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EP1404657A1 - Pyridazinones - Google Patents

Pyridazinones

Info

Publication number
EP1404657A1
EP1404657A1 EP02740725A EP02740725A EP1404657A1 EP 1404657 A1 EP1404657 A1 EP 1404657A1 EP 02740725 A EP02740725 A EP 02740725A EP 02740725 A EP02740725 A EP 02740725A EP 1404657 A1 EP1404657 A1 EP 1404657A1
Authority
EP
European Patent Office
Prior art keywords
mono
alkyl
substituted
optionally
alkylamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02740725A
Other languages
German (de)
English (en)
Inventor
Tobias Wunberg
Ulrich Betz
Sabine Hallenberger
Gerald Kleymann
Thomas Lampe
Susanne Nikolic
Jürgen Reefschläger
Franz Zumpe
Marcus Bauser
Wolfgang Bender
Rolf Grosser
Kerstein Henninger
Guy Hewlett
Axel Jensen
Jörg Keldenich
Holger Zimmermann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer Healthcare AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1404657A1 publication Critical patent/EP1404657A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring

Definitions

  • the present invention relates to new compounds, processes for their preparation and their use as medicaments, in particular as antivirals, in particular against cytomegaloviruses.
  • EP-A-071 102 describes benzotriazole substituted pyridazinones for cardiovascular diseases.
  • EP-A-8391 describes benzimidazole substituted pyridazinones for cardiovascular diseases and with antiviral activity.
  • the present invention relates to compounds of the general formula (I)
  • A is bonded to the aromatics via positions 2, 3, 5 or 6 and
  • A represents oxygen or NR 6 .
  • E represents oxygen, CR 9 R 10 or NR 7 ,
  • Y represents oxygen or NR
  • D and X are the same or different and each represents oxygen or sulfur, G represents hydrogen,
  • G represents C ö -C ⁇ o-aryl, where C 6 -C ⁇ o-aryl can be optionally substituted with up to three substituents selected from the group consisting of
  • C ⁇ -C6 alkoxy, Cj-C ö alkoxycarbonyl, mono- or di-C ⁇ -C 6 -alkylamino, mono- or di-C ⁇ -C 6 - alkylaminocarbonyl or C ⁇ -C 6 - alkyl can optionally be substituted with up selected to three substituents selected from the group consisting of halogen, hydroxy, -C ⁇ alkoxy, amino, mono- or di- -C ö alkylamino, hydroxycarbonyl, -Ce-alkoxycarbonyl, mono- or di-alkylaminocarbonyl and CrCö C ⁇ - Cio-aryl,
  • G is C ö -Cio-aryl, wherein C ö - o-aryl optionally may be substituted with phenyl,
  • Phenyl may optionally be substituted with up to three substituents selected from the group consisting of halogen, hydroxy, CrC 6 alkoxy, amino, mono- or di-Ci-Ce-alkylamino, hydroxycarbonyl, Q-Ce-alkoxycarbonyl, mono- or di - -Ce-alkylaminocarbonyl and Ci-C ⁇ - alkyl, Wonn
  • d-C ⁇ -alkyl can optionally be substituted with up to three substituents selected from the group consisting of hydroxy, dC 6 -alkoxy, amino, mono- or di-Ci-C ö -alkylamino, hydroxycarbonyl, Cj-C 6 -alkoxycarbonyl and mono- or di-dC 6 - alkylaminocarbonyl,
  • G represents C ⁇ -do-aryl, where C 6 -do-aryl can optionally be substituted by phenyl,
  • Phenyl can optionally be substituted by Cs-C ö heteroaryl or C 5 -C-heterocyclyl,
  • C 5 -C 6 heteroaryl or C 5 -C 7 heterocyclyl may in turn optionally be substituted with up to three substituents selected from the group consisting of halogen, dC 6 alkyl, dC 6 alkoxy, amino, mono- or di- d-Cö-alkylamino, hydroxycarbonyl, dC 6 -alkoxycarbonyl and mono- or di-d-Ce-alkylarninocarbonyl,
  • G is 6 -C 10 -aryl is C, said C ö -Cio-aryl may be optionally substituted with a group of the following formula
  • G represents Cs-Ciö-heteroaryl or C5-C 7 heterocyclyl, where C5-C 1 0- heteroaryl or Cs-d-heterocyclyl may be optionally substituted with up to three substituents selected from the group consisting of halogen, nitro, cyano , dC 6 -alkyl, C ⁇ -C 6 alkoxy, amino, mono- or di-C ⁇ -C 6 - alkylamino, hydroxycarbonyl, dC 6 -alkoxycarbonyl and mono- or di-d-Cö-alkylaminocarbonyl,
