WO2003000665A1 - Derives d'uracile antibacteriens - Google Patents

Derives d'uracile antibacteriens Download PDF

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WO2003000665A1
WO2003000665A1 PCT/EP2002/006325 EP0206325W WO03000665A1 WO 2003000665 A1 WO2003000665 A1 WO 2003000665A1 EP 0206325 W EP0206325 W EP 0206325W WO 03000665 A1 WO03000665 A1 WO 03000665A1
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alkyl
group
compounds
heterocyclyl
general formula
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PCT/EP2002/006325
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German (de)
English (en)
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Dietmar Flubacher
Kerstin Ehlert
Alexander Kuhl
Niels Svenstrup
Marcus Bauser
Jörg Keldenich
Michael Otteneder
Christoph Ladel
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Bayer Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • 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
    • 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
    • C07D487/08—Bridged systems
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the present invention relates to uraciles, processes for their preparation, they include pharmaceutical compositions and their use in the treatment of diseases in humans or animals.
  • Gram-positive eubacteria contain three different DNA polymerase ex-nucleases, which are referred to as Pol 1, Pol 2 and Pol 3.
  • Pol 3 is an enzyme that is necessary for the replicative synthesis of DNA.
  • WO 01/29 010 describes 3-aminocarbonyl-substituted phenylaminouracils.
  • WO 96/06614 describes 3-alkylidene-substituted uracils.
  • WO 00/71523 describes 3-alkanoyloxyalkyl uracils.
  • WO 00/20556 describes Uracile with a zinc finger active unit as antibacterial compounds.
  • An object of the present invention is therefore to provide new compounds with the same or improved antibacterial activity for the treatment of bacterial diseases in humans and animals.
  • derivatives of this class of compounds in which the amide is replaced by cyclic amides are highly antibacterial.
  • the present invention therefore relates to compounds of the general
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocycle
  • this heterocycle can be optionally substituted with 1 to 3 substituents independently selected from the group halogen, trifluoromethyl, trifluoromethoxy, nitro, dC 6 alkyl, dC ö alkoxy, C 3 -C 6 cycloalkyl, - (CH 2 ) P -C 6 -C ⁇ 0 aryl, - (CH 2 ) n heteroaryl, - (CH 2 ) m heterocyclyl, 1,2- (methylenedioxy) benzene, oxo, formyl, dC 6 alkylcarbonyl, dC 6 -alkoxy-carbonyl, amino, d-C ⁇ -alkylamino, -C-C 6 -dialkylamino, phenylamino, aminocarbonyl, C ⁇ -C 6 -alkylaminocarbonyl, dC 6 -dialkylarninocarbonyl,
  • Aminosulfonyl alkylaminosulfonyl ö dC, dC ⁇ dialkylaminosulfonyl, C 3 - C 8 -Cycloalkylaminosulfonyl, C 3 -C 8 -Dicycloalkylaminosulfonyl, C 6 -C 10 - arylaminosulfonyl, heteroarylaminosulfonyl, -CH 2 CH 2 OCH 2 CH 2 OH and
  • C ⁇ -C 6 -alkyl, C 6 alkoxy, C 3 -C 6 cycloalkyl, phenylamino, - (CH 2) P - C 6 -C 10 aryl, - (CH 2) m -heterocyclyl and - (CH 2 ) n -Heteroaryl can in turn be substituted with 1 to 4 substituents selected from the group Ci-C ⁇ -alkyl, hydroxy, Ci-C ö alkoxycarbonyl, amino, dC ⁇ -alkylam ⁇ no, dC ö -dialkylamino, dC ö - Alkylcarbonylamino, oxo, cyano, nitro, heterocyclicl, dC ö alkoxy and Ci-C ö thioalkyl,
  • R 1 "1 and R 1" 2 are identical or identical and are selected from the group consisting of hydrogen, Ci-C ⁇ -alkyl, -OCH 2 CH 2 OH, C 3 -C 6 cycloalkyl, C 6 -C 10- aryl, heteroaryl, -CC 6 alkylcarbonyl, CC 6 -
  • R ⁇ is a substituent of the following formula
  • R ⁇ -l and R3 "2 are independently selected from the group -C-C 6 alkyl, C2-C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl and halogen, or
  • R3 ⁇ l and R ⁇ '2 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl or heterocyclyl ring which can optionally be substituted by up to 3 halogen
  • A is a Ci-Cß-alkanediyl chain, which optionally contains one or more double or triple bonds and in which one carbon atom is optionally replaced by a nitrogen or oxygen atom, with at least 2 carbon atoms between the hetero atom in A and the nitrogen atom in the uracil ring , and where the
  • Heteroatom in A and the carbonyl carbon atom, which is adjacent to A, must have at least 1 carbon atom
  • the compounds of the general formula (I) according to the invention can occur in various stereoisomeric forms which either behave like images and mirror images (enantiomers) or do not behave like images and mirror images (diastereomers).
