WO2003000664A1 - Uracil derivatives and the use thereof for treating bacterial diseases - Google Patents

Uracil derivatives and the use thereof for treating bacterial diseases 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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compounds
general formula
alkyl
heterocyclyl
cycloalkyl
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PCT/EP2002/006311
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German (de)
French (fr)
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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/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic 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
    • C07D239/28Heterocyclic 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
    • C07D239/46Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52Two oxygen atoms
    • C07D239/54Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545Two 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10Heterocyclic 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
    • C07D231/12Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic 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
    • C07D233/56Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/081,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/12Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic 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
    • C07D403/12Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic 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
    • C07D405/02Heterocyclic 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
    • C07D405/12Heterocyclic 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

The invention relates to uracils, methods for the production thereof, pharmaceutical compositions containing said uracils, and the use of the same for treating diseases affecting humans or animals. The inventive compounds are of general formula (I).

Description

URACILDERIVATIVE UND IHRE VERWENDUNG BEI DER BEHANDLUNG BAKTERIELLER ERKRANKUNG ENURACIL DERIVATIVE AND THEIR USE IN TREATING BACTERIAL DISEASE
Die vorliegende Erfindung betrifft Uracile, Verfahren zur ihrer Herstellung, sie um- 5 fassen pharmazeutische Zusammensetzungen sowie ihre Verwendung bei der Behandlung von Erkrankungen bei Menschen oder Tieren.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 Eubakterien enthalten drei unterschiedliche DNA-Polymerase-Exo- Nucleasen, die als Pol 1 , Pol 2 und Pol 3 bezeichnet werden. Pol 3 ist ein Enzym, 10 welches für die replikative Synthese der DNA notwendig ist.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 beschreibt 3-Aminocarbonyl-substituierte Phenylaminouracile. WO 96/06614 beschreibt 3-Alkyliden-substituierte Uracile. WO 00/71523 beschreibt 3-Alkanoyloxyalkyluracile.WO 01/29010 describes 3-aminocarbonyl-substituted phenylaminouracils. WO 96/06614 describes 3-alkylidene-substituted uracils. WO 00/71523 describes 3-alkanoyloxyalkyl uracils.
15 WO 00/20556 beschreibt Uracile mit Zink-Finger-aktiver Einheit als antibakterielle15 WO 00/20556 describes Uracile with zinc finger active unit as an antibacterial
Verbindungen.Links.
In J Med. Chem., 1999, 42, 2035, Antimicro. Agents and Chemotherapy, 1999, 43, 1982 und Antimicro. Agents and Chemotherapy, 2000, 44, 2217 sind Phenylaminouracile als antibakterielle Verbindungen beschrieben.In J Med. Chem., 1999, 42, 2035, Antimicro. Agents and Chemotherapy, 1999, 43, 1982 and Antimicro. Agents and Chemotherapy, 2000, 44, 2217, phenylaminouracile are described as antibacterial compounds.
2020
Auf dem Markt sind zwar weitere, strukturell andersartige antibakteriell wirkende Mittel vorhanden, es kann aber regelmäßig zu einer Resistenzentwicklung kommen. Neue Mittel für eine bessere und wirksame Therapie sind daher wünschenswert.Although there are other structurally different antibacterial agents on the market, resistance can regularly develop. New means for better and more effective therapy are therefore desirable.
25 Eine Aufgabe der vorliegenden Erfindung ist es daher, neue Verbindungen mit gleicher oder verbesserter antibakterieller Wirkung zur Behandlung von bakteriellen Erkrankungen bei Menschen und Tieren zur Verfügung zu stellen.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.
Überraschenderweise wurde gefunden, dass Derivate dieser Verbindungsklasse, 30 worin das Amid durch Alkandiyl-substituierte Amide ersetzt wird, antibakteriell hoch wirksam sind. Gegenstand der vorliegenden Erfindung sind daher Verbindungen der allgemeinen Formel (I)Surprisingly, it has been found that derivatives of this class of compounds, 30 in which the amide is replaced by alkanediyl-substituted amides, are highly antibacterial. The present invention therefore relates to compounds of the general formula (I)
Figure imgf000004_0001
in welcher
Figure imgf000004_0001
in which
Rl für C3-C8-Cycloalkyl, Cö-CiQ-Ar l, Heterocyclyl, Heteroaryl, CrCö-Alkoxy, Cι-C6-Alkoxycarbonyl, Amino, Hydroxy, Cι-C6-Alkylamino, Cj-Cö-Dialkyl- amino, Aminocarbonyl, Cι-C6-Alkylaminocarbonyl, -Cö-Dialkylamino- carbonyl, d-Ce-Alkoxycarbonylamino, Aminosulfonyl, Ci-Cö-Alkylamino- sulfonyl, Cι-C6-Dialkylaminosulfonyl, C3-C8-Cycloalkylamino-sulfonyl, C3- C8-Dicycloalkylaminosulfonyl, C6-Cιo-Arylaminosulfonyl, Heteroarylamino- sulfonyl, -OCH2CH2OH oder -N(CH3)CH2CH2OH steht,Rl for C 3 -C 8 cycloalkyl, Cö-CiQ-Ar l, heterocyclyl, heteroaryl, CrC ö alkoxy, Cι-C 6 alkoxycarbonyl, amino, hydroxy, Cι-C 6 alkylamino, Cj-C ö dialkyl - amino, aminocarbonyl, -CC 6 -alkylaminocarbonyl, -C ö -dialkylamino-carbonyl, d-Ce-alkoxycarbonylamino, aminosulfonyl, Ci-C ö -alkylamino-sulfonyl, Cι-C 6 -dialkylaminosulfonyl, C 3 -C 8 - Cycloalkylaminosulfonyl, C 3 -C 8 -dicycloalkylaminosulfonyl, C 6 -Cιo-arylaminosulfonyl, heteroarylaminosulfonyl, -OCH 2 CH 2 OH or -N (CH 3 ) CH 2 CH 2 OH,
wobei Rl gegebenenfalls substituiert ist mit 1 bis 3 Substituenten Rl~l,where Rl is optionally substituted with 1 to 3 substituents Rl ~ l,
wobei die Substituenten R^'l unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Nitro, Cι-C6-Alkyl, C3-C8-Cycloalkyl, Cß-Cio-Aryl, Heterocyclyl, Heteroaryl, C]-C6-Alkoxy, Cι-C6-Alkoxycarbonyl, Aminocarbonyl, Cι-C6-Alkyl- aminocarbonyl, CrCό-Dialkylaminocarbonyl, Aminosulfonyl, d-C6-Alkyl- a inosulfonyl, Cι-C6-Dialkylaminosulfonyl, C3-C8-Cycloalkylaminosulfonyl, C3-C8-Dicycloalkylaminosulfonyl, Cö-Cio-Arylaminosulfonyl und Heteroaryl- aminosulfonyl, R2 für Wasserstoff, Cι-C6-Alkyl, C3-C8-Cycloalkyl, Cö-Cio-Aryl, Heterocyclyl, Heteroaryl, Cι-C6-Alkoxy, Ci-Cö-Alkoxycarbonyl, Amino, d-Cö-Alkyl- amino, Ci-Cö-Dialkylamino, Aminocarbonyl, Ci-Cö-Alkylaminocarbonyl, Ci-Cö-Dialkylaminocarbonyl, d-Cö-Alkoxycarbonylamino, Aminosulfonyl, Ci-Cö-Alkylaminosulfonyl, d-Ce-Dialkylaminosulfonyl, C3-C8-Cycloalkyl- aminosulfonyl, C3-C8-Dicycloalkylaminosulfonyl, Cö-C^-Arylaminosulfonyl, Heteroarylaminosulfonyl, -OCH2CH2OH oder -N(CH3)CH2CH2OH steht,wherein the 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, Cι-C 6 -alkyl- aminocarbonyl, CrCό-dialkylaminocarbonyl, aminosulfonyl, dC 6 -alkyl a inosulfonyl, Cι-C 6 -dialkylaminosulfonyl, C 3 -C 8- cycloalkylaminosulfonyl, C 3 -C 8 -dicycloalkylaminosulfonyl, C ö -Cio-arylaminosulfonyl and heteroaryl-aminosulfonyl, R 2 for hydrogen, -CC 6 alkyl, C 3 -C 8 cycloalkyl, Cö-Cio-aryl, heterocyclyl, heteroaryl, -C-C 6 alkoxy, Ci-C ö alkoxycarbonyl, amino, dC ö alkyl amino, Ci-C ö dialkylamino, aminocarbonyl, Ci-C ö alkylaminocarbonyl, Ci-Cö dialkylaminocarbonyl, dC ö alkoxycarbonylamino, aminosulfonyl, Ci-C ö alkylaminosulfonyl, d-Ce dialkylaminosulfonyl, C 3 -C 8 Cycloalkylaminosulfonyl, C 3 -C 8 -dicycloalkylaminosulfonyl, C ö -C ^ arylaminosulfonyl, heteroarylaminosulfonyl, -OCH 2 CH 2 OH or -N (CH 3 ) CH 2 CH 2 OH,
wobei Alkyl, Cycloalkyl, Aryl, Heterocyclyl, Heteroaryl, Alkoxy, Alkoxy- carbonyl, Alkylamino, Dialkylamino, Alkylaminocarbonyl, Dialkylamino- carbonyl, Alkoxycarbonylamino, Alkylaminosulfonyl, Dialkylaminosulfonyl, Cycloalkylaminosulfonyl, Dicycloalkylaminosulfonyl, Arylaminosulfonyl und Heteroarylaminosulfonyl gegebenenfalls substituiert ist mit 1 bis 3 Substituenten R2-1,where alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, alkoxycarbonyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, alkylaminosulfonyl, dialkylaminosulfonyl, cycloalkylaminosulfonyl, dicycloalkylaminosulfonyl with arylsulfonyl aryllaminosulfonyl, 1,
wobei die Substituenten R2_l unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Nitro, Ci-Cβ-Alkyl, C3-C8-Cycloalkyl, Cö-CiQ-Aryl, Heterocyclyl, Heteroaryl, Cι-C6- Alkoxy, Cι-C6-Alkoxycarbonyl, Aminocarbonyl, d-C6-Alkyl- aminocarbonyl, Cι-C6-Dialkylaminocarbonyl, Aminosulfonyl, d-Cö-Alkyl- aminosulfonyl, Cι-C6-Dialkylaminosulfonyl, C3-C8-Cycloalkylaminosulfonyl, C3-C8-Dicycloalkylaminosulfonyl, C6-do- Arylaminosulfonyl und Heteroarylaminosulfonyl,where the substituents R 2_ l are independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, nitro, Ci-Cβ-alkyl, C 3 -C 8 cycloalkyl, Cö-CiQ-aryl, heterocyclyl, heteroaryl, Cι-C 6 - alkoxy, -C-C 6 -alkoxycarbonyl, aminocarbonyl, dC 6 -alkyl-aminocarbonyl, Cι-C 6 -dialkylaminocarbonyl, aminosulfonyl, dC ö -alkyl-aminosulfonyl, Cι-C 6 -dialkylaminosulfonyl, C 3 -C 8 -cycloalkylaminosulfonyl , C3-C8-dicycloalkylaminosulfonyl, C 6 -do-arylaminosulfonyl and heteroarylaminosulfonyl,
R^ für einen Substituenten der folgenden Formel steht,R ^ represents a substituent of the following formula,
Figure imgf000005_0001
Figure imgf000005_0001
wobei R3-1 und R^"2 unabhängig voneinander ausgewählt werden aus der Gruppe Cι-C6-Alkyl, C2-C6-Alkenyl, C2-C6-Alkinyl, C3-C6-Cycloalkyl und Halogen, oderin which 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 und R^"2 bilden zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, einen d-Cö-Cycloalkyl- oder Heterocyclyl-Ring, der gegebenenfalls mit bis zu 3 Halogen substituiert ist,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 für eine Ci -Cg-Alkandiylkette steht, die gegebenenfalls eine oder mehrereA represents a Ci-Cg-alkanediyl chain, optionally one or more
Doppel- oder Dreifachbindungen enthält und in der gegebenenfalls ein Kohlenstoffatom durch ein Stickstoff- oder Sauerstoffatom ersetzt ist, wobei sich sowohl zwischen dem Heteroatom in A und dem Stickstoffatom im Uracilring mindestens 2 Kohlenstoffatome befinden müssen, und wobei sich dem Heteroatom in A und dem Carbonylkohlenstoffatom, welches zu A benachbart ist, mindestens 1 Kohlenstoffatom befinden muss,Contains double or triple bonds and in which a carbon atom is optionally replaced by a nitrogen or oxygen atom, where there must be at least 2 carbon atoms between the hetero atom in A and the nitrogen atom in the uracil ring, and where the hetero atom in A and the carbonyl carbon atom, which is adjacent to A, must have at least 1 carbon atom,
und die gegebenenfalls mit bis zu 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe Halogen, Nitro, Amino, Ci-Cö-Alkylamino, Ci- C6-Dialkylamino, Cι-C6-Acylamino, Trifluormethyl und Trifluormethoxy substituiert ist,and up to 3 substituents independently selected from the group halogen, nitro, amino, Ci-C ö alkylamino, Ci- C 6 dialkylamino, Cι-C 6 acylamino, trifluoromethyl and trifluoromethoxy is optionally substituted with,
E für eine Ci -Cg-Alkandiylkette steht, die gegebenenfalls eine oder mehrereE represents a Ci-Cg-alkanediyl chain, optionally one or more
Doppel- oder Dreifachbindungen enthält und die gegebenenfalls mit bis zu 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe Halogen,Contains double or triple bonds and optionally with up to 3 substituents, independently selected from the group halogen,
Nitro, Amino, CpCö-Alkylamino, d-C6-Dialkylamino, Cι-C6-Acylamino,Nitro, amino, CpC ö alkylamino, dC 6 dialkylamino, Cι-C 6 acylamino,
Trifluormethyl und Trifluormethoxy substituiert ist,Trifluoromethyl and trifluoromethoxy is substituted,
sowie deren pharmazeutisch verträgliche Salze, Solvate und Hydrate. Gegenstand der vorliegenden Erfindung sind auch Verbindungen der allgemeinen Formel (I)and their pharmaceutically acceptable salts, solvates and hydrates. The present invention also relates to compounds of the general formula (I)
wonnWonn
R1 C3-C8-Cycloalkyl, Cg-Cio-Aiyl, Heterocyclyl, Heteroaryl, d-C6- Alkoxy, d- Cö-Alkoxycarbonyl, Amino, Cι-C6-Alkylamino, d-Cö-Dialkylamino, Aminocarbonyl, C Cö-Alkylaminocarbonyl, CrCö-Dialkylaminocarbonyl, Cι-C6- Alkoxycarbonylamino, Aminosulfonyl, Ci-Cö-Alkylaminosulfonyl, Cι-C6- Dialkylaminosulfonyl, C3-C8-Cycloalkylaminosulfonyl, d-Cs-Dicyclo- alkylaminosulfonyl, Cö-do-Arylaminosulfonyl, Heteroarylaminosulfonyl, - OCH2CH2OH, -N(CH3)CH2CH2OH,R 1 C 3 -C 8 cycloalkyl, Cg-Cio-Ayl, heterocyclyl, heteroaryl, dC 6 -alkoxy, d- C ö -alkoxycarbonyl, amino, Cι-C 6 -alkylamino, d-Cö-dialkylamino, aminocarbonyl, CC ö alkylaminocarbonyl, CrC ö dialkylaminocarbonyl, Cι-C 6 - alkoxycarbonylamino, aminosulfonyl, Ci-C ö alkylaminosulfonyl, Cι-C 6 - dialkylaminosulfonyl, C 3 -C 8 -Cycloalkylaminosulfonyl, d-Cs-dicyclohexylmethane alkylaminosulfonyl, C ö -do-arylaminosulfonyl, heteroarylaminosulfonyl, - OCH 2 CH 2 OH, -N (CH 3 ) CH 2 CH 2 OH,
wobei Rl gegebenenfalls substituiert sein kann mit 1 bis 3 Substituenten Rl-1,where Rl can be optionally substituted with 1 to 3 substituents Rl-1,
wobei Rl-1 ausgewählt wird aus der Gruppe Halogen, Trifluormethyl, Trifluormethoxy, Nitro, Cι-C6-Alkyl, C3-C8-Cycloalkyl, Cö-Cjo-Aryl, Heterocyclyl, Heteroaryl, d-C6- Alkoxy, d-Cό-Alkoxycarbonyl, Aminocarbonyl, Cι-C6-Alkylaminocarbonyl, Cι-C6-Dialkylaminocarbonyl, Aminosulfonyl,where 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 ό - Alkoxycarbonyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, aminosulfonyl,
Ci-Cö-Alkylaminosulfonyl, d-C6-Dialkylaminosulfonyl, C3-C8-Cycloalkyl- aminosulfonyl, C3-C8-Dicycloalkylaminosulfonyl, C6-Cιo- Arylaminosulfonyl oder HeteroarylaminosulfonylCi-C ö alkylaminosulfonyl, dC 6 -dialkylaminosulfonyl, C 3 -C 8 -cycloalkylaminosulfonyl, C 3 -C 8 -dicycloalkylaminosulfonyl, C 6 -Cιo- arylaminosulfonyl or heteroarylaminosulfonyl
R2 Wasserstoff, d-C6-Alkyl, C3-C8-Cycloalkyl, Cg-Cio-Aryl, Heterocyclyl,R 2 is hydrogen, dC 6 -alkyl, C 3 -C 8 -cycloalkyl, Cg-Cio-aryl, heterocyclyl,
Heteroaryl, Cι-C6-Alkoxy, Cι-C6-Alkoxycarbonyl, Amino, Cι-C6-Alkyl- amino, Cj-Cö-Dialkylamino, Aminocarbonyl, Cj-C6-Alkylaminocarbonyl, Ci-Cö-Dialkylaminocarbonyl, Cj-Cό-Alkoxycarbonylamino, Aminosulfonyl, Ci-Cö-Alkylaminosulfonyl, Cι-C6-Dialkylaminosulfonyl, C3-C8-Cycloalkyl- aminosulfonyl, C3-C8-Dicycloalkylaminosulfonyl, C6-Cι0-Arylaminosulfonyl,Heteroaryl, -CC 6 -alkoxy, -C-C 6 -alkoxycarbonyl, amino, -C-C 6 -alkylamino, Cj-C ö -dialkylamino, aminocarbonyl, Cj-C 6 -alkylaminocarbonyl, Ci-C ö -dialkylaminocarbonyl, Cj-C ό -alkoxycarbonylamino, aminosulfonyl, Ci-C ö -alkylaminosulfonyl, Cι-C 6 -dialkylaminosulfonyl, C 3 -C 8 -cycloalkyl-aminosulfonyl, C 3 -C 8 -dicycloalkylaminosulfonyl, C 6 -Cι 0 -Arylaminosulfonyl,
Heteroarylaminosulfonyl, -OCH2CH2OH, -N(CH3)CH2CH2OH, wobei R2 gegebenenfalls substituiert sein kann mit 1 bis 3 Substituenten
Figure imgf000008_0001
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
Figure imgf000008_0001
wobei R2" ausgewählt wird aus der Gruppe Halogen, Trifluormethyl, Trifluormethoxy, Nitro, d-Cö-Alkyl, d-Cs-Cycloalkyl, Cö-Cjo-Aryl, Heterocyclyl, Heteroaryl, Cι-C6- Alkoxy, d-Cö-Alkoxycarbonyl, Aminocarbonyl, Ci-Cö-Alkylaminocarbonyl, Cι-C6-Dialkylaminocarbonyl, Aminosulfonyl, C ι -C6- Alkylaminosulfonyl, C i -C6-Dialkylaminosulfonyl, C3-C8-Cycloalkyl- aminosulfonyl, C3-C8-Dicycloalkylaminosulfonyl, C6-C- Arylaminosulfonyl oder Heteroarylaminosulfonylwhere 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, Cι-C 6 -dialkylaminocarbonyl, aminosulfonyl, C ι -C 6 - alkylaminosulfonyl, C i -C 6 -dialkylaminosulfonyl, C 3 -C 8 -cycloalkyl-aminosulfonyl, C 3 -C 8 - Dicycloalkylaminosulfonyl, C 6 -C arylaminosulfonyl or heteroarylaminosulfonyl
R3 ein Substituent der folgenden FormelR3 is a substituent of the following formula
Figure imgf000008_0002
Figure imgf000008_0002
worinwherein
R3"1 und R3"2 unabhängig voneinander ausgewählt werden aus der Gruppe Cι-C6-Alkyl, C2-C6-Alkenyl, C2-C6-Alkinyl, C3-C6-Cycloalkyl oderR3 "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
Halogen, oderHalogen, or
R "1 und R3-2 bilden zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen C3-C6-Cycloalkyl- oder Heterocyclyl-Ring, der ge- gebenenfalls mit bis zu 3 Halogen substituiert sein kann,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 ist eine Ci-Cß-Alkandiylkette, die gegebenenfalls eine oder mehrere Doppeloder Dreifachbindungen enthält und in der gegebenenfalls ein Kohlenstoffatom durch ein Stickstoff- oder Sauerstoffatom ersetzt ist, wobei sich sowohl zwischen dem Heteroatom in A und dem Stickstoffatom im Uracilring mindestens 2 Kohlenstoffatome befinden müssen, und wobei sich dem Heteroatom in A und dem Carbonylkohlenstoffatom, welches zu A benachbart ist, mindestens 1 Kohlenstoffatom befinden muss,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,
und die gegebenenfalls mit bis zu 3 Substituenten, ausgewählt aus der Gruppe Halogen, Nitro, Amino, d-C6-Alkylamino, d-C6-Dialkylamino, d-Cö-Acyl- amino, Trifluormethyl, Trifluormethoxy substituiert ist,and which is optionally substituted with up to 3 substituents selected from the group halogen, nitro, amino, dC 6 -alkylamino, dC 6 -dialkylamino, d-Co-acylamino, trifluoromethyl, trifluoromethoxy,
E ist eine Ci -Cg- Alkandiylkette, die gegebenenfalls eine oder mehrere Doppeloder Dreifachbindungen enthält und die gegebenenfalls mit bis zu 3 Substituenten, ausgewählt aus der Gruppe Halogen, Nitro, Amino, Cι-C6-Alkyl- amino, d-C6-Dialkylamino, d-C6-Acylamino, Trifluormethyl, Trifluormethoxy substituiert ist,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,
sowie deren pharmazeutisch verträgliche Salze, Solvate und Hydrate.and their pharmaceutically acceptable salts, solvates and hydrates.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) können in verschiedenen stereoisomeren Formen auftreten, die sich entweder wie Bild und Spiegelbild (Enantiomere), oder die sich nicht wie Bild und Spiegelbild (Diastereomere) verhalten.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).