  • G -do cycloalkyl is C 3 wherein C 3 may be -do cycloalkyl optionally substituted with up to three substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, dC 6 - alkyl, dC 6 alkoxy,
  • R 1 , R 2 , R 3 and R 4 are the same or different and each represents hydrogen
  • C 6 -C ⁇ o-aryl can be optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxy, dC 6 alkoxy, amino, mono- or di-dC 6 alkylamino, dC 6 alkylcarbonylamino, Hydroxycarbonyl, -C-C 6 alkoxycarbonyl, mono- or di-d- C 6 - alkylaminocarbonyl and dC ö - alkyl,
  • C 1 -C 6 -alkyl may optionally be substituted with up to three substituents selected from the group consisting of hydroxy, dC 6 -alkoxy, amino, mono- or di-dC 6 -alkylamino, C ⁇ -C 6 -alkylcarbonylamino, hydroxycarbonyl, dC 6- alkoxycarbonyl and mono- or di-dC 6 -alkylaminocarbonyl,
  • R 1 and R 2 or R 3 and R 4 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring, the C 3 -C 6 cycloalkyl ring
  • Ring may be optionally substituted with up to three substituents selected from selected the group consisting of halogen, hydroxy, C ⁇ -C 6 - alkyl, dC ö alkoxy, amino, mono- or di-dC 6 alkylamino, dC 6 alkyl carbonylamino , Hydroxycarbonyl, d-Ce-alkoxycarbonyl and mono- or di-d-Ce-alkylaminocarbonyl,
  • R 1 and R 3 together with the carbon atoms to which they are attached form a C 6 -C 6 -cycloalkyl ring, where the C 6 -C 6 -cycloalkyl ring may optionally be substituted with up to three substituents selected from the group Group consisting of halogen, hydroxyl, dC 6 -alkyl, Cj-C 6 -alkoxy, amino, mono- or di-dC 6 -alkylamino, dC 6 -alkylcarbonylamino, hydroxycarbonyl, dC 6 -alkoxycarbonyl and mono- or di-dC 6 Alkylaminocarbonyl,
  • R 5 represents hydrogen, halogen, hydroxyl, dd-alkoxy, amino, mono- or di- dC ö alkylamino or dC 6 alkyl, where d-Cg-alkoxy, mono- or di-dC 6 alkylamino or dC 6 Alkyl can optionally be substituted with up to three substituents selected from the group consisting of hydroxy, dC 6 alkoxy, amino, mono- or di-d-Cö-alkylamino,
  • R 6 , R 7 and R 8 are the same or different and each represents hydrogen or dC 6 -alkyl, where dC 6 -alkyl can optionally be substituted with up to three substituents selected from the group consisting of hydroxy, d- C 6 - Alkoxy, amino, mono- or di-dC 6 -alkylamino, dC 6 -alkylcarbonyl-amino, hydroxycarbonyl, -C-C 6 -alkoxycarbonyl and mono- or di-dC 6 - alkylaminocarbonyl,
  • R 9 and R 10 are the same or different and each represents hydrogen, NR ⁇ R ! 2 , OR 13 or dC 6 alkyl, where dC 6 alkyl can optionally be substituted with up to three substituents selected from the group consisting of hydroxy , dC 6 -alkoxy, amino, mono- or di-CrC 6 -alkylamino, d- C6-alkylcarbonylamino, hydroxycarbonyl, dC ö -alkoxycarbonyl and mono- or di-dC 6 -alkylaminocarbonyl,
  • R u , R 12 and R 13 are the same or different and each represents hydrogen or dd-alkyl, where d-C ⁇ -alkyl may optionally be substituted with up to three substituents selected from the group consisting of
  • C 1 -C 3 -alkyl, dC 4 -alkyl, dC 6 -alkyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 3, 1 to 4 or 1 to 6 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl and n-hexyl.
  • C 3 -C 6 cycloalkyl, C -C 1 o-cycloalkyl in the context of the invention represents a cycloalkyl group having 3 to 6 or 3 to 10 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.
  • d-d-alkox represents a straight-chain, branched or cyclic alkyl radical having 1 to 6 carbon atoms, which is bonded via an oxygen atom.
  • Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.
  • straight-chain or branched alkyl radicals having 1 to 6 carbon atoms are preferred, e.g. Methoxy and ethoxy.