  • the invention relates to both the enantiomers and the diastereomers and their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
  • Physiologically acceptable salts are preferred in the context of the invention.
  • Physiologically acceptable (pharmaceutically acceptable) salts can be salts of the compounds according to the invention with inorganic or organic acids. Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid are preferred, or salts with organic carboxylic or sulfonic acids such as acetic acid, propionic acid,
  • maleic acid fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
  • Physiologically acceptable salts can also be salts of the invention
  • Be compounds with bases such as metal or ammonium salts.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example magnesium or calcium salts
  • ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di- or Triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine.
  • the compounds according to the invention can also be present in the form of their solvates, in particular in the form of their hydrates.
  • the compounds of the present invention are distinguished by a broad spectrum of activity against Gram-positive bacteria, it also being possible to detect multi-resistant germs, in particular staphylococci, pneumococci and
  • Alkyl and the alkyl parts in alkoxy, mono- and dialkylamino stand for straight-chain or branched alkyl and, unless stated otherwise, comprise dC 6 -alkyl, in particular dC-alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert -butyl..
  • Alkenyl stands for a straight-chain or branched alkenyl radical with 2 to 6 carbon atoms.
  • a straight-chain or branched alkenyl radical having 2 to 4, particularly preferably 2 to 3, carbon atoms is preferred.
  • vinyl, allyl, n-Pro ⁇ -1-en-l-yl and n-but-2-en-l-yl may be mentioned: vinyl, allyl, n-Pro ⁇ -1-en-l-yl and n-but-2-en-l-yl.
  • Alkynyl is a straight-chain or branched alkenyl radical with 2 to 6 carbon atoms.
  • a straight-chain or branched alkenyl radical having 2 to 4, particularly preferably 2 to 3, carbon atoms is preferred.
  • the following may be mentioned: n-prop-1-in-1-yl and n-but-2-in-1-yl.
  • Cycloalkyl comprises polycyclic saturated hydrocarbon radicals with up to 14 C atoms, namely monocyclic C3-C12, preferably C 3 -C 8 alkyl, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and polycyclic alkyl , ie preferably bicyclic and tricyclic, optionally spirocyclic C -C -alkyl, such as bicyclo [2.2.1] -hept-l-yl,
  • Alkanediyl stands for a carbon chain that is terminally substituted at both terms. It can optionally be mono- or polyunsaturated, in the form of double or triple bonds. Saturated chains having 1 to 6 carbon atoms, in particular 2 to 4 carbon atoms, are preferred, unless stated otherwise.
  • CH 2 stands as a prefix for substituents for an alkanediyl chain with chain length n.
  • alkoxy preferably represents a straight-chain or branched alkoxy radical, in particular having 1 to 6, 1 to 4 or 1 to 3 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is preferred. The following may be mentioned by way of example and preferably: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, i-butoxy, n-pentoxy and n-hexoxy.
  • monoalkylamino represents an amino group with a straight-chain or branched alkyl substituent which preferably has 1 to 6, 1 to 4 or 1 to 2 carbon atoms.
  • a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms is preferred.
