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WO2003000664A1 - Derives d'uracile et leur utilisation pour traiter des maladies bacteriennes - Google Patents

Derives d'uracile et leur utilisation pour traiter des maladies bacteriennes Download PDF

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Publication number
WO2003000664A1
WO2003000664A1 PCT/EP2002/006311 EP0206311W WO03000664A1 WO 2003000664 A1 WO2003000664 A1 WO 2003000664A1 EP 0206311 W EP0206311 W EP 0206311W WO 03000664 A1 WO03000664 A1 WO 03000664A1
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Prior art keywords
compounds
general formula
alkyl
heterocyclyl
cycloalkyl
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PCT/EP2002/006311
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German (de)
English (en)
Inventor
Dietmar Flubacher
Kerstin Ehlert
Alexander Kuhl
Niels Svenstrup
Marcus Bauser
Jörg Keldenich
Michael Otteneder
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Bayer Aktiengesellschaft
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Publication of WO2003000664A1 publication Critical patent/WO2003000664A1/fr

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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
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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 uraciles, processes for their preparation, they comprise 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 10, which is necessary for the replicative synthesis of the DNA.
  • WO 01/29010 describes 3-aminocarbonyl-substituted phenylaminouracils.
  • WO 96/06614 describes 3-alkylidene-substituted uracils.
  • WO 00/71523 describes 3-alkanoyloxyalkyl uracils.
  • 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.
  • Rl is optionally substituted with 1 to 3 substituents Rl ⁇ l,
  • substituents R ⁇ 'l are selected independently of one another from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, nitro, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, Cß-Cio-aryl, heterocyclyl, heteroaryl, C ] -C 6 -alkoxy, -C-C 6 -alkoxycarbonyl, aminocarbonyl, C ⁇ -C 6 -alkyl- aminocarbonyl, CrC ⁇ -dialkylaminocarbonyl, aminosulfonyl, dC 6 -alkyl a inosulfonyl, C ⁇ -C 6 -dialkylaminosulfonyl, C 3 -C 8- cycloalkylaminosulfonyl, C 3 -C 8 -dicycloalkylaminosulfonyl, C ö -Cio-arylaminosulfonyl, C
  • substituents R 2_ l are independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, nitro, Ci-C ⁇ -alkyl, C 3 -C 8 cycloalkyl, Cö-CiQ-aryl, heterocyclyl, heteroaryl, C ⁇ -C 6 - alkoxy, -C-C 6 -alkoxycarbonyl, aminocarbonyl, dC 6 -alkyl-aminocarbonyl, C ⁇ -C 6 -dialkylaminocarbonyl, aminosulfonyl, dC ö -alkyl-aminosulfonyl, C ⁇ -C 6 -dialkylaminosulfonyl, C 3 -C 8 -cycloalkylaminosulfonyl , C3-C8-dicycloalkylaminosulfonyl, C 6 -do-arylaminosulfonyl and heteroarylaminosulf
  • R ⁇ represents a substituent of the following formula
  • R3-1 and R ⁇ " 2 are independently selected from the group -C-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl and halogen, or
  • R3-1 and R '2 form together with the carbon atoms to which they are attached form a cycloalkyl or dC ö heterocyclyl ring which is optionally substituted with up to 3 halogen,
  • A represents a Ci-Cg-alkanediyl chain, optionally one or more
  • E represents a Ci-Cg-alkanediyl chain, optionally one or more
  • the present invention also relates to compounds of the general formula (I)
  • R 1 C 3 -C 8 cycloalkyl, Cg-Cio-Ayl, heterocyclyl, heteroaryl, dC 6 -alkoxy, d- C ö -alkoxycarbonyl, amino, C ⁇ -C 6 -alkylamino, d-Cö-dialkylamino, aminocarbonyl, CC ö alkylaminocarbonyl, CrC ö dialkylaminocarbonyl, C ⁇ -C 6 - alkoxycarbonylamino, aminosulfonyl, Ci-C ö alkylaminosulfonyl, C ⁇ -C 6 - dialkylaminosulfonyl, C 3 -C 8 -Cycloalkylaminosulfonyl, d-Cs-dicyclohexylmethane alkylaminosulfonyl, C ö -do-arylaminosulfonyl, heteroarylaminosulfonyl,
  • Rl can be optionally substituted with 1 to 3 substituents Rl-1,
  • Rl-1 is selected from the group halogen, trifluoromethyl, trifluoromethoxy, nitro, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, Cö-Cjo-aryl, heterocyclyl, heteroaryl, dC 6 - alkoxy, dC ⁇ - Alkoxycarbonyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, aminosulfonyl,