Die Erfindung betrifft sowohl die Enantiomeren als auch die Diastereomeren sowie deren jeweilige Mischungen. Die Racemformen lassen sich ebenso wie die Diastereomeren in bekannter Weise in die stereoisomer einheitlichen Bestandteile trennen.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.
Weiterhin können bestimmte Verbindungen in tautomeren Formen vorliegen. Dies ist dem Fachmann bekannt, und derartige Verbindungen sind ebenfalls vom Umfang der Erfindung umfasst.Furthermore, certain compounds can exist in tautomeric forms. This is known to those skilled in the art and such compounds are also within the scope of the invention.
Die erfindungsgemäßen Stoffe der allgemeinen Formel (I) können auch als Salze vor- liegen. Im Rahmen der Erfindung sind physiologisch unbedenkliche Salze bevorzugt. Physiologisch unbedenkliche (pharmazeutisch verträgliche) Salze können Salze der erfindungsgemäßen Verbindungen mit anorganischen oder organischen Säuren sein. Bevorzugt werden Salze mit anorganischen Säuren wie beispielsweise Chlorwasserstoffsäure, Bromwasserstoffsäure, Phosphorsäure oder Schwefelsäure, oder Salze mit organischen Carbon- oder Sulfonsäuren wie beispielsweise Essigsäure, Propionsäure,The substances of the general formula (I) according to the invention can also be present as salts. 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,
Maleinsäure, Fumarsäure, Äpfelsäure, Zitronensäure, Weinsäure, Milchsäure, Ben- zoesäure, oder Methansulfonsäure, Ethansulfonsäure, Benzolsulfonsäure, Toluolsul- fonsäure oder Naphthalindisulfonsäure.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.
Physiologisch unbedenkliche Salze können ebenso Salze der erfindungsgemäßenPhysiologically acceptable salts can also be salts of the invention
Verbindungen mit Basen sein, wie beispielsweise Metall- oder Ammoniumsalze. Bevorzugte Beispiele sind Alkalimetallsalze (z.B. Natrium- oder Kaliumsalze), Erdalkalisalze (z.B. Magnesium- oder Calciumsalze), sowie Ammoniumsalze, die abgeleitet sind von Ammoniak oder organischen Aminen, wie beispielsweise Ethylamin, Di- bzw. Triethylamin, Ethyldiisopropylamin, Monoethanolamin, Di- bzw. Tri- ethanolamin, Dicyclohexylamin, Dimethylaminoethanol, Dibenzylamin, N-Methyl- morpholin, Dihydroabietylamin, 1 -Ephenamin, Methylpiperidin, Arginin, Lysin, Ethylendiamin oder 2-Phenylethylamin.Be compounds with bases, such as metal or ammonium salts. Preferred examples are alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), and also 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.
Die erfindungsgemäßen Verbindungen können auch in Form ihrer Solvate, insbesondere in Form ihrer Hydrate vorliegen.The compounds according to the invention can also be present in the form of their solvates, in particular in the form of their hydrates.
Die Verbindungen der vorliegenden Erfindung zeichnen sich durch ein breites Wirkspektrum gegenüber Gram-positiven Bakterien aus, wobei auch multiresistente Keime erfasst werden können, insbesondere Staphylokokken, Pneumokokken undThe 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
Enterokokken einschließlich Vancomycin-resistenter Stämme.Enterococci, including vancomycin-resistant strains.
Die Verbindungen weisen dabei in der Regel ausreichende Löslichkeit auf, um Lösungen für die parenterale Applikation herzustellen. Alkyl sowie die Alkylteile in Alkoxy, Mono- und Dialkylamino steht für geradliniges oder verzweigtes Alkyl und umfasst, wenn nicht anders angegeben, d-Cö- Alkyl, insbesondere Cι-C -Alkyl wie Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.- Butyl.The compounds generally have sufficient solubility to produce solutions for parenteral administration. 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 Cι-C alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert .- Butyl.
Alkenyl steht für einen geradkettigen oder verzweigten Alkenylrest mit 2 bis 6 Kohlenstoffatomen. Bevorzugt ist ein geradkettiger oder verzweigter Alkenylrest mit 2 bis 4, besonders bevorzugt mit 2 bis 3 Kohlenstoffatomen. Beispielsweise und vorzugsweise seien genannt: Vinyl, Allyl, n-Prop-1-en-l-yl und n-But-2-en-l-yl.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. For example and preferably, the following may be mentioned: vinyl, allyl, n-prop-1-en-1-yl and n-but-2-en-1-yl.
Alkinyl steht für einen geradkettigen oder verzweigten Alkenylrest mit 2 bis 6 Kohlenstoffatomen. Bevorzugt ist ein geradkettiger oder verzweigter Alkenylrest mit 2 bis 4, besonders bevorzugt mit 2 bis 3 Kohlenstoffatomen. Beispielsweise und vorzugsweise seien genannt: n-Prop-1-in-l-yl und n-But-2-in-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. For example and preferably, the following may be mentioned: n-prop-1-in-1-yl and n-but-2-in-1-yl.
Cycloalkyl umfasst polycyclische gesättigte Kohlenwasserstoffreste mit bis zu 14 C- Atomen, nämlich monocyclisches C3-Cι2-, vorzugsweise C3-C8-Alkyl, wie z.B. Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, Cyclooctyl, Cyclo- nonyl, und polycyclisches Alkyl, d.h. vorzugsweise bicyclisches und tricyclisches, gegebenenfalls spirocyclisches d-Cπ-Alkyl, wie z.B. Bicyclo[2.2.1]-hept-l-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-Cπ-alkyl, such as, for example, bicyclo [2.2.1] -hept-l-yl,
Bicyclo[2.2.1]-heρt-2-yl, Bicyclo[2.2.1]-hept-7-yl, Bicyclo[2.2.2]-oct-2-yl, Bicyclo- [3.2.1]-oct-2-yl, Bicyclo[3.2.2 ]-non-2-yl und Adamantyl.Bicyclo [2.2.1] -heρt-2-yl, bicyclo [2.2.1] -hept-7-yl, bicyclo [2.2.2] -oct-2-yl, bicyclo [3.2.1] -oct-2 -yl, bicyclo [3.2.2] -non-2-yl and adamantyl.
Alkandiyl steht für eine Kohlenstoffkette, die an beiden Termini endständig substituiert ist. Sie kann gegebenenfalls ein- oder mehrfach ungesättigt sein, und zwar in Form von Doppel- oder Dreifachbindungen. Bevorzugt sind gesättigte Ketten mit 1 bis 6 Kohlenstoffatomen, insbesondere 2 bis 4 Kohlenstoffatomen, wenn nichts anderes angegeben ist. (CH2)π- steht als Präfix vor Substituenten für eine Alkandiyl- kette der Kettenlänge n. Alkoxy steht im Rahmen der Erfindung vorzugsweise für einen geradkettigen oder verzweigten Alkoxyrest insbesondere mit 1 bis 6, 1 bis 4 bzw. 1 bis 3 Kohlenstoffatomen. Bevorzugt ist ein geradkettiger oder verzweigter Alkoxyrest mit 1 bis 3 Koh- lenstoffatomen. Beispielhaft und vorzugsweise seien genannt: Methoxy, Ethoxy, n-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 ) π - stands as a prefix before substituents for an alkanediyl chain of chain length n. In the context of the invention, 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-
Propoxy, Isopropoxy, t-Butoxy, i-Butoxy, n-Pentoxy und n-Hexoxy.Propoxy, isopropoxy, t-butoxy, i-butoxy, n-pentoxy and n-hexoxy.
Monoalkylamino steht im Rahmen der Erfindung für eine Amino-Gruppe mit einem geradkettigen oder verzweigten Alkylsubstituenten, der vorzugsweise 1 bis 6, 1 bis 4 bzw. 1 bis 2 Kohlenstoffatome aufweist. Bevorzugt ist ein geradkettiger oder verzweigter Monoalkylamino-Rest mit 1 bis 4 Kohlenstoffatomen. Beispielhaft und vorzugsweise seien genannt: Methylamino, Ethylamino, n-Propylamino, Isopropylamino, t-Butylamino, n-Pentylamino und n-Hexylamino.In the context of the invention, 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 steht im Rahmen der Erfindung für eine Amino-Gruppe mit zwei gleichen oder verschiedenen geradkettigen oder verzweigten Alkylsubstituenten, die vorzugsweise jeweils 1 bis 6, 1 bis 4 bzw. 1 bis 2 Kohlenstoffatome aufweisen. Bevorzugt sind geradkettige oder verzweigte Dialkylamino-Reste mit jeweils 1 bis 4 Kohlenstoffatomen. Beispielhaft und vorzugsweise seien genannt: N,N-Dimethyl- amino, N.N-Diethylamino, N-Ethyl-N-methylamino, N-Methyl-N-n-propylamino, N-In the context of the invention, 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-
Isopropyl-N-n-propylamino, N-t-Butyl-N-methylamino, N-Ethyl-N-n-pentylamino und N-n-Hexyl-JV-methylamino.Isopropyl-N-n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-JV-methylamino.
Mono- oder Dialkylaminocarbonyl steht im Rahmen der Erfindung für eine Amino- Gruppe, die über eine Carbonylgruppe verknüpft ist und die einen geradkettigen oder verzweigten bzw. zwei gleiche oder verschiedene geradkettige oder verzweigte Alkylsubstituenten mit vorzugsweise jeweils 1 bis 4 bzw. 1 bis 2 Kohlenstoffatomen aufweist. Beispielhaft und vorzugsweise seien genannt: Methylaminocarbonyl, Ethyl- aminocarbonyl, Isopropylaminocarbonyl, t-Butylaminocarbonyl, NN-Dimethylamino- carbonyl, N,N-Diethylaminocarbonyl, N-Ethyl-N-methylaminocarbonyl und N-t-Butyl-In the context of the invention, 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-
N-methylaminocarbonyl . Alkylcarbonylamino (Acylamino) steht im Rahmen der Erfindung für eine Amino- Gruppe mit einem geradkettigen oder verzweigten Alkanoylsubstituenten, der vorzugsweise 1 bis 6, 1 bis 4 bzw. 1 bis 2 Kohlenstoffatome aufweist und über die Carbonylgruppe verknüpft ist. Bevorzugt ist ein Monoacylamino-Rest mit 1 bis 2N-methylaminocarbonyl. In the context of the invention, alkylcarbonylamino (acylamino) 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
Kohlenstoffatomen. Beispielhaft und vorzugsweise seien genannt: Formamido, Acet- amido, Propionamido, n-Butyramido und Pivaloylamido.Carbon atoms. The following may be mentioned as examples and preferably: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.
C6-C o-Aryl steht im allgemeinen für einen aromatischen Rest mit 6 bis 10 Kohlen- Stoffatomen. Bevorzugte Arylreste sind Phenyl und Naphthyl.C6-C o-aryl generally represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
Heteroaryl steht für einen 5- bis 10-gliedrigen, insbesondere für einen 5- bis 6- gliedrigen aromatischen, gegebenenfalls über ein Stickstoffatom gebundenen mono- oder polycyclischen Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, O und/oder N, beispielsweise für Pyridyl, Pyrimidyl, Thienyl, Furyl, Pyrrolyl,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, 2-Benzimidazolyl oder Imidazolyl. Bevorzugt sind Pyridyl, Furyl, Thiazolyl und N-Triazolyl. Die Bezeichnung „Stickstoff-Heteroaryl", wie z.B. in „6-, 9 oder 10-gliedriges Stickstoff-(CH2)n-Heteroaryl", steht hierbei für einen Heteroarylring, der außer Stickstoff keine anderen Heteroatome aufweist.Thiazolyl, N-triazolyl, oxazolyl, 2-benzimidazolyl or imidazolyl. Pyridyl, furyl, thiazolyl and N-triazolyl are preferred. The term "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 (Heterocyclus) steht für einen gegebenenfalls über ein Stickstoffatom gebundenen mono- oder polycyclischen, heterocyclischen Rest mit 3 bis 11 Ringatomen und bis zu 3, vorzugsweise 1 Heteroatomen bzw. Heterogruppen aus der Reihe N, O, S, SO, SO2. Bei polycyclischen Resten können die Ringe kondensiert sein (d.h. mit einer [O]-Brücke) oder spiro-verknüpft sein. 4- bis 8-gliedriges, insbesondere 3-, 5- und 6-gliedriges Heterocyclyl ist bevorzugt. Mono- oder bi- cyclisches Heterocyclyl ist bevorzugt. Besonders bevorzugt ist monocyclisches Heterocyclyl. Als Heteroatome sind N und O bevorzugt. Die Heterocyclyl-Reste können gesättigt oder teilweise ungesättigt sein. Die ungesättigten Vertreter können eine oder mehrere Doppelbindungen im Ring enthalten oder, bei polycyclischenHeterocyclyl (heterocycle) 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. In the case of polycyclic residues, 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
Systemen, in einem Ring aromatisch sein, wie z.B. Benzoxazin. Gesättigte Heterocyclyl-Reste sind bevorzugt. Die Heterocyclyl-Reste können über ein Kohlenstoffatom oder ein Heteroatom gebunden sein. Er kann aus zwei Substituenten- gruppen zusammen mit dem Stickstoffatom, an das sie gebunden sind, gebildet werden. Besonders bevorzugt sind 5- bis 7-gliedrige, monocyclische gesättigte Heterocyclylreste mit bis zu zwei Heteroatomen aus der Reihe O, N und S.Systems, be aromatic in a ring, such as benzoxazine. saturated Heterocyclyl residues are preferred. The 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.