  • the following may be mentioned as examples and preferably: methylamino, ethylamino, n-propylamino, isopropylamino, t-butylamino, n-pentylamino and n-hexylamino.
  • dialkylamino stands for an amino group with two identical or different straight-chain or branched alkyl substituents, which preferably each have 1 to 6, 1 to 4 or 1 to 2 carbon atoms.
  • Straight-chain or branched dialkylamino radicals each having 1 to 4 carbon atoms are preferred.
  • the following may be mentioned by way of example and preferably: NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N- isopropyl-Nn-propylamino, Nt-butyl-N-methylamino, N- Ethyl-Nn-pentylamino and
  • mono- or dialkylaminocarbonyl 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 preferably having 1 to 4 or 1 to 2 carbon atoms ,
  • the following may be mentioned by way of example and preferably: methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, t-butylaminocarbonyl, NN-dimethylaminocarbonyl, NN-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl and Nt-butyl-N-methylaminocarbonyl.
  • alkylcarbonylamino represents an amino group having a straight-chain or branched alkanoyl substituent which preferably has 1 to 6, 1 to 4 or 1 to 2 carbon atoms and is linked via the carbonyl group.
  • a monoacylamino radical having 1 to 2 carbon atoms is preferred. The following may be mentioned as examples and preferably: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.
  • -Cio-aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • Heteroaryl represents a 5- to 10-membered, in particular a 5- to 6-membered aromatic, optionally bonded via a nitrogen atom mono- or polycyclic heterocycle with up to 3 heteroatoms from the series S, O and / or N, for example for Pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, N-triazolyl, oxazolyl or imidazolyl. Pyridyl, furyl,
  • nitrogen heteroaryl such as in “6-, 9 or 10-membered nitrogen (CH 2 ) n heteroaryl" stands for a heteroaryl ring which has no other heteroatoms apart from nitrogen.
  • Heterocyclyl stands for a mono- or polycyclic, heterocyclic radical with 3 to 11 ring atoms and up to 3, preferably 1 heteroatoms or hetero groups from the series N, O, S, SO, SO 2, which is optionally bonded via a nitrogen atom.
  • the rings can be condensed (for example with a [0] bridge) or spiro-linked.
  • 4- to 8-membered, in particular 5- and 6-membered, heterocyclyl is preferred.
  • Heterocyclyl is preferred. Monocyclic heterocyclyl is particularly preferred. N and O are preferred as heteroatoms.
  • the heterocyclyl residues can be saturated or partially unsaturated. The unsaturated representatives can contain one or more double bonds in the ring or, in the case of polycyclic systems, can be aromatic in a ring, such as, for example, benzoxazine. Saturated heterocyclyl residues are preferred.
  • the heterocyclyl radicals can have a carbon atom or a heteroatom be bound. It can be formed from two substituent groups together with the nitrogen atom to which they are attached. 5- to 7-membered, monocyclic, saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S are particularly preferred.
  • nitrogen-heterocyclyl as for example in “6-membered nitrogen- (CH 2 ) ⁇ -heterocyclyl”, stands for a heterocyclyl ring which has no other heteroatoms apart from nitrogen.
  • Halogen represents fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred unless otherwise stated.
  • Two substituents can also be attached to the same carbon atom.
  • cyclic substituents when bound to cyclic substituents, can be spiro-linked.
  • a symbol * on a bond means the point of attachment in the molecule.
  • radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of other combinations, regardless of the respectively specified combinations of the radicals.