  • dC 6 -alkoxycarbonyl represents a straight-chain, branched or cyclic alkoxy radical having 1 to 6 carbon atoms, which has one
  • Carbonyl group is bound. Examples include: methoxycarbonyl,
  • Ethoxycarbonyl n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
  • C 6 -CiQ aryl represents an aromatic radical having 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • mono-d-d-alkylamino represents an amino group with a straight-chain, branched or cyclic alkyl substituent which has 1 to 6
  • Has carbon atoms examples include: methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino, t-butylamino, n-pentylamino, cyclopentylamino and n-hexylamino.
  • di-C 6 -alkylamino represents an amino group with two identical or different straight-chain, branched or cyclic alkyl substituents, each! have up to 6 carbon atoms.
  • Examples include: NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-methyl-N-cyclopropylamino, N-isopropyl-Nn-propylamino, Nt-butyl- N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.
  • Monod-Ce alkylaminocarbonyl in the context of the invention represents an amino group with a straight-chain, branched or cyclic alkyl substituent which has 1 to 6 carbon atoms and which is bonded via a carbonyl group. Examples include: methylaminocarbonyl, ethylaminocarbonyl, n-
  • Propylaminocarbonyl isopropylaminocarbonyl, cyclopropylaminocarbonyl, t-butylaminocarbonyl, n-pentylaminocarbonyl, cyclopentylaminocarbonyl and n-hexylaminocarbonyl.
  • DiC 6 - alkylaminocarbonyl in the context of the invention represents an amino
  • Examples include: NN-dimethylaminocarbonyl, NN-diethylarninocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-methyl-N-cyclopropylaminocarbonyl, N-isopropyl pyl-Nn-propyl-aminocarbonyl, Nt-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn-hexyl-N-methylaminocarbonyl.
  • Halogen in the context of the invention generally represents fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred. Fluorine and
  • Cs-do-heteroaryl stands for 5- to 10-membered aromatic rings containing heteroatoms with at least one aromatic ring, which can contain 1 to 4 heteroatoms, which are selected from O, S and ⁇ .
  • Heteroaryl can itself be substituted by C or ⁇ .
  • Examples include: pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolicenyl, indolyl, benzo [b] thienyl, benzo [b] furyl, indazolyl, quinolyl, isoquinolyl, ⁇ aphthyridinyl, quinazolinyl
  • a 5- to 7-membered saturated or partially unsaturated heterocycle (“C 5 -C - heterocyclyl”) with up to 3 heteroatoms from the series S, ⁇ and / or O in the context of the invention generally represents a heterocycle which is one or can contain several double bonds and which is linked via a ring carbon atom or a ring nitrogen atom.
  • Heterocyclyl can itself be substituted by C or ⁇ . Examples include: tetrahydrofuryl, pyrroüdinyl, pyrroline, piperidinyl, dihydropyridinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl. Piperidinyl, morpholinyl and pyrrolidinyl are preferred.
  • preferred salts are physiologically acceptable salts of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds according to the invention can be acid addition salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, Ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • salts with customary bases can also be mentioned as salts, for example alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as for example diethylamine, triethylamine, ethyldiisopropylamine, Procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine, or derived from natural amino acids such as glycine, lysine, arginine or histidine.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example calcium or magnesium salts
  • ammonium salts derived from ammonia or organic amines such as for example diethylamine, triethylamine, ethyldiisopropylamine, Procaine, dibenzylamine, N-methylmorph
  • the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
  • the invention relates to both
  • Enantiomers or diastereomers or their respective mixtures can be separated into the stereoisomerically uniform constituents in a known manner.
  • the compounds according to the invention can also be present as prodrugs. This applies in particular to the hydroxy grappe at R 5 , which can be largely esterified without loss of activity.
  • These include, for example, and preferably aliphatic esters, for example butyl esters, aromatic esters, for example benzyl esters, or ⁇ -amino acid esters, for. B. succinic acid monoamide.