  • R 2 is hydrogen, dC 6 -alkyl, C 3 -C 8 -cycloalkyl, Cg-Cio-aryl, heterocyclyl,
  • Heteroarylaminosulfonyl -OCH 2 CH 2 OH, -N (CH 3 ) CH 2 CH 2 OH, where R 2 may optionally be substituted with 1 to 3 substituents
  • R 2 is selected from the group halogen, trifluoromethyl, trifluoromethoxy, nitro, dC ö alkyl, d Cs cycloalkyl, Cö Cjo aryl, heterocyclyl, heteroaryl, C 6 -C 6 alkoxy, dC ö alkoxycarbonyl, Aminocarbonyl, Ci-C ö -alkylaminocarbonyl, C ⁇ -C 6 -dialkylaminocarbonyl, aminosulfonyl, C ⁇ -C 6 - alkylaminosulfonyl, C i -C 6 -dialkylaminosulfonyl, C 3 -C 8 -cycloalkyl-aminosulfonyl, C 3 -C 8 - Dicycloalkylaminosulfonyl, C 6 -C I ⁇ arylaminosulfonyl or heteroarylaminosulfonyl
  • R3 is a substituent of the following formula
  • R3 "1 and R 3 " 2 are independently selected from the group -C-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or
  • R "1 and R3 2 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl or heterocyclyl ring, which may be substituted Where appropriate with up to 3 halogen,
  • A is a C 1 -C 6 -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, where both there must be at least 2 carbon atoms between the hetero atom in A and the nitrogen atom in the uracil ring, and the hetero atom in A and the carbonyl carbon atom which is adjacent to A must have at least 1 carbon atom,
  • E is a C 1 -C 6 -alkanediyl chain which optionally contains one or more double or triple bonds and which optionally has up to 3 substituents selected from the group consisting of halogen, nitro, amino, C 1 -C 6 -alkylamino, dC 6 -dialkylamino, dC 6 -acylamino, trifluoromethyl, trifluoromethoxy is substituted,
  • 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 moieties in alkoxy, mono- and dialkylamino stands for straight or branched alkyl and includes, unless otherwise indicated, dC ö - alkyl, in particular C ⁇ -C 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-prop-1-en-1-yl and n-but-2-en-1-yl is preferred.
  • 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 C 3 -C 2 -, preferably C 3 -C 8 alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and polycyclic alkyl, ie preferably bicyclic and tricyclic, optionally spirocyclic d-C ⁇ -alkyl, such as, for example, 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 before substituents for an alkanediyl chain of 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 as examples and preferably: methoxy, ethoxy, n-
  • 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. Examples include and are preferably: N, N-dimethylamino, N.N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-
  • 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, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl and N-t-butyl-
  • 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 is preferred
  • Carbon atoms The following may be mentioned as examples and preferably: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.
  • C6-C o-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,
  • N-triazolyl oxazolyl
  • 2-benzimidazolyl imidazolyl
  • Pyridyl, furyl, thiazolyl and N-triazolyl are preferred.
  • 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 (ie with an [O] bridge) or linked spiro.
  • 4- to 8-membered, in particular 3-, 5- and 6-membered heterocyclyl is preferred.
  • Mono- or bicyclic 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 ones
  • heterocyclyl radicals can be bonded via a carbon atom or a hetero atom. 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 ) n -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.
  • a symbol * on a bond means the point of attachment in the molecule.
  • cyclic substituents when bound to cyclic substituents, can be spiro-linked.
  • 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.
  • Rl Cß-aryl, heterocyclyl, heteroaryl, Ci-C ⁇ -alkoxy, Ci-Cö-alkoxycarbonyl, amino, CrCö-alkylamino, Cj-C ö -dialkylamino, aminocarbonyl, Ci-C ö -alkylaminocarbonyl, C ⁇ -C 6 -dialkylaminocarbonyl, Ci-C ⁇ -alkoxycarbonylamino, -OCH 2 CH 2 OH, -N (CH 3 ) CH 2 CH 2 OH,