  • heterocycle can be optionally substituted with 1 to 3 substituents independently selected from the group halogen, trifluoromethyl, trifluoromethoxy, nitro, dC 6 alkyl, Ci-C ö alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, - (CH 2 ) n heteroaryl, - (CH 2 ) m heterocyclyl, dC 6 alkoxycarbonyl, aminocarbonyl, dC ⁇ alkylaminocarbonyl, dC 6 dialkyl aminocarbonyl, aminosulfonyl, dC 6 -Alkylaminosulfonyl, dC ö -dialkyl-aminosulfonyl, d-Cs-cycloalkylaminosulfonyl, C 3 -C 8 -dicycloalkylaminosulfonyl, Ce-do-arylaminosulfonyl, heteroaryl
  • n and m are identical or different and are 2, 3 or 4,
  • dC ö alkyl, Ci-C ö alkoxy, C 3 -C 6 cycloalkyl, C 6 -C ⁇ 0 aryl, hetero- aryl in turn may be substituted with 1 to 3 substituents selected from the group of hydroxy, dC 6 - Alkoxycarbonyl, amino, dC 6 -alkylamino, C ⁇ -C 6 -dialkylamino, C ⁇ -C 6 - alkylcarbonylamino,
  • R 1 '1 and R 1' 2 are the same or identical, and C ⁇ -C 6 are selected from the group consisting of hydrogen, - alkyl, -OCH 2 CH 2 OH, dC ö cycloalkyl, C ö -do-aryl , Heteroaryl, dC 6 -alkylcarbonyl, CrC 6 - alkoxycarbonyl, C 3 -C 8 -cycloalkylcarbonyl, C 6 -do-arylcarbonyl, hetero-arylcarbonyl, aminocarbonyl, Cj-C ⁇ -alkylaminocarbonyl, C ⁇ -C 6 -dialkyl-aminocarbonyl, Ci-C ö alkylsulfonyl, C 3 -C 8 cycloalkylsulfonyl, C ö -Cio-arylsulfonyl and heteroarylsulfonyl, R3 is a substituent of the group consist
  • R3-1 and R3-2 are independently selected from the group dC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or halogen, or
  • R3 _ l and R3-2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl-dC ö ring which may be optionally substituted with up to 3 halogen,
  • A is a C 1 -C 6 -alkylidene chain, which optionally contains one or more double or triple bonds and in which one carbon atom is optionally replaced by a nitrogen or oxygen atom, both of the hetero atom in A and the nitrogen atom in the uracil ring having to have at least 2 carbon atoms , and where the hetero atom in A and the carbonyl carbon atom which is adjacent to A must have at least 1 carbon atom,
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycle
  • heterocycle can be optionally substituted with 1 to 3 substituents independently selected from the group halogen, trifluoromethyl, nitro, CC 6 alkyl, Ci-C ö alkoxy, C 3 -C 6 cycloalkyl, - (CH 2 ) P -C 6 - aryl, - (CH 2) n -heteroaryl, - (CH 2) m -heterocyclyl, l, 2- (methylenedioxy) benzene, oxo, formyl, methylcarbonyl, dC ö alkoxycarbonyl, amino, methylamino, Dimethylamino, phenylamino, aminocarbonyl, CrC 6 alkylaminocarbonyl, d -C 6 dialkylaminocarbonyl and -CH 2 CH 2 OCH 2 CH 2 OH
  • R ⁇ is a substituent of the following formula
  • R ⁇ -l and R3-2 are independently selected from the group -C-C 6 - alkyl, fluorine and chlorine, or
  • R3 "1 and R3- together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclic ring which is optionally substituted with up to 3 fluorine or chlorine can be,
  • A is a Ci -C4 alkanediyl chain
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a six-membered heterocycle, where this heterocycle can optionally be substituted with 1 to 3 substituents selected from the group halogen, dC 6 -alkyl, dC 6 -alkoxy, C 3 -C 6 cycloalkyl, C 6 -C ⁇ 0 -
  • R 'and R "are the same or identical, and C ⁇ -C 6 are selected from the group consisting of hydrogen, - alkyl, -OCH 2 CH 2 OH, dC ö cycloalkyl, C ö -do-aryl, heteroaryl, C ⁇ -C 6 -alkylcarbonyl, dC 6 - alkoxycarbonyl, C 3 -C 8 -cycloalkylcarbonyl, C 6 -C ⁇ o-arylcarbonyl, hetero-arylcarbonyl, aminocarbonyl, CrC ⁇ -alkylaminocarbonyl, C ⁇ -C 6 -dialkyl-aminocarbonyl, dC 6 -alkylsulfonyl , C 3 -C 8 cycloalkylsulfonyl, C 6 -C ⁇ o-arylsulfonyl and heteroarylsulfonyl,
  • R3 is a substituent of the following formula
  • R -1 and R ⁇ are independently selected from the group
  • R3-1 and R3-2 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring,
  • A is a -C-C3 alkylidene chain.
