synth. Comm., 1998, 28, 219-224)] is placed in water (concentration approx. 0.3 - 1 mol / 1) and triethylamine (1.5 - 3 eq.) Is added.
  • N-dimethylformamide (approx. 0.1 to 0.3 mol / 1) is added at 0 ° C first an equimolar amount of HATU and then the 3- [2-aminoalkanoyl] -2,5-pyrrolidinedione hydrochloride derivative (1 eq., Optionally as a solution in N, N-dimethylformamide or dichloromethane / N, N-dimethylformamide mixtures) added. Then at 0 ° C a solution of 2.5 - 3.5 eq.
  • the implementation can also be carried out according to the following procedure:
  • the residue is taken up in ethyl acetate or dichloromethane and the organic phase is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated.
  • the product can be purified by chromatography on silica gel (eluents: mixtures of cyclohexane / ethyl acetate or mixtures of dichloromethane and ethanol) or by RP-HPLC (eluents: variable gradients of water and acetonitrile), alternatively by a combination of the two methods.
  • the tert-butyloxycarbonyl (BOC) protected amine derivative (optionally as a solution in dioxane) is mixed with 4N hydrochloric acid solution in 1,4-dioxane (approx. 0.1 mol / 1) at 0 ° C or room temperature and for 2 - 24 h Room temperature stirred before being concentrated in vacuo.
  • the residue can be reacted further without further purification or is optionally treated with dichloromethane and diethyl ether.
  • the precipitated crystals are suctioned off and dried in a high vacuum.
  • the product is obtained as the hydrochloride.
  • N-dimethylformamide or a 1: 1 mixture of N, N-dimethylformamide and Dichloromethane (0.02 - 0.2 mol / 1) becomes a 0.2 - 1.0 molar solution of diisopropylethylamine (2.5 to 3.5 eq.)
  • N-dimethylformamide or a 1: 1 mixture of N, N-dimethylformamide and dichloromethane at 0 ° C added dropwise over the period of 1 h.
  • reaction mixture is stirred for a further 30 min at 0 ° C. and overnight at room temperature before the mixture is concentrated in vacuo.
  • the product can be obtained by chromatography on silica gel (eluents: mixtures of cyclohexane / ethyl acetate or mixtures of dichloromethane and ethanol) or by RP-HPLC (eluents: variable gradients of water and acetonitrile), alternatively by a combination of the two methods.
  • the implementation can also be carried out according to the following procedure:
  • the residue is taken up in ethyl acetate or dichloromethane and the organic phase is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated.
  • the product can be purified by chromatography on silica gel (eluents: mixtures of cyclohexane / ethyl acetate or mixtures of dichloromethane and ethanol) or by RP-HPLC (eluents: variable gradients of water and acetonitrile), alternatively by a combination of the two methods.
  • the compounds of example 26 and example 28 can be converted into the following compounds by treatment with hydrochloric acid in dioxane analogously to general instruction I.
  • the MIC is determined in the liquid dilution test. Overnight cultures of the test germs are diluted to a cell count of 10 5 germs per ml in isosensitest medium (Difco, Irvine, USA) and incubated with dilutions of the test substances (dilution levels 1: 2). Exceptions are the tests with S. pneumoniae G9A, in BHI broth (Difco) plus 20% bovine serum, and with H. influenzae, in BHI broth (Difco) plus 20% bovine serum, 10 ⁇ g / ml Haemin and 1% Isovitale (Becton Dickinson, New Jersey, USA).
  • the lowest substance concentration at which no visible bacterial growth occurs is defined as the MIC.
  • the MIC values in ⁇ mol 1 of some compounds according to the invention compared to Staphylococcus aureus are listed as examples in the table below.
  • S. aureus 133 cells are grown overnight in BH broth (Oxoid, New York, USA). The overnight culture is diluted 1: 100 in fresh bra broth and turned up for 3 hours. The bacteria in the logarithmic growth phase are centrifuged off and washed twice with buffered, physiological saline. A cell suspension in saline solution with an absorbance of 50 units is then set on the photometer (model LP 2W, Dr. Lange, Berlin, Germany). After a dilution step (1:15), this suspension is mixed 1: 1 with a 10% mucin suspension. 0.25 ml / 20 g mouse ip is applied from this infection solution. This corresponds to a cell count of approximately 1 x 10E 6 germs / mouse. The ip or iv therapy is given 30 minutes after the infection. Female CFW1 mice are used for the infection test. The survival of the animals is recorded over 6 days.
  • the substances according to the invention can be converted into pharmaceutical preparations as follows:
  • Example 1 100 mg of the compound of Example 1, 50 mg lactose (monohydrate), 50 mg corn starch, 10 mg polyvinylpyrolidone (PVP 25) (from BASF, Germany) and 2 mg magnesium stearate.
  • the mixture of the compound of Example 1, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are dried with the magnesium stearate for 5 min. mixed.
  • This mixture is ve ⁇ resst with a conventional tablet press (format of the tablet see above).
  • a single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.
  • Rhodigel is suspended in ethanol, the compound of Example 1 is added to the suspension. The water is added with stirring. The swelling of the Rhodigel is stirred for about 6 hours.
  • Example 1 The compound of Example 1 is dissolved together with polyethylene glycol 400 in the water with stirring.
  • the solution is sterile filtered (pore diameter 0.22 ⁇ m) and filled into heat-sterilized infusion bottles under aseptic conditions. These are closed with infusion stoppers and crimp caps.

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Abstract

L'invention concerne des composés de formule (I), des procédés permettant de les produire, des compositions pharmaceutiques les contenant, ainsi que l'utilisation desdits composés pour traiter et/ou prévenir des maladies chez des êtres humains ou des animaux, en particulier des maladies infectieuses bactériennes.
PCT/EP2004/005989 2003-06-16 2004-06-03 Alkylamides substitues WO2004113290A1 (fr)

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Citations (3)

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WO2003091212A1 (fr) * 2002-04-26 2003-11-06 Bayer Healthcare Ag Amides d'acide cinnamique
WO2004020432A1 (fr) * 2002-08-08 2004-03-11 Bayer Healthcare Ag Arylamides
DE10243201A1 (de) * 2002-09-18 2004-03-25 Bayer Ag Alkyl- und Alkenylamide

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WO2003091212A1 (fr) * 2002-04-26 2003-11-06 Bayer Healthcare Ag Amides d'acide cinnamique
WO2004020432A1 (fr) * 2002-08-08 2004-03-11 Bayer Healthcare Ag Arylamides
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