  • R * can be optionally substituted with 1 to 2 substituents R1-I,
  • R! "1 is selected from the group halogen, -C-C 6 alkyl, C 3 -C 8 cycloalkyl, Cg-Cio-aryl, heterocyclyl, heteroaryl,
  • R 2 is hydrogen or dC 6 - alkyl
  • R ⁇ 'l and R3 "2 are independently selected from the group C) -C 3 - alkyl or halogen, or
  • R3-1 and R " 2 together with the carbon atoms to which they are attached form a C 3 -C 6 cycloalkyl ring which can optionally be substituted with up to 3 halogen,
  • A is a C 1 -C 4 alkanediyl chain,
  • E is a C ⁇ -C3-alkanediyl chain.
  • R ⁇ is selected from the group
  • R 1 is a heterocyclyl ring which may optionally be substituted by 1 to 2 substituents selected from the group consisting of halogen, heteroaryl and C 1 -C 6 -alkyl.
  • A is ethane-1,2-diyl or propane-1,3-diyl, in particular propane-1,3-diyl.
  • 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.
  • Parenteral administration is preferred.
  • the active ingredient can be administered in suitable administration forms for these administration routes.
  • Non-coated and coated tablets eg enteric coatings
  • capsules dragees, granules, pellets, powders, emulsions, suspensions and solutions.
  • Parenteral administration can be done by bypassing a resorption step (intravenous, intraarterial, intracardial, intraspinal or intralumbal) or by switching on absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • Suitable forms of application for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders. Intravenous administration is preferred.
  • Inhaled drug forms e.g. powder inhalers, nebulizers
  • nasal drops / solutions, sprays e.g., nasal drops / solutions, sprays; tablets or capsules to be administered lingually, sublingually or buccally, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixes), lipophilic suspensions, ointments, creams, milk, pastes, powder or implants.
  • 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
  • iron oxides e.g. inorganic pigments
  • 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 be 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 short-term infusion and between 50 to 1000, in particular 100 up to 500 ml for long-term infusion.
  • the active ingredient in solid form (e.g. as a lyophilisate) and to dissolve it in the solution medium just 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
  • 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
  • Emulsifiers surface-active solubilizers, e.g. lecithin or Pluronic F 68, Solutol HS 15, Cremophor. Aqueous solutions are preferred.
  • Isotonic and euhydric formulations are largely suitable for parenteral administration, e.g. those with a pH between 3 and 11, especially 6 and
  • the injection solutions are packaged in suitable glass or plastic containers, for example 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. In the case of a lyophilizate, it is dissolved in the vial by injecting a suitable solvent and then removed.
  • the infusion solutions are packaged 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
  • R and R have the meaning given above.
  • reaction takes place 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-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • alkali carbonates e.g. Sodium or potassium carbonate, or bicarbonate
  • organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), l-hydroxybenzotriazole (HOBt) and triethylamine in dimethylformamide or HATU and diisopropylethylamine in dimethylformamide or 1-benzotriazolyloxytripyrrolidinophosphonium phosphonium is particularly preferred
  • the amines (III) are known or can be prepared by methods known from the literature.
  • 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 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
  • strictly anaerobic bacteria such as Clostridium, also mycoplasma (M. pneumoniae, M. hominis, M. urealyticum).
  • 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 compounds according to the invention are: Infectious diseases in humans such as, for. B. septic infections, bone and joint infections, skin infections, postoperative wound infections, abscesses,