Beispielsweise und vorzugsweise seien genannt: Oxetan-3-yl, Pyrrolidin-2-yl, Pyrrolidin-3-yl, Pyrrolinyl, Tetrahydrofuranyl, Tetrahydrothienyl, Pyranyl, Piperidinyl, Thiopyranyl, Morpholinyl, Perhydroazepinyl. Die Bezeichnung „Stickstoff-Heterocyclyl", wie z.B. in „6-gliedriges Stickstoff-(CH2)n-Heterocyclyl", steht hierbei für einen Heterocyclylring, der ausser Stickstoff keine anderen Heteroatome aufweist.Examples and preferably mentioned are: oxetan-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidinyl, thiopyranyl, morpholinyl, perhydroazepinyl. The term “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 steht für Fluor, Chlor, Brom oder Jod, wobei Fluor und Chlor bevorzugt sind, wenn nichts anderes angegeben ist.Halogen represents fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred unless otherwise stated.
Ein Symbol * an einer Bindung bedeutet die Verknüpfungsstelle im Molekül.A symbol * on a bond means the point of attachment in the molecule.
Zwei Substituenten können auch an dem gleichen Kohlenstoffatom gebunden sein. Ebenso können cyclische Substituenten (Cycloalkyl, Heterocyclyl), wenn sie an cyclische Substituenten gebunden sind, spiro-verknüpft sein.Two substituents can also be attached to the same carbon atom. Likewise, cyclic substituents (cycloalkyl, heterocyclyl), when bound to cyclic substituents, can be spiro-linked.
Die oben aufgeführten allgemeinen oder in Vorzugsbereichen angegebenen Restedefinitionen gelten sowohl für die Endprodukte der Formel (I) als auch entsprechend für die jeweils zur Herstellung benötigten Ausgangsstoffe bzw. Zwischenprodukte.The general or preferred radical definitions given above apply both to the end products of the formula (I) and correspondingly to the starting materials or intermediates required in each case for the preparation.
Die in den jeweiligen Kombinationen bzw. bevorzugten Kombinationen von Resten im einzelnen angegebenen Restedefinitionen werden unabhängig von den jeweilig angegebenen Kombinationen der Reste beliebig auch durch Restedefinitionen anderer Kombinationen ersetzt. Bevorzugt im Rahmen der vorliegenden Erfindungen sind Verbindungen der allgemeinen Formel (I), worinThe 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. In the context of the present inventions, preference is given to compounds of the general formula (I) in which
Rl Cß-Aryl, Heterocyclyl, Heteroaryl, Ci-Cό-Alkoxy, Ci-Cö-Alkoxycarbonyl, Amino, CrCö-Alkylamino, Cj-Cö-Dialkylamino, Aminocarbonyl, Ci-Cö-Alkylaminocarbonyl, Cι-C6-Dialkylaminocarbonyl, Ci-Cό-Alkoxycarbonyl- amino, -OCH2CH2OH, -N(CH3)CH2CH2OH,Rl Cß-aryl, heterocyclyl, heteroaryl, Ci-Cό-alkoxy, Ci-Cö-alkoxycarbonyl, amino, CrCö-alkylamino, Cj-C ö -dialkylamino, aminocarbonyl, Ci-C ö -alkylaminocarbonyl, Cι-C 6 -dialkylaminocarbonyl, Ci-Cό-alkoxycarbonylamino, -OCH 2 CH 2 OH, -N (CH 3 ) CH 2 CH 2 OH,
wobei R* gegebenenfalls substituiert sein kann mit 1 bis 2 Substituenten R1-I,where R * can be optionally substituted with 1 to 2 substituents R1-I,
wobei R!"1 ausgewählt wird aus der Gruppe Halogen, Cι-C6- Alkyl, C3-C8- Cycloalkyl, Cg-Cio-Aryl, Heterocyclyl, Heteroaryl,where R! "1 is selected from the group halogen, -C-C 6 alkyl, C 3 -C 8 cycloalkyl, Cg-Cio-aryl, heterocyclyl, heteroaryl,
R2 Wasserstoff oder d-C6- Alkyl ist,R 2 is hydrogen or dC 6 - alkyl,
R-> ein Substituent der folgenden FormelR-> a substituent of the following formula
Figure imgf000015_0001
Figure imgf000015_0001
worinwherein
R^'l und R3"2 unabhängig voneinander ausgewählt werden aus der Gruppe C)-C3- Alkyl oder Halogen, oderR ^ 'l and R3 "2 are independently selected from the group C) -C 3 - alkyl or halogen, or
R3-1 und R "2 bilden zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, einen C3-C6-Cycloalkyl-Ring, der gegebenenfalls mit bis zu 3 Halogen substituiert sein kann, A ist eine Cι-C4-Alkandiylkette,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 ist eine Cι-C3-Alkandiylkette.E is a Cι-C3-alkanediyl chain.
Bevorzugt im Rahmen der vorliegenden Erfindungen sind auch Verbindungen der allgemeinen Formel (I), worinIn the context of the present inventions, preference is also given to compounds of the general formula (I) in which
R^ ausgewählt wird aus der GruppeR ^ is selected from the group
Figure imgf000016_0001
Figure imgf000016_0001
Bevorzugt im Rahmen der vorliegenden Erfindungen sind auch Verbindungen der allgemeinen Formel (I), worin R eine GruppeIn the context of the present inventions, preference is also given to compounds of the general formula (I) in which R is a group
Figure imgf000016_0002
ist.
Figure imgf000016_0002
is.
Bevorzugt im Rahmen der vorliegenden Erfindungen sind auch Verbindungen der allgemeinen Formel (I), worin R3 eine Gruppe
Figure imgf000017_0001
ist.
In the context of the present inventions, preference is also given to compounds of the general formula (I) in which R 3 is a group
Figure imgf000017_0001
is.
Bevorzugt im Rahmen der vorliegenden Erfindungen sind auch Verbindungen der allgemeinen Formel (I), worin R1 ein Heterocyclylring ist, der gegebenenfalls substituiert sein kann mit 1 bis 2 Substituenten ausgewählt aus der Gruppe Halogen, Heteroaryl und Ci-Cö-Alkyl.In the context of the present inventions, preference is also given to compounds of the general formula (I) in which 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.
Bevorzugt im Rahmen der vorliegenden Erfindungen sind auch Verbindungen der allgemeinen Formel (I), worin R2 Wasserstoff oder Ci-d-Alkyl, insbesondereIn the context of the present inventions, preference is also given to compounds of the general formula (I) in which R 2 is hydrogen or Ci-d-alkyl, in particular
Methyl ist.Is methyl.
Bevorzugt im Rahmen der vorliegenden Erfindungen sind auch Verbindungen der allgemeinen Formel (I), worin A gleich Ethan-l,2-diyl oder Propan-l,3-diyl, ins- besondere Propan-l,3-diyl ist.Also preferred within the scope of the present invention are compounds of the general formula (I) in which A is ethane-1,2-diyl or propane-1,3-diyl, in particular propane-1,3-diyl.
Bevorzugt im Rahmen der vorliegenden Erfindungen sind auch Verbindungen der allgemeinen Formel (I), worin E gleich Ethan-l,2-diyl oder Propan-l,3-diyl ist.In the context of the present inventions, preference is also given to compounds of the general formula (I) in which E is ethane-1,2-diyl or propane-1,3-diyl.
Der Wirkstoff kann systemisch und/oder lokal wirken. Zu diesem Zweck kann er auf geeignete Weise appliziert werden, wie z.B. oral, parenteral, pulmonal, nasal, sublin- gual, lingual, buccal, rectal, transdermal, conjunctival, otisch oder als Implantat. Bevorzugt ist parenterale Applikation.The active substance can act systemically and / or locally. For this purpose 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.
Für diese Applikationswege kann der Wirkstoff in geeigneten Applikationsformen verabreicht werden.The active ingredient can be administered in suitable administration forms for these administration routes.
Für die orale Applikation eignen sich bekannte, den Wirkstoff schnell und/oder modifiziert abgebende Applikationsformen, wie z.B. Tabletten (nichtüberzogene sowie überzogene Tabletten, z.B. magensaftresistente Überzüge), Kapseln, Dragees, Granulate, Pellets, Pulver, Emulsionen, Suspensionen und Lösungen.Known application forms which release the active ingredient quickly and / or modified, such as tablets (non-coated and coated tablets, eg enteric coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions and solutions.
Die parenterale Applikation kann unter Umgehung eines Resorptionsschrittes ge- schehen (intravenös, intraarteriell, intrakardial, intraspinal oder intralumbal) oder unter Einschaltung einer Resorption (intramuskulär, subcutan, intracutan, percutan, oder intraperitoneal). Für die parenterale Applikation eignen sich als Applikationsformen u.a. Injektions- und Infusionszubereitungen in Form von Lösungen, Suspensionen, Emulsionen, Lyophilisaten und sterilen Pulvern. Bevorzugt ist intravenöse Applikation.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.
Für die sonstigen Applikationswege eignen sich z.B. Inhalationsarzneiformen (u.a. Pulverinhalatoren, Nebulizer), Nasentropfen /-lösungen, Sprays; lingual, sublingual oder buccal zu applizierende Tabletten oder Kapseln, Suppositorien, Ohren- und Augen-präparationen, Vaginalkapseln, wässrige Suspensionen (Lotionen, Schüttelmixturen), lipophile Suspensionen, Salben, Cremes, Milch, Pasten, Streupuder oder Implantate.For the other application routes, e.g. Inhaled drug forms (e.g. powder inhalers, nebulizers), 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.
Die Wirkstoffe können in an sich bekannter Weise in die angeführten Applikations- formen überführt werden. Dies geschieht unter Verwendung inerter nichttoxischer, pharmazeutisch geeigneter Hilfsstoffe. Hierzu zählen u.a. Trägerstoffe (z.B. mikrokristalline Cellulose), Lösungsmittel (z.B. flüssige Polyethylenglycole), Emulgatoren (z.B. Natriumdodecylsulfat), Dispergiermittel (z.B. Polyvinylpyrrolidon), synthetische und natürliche Biopolymere (z.B. Albumin), Stabilisatoren (z.B. Antioxidan- tien wie Ascorbinsäure), Farbstoffe (z.B. anorganische Pigmente wie Eisenoxide) oder Geschmacks- und/oder Geruchskorrigentien.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. These include 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.
Im allgemeinen hat es sich als vorteilhaft erwiesen, bei parenteraler ApplikationIn general, it has proven to be advantageous for parenteral administration
Mengen von etwa 0,001 bis 10 mg/kg, vorzugsweise etwa 0,01 bis 1 mg/kg Körper- gewicht zur Erzielung wirksamer Ergebnisse zu verabreichen. Bei oraler Applikation beträgt die Menge etwa 0,01 bis 500 mg/kg, vorzugsweise etwa 1 bis 10 mg/kg Körpergewicht.To administer amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 1 mg / kg body weight to achieve effective results. With oral application the amount is about 0.01 to 500 mg / kg, preferably about 1 to 10 mg / kg body weight.
Trotzdem kann es gegebenenfalls erforderlich sein, von den genannten Mengen abzu- weichen, und zwar in Abhängigkeit von Körpergewicht, Applikationsweg, individuellem Verhalten gegenüber dem Wirkstoff, Art der Zubereitung und Zeitpunkt bzw. Intervall, zu welchem die Applikation erfolgt.Nevertheless, it may be necessary to deviate from the quantities mentioned, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out.
Besonders bevorzugt ist die parenterale, insbesondere die intravenöse Applikation, z.B. als iv Bolus Injektion (d.h. als Einzelgabe, z.B. per Spritze), KurzzeitinfusionParenteral, in particular intravenous, e.g. as an iv bolus injection (i.e. as a single dose, e.g. by syringe), short-term infusion
(d.h. Infusion über einen Zeitraum von bis zu einer Stunde) oder Langzeitinfusion (d.h. Infusion über einen Zeitraum von mehr als einer Stunde). Das applizierte Volumen kann dabei in Abhängigkeit von den speziellen Bedingungen zwischen 0,5 bis 30, insbesondere 1 bis 20 ml bei der iv Bolus Injektion, zwischen 25 bis 500, insbesondere 50 bis 250 ml bei der Kurzzeitinfusion und zwischen 50 bis 1000, insbesondere 100 bis 500 ml bei der Langzeitinfusion betragen. Hierzu kann es vorteilhaft sein, den Wirkstoff in fester Form bereitzustellen (z.B. als Lyophilisat) und erst unmittelbar vor der Applikation im Lösungsmedium zu lösen.(i.e. infusion over a period of up to one hour) or long-term infusion (i.e. infusion over a period of more than one hour). Depending on the special conditions, 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. For this purpose, it may be advantageous to provide the active ingredient in solid form (e.g. as a lyophilisate) and to dissolve it in the solution medium just before application.
Hierbei (müssen die Applikationsformen steril und pyrogenfrei sein. Sie können auf wässrigen oder Mischungen aus wässrigen und organischen Lösungsmitteln basieren.The application forms must be sterile and pyrogen-free. They can be based on aqueous or mixtures of aqueous and organic solvents.
Dazu zählen z.B. wässrige Lösungen, Mischungen aus wässrigen und organischen Lösungsmitteln (insbesondere Ethanol, Polyethylenglykol (PEG) 300 oder 400), wässrige Lösungen enthaltend Cyclodextrine oder wässrige Lösungen enthaltendThese 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
Emulgatoren (grenzflächenaktive Lösungsvermittler, z.B. Lecithin oder Pluronic F 68, Solutol HS 15, Cremophor). Bevorzugt sind hierbei wässrige Lösungen.Emulsifiers (surface-active solubilizers, e.g. lecithin or Pluronic F 68, Solutol HS 15, Cremophor). Aqueous solutions are preferred.
Für die parenterale Applikation eignen sich weitgehend isotone und euhydrische Formulierungen, z.B. solche mit einem pH- Wert zwischen 3 und 11, besonders 6 undIsotonic and euhydric formulations are largely suitable for parenteral administration, e.g. those with a pH between 3 and 11, especially 6 and
8, insbesondere um 7,4. Die Verpackung der Injektionslösungen erfolgt in geeigneten Behältnissen aus Glas oder Kunststoff, z.B. in Durchstichflaschen (Vials). Diese können ein Volumen von 1 bis 1000, insbesondere 5 bis 50 ml aufweisen. Aus diesen kann die Lösung direkt entnommen und appliziert werden. Im Falle eines Lyophilisats wird sie in dem Vial aufgelöst durch Zuspritzen eines geeigneten Lösungsmittels und dann entnommen.8, especially around 7.4. 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.
Die Verpackung der Infusionslösungen erfolgt in geeigneten Behältnissen aus Glas oder Kunststoff, z.B. in Flaschen oder kollabierenden Kunststoffbeuteln. Diese können ein Volumen von 1 bis 1000, insbesondere 50 bis 500 ml aufweisen.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.
Die vorliegende Erfindung betrifft weiterhin ein Verfahren zur Herstellung der Verbindungen der allgemeinen Formel (I) durch Umsetzung von Verbindungen der allgemeinen Formel (II)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)
Figure imgf000020_0001
Figure imgf000020_0001
woπnembedded image in which
A und R die oben angegebene Bedeutung haben,A and R have the meaning given above,
und die Carbonsäure gegebenenfalls in aktivierter Form vorliegt,and the carboxylic acid is optionally present in activated form,
mit Verbindungen der allgemeinen Formel (III)
Figure imgf000021_0001
woπn
with compounds of the general formula (III)
Figure imgf000021_0001
embedded image in which
11
R und R die oben angegebene Bedeutung haben.R and R have the meaning given above.
Die Umsetzung erfolgt in inerten Lösungsmitteln, in Gegenwart von üblichen Kondensationsmitteln, gegebenenfalls in Gegenwart einer Base, bevorzugt in einem' Temperaturbereich von Raumtemperatur bis 50°C bei Normaldruck.The 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.
Inerte Lösungsmittel sind beispielsweise Halogenkohlenwasserstoffe wie Methylenchlorid, Trichlormethan, Tetrachlormethan, Trichlorethan, Tetrachlorethan, 1,2-Di- chlorethan oder Trichlorethylen, Ether wie Diethylether, Methyl-tert.-butylether, Dioxan, Tetrahydrofuran, Glykoldimethylether oder Diethylenglykoldimethylether, Kohlenwasserstoffe wie Benzol, Xylol, Toluol, Hexan, Cyclohexan oder Erdölfrak- tionen, oder andere Lösungsmittel wie Nitromethan, Ethylacetat, Aceton, Dimethylformamid, Dimethylacetamid, 1,2-Dimethoxyethan, Dimethylsulfoxid, Acetonitril oder Pyridin, bevorzugt sind Tetrahydrofuran, Dimethylformamid, 1,2-Dichlorethan oder Methylenchlorid.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, acetonitrile or pyridine; tetrahydrofuran, dimethylformamide, 1,2-dichloroethane or methylene chloride are preferred ,
Übliche Kondensationsmittel sind beispielsweise Carbodiimide wie z.B. N,N'-Common condensing agents are, for example, carbodiimides such as e.g. N, N'
Diethyl-, N,N,'-Dipropyl-, N,N'-Diisopropyl-, N,N'-Dicyclohexylcarbodiimid, N-(3- Dimethylaminoisopropyl)-N'-ethylcarbodiimid-Hydrochlorid (EDC), N-Cyclohexyl- carbodiimid-N'-propyloxymethyl-Polystyrol (PS-Carbodiimid) oder Carbonylverbin- dungen wie Carbonyldiimidazol, oder 1,2-Oxazoliumverbindungen wie 2-Ethyl-5- phenyl-l,2-oxazolium-3 -sulfat oder 2-tert.-Butyl-5-methyl-isoxazolium-perchlorat, oder Acylamino Verbindungen wie 2-Ethoxy-l-ethoxycarbonyl-l,2-dihydrochinolin, oder Propanphosphonsäureanhydrid, oder Isobutylchloroformat, oder Bis-(2-oxo-3- oxazolidinyl)-phosphorylchlorid oder 1 -Benzotriazolyloxytripyrrolidinphosphonium- hexafluorophosphat (PyBOP) oder O-(Benzotriazol-l-yl)-N,N,N',N'-tetra-methyluro- niumhexafluorophosphat (HBTU), 2-(2-Oxo- 1 -(2H)-pyridyl)- 1 , 1 ,3 ,3 -tetramethyl- uroniumtetrafluoroborat (TPTU) oder O-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetra- methyluroniumhexafluorophosphat (HATU), oder l-Hydroxybenztriazol (HOBt), oder Benzotriazol- 1 -yloxy ris(dimethylamino)-phosphonium exafluoro-phosphat (BOP), oder Mischungen aus diesen.Diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), 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 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 1- Benzotriazolyloxytripyrrolidinphosphonium hexafluorophosphate (PyBOP) or O- (Benzotriazol-l-yl) -N, N, N ', N'-tetra-methyluro- nium hexafluorophosphate (HBTU), 2- (2-oxo-1 - (2H) -pyridyl) - 1, 1, 3, 3 -tetramethyl-uronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-l-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), or l-hydroxybenzetriazole (HOBt), or benzotriazole-1-yloxy ris (dimethylamino) phosphonium exafluorophosphate (BOP), or mixtures of these.