  • A is bonded to the aromatics via positions 2, 3, 5 or 6, and
  • A represents oxygen or NR 6 , represents oxygen, CR 9 R 10 or NR 7 ,
  • Y represents oxygen or NR 8 ,
  • D and X are the same or different and each represents oxygen or sulfur
  • G represents hydrogen
  • G is C 6 -do-aryl where C 6 -C ⁇ 0 aryl may be optionally substituted with up to three substituents which are independently selected from the group consisting of halogen, hydroxy, nitro, cyano, Ci- COE Alkoxy, hydroxycarbonyl, Ci-Cö-alkoxycarbonyl, amino, mono- or di-dC 6 -alkylamino, mono- or di-dC ö - alkylaminocarbonyl and dC 6 - alkyl,
  • dC 6 -alkoxy, d-Cö-alkoxycarbonyl, mono- or di-dC 6 -alkylamino, mono- or di-dC 6 -alkylaminocarbonyl or dC ö -alkyl can optionally be substituted with up to three substituents which are selected independently of one another from the group consisting of halogen, hydroxy, C 1 -C 6 -alkoxy, amino, mono- or di-C 1 -C 6 -alkylamino, hydroxycarbonyl, d-Qs-alkoxycarbonyl, mono- or di-d-Ce-alkylaminocarbonyl and C 6 -C 10 aryl,
  • G is C 6 -C ⁇ 0 is aryl, wherein C 6 -C 10 aryl may be optionally substituted with phenyl,
  • Phenyl can optionally be substituted with up to three substituents which are selected independently of one another from the group consisting of halogen, hydroxy, C 1 -C 6 -alkoxy, amino, mono- or di-dC 6 -alkylamino, hydroxycarbonyl, d-Ce Alkoxycarbonyl, mono- or di-dC ö -alkylamino-carbonyl and dC 6 - alkyl,
  • C 1 -C 6 -Alkyl may in turn be optionally substituted with up to three substituents which are selected independently of one another from the
  • G represents C 6 -do-aryl, where C 6 -C 10 -aryl can optionally be substituted by phenyl,
  • Phenyl can optionally be substituted with Cs-C ö heteroaryl or C 5 -C 7 heterocyclyl,
  • C 5 -C 6 heteroaryl or C 5 -C 7 heterocyclyl may in turn optionally be substituted with up to three substituents which are selected independently of one another from the group consisting of halogen, Ci-C 6 -alkyl, dC 6 -alkoxy, Amino, mono- or di-CrC 6 -alkylamino, hydroxycarbonyl, dC 6 -alkoxycarbonyl and mono- or di-dd-
  • G represents C 6 -C ⁇ o-aryl, where C 6 -do-aryl may optionally be substituted with a group of the following formula
  • G is d-Cioè-heteroaryl, or Cs-e-heterocyclyl, where C 5 -C 1 0-heteroaryl, or C5-C7 heterocyclyl may be optionally substituted with up to three substituents consisting, which are independently selected from the group from halogen, nitro, cyano, dC 6 -alkyl, dd- alkoxy, amino, mono- or di-CrC ö -alkylamino, hydroxycarbonyl, dC 6 -
  • G represents C 3 -do-cycloalkyl, where d-do-cycloalkyl can optionally be substituted with up to three substituents which are selected independently of one another from the group consisting of halogen, Nitro, cyano, hydroxy, dC 6 -alkyl, dC 6 -alkoxy, amino, mono- or di- Cj-C ⁇ -alkylamino, dC 6 -alkylcarbonylamino, hydroxycarbonyl, dQ- alkoxycarbonyl and mono- or di-d-Ce-alkylaminocarbonyl .
  • R 1 , R 2 , R 3 and R 4 are the same or different and each represents hydrogen
  • d-do-aryl may be optionally substituted with up to three substituents selected from the group consisting of halogen, hydroxy, dC 6 -alkoxy, amino, mono- or di-dd-alkylamino, dd-alkylcarbonylamino, hydroxycarbonyl, dC 6- alkoxycarbonyl, mono- or di-Ci- C 6 -alkylaminocarbonyl and dd-alkyl,
  • dC 6 -alkyl may optionally be substituted with up to three substituents which are selected independently of one another from the group consisting of hydroxyl, -CC 6 -alkoxy, amino, mono- or di-dC 6 -alkylamino, dd Alkylcarbonylamino, hydroxycarbonyl, dd-alkoxycarbonyl and mono- or di-dd-alkylarriinocarbonyl,
  • R 1 , R 2 , R 3 and R 4 are not simultaneously hydrogen, or
  • R 1 and R 2 or R 3 and R 4 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring, where the C 3 -C 6 cycloalkyl ring can optionally be substituted with up to three substituents which are selected independently of one another from the group consisting of halogen, hydroxy, dC 6 -alkyl, dC 6 -alkoxy, amino, mono- or di-Cj-C 6 -alkylamino, dd-alkylcarbonylamino, hydroxycarbonyl, dC 6 - alkoxycarbonyl and mono- or di -CC 6 alkylaminocarbonyl,