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a pyrrolidine-piperidine, piperazine or thiomopholine ring,
  • this pyrrolidine-piperidine, piperazine or thiomophole ring may optionally be substituted with 1 to 3 substituents independently selected from the group fluorine, chlorine, nitro, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, - (CH 2 ) P - Phenyl, 6-, 9- or 10-membered
  • R ⁇ is a substituent of the following formula
  • R ⁇ -l and R-3- are independently selected from the group methyl, ethyl, fluorine and chlorine, or
  • R3 _ 1 and R3-2 together with the carbon atom to which they are attached form a cyclopentyl ring
  • A is a Ci -C4 alkanediyl chain
  • R ⁇ is selected from the group consisting of:
  • the active substance can act systemically and / or locally.
  • it can be applied in a suitable way, 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 release 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.
  • Inhalation drug forms e.g.
  • the active compounds can be converted into the application 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 or taste and / or smell.
  • the amount is approximately 0.01 to 500 mg / kg, preferably approximately 1 to 10 mg / kg body weight.
  • Parenteral in particular intravenous, e.g. as an iv bolus injection (i.e. as a single dose, e.g. by syringe), short-term infusion
  • the volume applied can, depending on the special conditions, between 0.5 to 30, in particular 1 to 20 ml in the case of the iv bolus injection, between 25 to 500, in particular 50 to 250 ml in the case of the short-term infusion and between 50 to 1000. in particular 100 to 500 ml for long-term infusion.
  • the active substance in solid form (eg as a lyophilisate) and to dissolve it in the solution medium only immediately before application.
  • the application forms must be sterile and pyrogen-free. They can be based on aqueous or mixtures of aqueous and organic solvents.
  • aqueous solutions include e.g. aqueous solutions, mixtures of aqueous and organic solvents (in particular ethanol, polyethylene glycol (PEG) 300 or 400), aqueous solutions containing cyclodextrins or aqueous solutions containing emulsifiers (surface-active solubilizers, e.g. lecithin or Pluronic
  • Isotonic and euhydric formulations are largely suitable for parenteral administration, e.g. those with a pH between 3 and 11, especially 6 and 8, especially around 7.4.
  • the injection solutions are packed in suitable containers made of glass or plastic, e.g. in vials. These can have a volume of 1 to 1000, in particular 5 to 50 ml.
  • the solution can be taken directly from these and applied.
  • a lyophilizate it is dissolved in the vial by injecting a suitable solvent and then removed.
  • the infusion solutions are packed in suitable glass or plastic containers, e.g. in bottles or collapsing plastic bags. These can have a volume of 1 to 1000, in particular 50 to 500 ml.
  • the present invention further relates to a process for the preparation of the compounds of the general formula (I) by reacting compounds of the general formula (II)
  • carboxylic acid is optionally present in activated form
  • reaction is carried out in inert solvents, in the presence of customary condensing agents, if appropriate in the presence of a base, preferably in a temperature range from room temperature to 50 ° C. at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol such as benzyl xylene glycol such as benzyl xylene glycol, such as xylene glycol, such as xylene glycol , Toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, Dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, dimethyl sulfoxide, aceton
  • Common condensing agents are, for example, carbodiimides such as e.g. N, N'
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or bicarbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-Methylmo ⁇ holin, N-Methylpiperidin, 4-Dimethylaminopyridin or Diisopropylethylamin.
  • alkali carbonates e.g. Sodium or potassium carbonate, or bicarbonate
  • organic bases such as trialkylamines e.g. Triethylamine, N-Methylmo ⁇ holin, N-Methylpiperidin, 4-Dimethylaminopyridin or Diisopropylethylamin.