Basen sind beispielsweise Alkalicarbonate, wie z.B. Natrium- oder Kaliumcarbonat, oder -hydrogencarbonat, oder organische Basen wie Trialkylamine z.B. Triethylamin, N-Methylmorpholin, N-Methylpiperidin, 4-Dimethylaminopyridin oder Diisopropyl- ethylamin.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.
Besonders bevorzugt ist die Kombination von N-(3-Dimethylaminoisopropyl)-N'- ethylcarbodiimid-Hydrochlorid (EDC), l-Hydroxybenztriazol (HOBt) und Triethylamin in Dimethylformamid oder HATU und Diisopropylethylamin in Dimethyl- formamid oder 1-Benzotriazolyloxytripyrrolidinphosphonium-hexafluoro-phosphatThe combination of 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
(PyBOP) und Diisopropylethylamin in Dimethylformamid.(PyBOP) and diisopropylethylamine in dimethylformamide.
Die Amine (III) sind bekannt oder können nach literaturbekannten Methoden hergestellt werden.The amines (III) are known or can be prepared by methods known from the literature.
Ein Verfahren zur Synthese der Verbindungen der Formel (II) befinden sich im Teil A. Beispiele (siehe allgemeine Arbeitsvorschriften 1 bis 6).A process for the synthesis of the compounds of the formula (II) can be found in part A. Examples (see general working instructions 1 to 6).
Der Herstellungsweg soll durch folgendes Schema 1 beispielhaft erläutert werden:
Figure imgf000023_0001
The production route is to be explained using the following scheme 1 as an example:
Figure imgf000023_0001
H2N— R° (VI)H 2 N - R ° (VI)
Figure imgf000023_0002
Figure imgf000023_0002
(II)(II)
(IV)(IV)
Figure imgf000023_0003
Figure imgf000023_0003
(I)(I)
Schema 1 Die erfindungsgemäßen Verbindungen zeigen ein nicht vorhersehbares, wertvolles pharmakologisches und pharmakokinetisches Wirkspektrum. Sie eignen sich daher zur Verwendung als Arzneimittel zur Behandlung und/oder Prophylaxe von Krankheiten bei Menschen und Tieren.Scheme 1 The compounds according to the invention show an unforeseeable, valuable pharmacological and pharmacokinetic spectrum of action. They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.
Besonders wirksam sind die erfindungsgemäßen Verbindungen gegen Bakterien und bakterienähnliche Mikroorganismen, insbesondere Gram-positive Bakterien. Sie sind daher besonders gut zur Prophylaxe und Chemotherapie von lokalen und gegebenenfalls systemischen Infektionen in der Human- und Tiermedizin geeignet, die durch diese Erreger hervorgerufen werden.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.
Beispielsweise können lokale und/oder systemische Erkrankungen behandelt und/oder verhindert werden, die durch die folgenden Erreger oder durch Mischungen der folgenden Erreger verursacht werden: Gram-positive Kokken, z.B. Staphylokokken (Staph. aureus, Staph. epidermidis) undFor example, 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
Streptokokken (Strept. agalactiae, Strept. faecalis, Strept. pneumoniae, Strept. pyogenes) sowie strikt anaerobe Bakterien wie z.B. Clostridium, ferner Mykoplasmen (M. pneumoniae, M. hominis, M. urealyticum).Streptococci (Strept.agalactiae, Strept.faecalis, Strept.pneumoniae, Strept.pyogenes) and strictly anaerobic bacteria such as Clostridium, also mycoplasma (M. pneumoniae, M. hominis, M. urealyticum).
Die obige Aufzählung von Erregern ist lediglich beispielhaft und keineswegs beschränkend aufzufassen. Als Krankheiten, die durch die genannten Erreger oder Mischinfektionen verursacht und durch die erfindungsgemäßen Verbindungen verhindert, gebessert oder geheilt werden können, seien beispielsweise genannt: Infektionskrankheiten beim Menschen wie z. B. septische Infektionen, Knochen- und Gelenkinfektionen, Hautinfektionen, postoperative Wundinfektionen, Abszesse,The above list of pathogens is only an example and is in no way to be interpreted as limiting. Examples of 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,
Phlegmone, Wundinfektionen, infizierte Verbrennungen, Brandwunden, Infektionen im Mundbereich, Infektionen nach Zahnoperationen, septische Arthritis, Mastitis, Tonsillitis, Genital-Infektionen und Augeninfektionen.Phlegmon, wound infections, infected burns, burns, mouth infections, infections after dental surgery, septic arthritis, mastitis, tonsillitis, genital infections and eye infections.
Außer beim Menschen können bakterielle Infektionen auch bei anderen Spezies behandelt werden. Beispielhaft seien genannt: Schwein: Sepsis, Metritis-Mastitis-Agalaktiae-Syndrom, Mastitis; Wiederkäuer (Rind, Schaf, Ziege): Sepsis, Bronchopneumonie, Mykoplasmose, Genitalinfektionen;In addition to humans, 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;
Pferd: Bronchopneumonien, puerperale und postpuerperale Infektionen; Hund und Katze: Bronchopneumonie, Dermatitis, Otitis, Harnwegsinfekte,Horse: bronchopneumonia, puerperal and post-puerperal infections; Dog and cat: bronchopneumonia, dermatitis, otitis, urinary tract infections,
Prostatitis;prostatitis;
Geflügel (Huhn, Pute, Wachtel, Taube, Ziervögel und andere): Mycoplasmose, chronische Luftwegserkrankungen, Psittakose.Poultry (chicken, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, chronic respiratory diseases, psittacosis.
Ebenso können bakterielle Erkrankungen bei der Aufzucht und Haltung von Nutz- und Zierfischen behandelt werden, wobei sich das antibakterielle Spektrum über die vorher genannten Erreger hinaus auf weitere Erreger wie z.B. Brucella, Campylobacter, Listeria, Erysipelothris, Nocardia erweitert.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.
A. Bewertung der pharmakologischen WirksamkeitA. Assessment of pharmacological effectiveness
in viVro-Wirkungwith viVro effect
Die in vitro- Wirkung der erfindungsgemäßen Verbindungen kann in folgenden Assays gezeigt werden:The in vitro activity of the compounds according to the invention can be shown in the following assays:
Klonierung, Expression und Reinigung von Pol III aus S. aureusCloning, expression and purification of Pol III from S. aureus
Zur Klonierung von polC mit einem N-terminalem His-Tag wird das Strukturgen polC mit Hilfe der PCR aus genomischer DNA von S. aureus amplifiziert. Mit Hilfe der Primer SAPoBl 5'-GCGCCATATGGACAGAGCAACAAAAATTTAA-3' und SAPolrev 5'-GCGCGGATCCTTACATATCAAATATCGAAA-3' werden die Restriktionsschnittstellen Ndel und BamHI vor bzw. hinter dem amplifizierten Gen eingeführt. Nachdem das 4300 bp große PCR-Produkt mit Ndel und BamHI verdaut worden ist, wird es in den ebenfalls mit Ndel und BamHI verdauten Vektor pET15b (Novagen, USA) ligiert und in E. coli XL-1 Blue transformiert. Nach Transformation in E. coli BL21(DE3) werden die Zellen zur Expression von PolC bei 30°C in LB-Medium mit 100 μg/ml Ampicillin bis zu einer OD595nm von 0,5 kultiviert, auf 18°C abgekühlt und nach Zusatz von 1 mM IPTG 20 Stunden weiter inkubiert. Die Zellen werden durch Zentrifugation geerntet, einmal in PBS mit 1 mM PMSF gewaschen und in 50 mM NaH2PO4 pH 8,0, 10 mM Imidazol, 2 mM ß-Mercaptoethanol, 1 mM PMSF, 20 % Glycerin aufgenommen. Die Zellen werden mit Hilfe einer French Press bei 12.000 psi aufgeschlossen, die Zelltrümmer abzentri- fugiert (27.000xg, 120 min, 4°C) und der Überstand mit einer entsprechenden Menge Ni-NTA-Agarose (Fa. Quiagen, Deutschland) 1 Stunde bei 4°C gerührt. Nach dem Einfüllen in eine Säule wird die Gelmatrix mit 50 mM NaH2PO pH 8,0, 2 mM ß-Mercaptoethanol, 20 mM Imidazol, 10 % Glycerin gewaschen und das gereinigte Protein wird anschließend mit demselbem Puffer, welcher 100 mM Imidazol enthält, eluiert. Das gereinigte Protein wird mit 50 % Glycerin versetzt und bei -20°C gelagert.To clone polC with an N-terminal His tag, the structural gene polC is amplified with the help of PCR from genomic DNA from S. aureus. With the help of 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. 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. After transformation in E. coli BL21 (DE3), the cells for expression of PolC are cultivated at 30 ° C. in LB medium with 100 μg / 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 β-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. After filling into a column, the gel matrix is washed with 50 mM NaH 2 PO pH 8.0, 2 mM β-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.
Inhibitions AssayInhibition assay
Die Aktivität von PolC wird in einer enzymatisch gekoppelten Reaktion gemessen, wobei das während der Polymerisation gebildete Pyrophosphat mit Hilfe der ATP- Sulfurylsae in ATP umgewandelt wird, welches mit Hilfe der Firefly-Luciferase de- tektiert wird. Der Reaktionsansatz enthält in einem Endvolumen von 50 μl 50 mMThe 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 μl
Tris/Cl pH 7,5; 5 mM DTT, 10 mM MgCl2, 30 mM NaCl, 0,1 mg/ml BSA, 10 % Glycerol, je 20 μM dATP, dTTP, dCTP, 2U/ml aktivierte Kalbsthymus-DNA (Fa. Worthington, USA), 20 μM APS und 0,06 mM Luciferin. Die Reaktion wird durch Zusatz von gereinigter PolC in einer Endkonzentration von ~2 nM, gestartet und 30 min bei 30°C inkubiert. Die Menge an gebildetem Pyrophosphat wird anschließend durch Zugabe von ATP-Sulfurylase (Sigma, USA) in einer Endkonzentration von 5 nM und Inkubation bei 30°C für 15 min in ATP umgewandelt. Nach Zugabe von 0,2 nM Firefly-Luciferase wird die Lumineszenz in einem Luminometer für 60 s gemessen. Als IC50 wird die Konzentration eines Inhibitors angegeben, die zu einer 50%igen Inhibition der Enzymaktivität von PolC führt. Tabelle ATris / Cl pH 7.5; 5 mM DTT, 10 mM MgCl 2 , 30 mM NaCl, 0.1 mg / ml BSA, 10% glycerol, each 20 μM dATP, dTTP, dCTP, 2U / ml activated calf thymus DNA (Worthington, USA), 20 µM APS and 0.06 mM luciferin. 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
Figure imgf000027_0001
Figure imgf000027_0001
in v vo- Wirkungin vo effect
Die Eignung der erfindungsgemäßen Verbindungen zur Behandlung bakterieller Infektionen kann in folgenden Tiermodellen gezeigt werden:The suitability of the compounds according to the invention for the treatment of bacterial infections can be shown in the following animal models:
Bestimmung der minimalen Hemmkonzentrationen (MHK) gegenüber einer Reihe von KeimenDetermination of the minimum inhibitory concentrations (MIC) against a number of germs
Die MHK- Werte gegen verschiedene Bakterienstämme (S. aureus, S. pneumoniae, E. faecalis) werden unter Verwendung der Mikrodilutionsmethode in BHI-Bouillon durchgeführt. Die Bakterienstämme werden über Nacht in BHI-Bouillon (Staphylokokken) bzw. BHI-Bouillon + 10% Rinderserum (Streptokokken, Enterokokken) angezüchtet. Die Testsubstanzen werden in einem Konzentrationsbereich von 0,5 bis 256 μg/ml geprüft. Nach serieller Verdünnung der Testsubstanzen werden die Microtiterplatten mit den Testkeimen beimpft. Die Keimkonzentration liegt bei ca. lxl 06 Keimen/ml Suspension. Die Platten werden bei 37°C unter 8 % CO2 (für Streptokokken, Enterokokken) für 20 h inkubiert. Als MHK- Wert wird die niedrigste Konzentration protokolliert, bei der das sichtbare Wachstum der Bakterien vollständig inhibiert wird. Systemische Infektion mit S. ureus 133The MIC values against various bacterial strains (S. aureus, S. pneumoniae, E. faecalis) 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 μg / ml. After serial dilution of the test substances, the microtiter plates are inoculated with the test germs. The germ concentration is about lxl 0 6 germs / ml of 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. Systemic infection with S. ureus 133
S.aureus 133 Zellen werden über Nacht in BH-Bouillon angezüchtet. Die Übernacht- kultur wird 1:100 in frische BH-Bouillon verdünnt und für 3 Stunden hochgedreht. Die in der logarithmischen Wachstumsphase befindlichen Bakterien werden abzentrifugiert und 2 x mit gepufferter, physiologischer Kochsalzlösung (303) gewaschen. Danach wird am Photometer (Modell LP 2W, Fa. Dr. Lange, Deutschland) eine Zellsuspension mit einer Extinktion von 50 Einheiten in 303 eingestellt. Nach einem Verdünnungsschritt (1 :15) wird diese Suspension 1 :1 mit einer 10 % igen Mucinsuspension gemischt. Von dieser Infektionslösung werden 0,25 ml/20 g Maus ip appliziert. Dies entspricht einer Zellzahl von etwa 1 x 10E6 Keimen/Maus. Die ip- Therapie erfolgt 30 Minuten nach der Infektion. Für den Infektionsversuch werden weibliche CFW1 -Mäuse verwendet. Das Überleben der Tiere wird über 6 Tage protokolliert.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.
B. BeispieleB. Examples
Abkürzungen:Abbreviations:
aq. wässrigaq. watery
Bn BenzylBn benzyl
DIPEA Diisopropylamin (Hünig Base)DIPEA Diisopropylamine (Hünig Base)
DMSO DimethylsulfoxidDMSO dimethyl sulfoxide
DMF Dimethylformamid d. Th. der Theorie eq. ÄquivalentDMF dimethylformamide d. Th. Of theory eq. equivalent to
ESI Elektrospray-Ionisation (bei MS) in vacuo im VakuumESI electrospray ionization (for MS) in vacuo in a vacuum
HATU O-(7-Azabenzotriazol- 1 -yl)-N, N, N', N -tetramethyluronium-HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N -tetramethyluronium-
Hexafluorphosphat h StundeHexafluorophosphate h hour
HPLC Hochdruck-, Hochleistungsflüssigchromatographie LC-MS Flüssigchromatographie-gekoppelte MassenspektroskopieHPLC high pressure, high performance liquid chromatography LC-MS liquid chromatography-coupled mass spectroscopy
MeCN AcetonitrilMeCN acetonitrile
MS MassenspektroskopieMS mass spectroscopy
NMR KemresonanzspektroskopieNMR nuclear magnetic resonance spectroscopy
Pd/C Palladium/KohlePd / C palladium / carbon
PS-Trisamin-Harz N-[2-Amino-N',N'-bis(2-aminoethyl)-ethyl]aminopolystyrolPS trisamine resin N- [2-amino-N ', N'-bis (2-aminoethyl) ethyl] aminopolystyrene
PyBOP Benzotriazol- 1 -yl-oxy-tris-pyrrolidino-phosphonium-PyBOP Benzotriazol- 1 -yl-oxy-tris-pyrrolidino-phosphonium-
Hexafluorophosphathexafluorophosphate
RP-HPLC Reverse Phase HPLCRP-HPLC reverse phase HPLC
RT RaumtemperaturRT room temperature
Rt Retentionszeit (bei HPLC) Rt retention time (with HPLC)
HPLC- und LC-MS-Methoden:HPLC and LC-MS methods:
Methode 1:Method 1:
Figure imgf000030_0001
Methode 2:
Figure imgf000030_0001
Method 2:
Figure imgf000031_0001
Figure imgf000031_0001
Methode 3:Method 3:
Figure imgf000032_0001
Figure imgf000032_0001
Allgemeine Synthesevorschriften:General synthesis instructions:
Allgemeine Arbeitsvorschrift 1:General working instructions 1:
Amidkupplungamide coupling
Die Darstellung von Aminocarbonyl-substituierten Phenylaminouracilen (I) erfolgt ausgehend von Carboxy-substituierten Phenylaminouracilen (II) durch Amidbildung:
Figure imgf000033_0001
Aminocarbonyl-substituted phenylaminouracils (I) are prepared starting from carboxy-substituted phenylaminouracils (II) by amide formation:
Figure imgf000033_0001
(II) (III) (I)(II) (III) (I)
Die Carbonsäure (0,10 mmol), das Amin (0,11 mmol) und PyBOP (0,11 mmol) werden in trockenem DMF (3 mL) unter Argonatmosphäre aufgelöst und gerührt, wäh- rend Hünigs Base (DIPEA; 0,2 mmol) tropfenweise zugegeben wird. Die Reaktion wird für 12 Stunden gerührt und das Lösungsmittel wird in vacuo entfernt. Der Rückstand wird mit präparativer HPLC (Standardprogramm, Gradient von 10 % bis 90 % MeCN in Wasser) gereinigt. Die Produkte werden nach Entfernung des Lösungsmittels in vacuo als Öle, Gläser oder Schäume in Ausbeuten von 5 bis 90 % er- halten.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. 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%.