  • R and R together with the carbon atoms to which they are attached form a C 3 -C 6 -cycloalkyl ring, whereby the dd-cycloalkyl ring can optionally be substituted with up to three substituents which are selected independently of one another from the group consisting of halogen, hydroxy, dC 6 -alkyl, dC 6 -alkoxy, amino, mono- or di-dC 6 -alkylamino, dC 6 -alkylcarbonylamino, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl and mono- or di-dC 6 alkylaminocarbonyl,
  • R 5 represents hydrogen, halogen, hydroxyl, dC 6 -alkoxy, amino, mono- or di- d-Ce-alkylamino or -CC 6 alkyl, where dC ö alkoxy, mono- or di-dC 6 -alkylamino or dC 6 -alkyl may optionally be substituted with up to three substituents which are selected independently of one another from the group consisting of hydroxy, dC 6 -alkoxy, amino, mono- or di-dC 6 -alkylamino, hydroxycarbonyl, dC 6 -alkoxycarbonyl and mono- or di-dC 6 -alkylaminocarbonyl,
  • R 6 , R 7 and R 8 are the same or different and each represent hydrogen or dC 6 -alkyl, where dd-alkyl can optionally be substituted with up to three substituents which are selected independently of one another from the Group consisting of hydroxy, dC 6 -alkoxy, amino, mono- or di-dC 6 -alkylamino, dC 6 -alkylcarbonylamino, hydroxycarbonyl, dC 6 -alkoxycarbonyl and mono- or di-C ⁇ -C 6 - alkylaminocarbonyl,
  • R 9 and R 10 are the same or different and each represents hydrogen, NR n R 12 ,
  • dC 6 alkyl may optionally be substituted with up to three substituents which are selected independently from the group consisting of hydroxy, dC 6 alkoxy, amino, mono- or di- dd-alkylamino, dd-alkylcarbonylamino, hydroxycarbonyl, dC 6 -alkoxycarbonyl and mono- or di-dC 6 - alkylaminocarbonyl,
  • R 11 , R 12 and R 13 are the same or different and each represent hydrogen or dC 6 -alkyl, where dC 6 -alkyl can optionally be substituted with up to three substituents selected from the group consisting of
  • A is bonded to the aromatics via positions 2, 3, 5 or 6 and
  • A stands for NR 6 .
  • Y stands for NR 8 , D and X represent oxygen
  • G represents C 6 -C 10 aryl, where C 6 -do-aryl can optionally be substituted with up to three substituents which are selected independently of one another from the group consisting of halogen, hydroxy, cyano and dC 6 alkyl,
  • dC 6 - alkyl can optionally be substituted with up to three substituents of halogen
  • G represents C 5 -C 6 heteroaryl, where dd-heteroaryl may optionally be substituted with up to three substituents which are selected independently of one another from the group consisting of halogen and dC 3 alkyl,
  • G represents d-cycloalkyl, where C 3 -do-cycloalkyl can optionally be substituted with up to three substituents dC 6 -alkyl,
  • R 1 , R 2 and R 3 are the same or different and each represents hydrogen or d-
  • R 4 represents hydrogen, C 6 -C 10 aryl or dC 6 alkyl, where dC 6 alkyl may optionally be substituted with up to three substituents which are selected independently of one another from the group consisting of
  • C 6 -C 10 aryl may optionally be substituted with up to three substituents which are selected independently of one another from the group consisting of halogen, hydroxy, dC 6 alkoxy and C 1 -C 6 alkyl,
  • R 1 , R 2 , R 3 and R 4 are not simultaneously hydrogen
  • R 5 represents hydrogen, halogen, hydroxy, amino, mono- or di-dC 6 -alkylamino or dC 6 -alkyl, where dC 6 -alkyl can optionally be substituted with up to three substituents which are selected independently of one another from the group consisting of hydroxy, d-
  • R 'and R s are hydrogen
  • A is bonded to the aromatics via positions 2, 3, 5 or 6 and
  • A stands for NR 6 .
  • E stands for NR 7 .
  • Y stands for NR 8 .
  • G represents C 6 -do-aryl, where d-do-aryl may optionally be substituted with up to three substituents selected from the group consisting of
  • dC 6 -alkyl can optionally be substituted with up to three substituents of halogen, preferably fluorine,
  • R 1 , R 2 , R 3 and R 4 are the same or different and each represents hydrogen or dC 3 alkyl, R 5 represents hydrogen,
  • R 6 , R 7 and R 8 represent hydrogen
  • A is bonded to the aromatics via positions 2, 3, 5 or 6 and
  • A stands for NR 6 .