  • Phlegmon wound infections, infected burns, burns, mouth infections, infections after dental surgery, septic arthritis, mastitis, tonsillitis, genital infections and eye infections.
  • bacterial infections can also be treated in other species. Examples include: Pig: sepsis, metritis-mastitis-agalaktiae syndrome, mastitis; Ruminants (cattle, sheep, goats): sepsis, bronchopneumonia, mycoplasmosis, genital infections;
  • Horse bronchopneumonia, puerperal and post-puerperal infections
  • Dog and cat bronchopneumonia, dermatitis, otitis, urinary tract infections
  • 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 SAPoBl 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 After the 4300 bp PCR product has been digested with Ndel and BamHI, it is ligated into the vector pET15b (Novagen, USA), likewise digested with Ndel and BamHI, and transformed into E. coli XL-1 Blue.
  • the cells for expression of PolC are cultivated at 30 ° C. in LB medium with 100 ⁇ g / ml ampicillin up to an OD 595 nm of 0.5, cooled to 18 ° C. and after addition incubated further from 1 mM IPTG for 20 hours.
  • 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 off (27,000 ⁇ g, 120 min, 4 ° C.) and the supernatant with an appropriate amount of Ni-NTA agarose (from Quiagen, Germany) for 1 hour stirred at 4 ° C.
  • 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 being converted to ATP using the ATP-Sulfurylsae, which is detected using the Firefly luciferase.
  • the reaction mixture contains 50 mM in a final volume of 50 ⁇ l
  • the reaction is started by adding purified PolC in a final concentration of ⁇ 2 nM and incubated at 30 ° C. for 30 min.
  • the amount of pyrophosphate formed is then converted to ATP by adding ATP sulfurylase (Sigma, USA) at a final concentration of 5 nM and incubating at 30 ° C for 15 min. After adding 0.2 nM Firefly luciferase, the luminescence is measured in a luminometer for 60 s. The concentration of an inhibitor is given as IC 50 , which leads to a 50% inhibition of the enzyme activity of PolC. Table A
  • 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 tested in a concentration range from 0.5 to 256 ⁇ g / ml.
  • the microtiter plates are inoculated with the test germs.
  • the germ concentration is about lxl 0 6 germs / ml of suspension.
  • 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.
  • Aminocarbonyl-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 phenylaminouracile (II) are derived from the corresponding
  • the crude product can be purified by chromatography on silica gel (eluent: mixtures of dichloromethane and methanol) or by preparative RP- ⁇ PLC.
  • Chloruracile can be prepared as follows:
  • 3-substituted 6-chloro-2,4- (1H, 3H) -pyrimidinediones (V) can also be reacted with phenylphosphorus oxychloride (J Heterocyclic Chem., 1985, 22, 873) or by phosphorus oxychloride in the presence according to the literature small amounts of water (J. Am. Chem. Soc. 1980, 102, 5036; Tetrahedron Asymmetrie, 1997, 8, 2319) from the corresponding 1-substituted 2,4,6 (1H, 3H, 5H) -pyrimide intrions ,
  • the residue of the filtrate can then be obtained in pure form by chromatography on silica gel (typically with solvent mixtures such as toluene / methanol or dichloromethane / methanol).
  • reaction solution is poured onto 10 g of ice and neutralized with ammonia. It is extracted twice with dichloromethane, dried over sodium sulfate and concentrated in vacuo. It is cleaned over silica gel 60 (eluent: ethyl acetate). Yield: 79% of theory Th.
  • Example I The presentation is as described for Example I from the corresponding starting materials.
  • 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 10 g (27.33 mmol) of the compound from example VUI.
  • the preparation is carried out from 6.96 g (19.36 mmol) of the compound from example IX.
  • Example 10 4- [4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl] -
  • the substances according to the invention can be converted into pharmaceutical preparations as follows:
  • Composition 100 mg of the compound of Example 1, 50 mg lactose (monohydrate), 50 mg
  • 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.