  • the compounds according to the invention are particularly effective against bacteria and bacteria-like microorganisms, in particular Gram-positive bacteria. They are therefore particularly well suited for the prophylaxis and chemotherapy of local and possibly 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) and Streptococci (Strept. Agalactiae, Strept. Faecalis, Strept. Pneumoniae, Strept. Pyogenes) as well as strictly anaerobic bacteria such as e.g. Clostridium, also mycoplasma (M. pneumoniae, M. hominis, M. ureaiyticum).
  • pathogens are only an example and is in no way to be interpreted as limiting.
  • diseases which can be caused by the pathogens or mixed infections mentioned and which can be prevented, improved or cured by the compounds according to the invention are:
  • Infectious diseases in humans such.
  • bacterial infections can also be treated in other species. Examples include:
  • Ruminants (cattle, sheep, goats): sepsis, bronchopneumonia, mycoplasmosis, genital infections;
  • Horse bronchopneumonia, pue ⁇ erale and postpue ⁇ erale infections
  • Dog and cat bronchopneumonia, dermatitis, otitis, urinary tract infections, prostatitis;
  • Poultry (chicken, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, chronic respiratory diseases, 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. Brucella, Campylobacter, Listeria, Erysipelothris, Nocardia expanded.
  • pathogens e.g. Brucella, Campylobacter, Listeria, Erysipelothris, Nocardia expanded.
  • the structural gene polC is amplified with the help of PCR from genomic DNA from S. aureus.
  • the primers SAPol31 5'-GCGCCATATGGACAGAGCAACAAAAATTTAA-3 'and SAPolrev 5'-GCGCGGATCCTTACATATCAAATATCGAAA-3' the restriction sites Ndel and BamHI are introduced before and after the amplified gene.
  • the 4300 bp PCR product has been digested with Ndel and BamHI, it is converted into the vector pET15b, also digested with Ndel and BamHI
  • the cells are harvested by centrifugation, washed once in PBS with 1 mM PMSF and taken up in 50 mM NaH 2 PO 4 pH 8.0, 10 mM imidazole, 2 mM ⁇ -mercaptoethanol, 1 mM PMSF, 20% glycerol.
  • the cells are disrupted using a French press at 12,000 psi, the cell debris centrifuged (27,000xg, 120 min, 4 ° C) and the supernatant with an appropriate
  • Ni-NTA agarose from Quiagen, Germany
  • the gel matrix is washed with 50 mM NaH 2 PO pH 8.0, 2 mM ⁇ -mercaptoethanol, 20 mM imidazole, 10% glycerol and the purified protein is then washed with the same buffer containing 100 mM imidazole. eluted.
  • the purified protein is mixed with 50% glycerol and stored at -20 ° C.
  • the activity of PolC is measured in an enzymatically coupled reaction, the pyrophosphate formed during the polymerization using the ATP
  • the reaction mixture contains 50 mM Tris / Cl pH 7.5 in a final volume of 50 ⁇ l; 5 mM DTT, 10 mM MgCl 2 , 30 mM NaCl, 0.1 mg / ml BSA, 10% glycerol, each 20 ⁇ M dATP, dTTP, dCTP, 2U / ml activated calf thymus DNA (Worthington, USA), 20 ⁇ M APS and 0.06 mM luciferin.
  • the reaction is through
  • the MIC values against various bacterial strains are carried out using the microdilution method in BHI broth.
  • the bacterial strains are grown overnight in BHI broth (staphylococci) or BHI broth + 10% bovine serum (streptococci, enterococci).
  • the test substances are in a concentration range from 0.5 to 256 ⁇ g / ml checked.
  • the microtite plates are inoculated with the test germs. The germ concentration is approx. LxlO 6 germs / ml suspension.
  • the plates are incubated at 37 ° C under 8% CO2 (for streptococci, enterococci) for 20 h. The lowest concentration at which the visible growth of the bacteria is completely inhibited is recorded as the MIC value.
  • S. aureus 133 cells are grown overnight in BH broth.
  • 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 (303).