  • E stands for NR 7 .
  • G is C 6 -C ⁇ o-aryl, where C ö -Cjo-aryl may be optionally substituted with up to three substituents selected from selected the group consisting of halogen or C 6 - alkyl,
  • d-d-alkyl can optionally be substituted with up to three substituents of halogen, preferably fluorine,
  • R 1 , R 2 , R 3 and R 4 are the same or different and each represents hydrogen or dC 3 alkyl, where R 1 , R 2 , R 3 and R 4 are not simultaneously hydrogen,
  • R 5 represents hydrogen
  • R 6 , R 7 and R 8 represent hydrogen
  • radical A in the compounds of the general formula (I) is bonded to the aromatic system via position 3.
  • the compounds of the general formula (I) for D and X have oxygen.
  • the compounds of the general formula (I) for A, E and Y have NH.
  • G is substituted phenyl in the compounds of the general formula (I).
  • the compounds of the general formula (I) have hydrogen for R 1 , R 2 and R 5 and methyl for R 3 and R 4 .
  • the compounds of the general formula (I) for R 5 have hydrogen, hydroxy, chlorine or fluorine.
  • the invention further relates to processes for the preparation of the compounds of formula (I).
  • A is bonded to the aromatics via positions 2, 3, 5 or 6 and
  • R 1 , R 2 , R 3 , R 4 , R 5 , A, X and Y have the meaning given above,
  • A is bonded to the aromatics via positions 2, 3, 5 or 6, and
  • R 1 , R 2 , R 3 , R 4 , R 5 , A, D, G, X and Y have the meaning given above,
  • inert solvents these include 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, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, gly - Koldimethylether or Diethylenglykoldimethylether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethyl acetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, preferred solvents are methylene chloride or m
  • the compounds of the general formula (III) are known or can be synthesized from the corresponding starting materials by known processes.
  • L 1 represents p-nitrophenyl or halogen, preferably bromine or chlorine
  • A is bonded to the aromatics via positions 2, 3, 5 or 6, and R 1 , R 2 , R 3 , R 4 , R 5 , A, D, E, G, X and Y have the meaning given above,
  • inert solvents these include 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, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, gly - koldimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethyl acetamide, 2-butanone, acetonitrile or pyridine, preferred solvents are tetrahydrofuran or methylene chloride, if
  • the compounds of the general formula (IV) are known or can be synthesized from the corresponding starting materials by known processes.
  • -NCD is bonded to the aromatics via positions 2, 3, 5 or 6, and
  • R 1 , R 2 , R 3 , R 4 , R 5 , D, X and Y have the meaning given above,
  • M represents oxygen or NR 7 ,
  • R 1 , R 2 , R 3 , R 4 , R 5 , D, G, M, X and Y have the meaning given above,
  • inert solvents these include 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, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethyl acetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, preferred solvents are tetrahydrofuran or methylene chloride,
  • NH 2 is bonded to the aromatics via positions 2, 3, 5 or 6 and
  • R 1 , R 2 , R 3 , R 4 , R 5 , X and Y have the meaning given above,
  • NO 2 is bonded to the aromatics via positions 2, 3, 5 or 6 and
  • R 1 , R 2 , R 3 , R 4 and R 5 have the meaning given above,
  • R 8 has the meaning given above
  • Reactions can take place in one or two reaction steps.
  • hydrazine and palladium-on-carbon are used simultaneously in inert solvents, including ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, Ethanol, n-propanol, iso-propanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylacetamide, acetonitrile or pyridine, preferred solvents are ethanol or iso -Propanol, preferably in a temperature range from room temperature to the reflux of the solvent at normal pressure.
  • solvents including ethers such as diethyl ether, methyl ter
  • hydrazine, hydroxylamine or a compound of the general formula (VIII) in inert solvents including ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, Alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl acetamide, acetonitrile or pyridine, preferably ethanol or iso-propanol, preferably in a temperature range from room temperature to the reflux of the solvents under normal pressure, are used as solvents.
  • solvents including ethers
  • these include ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or Diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or
  • Petroleum fractions, or other solvents such as ethyl acetate, dimethylformamide, dimethylacetamide, acetonitrile or pyridine are preferably ethanol, isopropanol or in the case of tin dichloride in dimethylformamide, preferably in a temperature range from room temperature to the reflux of the solvents at normal pressure to 3 bar, implemented.