Allgemeine Arbeitsvorschrift 2:General working instruction 2:
Hydrolyse von Estern des Typs IVHydrolysis of Type IV Esters
Die Carboxy-substituierten Phenylaminouracile (II) werden aus den entsprechendenThe carboxy-substituted phenylaminouracile (II) are derived from the corresponding
Alkoxycarbonyl-substituierten Phenylaminouracilen (IV) durch Hydrolyse dargestellt:Alkoxycarbonyl-substituted phenylaminouracils (IV) represented by hydrolysis:
Figure imgf000033_0002
Figure imgf000033_0002
Der entsprechende Ester IV (10 mmol) wird in 4N-Natiumhydroxydlösung unterThe corresponding ester IV (10 mmol) is in 4N sodium hydroxide solution
Argon bei Raumtemperatur aufgelöst, und bis zur vollständigen Umsetzung laut Dünnschichtchromatographie oder HPLC gerührt, im Normalfall zwischen einer halben und zwei Stunden. Die resultierende klare Lösung wird mit konzentrierter Salz- säure bis zum pH 3 angesäuert, wobei gekühlt wird, sodass die Temperatur nicht über 30°C steigt. Die Lösung wird für eine Stunde auf 0° abgekühlt und der resultierende Niederschlag wird abfiltriert, mit kaltem Wasser gewaschen und im Vakuum bei 50°C getrocknet, um die resultierende Carbonsäure II als weißes Pulver in Ausbeuten zwischen 60 und 100 % zu erhalten.Dissolved argon at room temperature and stirred until complete reaction according to thin layer chromatography or HPLC, normally between half an hour and two hours. The resulting clear solution is washed with concentrated salt acidified to pH 3, 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%.
Allgemeine Arbeitsvorschrift 3:General working instruction 3:
Alkoxycarbonyl-substituierte Phenylamino-Uracile (IV)Alkoxycarbonyl-substituted phenylamino-uracils (IV)
Ausgehend von 3-Alkoxycarbonyl-substituierten 6-Chlor-2,4-(lH,3H)-Pyrimid- indionen (V):Starting from 3-alkoxycarbonyl-substituted 6-chloro-2,4- (1H, 3H) -pyrimide indions (V):
Figure imgf000034_0001
Figure imgf000034_0001
(V) (VI) (IV)(V) (VI) (IV)
Eine Mischung aus 3-substituiertem 6-Chlor-2,4-(lH,3H)-Pyrimidindion (V) (1.0 eq.) und Anilin-Derivat (VI) (1.5 bis 2.5 eq) wird, gegebenenfalls unter Zusatz einer tertiären Aminbase (ca. 2.0 eq.), in einem hochsiedenden Lösungsmittel (z.B.: 1,4-Dioxan, Diglyme oder 1-Methylpyrrolidinon) 1 h bis 36 h bei 100 bis 150°C gerührt, bevor nach wässriger Aufarbeitung im Vakuum konzentriert wird. Das Rohprodukt kann durch Chromatographie an Silicagel (Eluenten: Gemische von Dichlor- methan und Methanol) oder durch präparative RP-ΗPLC gereinigt werden.A mixture of 3-substituted 6-chloro-2,4- (1H, 3H) -pyrimidinedione (V) (1.0 eq.) And aniline derivative (VI) (1.5 to 2.5 eq) is added, optionally with the addition of a tertiary amine base (approx. 2.0 eq.), in a high-boiling solvent (for example: 1,4-dioxane, diglyme or 1-methylpyrrolidinone), stirred at 100 to 150 ° C. for 1 h to 36 h before being concentrated in vacuo after aqueous work-up. The crude product can be purified by chromatography on silica gel (eluent: mixtures of dichloromethane and methanol) or by preparative RP-ΗPLC.
Allgemeine Arbeitsvorschrift 4:General working instruction 4:
6-Chloruracile6-Chloruracile
Die entsprechenden 3 -substituierten 6-Chlor-2,4-(lH,3H)-Pyrimidindionen (V) (6-The corresponding 3-substituted 6-chloro-2,4- (1H, 3H) -pyrimidinediones (V) (6-
Chloruracile) lassen sich folgendermaßen herstellen:
Figure imgf000035_0001
Chloruracile) can be prepared as follows:
Figure imgf000035_0001
(VIII) (V)(VIII) (V)
Eine Mischung aus 1 -substituiertem 2,4,6(lH,3H,5H)-Pyrimidintrion (1.0 eq.), Benzyltriethylammomumchlorid (ca. 2.0 eq.) und Phosphoroxychiorid (ca. 8 bis 12.0 eq.) wird unter Inertgas 2 bis 4 h auf 50-60°C erhitzt. Nach Abkühlen wird dasA mixture of 1 -substituted 2,4,6 (1H, 3H, 5H) -pyrimidine trione (1.0 eq.), Benzyltriethylammomum chloride (approx. 2.0 eq.) And phosphorus oxychloride (approx. 8 to 12.0 eq.) Is 2 to Heated to 50-60 ° C for 4 h. After cooling it will
Reaktionsgemisch auf Eiswasser gegeben und vorsichtig mit konzentrierter Natronlauge (alternativ mit konzentrierter Ammoniak-Lösung) auf neutral eingestellt (pΗ- Papier). Das Gemisch wird gründlich mit Dichlormethan extrahiert. Die organischen Phasen werden vereinigt, getrocknet und im Vakuum konzentriert. Gegebenenfalls kann entweder eine Reinigung des Produkts durch Chromatographie an SilicagelPour the reaction mixture onto ice water and carefully adjust it to neutral with concentrated sodium hydroxide solution (alternatively with concentrated ammonia solution) (pΗ paper). The mixture is extracted thoroughly with dichloromethane. The organic phases are combined, dried and concentrated in vacuo. If necessary, either purification of the product by chromatography on silica gel
(Eluenten: Gemische von Dichlormethan und Methanol oder Essigester und Ethanol) oder durch Kristallisation aus Dichlormethan erfolgen.(Eluents: mixtures of dichloromethane and methanol or ethyl acetate and ethanol) or by crystallization from dichloromethane.
Alternativ lassen sich 3 -substituierte 6-Chlor-2,4-(lH,3H)-Pyrimidindione (V) gemäß Literaturvorschriften auch durch Reaktion mit Phenylphosphoroxychlorid (J Hetero- cyclic Chem., 1985, 22, 873) oder durch Phosphoroxychiorid in Gegenwart geringer Mengen Wasser (J. Am. Chem. Soc, 1980, 102, 5036; Tetrahedron Asymmetrie, 1997, 8, 2319) aus den entsprechenden 1 -substituierten 2,4,6(1H,3H,5H)-Pyrimid- intrionen darstellen.Alternatively, 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 ,
Allgemeine Arbeitsvorschrift 5:General working instruction 5:
Die Darstellung der 1 -substituierten 2,4,6(1 H,3H,5H)-Pyrimidintrione (VIII) ausgehend von Harnstoffen (IX) kann auf verschiedenen Wegen (Methoden [5A] und [5B]) geschehen:
Figure imgf000036_0001
The representation of the 1 -substituted 2,4,6 (1 H, 3H, 5H) -pyrimidintrione (VIII) starting from urea (IX) can be done in different ways (methods [5A] and [5B]):
Figure imgf000036_0001
(IX) (VIII)(IX) (VIII)
[5 A] Basische Reaktionsführung mit Ethanolat und Malonsäurediester.[5 A] Basic reaction with ethanolate and malonic acid diester.
Zu einer aus Natrium und absolutem Ethanol frisch bereiteten Lösung (1.0 bisTo a solution freshly prepared from sodium and absolute ethanol (1.0 to
1.8 mol 1) von Natriumethanolat (1.8 bis 2.5 eq.) in Ethanol werden unter Inertgas Harnstoff-Derivat (1.0 eq.) und Malonsäurediethylester (1.0 bis 1.2 eq) hinzugefügt. Die Mischung wird ca. 4 bis 8 h unter Rückfluss erhitzt und nach dem Erkalten mit Salzsäure auf ca. pH = 1 gestellt. Im Vakuum werden alle flüchtigen Komponenten entfernt. Der Rückstand wird in Dichlormethan aufgenommen und mit Wasser gewaschen. Die organische Phase wird getrocknet und im Vakuum zur Trockne eingeengt. Gegebenenfalls kann eine Reinigung des Produkts durch Chromatographie an Silicagel (Eluent: Gemische von Dichlormethan und Methanol unter Zusatz von Essigsäure) erfolgen.1.8 mol 1) of sodium ethanolate (1.8 to 2.5 eq.) In ethanol are added under an inert gas to urea derivative (1.0 eq.) And malonic acid diethyl ester (1.0 to 1.2 eq). The mixture is heated under reflux for about 4 to 8 h and, after cooling, is adjusted to about pH = 1 with hydrochloric acid. All volatile components are removed in a vacuum. The residue is taken up in dichloromethane and washed with water. The organic phase is dried and evaporated to dryness in vacuo. If necessary, the product can be purified by chromatography on silica gel (eluent: mixtures of dichloromethane and methanol with the addition of acetic acid).
[5B] Saure Reaktionsführung mit Acetanhydrid und Malonsäure (J. Heterocyclic Chem., 1985, 22, 873):[5B] Acidic reaction with acetic anhydride and malonic acid (J. Heterocyclic Chem., 1985, 22, 873):
Zu einer Lösung von entsprechendem Harnstoff-Derivat (IX) (1.0 eq.) und Malon- säure (1.3 bis 1.8 eq) in Eisessig (ca. 1 bis 3 mol/1) wird unter Inertgas bei ca. 60°CA solution of the corresponding urea derivative (IX) (1.0 eq.) And malonic acid (1.3 to 1.8 eq) in glacial acetic acid (approx. 1 to 3 mol / 1) is added under inert gas at approx. 60 ° C
Essigsäureanhydrid (ca. 3.0 eq.) hinzugefügt. Nach Ende der Zugabe wird die Temperatur erhöht und die Mischung 4-8 h bei ca. 90°C gerührt. Nach Abkühlen werden die flüchtigen Bestandteile der Reaktionsmischung im Vakuum entfernt. Aus dem Rückstand kann durch Umkristallisieren (gegebenenfalls wiederholt) aus alkoho- lischen Lösungsmitteln (z.B. Ethanol) das Produkt isoliert werden. Alternativ kann das Produkt durch RP-HPLC aus dem Eindampfrückstand gewonnen werden. Allgemeine Arbeitsvorschrift 6:Acetic anhydride (approx. 3.0 eq.) Added. After the addition has ended, the temperature is raised and the mixture is stirred at about 90 ° C. for 4-8 h. After cooling, the volatile constituents of the reaction mixture are removed in vacuo. The product can be isolated from the residue by recrystallization (if necessary repeatedly) from alcoholic solvents (eg ethanol). Alternatively, the product can be obtained from the evaporation residue by RP-HPLC. General working instruction 6:
Darstellung von Harnstoffen (LX) ausgehend von Ammoniumhydrochloriden (X)Presentation of urea (LX) starting from ammonium hydrochloride (X)
Figure imgf000037_0001
Figure imgf000037_0001
(X) (IX)(X) (IX)
Zu einer Mischung von primärem Amin in Wasser (ca. 0.5 bis 2.0 mol/1) wird unter Eiskühlung konz. Salzsäure bis zur leicht sauren Reaktion eingetragen. Alternativ kann auch direkt das Hydrochlorid des primären Amins verwendet und in Wasser ge- löst werden (0.5 bis 2.0 mol/1). Zur Lösung werden bei Raumtemperatur Kaliumoder Natriumcyanat (1.0 bis 1.25 eq.) gegeben und die Lösung wird für 2.0 bis 6.0 h auf Rückfluss erhitzt. Nach Erkalten setzt zumeist direkt und oder nach Einengen Ausfall von Feststoff ein. Der Feststoff wird durch Filtration gewonnen, es wird nachgewaschen mit Wasser und gründlich im Vakuum getrocknet. Alternativ kann nach Entfernen des Wassers im Vakuum und Aufnahme des Rückstands mit Ethanol in der Hitze abfiltriert werden; aus dem Rückstand des Filtrats kann dann durch Chromatographie an Silicagel (typischerweise mit Lösungsmittelgemischen wie Toluol/Methanol oder Dichlormethan/ Methanol) das Produkt in reiner Form erhalten werden. Concentrated to a mixture of primary amine in water (about 0.5 to 2.0 mol / 1) with ice cooling. Hydrochloric acid entered until the reaction is slightly acidic. Alternatively, the hydrochloride of the primary amine can be used directly and dissolved in water (0.5 to 2.0 mol / 1). Potassium or sodium cyanate (1.0 to 1.25 eq.) Are added to the solution at room temperature and the solution is heated to reflux for 2.0 to 6.0 h. After cooling, it usually begins immediately or after the solid has failed. The solid is obtained by filtration, it is washed with water and dried thoroughly in vacuo. Alternatively, after removing the water in vacuo and taking up the residue, filter with ethanol while hot; 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).
Ausgangsverbindungen:Starting Compounds:
Beispiel IExample I
(4-Chlor-2,6-dioxo-3 ,6-dihydro- 1 (2H)-pyrimidinyl)essigsäureethylester(4-Chloro-2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl) ethyl acetate
Figure imgf000038_0001
Figure imgf000038_0001
1.5 g (7 mmol) (2,4,6-Trioxotetrahydro-l(2H)-pyrimidinyl)essigsäureethylester werden mit 1.19 ml (8.41 mmol) Phenylphosphoroxychlorid versetzt und 20 Minuten bei 150 °C gerührt.1.5 g (7 mmol) (2,4,6-trioxotetrahydro-l (2H) -pyrimidinyl) ethyl acetate are mixed with 1.19 ml (8.41 mmol) phenylphosphorus oxychloride and stirred at 150 ° C for 20 minutes.
Die Reaktionslösung wird auf 10 g Eis gegeben und mit Ammoniak neutralisiert. Man extrahiert zweimal mit Dichlormethan, trocknet über Natriumsulfat und engt im Vakuum ein. Es wird über Kieselgel 60 gereinigt (Laufmittel: Ethylacetat). Ausbeute: 79% d. Th.The 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.
Η-NMR (300MHz, DMSO-d6): δ = 1.2 (t, 3H), 4.13 (q, 2H), 4.48 (s, 2H), 6.0 (s,Η-NMR (300MHz, DMSO-d 6 ): δ = 1.2 (t, 3H), 4.13 (q, 2H), 4.48 (s, 2H), 6.0 (s,
1H), 12.63 (s, 1H).1H), 12.63 (s, 1H).
MS (Eι): m/z = 232 (M)+ MS (Eι): m / z = 232 (M) +
(vgl. Literatur: J.Heterocycl. Chem., 1985, 22, 873-878)(see literature: J. Heterocycl. Chem., 1985, 22, 873-878)
Beispiel IIExample II
4-(4-Chlor-2,6-dioxo-3 ,6-dihydro- 1 (2H)-pyrimidinyl)butansäureethylester4- (4-Chloro-2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl) butanoic acid ethyl ester
Figure imgf000038_0002
Die Darstellung erfolgt wie für Beispiel I beschrieben aus den entsprechenden Edukten.
Figure imgf000038_0002
The presentation is as described for Example I from the corresponding starting materials.
Beispiel III l-[(Benzyloxy)methyl]-6-chlor-2,4(lH,3H)-pyrimidindionExample III 1 - [(Benzyloxy) methyl] -6-chloro-2,4 (1H, 3H) pyrimidinedione
Figure imgf000039_0001
Figure imgf000039_0001
4.00 g (27.3 mmol) Chloruracil werden mit 100 ml wasserfreiem Dimethylformamid versetzt. Man kühlt auf 0°C und gibt vorsichtig 0.33 g (41.5 mmol) Lithiumhydrid hinzu (stark exotherm). Man rührt 10 Minuten nach. Dann werden 7.26 g Chlor- methylbenzylether in einem Zeitraum von 10 Minuten langsam zugetropft. Man rührt 90 Minuten bei 0°C nach. Die Reaktionslösung wird mit 200 ml 2%iger Natriumhydroxidlösung verdünnt und mit 250 ml Toluol extrahiert. Die organische Phase wird noch einmal mit 100 ml 2%iger Natriumhydroxidlösung gewaschen. Die vereinigte wässrige Phase wird mit 1 N Schwefelsäure auf pH 3 gestellt. Der entstehende Niederschlag wird filtriert und getrocknet. Man erhält 3.6 g (49% d. Th.) Produkt.4.00 g (27.3 mmol) of chlorouracil are mixed with 100 ml of anhydrous dimethylformamide. It is cooled to 0 ° C. and 0.33 g (41.5 mmol) of lithium hydride is carefully added (strongly exothermic). Stir for 10 minutes. Then 7.26 g of chloromethylbenzyl ether are slowly added dropwise over a period of 10 minutes. The mixture is stirred at 0 ° C for 90 minutes. The reaction solution is diluted with 200 ml of 2% sodium hydroxide solution and extracted with 250 ml of toluene. The organic phase is washed once more with 100 ml of 2% sodium hydroxide solution. The combined aqueous phase is adjusted to pH 3 with 1 N sulfuric acid. The resulting precipitate is filtered and dried. 3.6 g (49% of theory) of product are obtained.