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Abstract

La présente invention concerne des uraciles, des procédés pour les produire, des compositions pharmaceutiques les renfermant, ainsi que leur utilisation pour traiter des maladies chez l'homme ou les animaux. Les composés selon cette invention présentent la formule générale (I).
PCT/EP2002/006311 2001-06-22 2002-06-10 Derives d'uracile et leur utilisation pour traiter des maladies bacteriennes WO2003000664A1 (fr)

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Cited By (1)

* 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

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US2969364A (en) * 1957-12-26 1961-01-24 Upjohn Co Derivatives of 5-amino uracil
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FR2232320A1 (en) * 1973-06-08 1975-01-03 Wuelfing Johann A 4-Amino-uracil derivs - hypocholesterolemiant having diuretic activity
US3957786A (en) * 1969-08-20 1976-05-18 Byk Gulden Aryl-substituted piperazinyl-alkylamino-uracils, -uracil ethers and -uracil thioethers and method for their production
US4576948A (en) * 1983-01-20 1986-03-18 Trustees Boston University Composition and method for inhibiting terminal deoxyribonucleotidyl transferase activity
WO1996006614A1 (fr) * 1994-08-30 1996-03-07 University Of Massachusetts Medical Center Nouveaux composes antibiotiques et procedes de traitement d'infections a bacteries gram positif et a mycoplasmes
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
US6177437B1 (en) * 1998-09-04 2001-01-23 University Of Massachusetts Medical Center Inhibitors of Herpes Simplex virus uracil-DNA glycosylase
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GB618826A (en) * 1946-11-12 1949-02-28 Burroughs Wellcome Co Derivatives of 5-aminouracil
US2969364A (en) * 1957-12-26 1961-01-24 Upjohn Co Derivatives of 5-amino uracil
FR1294809A (fr) * 1961-04-17 1962-06-01 Nouveau dérivé de l'amino-4 diméthyl-1, 3 uracile et son procédé de préparation
US3957786A (en) * 1969-08-20 1976-05-18 Byk Gulden Aryl-substituted piperazinyl-alkylamino-uracils, -uracil ethers and -uracil thioethers and method for their production
FR2232320A1 (en) * 1973-06-08 1975-01-03 Wuelfing Johann A 4-Amino-uracil derivs - hypocholesterolemiant having diuretic activity
US4576948A (en) * 1983-01-20 1986-03-18 Trustees Boston University Composition and method for inhibiting terminal deoxyribonucleotidyl transferase activity
WO1996006614A1 (fr) * 1994-08-30 1996-03-07 University Of Massachusetts Medical Center Nouveaux composes antibiotiques et procedes de traitement d'infections a bacteries gram positif et a mycoplasmes
US6177437B1 (en) * 1998-09-04 2001-01-23 University Of Massachusetts Medical Center Inhibitors of Herpes Simplex virus uracil-DNA glycosylase
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

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TARANTINO P M ET AL: "INHIBITORS OF DNA POLYMERASE III AS NOVEL ANTIMICROBIAL AGENTS AGAINST GRAM-POSITIVE EUBACTERIA", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, AMERICAN SOCIETY FOR MICROBIOLOGY, WASHINGTON, DC, US, vol. 43, no. 8, August 1999 (1999-08-01), pages 1982 - 1987, XP002939034, ISSN: 0066-4804 *
TARANTINO P.M. ET AL.: "6-Anilinouracil-Based Inhibitors of Bacillus subtilis DNA Polymerase III: Antipolymerase and Antimicrobial Structure-Activity Relationships Based on Substitution at Uracil N3", J. MED. CHEM., vol. 42, 1999, pages 2035 - 2040, XP002213503 *

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* 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

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