  • a cell suspension with an absorbance of 50 units in 303 is then set on the photometer (model LP 2W, Dr. Lange, 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 therapy takes place 30 minutes after the infection.
  • Female CFW1 mice are used for the infection attempt. The survival of the animals is recorded over 6 days.
  • Ammocarbonyl-substituted phenylaminouracils (I) are prepared starting from carboxy-substituted phenylaminouracils (II) by amide formation:
  • the carboxylic acid (0.10 mmol), the amine (0.11 mmol) and PyBOP (0.11 mmol) are dissolved in dry DMF (3 mL) under an argon atmosphere and stirred while Hünig's base (DIPEA; 0.2 mmol) is added dropwise.
  • DIPEA Hünig's base
  • the reaction is stirred for 12 hours and the solvent is removed in vacuo.
  • the residue is purified using preparative HPLC (standard program, gradient from 10% to 90% MeCN in water). After removal of the solvent, the products are obtained in vacuo as oils, glasses or foams in yields of 5 to 90%.
  • the carboxy-substituted phenylaminouracils (II) are prepared from the corresponding alkoxycarbonyl-substituted phenylaminouracils (IV) by hydrolysis:
  • the corresponding ester IV (10 mmol) is dissolved in 4N sodium hydroxide solution under argon at room temperature and stirred until the reaction is complete by thin layer chromatography or HPLC, normally between half an hour and two hours.
  • the resulting clear solution is acidified to pH 3 with concentrated hydrochloric acid, cooling so that the temperature does not rise above 30 ° C.
  • the solution is cooled to 0 ° for one hour and the resulting precipitate is filtered off, washed with cold water and dried in vacuo at 50 ° C. in order to obtain the resulting carboxylic acid II as a white powder in yields between 60 and 100%.
  • a high-boiling solvent e.g.: 1,4-dioxane, diglyme or 1-methylpyrrolidinone
  • the crude product can be purified by chromatography on silica gel (eluent: mixtures of dichloromethane and methanol) or by preparative RP-HPLC.
  • Literature regulations also by reaction with phenylphosphorus oxychloride (J Heterocyclic Chem., 1985, 22, 873) or by phosphorus oxychloride in the presence of less Amounts of water (J Am. Chem. Soc, 1980, 102, 5036; Tetrahedron Asymmetry, 1997, 8, 2319) from the corresponding 1 -substituted 2,4,6 (1H, 3H, 5H) pyrimide intrions.
  • Example III 1 - [(Benzyloxy) methyl] -6-chloro-2,4 (1H, 3H) pyrimidinedione
  • reaction solution is concentrated in vacuo and the residue is taken up in 50 ml of water. It is extracted once with 150 ml of ethyl acetate and dried over sodium sulfate.
  • the preparation is carried out as for example VI from 3.23 g (13.885 mmol) of the compound from example I and 7.39 g (55.54 mmol) of 5-aminoindane.
  • the preparation is carried out from 1.46 g (5.63 mmol) of the compound from example II, 1.16 g (6.75 mmol) of 3-ethyl-4-methylaniline hydrochloride and 2.15 ml (12.39 mmol) of N, N-diisopropylethylamine.
  • the preparation is carried out as for example XI from 10 g (27.33 mmol) of the compound from example VIII.
  • the preparation is carried out from 6.96 g (19.36 mmol) of the compound from example IX.
  • the substances according to the invention can be converted into pharmaceutical preparations as follows:
  • Composition 100 mg of the compound from Example 1, 50 mg lactose (monohydrate), 50 mg corn starch (native), 10 mg polyvinylpyrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.
  • the mixture of active ingredient, 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 compressed with a conventional tablet press (tablet format see above).
  • Pressing a pressure force of 15 kN is used.
  • a single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension. production:
  • Rhodigel is suspended in ethanol, the active ingredient 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.

Abstract

La présente invention concerne les uraciles de la formule générale (1), où R?1, R2 et R3¿ ont la signification donnée dans la description. L'invention concerne également leur procédé de production, les compositions pharmaceutiques les contenant et leur utilisation dans le traitement de maladies d'êtres humains ou d'animaux.