1H-NMR (200 MHz, CDC13): δ = 4.69 (s, 2H), 5.54 (s, 2H), 5.87 (s, 1H), 7.35 (m, 5H), 8.45 (s, 1H). Beispiel IV1H-NMR (200 MHz, CDC1 3 ): δ = 4.69 (s, 2H), 5.54 (s, 2H), 5.87 (s, 1H), 7.35 (m, 5H), 8.45 (s, 1H). Example IV
5-[3-[(Benzyloxy)methyl]-4-chlor-2,6-dioxo-3,6-dihydro-l(2H)-pyrimidinyl]pentan- säureethylester5- [3 - [(Benzyloxy) methyl] -4-chloro-2,6-dioxo-3,6-dihydro-l (2H) -pyrimidinyl] ethyl pentanoate
Figure imgf000040_0001
Figure imgf000040_0001
1.33 g (5 mmol) der Verbindung aus Beispiel III werden in 50 ml Dimethylformamid gelöst. Man gibt 3.25 g (10 mmol) Cäsiumcarbonat hinzu und rührt 10 Minuten nach. Dann versetzt man mit 1.045 g (5 mmol) 5-Bromvaleriansäureethylester. Man rührt 3 Tage bei Raumtemperatur.1.33 g (5 mmol) of the compound from Example III are dissolved in 50 ml of dimethylformamide. 3.25 g (10 mmol) of cesium carbonate are added and stirring is continued for 10 minutes. Then 1,045 g (5 mmol) of 5-bromovaleric acid ethyl ester are added. The mixture is stirred for 3 days at room temperature.
Die Reaktionslösung wird im Vakuum eingeengt und der Rückstand in 50 ml Wasser aufgenommen. Es wird einmal mit 150 ml Ethylacetat extrahiert und über Natriumsulfat getrocknet.The 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.
Es wird über Kieselgel 60 gereinigt. (Laufmittel : Cyclohexan / Ethylacetat = 2:1).It is cleaned over silica gel 60. (Mobile phase: cyclohexane / ethyl acetate = 2: 1).
Man erhält 1.04 g (53% d. Th.) Produkt.1.04 g (53% of theory) of product are obtained.
1H-NMR (200 MHz, CDC13): δ = 1.24 (t, 3H), 1.63-1.66 (m, 4H), 2.33 (t, 2H), 3.871H-NMR (200 MHz, CDC1 3 ): δ = 1.24 (t, 3H), 1.63-1.66 (m, 4H), 2.33 (t, 2H), 3.87
(t, 2H), 4.11 (q, 2H), 4.69 (s, 2H), 5.56 (s, 2H), 5.88 (s, 1H), 7.32-7.33 (m, 5H).(t, 2H), 4.11 (q, 2H), 4.69 (s, 2H), 5.56 (s, 2H), 5.88 (s, 1H), 7.32-7.33 (m, 5H).
LCMS (Methode 1): Rt = 2.71 min MS (ESIpos): m z = 395 (M+H)+ Beispiel VLCMS (method 1): R t = 2.71 min MS (ESIpos): mz = 395 (M + H) + Example V
5-(4-Chlor-2,6-dioxo-3,6-dihydro-l(2H)-pyrimidinyl)pentansäureethylester5- (4-chloro-2,6-dioxo-3,6-dihydro-l (2H) -pyrimidinyl) pentanoate
Figure imgf000041_0001
Figure imgf000041_0001
0.99 g (2.5 mmol) der Verbindung aus Beispiel IV werden mit 19 ml (250 mmol) Trifluoressigsäure versetzt und 2 Stunden unter Rückfluss gerührt. Die Reaktionslösung wird im Vakuum eingeengt. Der Rückstand wird in 10 ml Methanol aufgenommen und erneut einrotiert. Der erhaltene Feststoff wird aus 10 ml Methanol umkristallisiert.0.99 g (2.5 mmol) of the compound from Example IV are mixed with 19 ml (250 mmol) of trifluoroacetic acid and stirred under reflux for 2 hours. The reaction solution is concentrated in vacuo. The residue is taken up in 10 ml of methanol and evaporated again. The solid obtained is recrystallized from 10 ml of methanol.
Man erhält 0.176 g (25% d. Th.) Produkt. LCMS (Methode 3): R, = 2.94 min MS (ESIneg): m/z = 273 (M-H)0.176 g (25% of theory) of product is obtained. LCMS (method 3): R, = 2.94 min MS (ESIneg): m / z = 273 (M-H)
Beispiel VIExample VI
4-[4-(2,3-Dihydro-lH-inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)-pyrimi- dinyljbutan-säureethylester4- [4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyljbutanoic acid ethyl ester
Figure imgf000041_0002
Figure imgf000041_0002
7.67 g (29.42 mmol) der Verbindung aus Beispiel II und 15.68 g (117.69 mmol) 5- Aminoindan werden zusammen auf 150°C erhitzt. Man rührt 40 min. nach. Die Reaktionslösung wird mit 5 ml Ethanol versetzt und über Nacht im Kühlschrank gelagert. Man engt im Vakuum ein. Der Rückstand wird über Kieselgel gereinigt (Laufmittel: Dichlormethan -> Dichlor- methan/Methanol 100:5). Man erhält 10 g (95% d. Th.) Produkt. 1H-NMR (300 MHz, DMSO-d6 ): δ = 1.17 (t, 3H), 1.75 (quintett, 2H), 2.02 (quintett,7.67 g (29.42 mmol) of the compound from Example II and 15.68 g (117.69 mmol) of 5-aminoindane are heated together to 150 ° C. The mixture is stirred for 40 min. to. The reaction solution is mixed with 5 ml of ethanol and stored in the refrigerator overnight. It is concentrated in a vacuum. The residue is purified on silica gel (mobile phase: dichloromethane -> dichloromethane / methanol 100: 5). 10 g (95% of theory) of product are obtained. 1H-NMR (300 MHz, DMSO-d 6 ): δ = 1.17 (t, 3H), 1.75 (quintet, 2H), 2.02 (quintet,
2H), 2.26 (t, 2H), 2.85 (q, 4H), 3.72 (t, 2H), 4.03 (q, 2H), 4.70 (s, IH), 6.95 (d, IH), 7.06 (s, IH), 7.22 (d, IH), 8.06 (s, IH), 10.34 (s, IH).2H), 2.26 (t, 2H), 2.85 (q, 4H), 3.72 (t, 2H), 4.03 (q, 2H), 4.70 (s, IH), 6.95 (d, IH), 7.06 (s, IH ), 7.22 (d, IH), 8.06 (s, IH), 10.34 (s, IH).
Beispiel VII [4-(2,3 -Dihydro- 1 H-inden-5-ylamino)-2,6-dioxo-3,6-dihydro- 1 (2H)-pyrimi- dinyljessigsäure-ethylesterExample VII [4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyljacetic acid, ethyl ester
Figure imgf000042_0001
Figure imgf000042_0001
Die Darstellung erfolgt wie für Beispiel VI aus 3.23 g (13.885 mmol) der Verbindung aus Beispiel I und 7.39 g (55.54 mmol) 5-Aminoindan.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.
Man erhält 2.37 g (51% d. Th.) Produkt.2.37 g (51% of theory) of product are obtained.
1H-NMR (200 MHz, DMSO-d6): δ = 1.19 (t, 3H), 2.02 (quintett, 2H), 2.85 (q, 4H), 4.11 (q, 2H), 4.42 (s, 2H), 4.73 (s, IH), 6.97 (d, IH), 7.09 (s, IH), 7.23 (d, IH), 8.24 (s, IH), 10.66 (s,lH).1H-NMR (200 MHz, DMSO-d 6 ): δ = 1.19 (t, 3H), 2.02 (quintet, 2H), 2.85 (q, 4H), 4.11 (q, 2H), 4.42 (s, 2H), 4.73 (s, IH), 6.97 (d, IH), 7.09 (s, IH), 7.23 (d, IH), 8.24 (s, IH), 10.66 (s, lH).
Beispiel VIIIExample VIII
4- [4- [(3 -Chlor-4-methylphenyl)amino]-2,6-dioxo-3 ,6-dihydro- 1 (2H)-pyrimi- dinyljbutansäure-ethylester 4- [4- [(3-Chloro-4-methylphenyl) amino] -2,6-dioxo-3, 6-dihydro-1 (2H) -pyrimidinyljbutanoic acid ethyl ester
Figure imgf000043_0001
Figure imgf000043_0001
Die Darstellung erfolgt wie für Beispiel VI aus 0.476 g (1.826 mmol) der Verbindung aus Beispiel II und 1.03 g (7.3 mmol) 3-Chlor-4-methylanilin. Man erhält 0.35 g (52% d. Th.) Produkt.The preparation is carried out as for example VI from 0.476 g (1.826 mmol) of the compound from example II and 1.03 g (7.3 mmol) of 3-chloro-4-methylaniline. 0.35 g (52% of theory) of product is obtained.
1H-NMR (300 MHz, DMSO-d6): δ = 1.17 (t, 3H), 1.76 (quintett, 2H), 2.24-2.31 (m,1H-NMR (300 MHz, DMSO-d 6 ): δ = 1.17 (t, 3H), 1.76 (quintet, 2H), 2.24-2.31 (m,
5H), 3.73 (t, 2H), 4.03 (q, 2H), 4.78 (s, IH), 7.08-7.35 (m, 3H), 8.31 (s, IH), 10.565H), 3.73 (t, 2H), 4.03 (q, 2H), 4.78 (s, IH), 7.08-7.35 (m, 3H), 8.31 (s, IH), 10.56
(s, IH).(s, IH).
LCMS (Methode 2): Rt = 3.63 min MS (ESIpos): m/z = 366 (M+H)+ LCMS (method 2): R t = 3.63 min MS (ESIpos): m / z = 366 (M + H) +
Beispiel IXExample IX
4-[4-[(3-Ethyl-4-methylphenyl)amino]-2,6-dioxo-3,6-dihydro-l(2H)-pyrimi- dinyljbutansäure-ethylester4- [4 - [(3-Ethyl-4-methylphenyl) amino] -2,6-dioxo-3,6-dihydro-l (2H) -pyrimidinyljbutanoic acid ethyl ester
Figure imgf000043_0002
Figure imgf000043_0002
Die Darstellung erfolgt wie für Beispiel VI aus 1.46 g (5.63 mmol) der Verbindung aus Beispiel II, 1.16 g (6.75 mmol) 3-Ethyl-4-methylanilin Hydrochlorid und 2.15 mlThe preparation is carried out as for example VI 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) N,N-Diisopropylethylamin. Man erhält 1.86 g (91% d. Th.) Produkt.(12.39 mmol) N, N-diisopropylethylamine. 1.86 g (91% of theory) of product are obtained.
1H-NMR (200 MHz, DMSO-d6): δ = 1.09-1.20 (m, 6H), 1.75 (quintett, 2H), 2.17-2.51H-NMR (200 MHz, DMSO-d 6 ): δ = 1.09-1.20 (m, 6H), 1.75 (quintet, 2H), 2.17-2.5
(m, 5H), 3.72 (t, 2H), 4.03 (q, 2H), 4.71 (s, IH), 6.97 (s, IH), 7.05 (dd, 2H), 8.10 (s,(m, 5H), 3.72 (t, 2H), 4.03 (q, 2H), 4.71 (s, IH), 6.97 (s, IH), 7.05 (dd, 2H), 8.10 (s,
IH), 10.4 (s, IH).IH), 10.4 (s, IH).
LCMS (Methode 3): R, = 3.69 min MS (ESIpos): m/z = 360 (M+H)+ Beispiel XLCMS (method 3): R, = 3.69 min MS (ESIpos): m / z = 360 (M + H) + Example X
5-[4-(2,3-Dihydro-lH-inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)-pyrimi- dinyljpentan-säureethylester5- [4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyljpentanoic acid ethyl ester
Figure imgf000044_0001
Figure imgf000044_0001
Die Darstellung erfolgt analog Beispiel VI. LCMS (Methode 2): Rt = 3.85 min MS (ESIpos): m/z = 372 (M+H)+ The presentation is analogous to Example VI. LCMS (method 2): R t = 3.85 min MS (ESIpos): m / z = 372 (M + H) +
Beispiel XIExample XI
4-[4-(2 ,3 -Dihydro- 1 H-inden-5-ylamino)-2,6-dioxo-3 ,6-dihydro- 1 (2H)-pyrimi- dinyljbutansäure4- [4- (2,3-dihydro-1 H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyljbutanoic acid
Figure imgf000044_0002
Figure imgf000044_0002
0.3 g (0.84 mmol) der Verbindung aus Beispiel VI werden mit 20 ml 2M Natrium- hydroxidlösung versetzt und 1,5 Stunden bei Raumtemperatur gerührt. Die Reaktionslösung wird filtriert. Das Filtrat wird mit konzentrierter Salzsäure auf pH 3-4 gestellt und im Kühlschrank abgekühlt. Der Niederschlag wird abfiltriert und mit Wasser nachgewaschen. Man trocknet im Hochvakuumofen bei 60°C. Man erhält 0.256 g (99% d. Th.) Produkt. 1H-NMR (300 MHz, DMSO-d6): δ = 1.72 (quintett, 2H), 2.02 (quintett, 2H), 2.19 (t,0.3 g (0.84 mmol) of the compound from Example VI are mixed with 20 ml of 2M sodium hydroxide solution and stirred at room temperature for 1.5 hours. The reaction solution is filtered. The filtrate is adjusted to pH 3-4 with concentrated hydrochloric acid and cooled in the refrigerator. The precipitate is filtered off and washed with water. It is dried in a high vacuum oven at 60 ° C. 0.256 g (99% of theory) of product is obtained. 1H-NMR (300 MHz, DMSO-d 6 ): δ = 1.72 (quintet, 2H), 2.02 (quintet, 2H), 2.19 (t,
2H), 2.84 (q, 4H), 3.72 (t, 2H), 4.72 (s, IH), 6.95 (d, IH), 7.06 (s, IH), 7.22 (d, IH), 8.43 (s, IH), 10.47 (s, IH), 12.0 (s, IH). LCMS (Methode 2): R, = 3.16 min MS (ESIpos): m/z = 330 (M+H)+ Beispiel XH2H), 2.84 (q, 4H), 3.72 (t, 2H), 4.72 (s, IH), 6.95 (d, IH), 7.06 (s, IH), 7.22 (d, IH), 8.43 (s, IH ), 10.47 (s, IH), 12.0 (s, IH). LCMS (method 2): R, = 3.16 min MS (ESIpos): m / z = 330 (M + H) + Example XH
[4-(2,3-Dihydro-lH-inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)-pyrimi- dinyl]essigsäure[4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl] acetic acid
Figure imgf000045_0001
Figure imgf000045_0001
Die Darstellung erfolgt wie für Beispiel XI aus 2.37 g (7.19 mmol) der Verbindung aus Beispiel VII.The preparation is carried out as for example XI from 2.37 g (7.19 mmol) of the compound from example VII.
Man erhält 1.71 g (78% d. Th.) Produkt. 1H-NMR (400 MHz, DMSO-d6): δ = 2.02 (quintett, 2H), 2.85 (q, 4H), 4.33 (s, 2H),1.71 g (78% of theory) of product are obtained. 1H-NMR (400 MHz, DMSO-d 6 ): δ = 2.02 (quintet, 2H), 2.85 (q, 4H), 4.33 (s, 2H),
4.72 (s, IH), 6.96 (d, IH), 7.09 (s, IH), 7.23 (d, IH), 8.26 (s, IH), 10.65 (s, IH),4.72 (s, IH), 6.96 (d, IH), 7.09 (s, IH), 7.23 (d, IH), 8.26 (s, IH), 10.65 (s, IH),
12.81 (s, IH).12.81 (s, IH).
LCMS (Methode 3): Rt = 3.06 minLCMS (method 3): R t = 3.06 min
MS (ESIpos): m/z = 302 (M+H)+ MS (ESIpos): m / z = 302 (M + H) +
Beispiel XIHExample XIH
4-[4-[(3-Chlor-4-ι nethylphenyl)amino]-2,6-dioxo-3,6-dihydro-l(2H)-pyrimi- dinyljbutansäure4- [4 - [(3-chloro-4-ι ethylphenyl) amino] -2,6-dioxo-3,6-dihydro-l (2H) -pyrimidinyljbutanoic acid
Figure imgf000045_0002
Figure imgf000045_0002
Die Darstellung erfolgt wie für Beispiel XI aus 10 g (27.33 mmol) der Verbindung aus Beispiel VUI .As for example XI, the preparation is carried out from 10 g (27.33 mmol) of the compound from example VUI.
Man erhält 6.26 g (67% d. Th.) Produkt.6.26 g (67% of theory) of product are obtained.
LCMS (Methode 2): Rt = 3.13 min MS (ESIpos): m/z = 338 (M+H)+ Beispiel XIVLCMS (method 2): R t = 3.13 min MS (ESIpos): m / z = 338 (M + H) + Example XIV
4-[4-[(3-Ethyl-4-methylphenyl)amino]-2,6-dioxo-3,6-dihydro-l(2H)-pyrimi- dinyl]butansäure4- [4 - [(3-Ethyl-4-methylphenyl) amino] -2,6-dioxo-3,6-dihydro-l (2H) pyrimidinyl] butanoic acid
Figure imgf000046_0001
Figure imgf000046_0001
Die Darstellung erfolgt wie für Beispiel XI aus 6.96 g (19.36 mmol) der Verbindung aus Beispiel IX.As for example XI, the preparation is carried out from 6.96 g (19.36 mmol) of the compound from example IX.