  • hydrazine, hydroxylamine or a compound of the general formula (VIII) in inert solvents including ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, Alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine, as solvents are preferably ethanol or iso-propanol, preferred in a temperature range from room temperature to reflux of the solvents at normal pressure.
  • solvents are preferably ethanol or iso-
  • Lawesson's reagent is used in inert solvents, including 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 dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, 1,2-dimethoxyethane, dimethyl sulfoxide or pyridine, toluene, xylene or dioxane are preferred, preferably in a temperature range from room temperature to Reflux of the
  • hydrogen donors preferably hydrazine or hydrogen and with palladium on carbon, or with tin dichloride in inert solvents
  • ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, Glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine, the preferred solvents are ethanol, isopropanol or, in the case of tin dichloride, dimethylformamide, preferably in a temperature
  • NHR 6 is bonded to the aromatics via positions 2, 3, 5 or 6 and
  • R has the meaning given above, and L 2 represents halogen, preferably bromine or iodine,
  • inert solvents including ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene,
  • Sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium, or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, preferably diisopropylethylamine, potassium tert-butylate or DBU, preferably in a temperature range from room temperature to the reflux of the solvents
  • the compounds of the general formula (IX) are known or can be synthesized from the corresponding starting materials by known processes.
  • R 1 , R 2 , R 3 , R 4 , R 5 , X and Y have the meaning given above,
  • 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, 1,2-dimethoxyethane, dioxane, tetrahydrofuran or diethylene glycol ether , Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone,
  • Dimethylformamide, dimethylacetamide, 2-butanone, acetonitrile or pyridine implemented.
  • Preferred solvents are tetrahydrofuran or dichloromethane, optionally in the presence of a base, such as, for example, 1,8-bis (dimethylamino) naphthalene, DBU, triethylamine or diisopropylethylamine, preferably 1,8-bis (dimethylamino) naphthalene, preferably in one Temperature range from room temperature to the reflux of the solvents at normal pressure.
  • fuming nitric acid, concentrated nitric acid or nitrating acid preferably in a temperature range from -30 ° C to 0 ° C at normal pressure.
  • R 5 has the meaning given above
  • Lewis acids preferably aluminum trichloride
  • inert solvents these include 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, 1,2-dimethoxyethane, dioxane, tetrahydrofuran or diethylene glycol dimethyl ether , Hydrocarbons such as benzene, nitrobenzene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine (the preferred solvent is 1,2-dichloroethane) in a temperature range of -20 ° C to room temperature at normal pressure
  • R 2 represents hydrogen, Compounds of the general formula (XHIa),
  • R 1 , R 3 , R 4 and R 5 have the meaning given above, and
  • R 14 represents (Ci-Qd-alkyl, preferably methyl and ethyl,
  • bases such as, for example, alkali metal hydroxides such as sodium, lithium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, preferably sodium hydroxide, in inert solvents, these include halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,1 2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert , -Butanol, hydrocarbons such as benzene, benz
  • the compounds of the general formula (X) can also be prepared analogously to the synthetic route described for processes of the compounds of the general formula (Xa) from the compounds of the general formula (XIII).
  • compounds of the general formula (XIV) are used
  • R 1 , R 3 , R 4 , R 5 and R 14 have the meaning given above,
  • 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, 1,2-dimethoxyethane, dioxane, tetrahydrofuran or diethylene glycol dimethyl ether , Alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, dimethylformamide, Dimethylacetamide,
  • R 5 has the meaning given above
  • R 1 , R 3 , R 4 and R 14 have the meaning given above,
  • inert solvents including ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofiiran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, ethylbenzene, xylene,
  • R 5 has the meaning given above
  • halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene
  • ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, Glycol dimethyl ether or diethylene glycol dimethyl ether
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol
  • hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone , Di
  • L 3 represents halogen, preferably bromine or iodine
  • inert solvents including ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, ethylbenzene, xylene, toluene, preferred solvents are tetrahydrofuran or toluene, if appropriate in the presence of a base, such as, for example, amides such as sodium amide, lithium hexamethyl disilazide, potassium hexamethyl disilazide, lithium disopropyl amide, or other bases such as sodium hydride, DBU or diisopropylethyl amine, preferably sodium amide, lithium hexamethyl disilazide, potassium hexamethyl disilazide or lithium diisopropyl amide, preferably in a temperature range from ether
  • R 1 and R 2 represent hydrogen
  • R 3 , R 4 , R 5 and R 14 have the meaning given above,
  • reaction is carried out analogously to the first stage of the two-stage process described for the preparation of the compounds of the general formula (Ila).