PCT/EP2002/006325 2001-06-22 2002-06-10 Derives d'uracile antibacteriens WO2003000665A1 (fr)

Applications Claiming Priority (4)

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DE10130149 2001-06-22
DE10130149.9 2001-06-22
DE10200485.4 2002-01-09
DE10200485 2002-01-09

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003072574A1 (fr) * 2002-02-26 2003-09-04 Bayer Healthcare Ag Piperidine ouracile en tant que medicament pour traiter des infections bacteriennes
US6777420B2 (en) * 2001-06-15 2004-08-17 Microbiotix, Inc. Heterocyclic antibacterial compounds
WO2006099561A1 (fr) 2005-03-14 2006-09-21 Boehringer Ingelheim Vetmedica, Inc. Compositions immunogenes comprenant de la lawsonia intracellularis
EP2204184A1 (fr) 2005-07-15 2010-07-07 BOEHRINGER INGELHEIM VETMEDICA, Inc. Vaccin contre lawsonia et procédés d'utilisation de celui-ci

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5516905A (en) * 1994-08-30 1996-05-14 University Of Massachusetts Medical Center Antibiotic compounds and methods to treat gram-positive bacterial and mycoplasmal infections
WO2000020556A2 (fr) * 1998-10-07 2000-04-13 University Of Massachusetts Composes antimicrobiens reagissant aux doigts de zinc
WO2000071523A1 (fr) * 1999-05-24 2000-11-30 University Of Massachusetts Promedicaments antibiotiques
WO2001029010A1 (fr) * 1999-10-21 2001-04-26 Merck & Co., Inc. Composes antibacteriens a selectivite gram-positif, compositions contenant ces composes et methodes therapeutiques
DE10064778A1 (de) * 2000-12-22 2002-06-27 Bayer Ag Cyclisch substituierte Phenylamino-uracile

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5516905A (en) * 1994-08-30 1996-05-14 University Of Massachusetts Medical Center Antibiotic compounds and methods to treat gram-positive bacterial and mycoplasmal infections
WO2000020556A2 (fr) * 1998-10-07 2000-04-13 University Of Massachusetts Composes antimicrobiens reagissant aux doigts de zinc
WO2000071523A1 (fr) * 1999-05-24 2000-11-30 University Of Massachusetts Promedicaments antibiotiques
WO2001029010A1 (fr) * 1999-10-21 2001-04-26 Merck & Co., Inc. Composes antibacteriens a selectivite gram-positif, compositions contenant ces composes et methodes therapeutiques
DE10064778A1 (de) * 2000-12-22 2002-06-27 Bayer Ag Cyclisch substituierte Phenylamino-uracile

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6777420B2 (en) * 2001-06-15 2004-08-17 Microbiotix, Inc. Heterocyclic antibacterial compounds
WO2003072574A1 (fr) * 2002-02-26 2003-09-04 Bayer Healthcare Ag Piperidine ouracile en tant que medicament pour traiter des infections bacteriennes
WO2006099561A1 (fr) 2005-03-14 2006-09-21 Boehringer Ingelheim Vetmedica, Inc. Compositions immunogenes comprenant de la lawsonia intracellularis
EP2992897A1 (fr) 2005-03-14 2016-03-09 Boehringer Ingelheim Vetmedica, Inc. Compositions immunogènes comprenant du lawsonia intercellularis
EP3354279A2 (fr) 2005-03-14 2018-08-01 Boehringer Ingelheim Vetmedica, Inc. Compositions immunogènes comprenant du lawsonia intracellularis
EP3906941A1 (fr) 2005-03-14 2021-11-10 Boehringer Ingelheim Animal Health USA Inc. Compositions immunogènes comprenant du lawsonia intercellularis
EP2204184A1 (fr) 2005-07-15 2010-07-07 BOEHRINGER INGELHEIM VETMEDICA, Inc. Vaccin contre lawsonia et procédés d'utilisation de celui-ci

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