Man erhält 5.37 g (83% d. Th.) Produkt. LCMS (Methode 3): Rt = 3.23 min MS (ESIpos): m/z = 332 (M+H)+ 5.37 g (83% of theory) of product are obtained. LCMS (method 3): R t = 3.23 min MS (ESIpos): m / z = 332 (M + H) +
Beispiel XVExample XV
5-[4-(2,3-Dihydro-lH-inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)-pyrimi- dinyl]pentan-säure5- [4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl] pentanoic acid
Figure imgf000046_0002
Figure imgf000046_0002
545 mg (1.46 mmol) der Verbindung aus Beispiel X werden in 54 ml Methanol gelöst und mit 27 ml gesättigter Natriumcarbonatlösung versetzt. Man rührt 6 Stunden bei Raumtemperatur.545 mg (1.46 mmol) of the compound from Example X are dissolved in 54 ml of methanol and 27 ml of saturated sodium carbonate solution are added. The mixture is stirred for 6 hours at room temperature.
Methanol wird im Vakuum abdestilliert. Der Rückstand wird unter rühren, bei 0°C auf 85 ml 1 M Schwefelsäure gegeben. Der entstandene Niederschlag wird abgesaugt und im Hochvakuum bei 50 °C getrocknet.Methanol is distilled off in vacuo. The residue is stirred, added to 85 ml of 1 M sulfuric acid at 0 ° C. The resulting precipitate is filtered off and dried at 50 ° C in a high vacuum.
Man erhält 470 mg (93% d. Th.) Produkt.470 mg (93% of theory) of product are obtained.
LCMS (Methode 3): R, = 3.21 min MS (ESIpos): m/z = 344 (M+H)+ HerstellungsbeispieleLCMS (method 3): R, = 3.21 min MS (ESIpos): m / z = 344 (M + H) + Preparation Examples
Beispiel 1 2-[4-[(3-(IΛlor-4-methylphenyl)ammo]-2,6-dioxo-3,6-d ydro-l(2H)-pyrimidinyl]-N-Example 1 2- [4 - [(3- (chloro-4-methylphenyl) ammo] -2,6-dioxo-3,6-d ydro-l (2H) pyrimidinyl] -N-
[2-(2-hydroxyethoxy)ethyl]acetamid[2- (2-hydroxyethoxy) ethyl] acetamide
Figure imgf000047_0001
Figure imgf000047_0001
Die Synthese erfolgt analog zu Beispiel 5.The synthesis is carried out analogously to Example 5.
Ausbeute: 27% d. Th.Yield: 27% of theory Th.
IH-NMR (400 MHz, DMSO-dö): δ = 2.30 (s, 3H), 3.22 ( , 2H), 3.40 (m, 4H), 3.50 (br m, 2H), 4.28 (s, 2H), 4.56 (br s, IH), 4.80 (s, IH), 7.12 (dd, J = 8.0, 2.0 Hz, IH), 7.27 (d, J = 2.0 Hz, IH), 7.35 (d, J = 8.0 Hz, IH), 8.03 (t, J = 6.0 Hz, IH), 8.42 (br s, IH), 10.67 (br s, IH).IH-NMR (400 MHz, DMSO-dö): δ = 2.30 (s, 3H), 3.22 (, 2H), 3.40 (m, 4H), 3.50 (br m, 2H), 4.28 (s, 2H), 4.56 (br s, IH), 4.80 (s, IH), 7.12 (dd, J = 8.0, 2.0 Hz, IH), 7.27 (d, J = 2.0 Hz, IH), 7.35 (d, J = 8.0 Hz, IH) ), 8.03 (t, J = 6.0 Hz, IH), 8.42 (br s, IH), 10.67 (br s, IH).
LCMS (Methode 1): Rt = 1.90 min MS (ESIpos): m z = 397 (M+H)+ LCMS (method 1): R t = 1.90 min MS (ESIpos): mz = 397 (M + H) +
Beispiel 2Example 2
2-[4-(2,3-Dihydro-lH-inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)-pyrimidinyl]- N-methyl-N-[2-(l-piperidinyl)ethyl]acetamid2- [4- (2,3-Dihydro-lH-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-l (2H) -pyrimidinyl] - N-methyl-N- [2- (l-piperidinyl) ethyl] acetamide
Figure imgf000048_0001
Figure imgf000048_0001
Die Synthese erfolgt analog zu Beispiel 5. Ausbeute: 89% d. Th.The synthesis is carried out analogously to Example 5. Yield: 89% of theory. Th.
1H-NMR (400 MHz, DMSO-d6): δ = 1.36-1.82 (m, 6H), 2.02 (quintett, 2H), 2.82- 2.92 (m, 7H), 3.08 (s, 3H), 3.18 (q, 2H), 3.64 (t, 2H), 4.53 (s, 2H), 4.72 (s, IH), 6.961H-NMR (400 MHz, DMSO-d 6 ): δ = 1.36-1.82 (m, 6H), 2.02 (quintet, 2H), 2.82-2.92 (m, 7H), 3.08 (s, 3H), 3.18 (q , 2H), 3.64 (t, 2H), 4.53 (s, 2H), 4.72 (s, IH), 6.96
(d, IH), 7.08 (s, IH), 7.23 (d, IH), 8.29 (s, IH), 8.91 (s, IH), 10.6 (s, IH). LCMS (Methode 2): Rt = 2.47 min MS (ESIpos): m z = 426 (M+H)+ (d, IH), 7.08 (s, IH), 7.23 (d, IH), 8.29 (s, IH), 8.91 (s, IH), 10.6 (s, IH). LCMS (method 2): R t = 2.47 min MS (ESIpos): mz = 426 (M + H) +
Beispiel 3Example 3
4-[4-(2,3-Dihydro-lH-inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)-pyrimidinyl]- N-[2-(dimethylamino)ethyl]-N-methylbutanamid4- [4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl] - N- [2- (dimethylamino) ethyl ] -N-methyl butanamide
Figure imgf000048_0002
Figure imgf000048_0002
Die Synthese erfolgt analog zu Beispiel 5. Ausbeute: 73% d. Th. LCMS (Methode 2): R, = 2.43 min MS (ESIpos): m/z = 414 (M+H)+ Beispiel 4The synthesis is carried out analogously to Example 5. Yield: 73% of theory. Th. LCMS (method 2): R, = 2.43 min MS (ESIpos): m / z = 414 (M + H) + Example 4
4-[4-(2,3-Dihydro-lH-inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)-pyrimidinyl]- N-[2-(2-pyridinyl)ethyl]butanamid4- [4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl] - N- [2- (2-pyridinyl ) ethyl] butanamide
Figure imgf000049_0001
Figure imgf000049_0001
Die Synthese erfolgt analog zu Beispiel 5. Ausbeute: 70% d. Th. LCMS (Methode 2): Rt = 2.48 minThe synthesis is carried out analogously to Example 5. Yield: 70% of theory. Th. LCMS (method 2): R t = 2.48 min
MS (ESIpos): m/z = 434 (M+H)+ MS (ESIpos): m / z = 434 (M + H) +
Beispiel 5Example 5
N-Benzyl-4-[4-(2,3-dihydro-lH-inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)- pyrimidinyl]-butanamidN-benzyl-4- [4- (2,3-dihydro-lH-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-l (2H) -pyrimidinyl] butanamide
Figure imgf000049_0002
Figure imgf000049_0002
0.045 g (0.137 mmol) der Verbindung aus Beispiel VUL 0.016 g (0.15 mmol) Benzylamin und 0.078 g (0.15 mmol) 1-Benzotriazolyloxytripyrrolidinphosphonium- hexafluorophosphat werden in 4 ml Dimethylformamid zusammengegeben und mit0.045 g (0.137 mmol) of the compound from Example VUL 0.016 g (0.15 mmol) of benzylamine and 0.078 g (0.15 mmol) of 1-benzotriazolyloxytripyrrolidinphosphonium hexafluorophosphate are combined in 4 ml of dimethylformamide and mixed with
0.035 g (0.237 mmol) N,N-Diisopropylethylamin versetzt. Man rührt 24 Stunden bei Raumtemperatur. Die Reaktionslösung wird im Vakuum eingeengt. Man reinigt über Kieselgel 60 (Laufmittel: Dichlormethan-Methanol (10%)). Man erhält 3.9 mg (6% d. Th.) Produkt. LCMS (Methode 3): Rt = 3.61 min MS (ESIpos): m/z = 419 (M+H)+ 0.035 g (0.237 mmol) of N, N-diisopropylethylamine was added. The mixture is stirred at room temperature for 24 hours. The reaction solution is concentrated in vacuo. It is cleaned over silica gel 60 (mobile phase: dichloromethane-methanol (10%)). 3.9 mg (6% of theory) of product are obtained. LCMS (method 3): R t = 3.61 min MS (ESIpos): m / z = 419 (M + H) +
Die nachfolgenden Beispiele werden in analoger Weise zu Beispiel 5 aus den entsprechenden Edukten hergestellt.The following examples are prepared in a manner analogous to example 5 from the corresponding starting materials.
Beispiel 6Example 6
4-[4-(2,3-Dihydro-lH-inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)-pvrimidinyl]- N-[3-(dimethylamino)propyl]-N-methylbutanamid4- [4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pvrimidinyl] - N- [3- (dimethylamino) propyl ] -N-methyl butanamide
Figure imgf000050_0001
Figure imgf000050_0001
LCMS (Methode 3): Rt = 2.45 min MS (ESIpos): m/z = 428 (M+H)+ LCMS (method 3): R t = 2.45 min MS (ESIpos): m / z = 428 (M + H) +
Beispiel 7Example 7
4-[4-(2,3-Dihydro-lH-inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)-pyrimidinyl]- N-methyl-N-[2-(l-piperidinyl)ethyl]butanamid4- [4- (2,3-dihydro-lH-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-l (2H) -pyrimidinyl] - N-methyl-N- [2- (l-piperidinyl) ethyl] butanamide
Figure imgf000051_0001
LCMS (Methode 3): Rt = 2.57 min
Figure imgf000051_0001
LCMS (method 3): R t = 2.57 min
MS (ESIpos): m z = 454 (M+H)+ MS (ESIpos): mz = 454 (M + H) +
Beispiel 8Example 8
4-[4-(2,3-Dihydro-lH-inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)-pyrimidinyl]- N-[3 -(2-ethyl-4-methyl- 1 H-imidazol- 1 -yl)propyl]butanamid4- [4- (2,3-Dihydro-lH-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-l (2H) -pyrimidinyl] - N- [3 - (2-ethyl -4-methyl-1 H-imidazole-1-yl) propyl] butanamide
Figure imgf000051_0002
Figure imgf000051_0002
LCMS (Methode 3): R, = 2.53 min MS (ESIpos): m z = 479 (M+H)+ Beispiel 9LCMS (method 3): R, = 2.53 min MS (ESIpos): mz = 479 (M + H) + Example 9
4-[4-(23-Dihydro- -inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)-pyrimidinyl]- N-{2-[(2-hydroxyethyl)(methyl)amino]ethyl}butanamid4- [4- (23-Dihydro- -inden-5-ylamino) -2,6-dioxo-3,6-dihydro-l (2H) -pyrimidinyl] - N- {2 - [(2-hydroxyethyl) ( methyl) amino] ethyl} butanamide
Figure imgf000052_0001
Figure imgf000052_0001
LCMS (Methode 3): Rt = 2.33 minLCMS (method 3): R t = 2.33 min
MS (ESIpos): m/z = 430 (M+H)+ MS (ESIpos): m / z = 430 (M + H) +
Beispiel 10 4-[4-(2,3-Dihydro- 1 H-inden-5-ylamino)-2,6-dioxo-3 ,6-dihydro- 1 (2H)-pyrimidinyl]-Example 10 4- [4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl] -
N-(2-furylmethyl)-N-methylbutanamidN- (2-furylmethyl) -N-methylbutanamide
Figure imgf000052_0002
Figure imgf000052_0002
LCMS (Methode 1): Rt = 2.47 min MS (ESIpos): m z = 423 (M+H)+ Beispiel 11LCMS (method 1): R t = 2.47 min MS (ESIpos): mz = 423 (M + H) + Example 11
2-[4-(2,3-Dihydro-lH-inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)-pyrimidinyl]- N-isopropyl-N-[3-( 1 -pyrrolidinyl)propyl]acetamid2- [4- (2,3-Dihydro-lH-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-l (2H) -pyrimidinyl] - N-isopropyl-N- [3- (1-pyrrolidinyl) propyl] acetamide
Figure imgf000053_0001
Figure imgf000053_0001
LCMS (Methode 1): Rt = 1.72 minLCMS (method 1): R t = 1.72 min
MS (ESIpos): m/z = 454 (M+H)+ MS (ESIpos): m / z = 454 (M + H) +
Beispiel 12 N-{2-[4-(Aminosulfonyl)phenyl]ethyl}-4-[4-[(3-chlor-4-methylphenyl)amino]-2,6- dioxo-3 ,6-dihydro- 1 (2H)-pyrimidinyl]butanamidExample 12 N- {2- [4- (aminosulfonyl) phenyl] ethyl} -4- [4 - [(3-chloro-4-methylphenyl) amino] -2,6-dioxo-3,6-dihydro-1 ( 2H) -pyrimidinyl] butanamide
Figure imgf000053_0002
Figure imgf000053_0002
LCMS (Methode 3): Rt = 3.29 min MS (ESIpos): m/z = 520 (M+H)+ LCMS (method 3): R t = 3.29 min MS (ESIpos): m / z = 520 (M + H) +
Beispiel 13Example 13
4-[4-[(3-( hlor-4-methylphenyl)amino]-2,6-dioxo-3,6-dihydro-l(2H)-pyrimidinyl]-N- [3 -(2-ethyl-4-methyl- 1 H-imidazol- 1 -yl)propyl]butanamid4- [4 - [(3- (hlor-4-methylphenyl) amino] -2,6-dioxo-3,6-dihydro-l (2H) pyrimidinyl] -N- [3 - (2-ethyl-4 -methyl-1 H-imidazole-1-yl) propyl] butanamide
Figure imgf000054_0001
Figure imgf000054_0001
LCMS (Methode 3): Rt = 2.61 min MS (ESIpos): m/z = 487 (M+H)+ LCMS (method 3): R t = 2.61 min MS (ESIpos): m / z = 487 (M + H) +
Beispiel 14Example 14
N-(lH-Benzimidazol-2-ylmethyl)-4-[4-[(3-ethyl-4-methylphenyl)amino]-2,6-dioxo- 3,6-dihydro-l(2H)-pyrimidinyl]butanamidN- (1H-Benzimidazol-2-ylmethyl) -4- [4 - [(3-ethyl-4-methylphenyl) amino] -2,6-dioxo-3,6-dihydro-l (2H) pyrimidinyl] butanamide
Figure imgf000055_0001
Figure imgf000055_0001
LCMS (Methode 3): R, = 2.79 min MS (ESIpos): m/z = 461 (M+H)+ LCMS (method 3): R, = 2.79 min MS (ESIpos): m / z = 461 (M + H) +
Beispiel 15 5-[4-(2,3-Dihydro-lH-inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)-pyrimidinyl]-Example 15 5- [4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl] -
N-(2-pyridinylmethyl)pentanamidN- (2-pyridinylmethyl) pentanamide
Figure imgf000055_0002
Figure imgf000055_0002
LCMS (Methode 2): R, = 2.77 minLCMS (method 2): R, = 2.77 min
MS (ESIpos): m z = 434 (M+H)+ Beispiel 16MS (ESIpos): mz = 434 (M + H) + Example 16
5-[4-(2,3-Dihydro-lH-inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)-pyrimidinyl]- N-(3-pyridinylmethyl)pentanamid5- [4- (2,3-Dihydro-1H-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-1 (2H) -pyrimidinyl] - N- (3-pyridinylmethyl) pentanamide
Figure imgf000056_0001
Figure imgf000056_0001
LCMS (Methode 2): Rt = 2.61 min MS (ESIpos): m/z = 434 (M+H)+ LCMS (method 2): R t = 2.61 min MS (ESIpos): m / z = 434 (M + H) +
Beispiel 17Example 17
5-[4-(2,3-Dihydro-lH-inden-5-ylamino)-2,6-dioxo-3,6-dihydro-l(2H)-pyrimidinyl]- N-[3-(l H-imidazol- 1 -yl)propyl]pentanamid5- [4- (2,3-Dihydro-lH-inden-5-ylamino) -2,6-dioxo-3,6-dihydro-l (2H) -pyrimidinyl] - N- [3- (l H- imidazole-1-yl) propyl] pentanamide
Figure imgf000056_0002
Figure imgf000056_0002
LCMS (Methode 2): Rt = 2.49 minLCMS (method 2): R t = 2.49 min
MS (ESIpos): m z = 451 (M+H)+ MS (ESIpos): mz = 451 (M + H) +
C. Ausführungsbeispiele für pharmazeutische ZusammensetzungenC. Examples of pharmaceutical compositions
Die erfindungsgemäßen Substanzen können folgendermaßen in pharmazeutische Zubereitungen überfuhrt werden:The substances according to the invention can be converted into pharmaceutical preparations as follows:
Tablette:Tablet:
Zusammensetzung: 100 mg der Verbindung von Beispiel 1, 50 mg Lactose (Monohydrat), 50 mgComposition: 100 mg of the compound of Example 1, 50 mg lactose (monohydrate), 50 mg
Maisstärke (nativ), 10 mg Polyvinylpyrolidon (PVP 25) (Fa. BASF, Ludwigshafen, Deutschland) und 2 mg Magnesiumstearat.Corn starch (native), 10 mg polyvinylpyrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.
Tablettengewicht 212 mg. Durchmesser 8 mm, Wölbungsradius 12 mm.Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.
Herstellung:production:
Die Mischung aus Wirkstoff, Lactose und Stärke wird mit einer 5%-igen Lösung (m/m) des PVPs in Wasser granuliert. Das Granulat wird nach dem Trocknen mit dem Magnesiumstearat für 5 min. gemischt. Diese Mischung wird mit einer üblichen Tablettenpresse verpresst (Format der Tablette siehe oben). Als Richtwert für dieThe 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). As a guideline for the
Verpressung wird eine Pesskraft von 15 kN verwendet.Pressing a pressure force of 15 kN is used.
Oral appüzierbare Suspension:Oral application suspension:
Zusammensetzung:Composition:
1000 mg der Verbindung von Beispiel 1, 1000 mg Ethanol (96%), 400 mg Rhodigel (Xanthan gum der Fa. FMC, Pennsylvania, USA) und 99 g Wasser.1000 mg of the compound from Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.
Einer Einzeldosis von 100 mg der erfindungsgemäßen Verbindung entsprechen 10 ml orale Suspension. Herstellung:A single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension. production:
Das Rhodigel wird in Ethanol suspendiert, der Wirkstoff wird der Suspension zugefügt. Unter Rühren erfolgt die Zugabe des Wassers. Bis zum Abschluß der Quellung des Rhodigels wird ca. 6h gerührt.The 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.
Intravenös applizierbare Lösung:Solution that can be administered intravenously:
Zusammensetzung:Composition:
1 mg der Verbindung von Beispiel 1, 15 g Polyethylenglykol 400 und 250g Wasser für Inj ektionsz wecke.1 mg of the compound from Example 1, 15 g of polyethylene glycol 400 and 250 g of water for injection purposes.
Herstellung:production:
Die Verbindung von Beispiel 1 wird zusammen mit Polyethylenglykol 400 in dem Wasser unter Rühren gelöst. Die Lösung wird sterilfiltriert (Porendurchmesser 0,22 μm) und unter aseptischen Bedingungen in hitzesterilisierte Infusionsflaschen abgefüllt. Diese werden mit Infusionsstopfen und Bördelkappen verschlossen. 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 μm) and filled into heat-sterilized infusion bottles under aseptic conditions. These are closed with infusion stoppers and crimp caps.

Claims

Paten tanspr ü eheGodparent claims
1. Verbindungen der allgemeinen Formel (I)1. Compounds of the general formula (I)
Figure imgf000059_0001
in welcher
Figure imgf000059_0001
in which
Rl für CrCs-Cycloalkyl, Cö-Cio-Aryl, Heterocyclyl, Heteroaryl, d-Cβ- Alkoxy, d-Cβ-Alkoxycarbonyl, Amino, Hydroxy, d-Cö-Alkylamino, CrCö-Dialkylamino, Aminocarbonyl, d-Cö-Alkylaminocarbonyl, d-Rl for CrCs-cycloalkyl, Cö-Cio-aryl, heterocyclyl, heteroaryl, d-Cβ-alkoxy, d-Cβ-alkoxycarbonyl, amino, hydroxy, d-Cö-alkylamino, CrC ö -dialkylamino, aminocarbonyl, dC ö -alkylaminocarbonyl, d-
Cö-Dialkyla inocarbonyl, d-Cδ-Alkoxycarbonylamino, Aminosulfonyl, d-Cö-Alkylaminosulfonyl, d-Cö-Dialkylaminosulfonyl, C3-C8- Cycloalkylamino-sulfonyl, C3-C8-Dicycloalkylaminosulfonyl, Cβ-Cio- Arylaminosulfonyl, Heteroarylaminosulfonyl, -OCH2CH2OH oder - N(CH3)CH2CH2OH steht,C ö -dialkyla inocarbonyl, d-Cδ-alkoxycarbonylamino, aminosulfonyl, dC ö -alkylaminosulfonyl, dC ö -dialkylaminosulfonyl, C 3 -C 8 - cycloalkylaminosulfonyl, C 3 -C 8 -dicycloalkylaminosulfonyl, Cβ-cyclo-arylaminonyl-arylaminonyl-arylaminonyl-arylamino-sulfonyl -OCH 2 CH 2 OH or - N (CH 3 ) CH 2 CH 2 OH,
wobei Rl gegebenenfalls substituiert ist mit 1 bis 3 Substituenten Rl-1,where Rl is optionally substituted with 1 to 3 substituents Rl-1,
wobei die Substituenten R^'l unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Nitro, Cι-C6-Alkyl, C3-C8-Cycloalkyl, C -Ci o-Aryl, Heterocyclyl, Heteroaryl, Cj-Cβ-Alkoxy, Ci-Cö-Alkoxycarbonyl, Aminocarbonyl, d-Cö-Alkylaminocarbonyl, d-Cβ-Dialkylamino- carbonyl, Aminosulfonyl, Ci-Cö-Alkylaminosulfonyl, Ci-Cö-Dialkyl- aminosulfonyl, C3-C8-Cycloalkylaminosulfonyl, C3-C8-Dicycloalkyl- aminosulfonyl, Q-do-Arylaminosulfonyl und Heteroarylaminosulfonyl,where the 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, C -C 10 -aryl-aryl, heterocyclyl, heteroaryl, Cj -Cβ-alkoxy, Ci-C ö alkoxycarbonyl, aminocarbonyl, dC ö alkylaminocarbonyl, d-Cβ-dialkylamino-carbonyl, aminosulfonyl, Ci-Cö-alkylaminosulfonyl, Ci-Cö-dialkylaminosulfonyl, C 3 -C 8 cycloalkylaminosulfonyl , C 3 -C 8 dicycloalkyl- aminosulfonyl, Q-do-arylaminosulfonyl and heteroarylaminosulfonyl,
R2 für Wasserstoff, d-C6- Alkyl, C3-C8-Cycloalkyl, C6-Cιo-Aryl, Heterocyclyl, Heteroaryl, d-Cö-Alkoxy, d-C6-Alkoxycarbonyl,R 2 for hydrogen, dC 6 -alkyl, C 3 -C 8 -cycloalkyl, C6-Cιo-aryl, heterocyclyl, heteroaryl, dC ö -alkoxy, dC 6 -alkoxycarbonyl,
Amino, Ci-Cö-Alkylamino, Ci-Cö-Dialkylamino, Aminocarbonyl, Ci- Cö-Alkylaminocarbonyl, d-Cö-Dialkylaminocarbonyl, Ci-Cö-Alkoxy- carbonylamino, Aminosulfonyl, Cι-C6-AlkylaminosuIfonyl, d-Ce- Dialkylaminosulfonyl, C3-Cg-Cycloalkylaminosulfonyl, C3-Cg-Di- cycloalkylaminosulfonyl, Cg-Cio-Arylaminosulfonyl, Heteroarylaminosulfonyl, -OCH2CH2OH oder -N(CH3)CH2CH2OH steht,Amino, Ci-COE-alkylamino, Ci-COE-dialkylamino, aminocarbonyl, Ci- C ö alkylaminocarbonyl, dC ö dialkylaminocarbonyl, Ci-C ö alkoxy carbonylamino, aminosulfonyl, Cι-C6-AlkylaminosuIfonyl, d-Ce dialkylaminosulfonyl , C 3 -Cg-cycloalkylaminosulfonyl, C 3 -Cg -dicycloalkylaminosulfonyl, Cg-Cio-arylaminosulfonyl, heteroarylaminosulfonyl, -OCH 2 CH 2 OH or -N (CH 3 ) CH 2 CH 2 OH,
wobei Alkyl, Cycloalkyl, Aryl, Heterocyclyl, Heteroaryl, Alkoxy,where alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy,
Alkoxycarbonyl, Alkylamino, Dialkylamino, Alkylaminocarbonyl, Dialkylamino-carbonyl, Alkoxycarbonylamino, Alkylaminosulfonyl,Alkoxycarbonyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylamino-carbonyl, alkoxycarbonylamino, alkylaminosulfonyl,
Dialkylaminosulfonyl, Cycloalkylaminosulfonyl, Dicycloalkylamino- sulfonyl, Arylaminosulfonyl und Heteroarylaminosulfonyl gegebenenfalls substituiert ist mit 1 bis 3 Substituenten R2-*,Dialkylaminosulfonyl, Cycloalkylaminosulfonyl, Dicycloalkylaminosulfonyl, Arylaminosulfonyl and Heteroarylaminosulfonyl is optionally substituted with 1 to 3 substituents R 2- *,
wobei die Substituenten R2~l unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Nitro, d-Cβ- Alkyl, d-Cs-Cycloalkyl, C^-C\Q~Aτyl, Heterocyclyl, Heteroaryl, d-Cö-Alkoxy, d-C6- Alkoxycarbonyl, Aminocarbonyl, Cι-C6 -Alkylaminocarbonyl, d-Cö-Dialkylamino- carbonyl, Aminosulfonyl, d-Cö-Alkylaminosulfonyl, Cι-C6-wherein the substituents R 2 ~ l are independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, nitro, d-Cβ-alkyl, d-Cs-cycloalkyl, C ^ -C \ Q ~ Aτyl, heterocyclyl, heteroaryl, dC ö -alkoxy, dC 6 - alkoxycarbonyl, aminocarbonyl, Cι-C 6 -alkylaminocarbonyl, d-Cö-dialkylamino-carbonyl, aminosulfonyl, dC ö -alkylaminosulfonyl, Cι-C 6 -
Dialkylaminosulfonyl, C3-Cg-Cycloalkylaminosulfonyl, C3-Cg-Di- cycloalkylaminosulfonyl, Cö-do-Arylaminosulfonyl und Heteroarylaminosulfonyl,Dialkylaminosulfonyl, C 3 -Cg-cycloalkylaminosulfonyl, C 3 -Cg -dicycloalkylaminosulfonyl, C ö -do-arylaminosulfonyl and heteroarylaminosulfonyl,
R^ für einen Substituenten der folgenden Formel steht,
Figure imgf000061_0001
R ^ represents a substituent of the following formula,
Figure imgf000061_0001
wobeiin which
R3"l und R^-2 unabhängig voneinander ausgewählt werden aus derR3 "l and R ^ -2 are independently selected from the
Gruppe d-Ce-Alkyl, C2-C6-Alkenyl, C2-C6-Alkinyl, C3-C6-Cycloalkyl und Halogen, oderGroup d-Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl and halogen, or
R3-1 und R - bilden zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, einen C3-C6-Cycloalkyl- oder Heterocyclyl-Ring, der gegebenenfalls mit bis zu 3 Halogen substituiert ist,R3-1 and R - together with the carbon atoms to which they are attached form a C 3 -C 6 cycloalkyl, or heterocyclyl ring is optionally substituted with up to 3 halogen,
A für eine Ci -Cö-Alkandiylkette steht, die gegebenenfalls eine oder mehrere Doppel- oder Dreifachbindungen enthält und in der gegebenenfalls ein Kohlenstoffatom durch ein Stickstoff- oderA stands for a Ci -Cö-alkanediyl chain, which optionally contains one or more double or triple bonds and in which a carbon atom is optionally replaced by a nitrogen or
Sauerstoffatom ersetzt ist, wobei sich sowohl zwischen dem Heteroatom in A und dem Stickstoffatom im Uracilring mindestens 2 Kohlenstoffatome befinden müssen, und wobei sich dem Heteroatom in A und dem Carbonylkohlenstoffatom, welches zu A benachbart ist, mindestens 1 Kohlenstoffatom befinden muss,Oxygen atom is replaced, where at least 2 carbon atoms must be between both the hetero atom in A and the nitrogen atom in the uracil ring, and where the hetero atom in A and the carbonyl carbon atom which is adjacent to A must have at least 1 carbon atom,
und die gegebenenfalls mit bis zu 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe Halogen, Nitro, Amino, d- C6-Alkylamino, Ci-Cö-Dialkylamino, Ci-Cö-Acylamino, Trifluor- methyl und Trifluormethoxy substituiert ist,and which is optionally substituted with up to 3 substituents independently selected from the group halogen, nitro, amino, d-C6-alkylamino, Ci-Cö-dialkylamino, Ci-Cö-acylamino, trifluoromethyl and trifluoromethoxy,
E für eine Ci -Cg-Alkandiylkette steht, die gegebenenfalls eine oder mehrere Doppel- oder Dreifachbindungen enthält und die gegebenenfalls mit bis zu 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe Halogen, Nitro, Amino, Ci-d-Alkyl- amino, d-Cβ-Dialkylamino, Ci-Cö-Acylamino, Trifluormethyl und Trifluormethoxy substituiert ist,E represents a Ci-Cg-alkanediyl chain, which optionally contains one or more double or triple bonds and which optionally have up to 3 substituents, independently of one another selected from the group halogen, nitro, amino, Ci-d-alkylamino, d-Cβ-dialkylamino, Ci-Cö-acylamino, trifluoromethyl and trifluoromethoxy is substituted,
sowie deren pharmazeutisch verträgliche Salze, Solvate und Hydrate.and their pharmaceutically acceptable salts, solvates and hydrates.
2. Verbindungen der allgemeinen Formel (1) nach Anspruch 1 , worin2. Compounds of general formula (1) according to claim 1, wherein
Rl Cö-Aryl, Heterocyclyl, Heteroaryl, d-Cö-Alkoxy, Cι-C6-Alkoxycar- bonyl, Amino, Ci-Cö-Alkylamino, Ci-Cö-Dialkylamino, Aminocarbonyl, d-Cö-Alkylaminocarbonyl, Ci-Cö-Dialkylaminocarbonyl, d-Cö- Alkoxycarbonylamino, -OCH2CH2OH, -N(CH3)CH2CH2OH,Rl Cö-aryl, heterocyclyl, heteroaryl, dC ö -alkoxy, Cι-C 6 -alkoxycarbonyl, amino, Ci-Cö-alkylamino, Ci-C ö -dialkylamino, aminocarbonyl, dC ö -alkylaminocarbonyl, Ci-C ö - Dialkylaminocarbonyl, dC ö - alkoxycarbonylamino, -OCH 2 CH 2 OH, -N (CH 3 ) CH 2 CH 2 OH,
wobei Rl gegebenenfalls substituiert sein kann mit 1 bis 2 Substi- ruenten R1"!,where Rl can be optionally substituted with 1 to 2 substituents R 1 "!
wobei R!"1 ausgewählt wird aus der Gruppe Halogen, d-Cö- Alkyl, C3-Cg-Cycloalkyl, Cg-Cjo-Aryl, Heterocyclyl, Heteroaryl,where R! " 1 is selected from the group halogen, d-Cö-alkyl, C 3 -Cg-cycloalkyl, Cg-Cjo-aryl, heterocyclyl, heteroaryl,
R2 Wasserstof oder Ci-Ce-Alkyl ist,R 2 is hydrogen or Ci-Ce-alkyl,
R- ein Substituent der folgenden FormelR- is a substituent of the following formula
Figure imgf000062_0001
Figure imgf000062_0001
worinwherein
R^-l und R^"2 unabhängig voneinander ausgewählt werden aus der Gruppe Cι-C3- Alkyl oder Halogen, oder R- -! und R- -2 bilden zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen C3-C6-Cycloalkyl-Ring, der gegebenenfalls mit bis zu 3 Halogen substituiert sein kann,R ^ -l and R ^ " 2 are independently selected from the group -C-C 3 - alkyl or halogen, or R- - ! and R-- 2 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring which can optionally be substituted with up to 3 halogen,
A ist eine Cι-C4-Alkylidenkette,A is a C 1 -C 4 alkylidene chain,
E ist eine Cι-C3-Alkylidenkette.E is a -C-C3 alkylidene chain.
3. Verbindungen der allgemeinen Formel (I) nach Anspruch , worin3. Compounds of general formula (I) according to claim, wherein
R ausgewählt wird aus der GruppeR is selected from the group
Figure imgf000063_0001
Figure imgf000063_0001
Figure imgf000063_0002
Figure imgf000063_0002
Verbindungen der allgemeinen Formel (I) nach Anspruch 1,Compounds of the general formula (I) according to Claim 1,
woπnembedded image in which
R3 eine GruppeR 3 is a group
Figure imgf000063_0003
Figure imgf000063_0003
5. Verbindungen der allgemeinen Formel (I) nach Anspruch 1, worin R1 ein Heterocyclylring ist, der gegebenenfalls substituiert sein kann mit 1 bis 2 Substituenten ausgewählt wird aus der Gruppe Halogen, Heteroaryl und Ci-Cδ- Alkyl.5. Compounds of general formula (I) according to claim 1, wherein R 1 is a heterocyclyl ring, may be the optionally substituted with 1 to 2 substituents selected from the group halogen, heteroaryl and Ci-C δ - alkyl.
6. Verbindungen der allgemeinen Formel (I) nach Ansprüche 1, worin A gleich Ethylen oder Propylen ist.6. Compounds of the general formula (I) according to Claim 1, in which A is ethylene or propylene.
7. Verbindungen der allgemeinen Formel (I) nach Anspruch 1, worin E eine C2- oder C3-Alkylidenkette ist.7. Compounds of general formula (I) according to claim 1, wherein E is a C 2 - or C 3 -alkylidene chain.
8. Verfahren zur Herstellung der Verbindung der allgemeinen Formel (I) nach Anspruch 1 durch Umsetzung von Verbindungen der allgemeinen Formel (H)8. A process for the preparation of the compound of general formula (I) according to claim 1 by reacting compounds of general formula (H)
Figure imgf000064_0001
Figure imgf000064_0001
worinwherein
A und R3 die oben angegebene Bedeutung haben,A and R 3 have the meaning given above,
und die Carbonsäure gegebenenfalls in aktivierter Form vorliegt,and the carboxylic acid is optionally present in activated form,
mit Verbindungen der allgemeinen Formel (IH)with compounds of the general formula (IH)
RR
I (m)In the)
R1' Ή wonnR 1 'Ή Wonn
11
R und R die oben angegebene Bedeutung haben.R and R have the meaning given above.
9. Verbindungen der allgemeinen Formel (I) nach Anspruch 1 zur Bekämpfung von Erkrankungen.9. Compounds of general formula (I) according to claim 1 for combating diseases.
10. Arzneimittel, enthaltend Verbindungen der allgemeinen Formel (I) nach Anspruch 1 und Hilfsstoffe.10. Medicament containing compounds of general formula (I) according to claim 1 and excipients.
11. Verwendung von Verbindungen der allgemeinen Formel (I) nach Anspruch 1 zur Herstellung eines Arzneimittels zur Behandlung von bakteriellen Erkrankungen. 11. Use of compounds of general formula (I) according to claim 1 for the manufacture of a medicament for the treatment of bacterial diseases.
PCT/EP2002/006311 2001-06-22 2002-06-10 Uracil derivatives and the use thereof for treating bacterial diseases WO2003000664A1 (en)

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