  • reaction is carried out analogously to the second stage of the two-stage process described for the preparation of the compounds of the general formula (Ila).
  • R 3 , R 4 , R 5 and R 14 have the meaning given above,
  • the compounds of the general formula (XXII) can be synthesized from the corresponding starting materials by the process described for the compounds of the general formula (XIII).
  • R 15 represents allyl or benzyl, in the case of benzyl with reducing agents.
  • the reaction is carried out analogously to the second stage of the two-stage process described for the preparation of the compounds of the general formula (Ila).
  • N, N-Dimethylbarbiturklare used see F. Garro-Helion, A. Merzouk, F. Guibe, J. Org. Chem. 1993, 58, 6109-6113.
  • the compounds of the general formula (XXLU) can be synthesized from the corresponding starting materials by the process described for the compounds of the general formula (XIII).
  • the compounds of the general formula (I) according to the invention have an unforeseeable spectrum of active effects. They show an antiviral activity against representatives of the group of herpes viridae, especially against the human cytomegalovirus (HCMV). They are therefore suitable for the treatment and prophylaxis of diseases caused by herpes viridae, in particular diseases caused by human cytomegaloviruses.
  • HCMV human cytomegalovirus
  • the compounds according to the invention are valuable active ingredients for the treatment and prophylaxis of human cytomegalovirus infections and diseases caused thereby.
  • indications which may be mentioned are: 1) Treatment and prophylaxis of HCMV infections in ATDS patients (retinitis, pneumonitis, gastrointestinal infections).
  • the new active ingredients can be used alone and, if necessary, in combination with other antiviral active ingredients such as Gancyclovir or Acyclovir.
  • test compounds are used as 50 millimolar (mM) solutions in dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • Ganciclovir, foscarnet and cidofovir serve as reference compounds.
  • 96-well plate performed.
  • the wells in rows 1 and 12 each contain 50 ⁇ l Mediu.
  • Row 12 (without substance) serves as a virus control.
  • the final test concentrations are 250-0.0005 ⁇ M.
  • the plates are incubated for 6 days at 37 ° C / 5% CO 2 , ie until all cells in the virus controls are infected (100% cytopathogenic effect [CPE]).
  • CPE cytopathogenic effect
  • the wells are then fixed by adding a mixture of formalin and Giemsa's dye and colored (30 minutes), with aqua bidest. washed and in the drying cabinet
  • CC 50 substance concentration in ⁇ M at which no visible cytostatic effects on the cells can be seen compared to the untreated cell control;
  • EC 50 substance concentration in ⁇ M that inhibits the CPE (cytopathic effect) by 50% compared to the untreated virus control;
  • SI (selectivity index) CC 50 (NHDF) / EC 50 (HCMV).
  • SCID-NOD or SCID-beige are used by commercial breeders (Bomholtgaard, Jackson). The animals are kept in isolators under sterile conditions (including litter and feed).
  • Virus cultivation Human cytomegalovirus (HCMV), DavisSmith strain, is grown in vitro on human embryonic foreskin fibroblasts (NHDF cells). After infection of the NHDF cells with a multiplicity of infection (MOI) of 0.01, the virus-infected cells are harvested 5-7 days later and in the presence of Minimal Essential Medium (MEM), 10% fetal calf serum (FKS) with 10% DMSO at - Store at -40 ° C. After serial dilution of the virus-infected cells in steps of ten, the titer is determined on 24-well plates of confluent NHDF cells after vital staining with neutral red.
  • MOI multiplicity of infection
  • FKS fetal calf serum
  • the infected sponges are incubated with 25 ⁇ l PBS / 0.1% BSA / 1 mM DTT with 5 ng / ⁇ l basic fibroblast growth factor (bFGF).
  • the immunodeficient mice are anesthetized with avertine, the dorsal coat removed with the help of a dry razor, the epidermis opened 1-2 cm, relieved and the moist sponges transplanted under the dorsal skin.
  • the surgical wound is closed with tissue glue.
  • the mice were treated orally with substance three times a day (7 a.m. and 2 p.m. and 7 p.m.) over a period of 8 days.
  • the dose is 7 or 15 or 30 or 60 mg / kg body weight, the application volume 10 ml / kg body weight.
  • the substances are formulated in the form of a 0.5% tylose suspension with 2% DMSO. 9 days after the transplant and 16 hours after the last substance application, the animals are killed painlessly and the sponge is removed. The virus-infected cells are released from the sponge by collagenase digestion (330 U / 1.5 ml) and stored at -140 ° C. in the presence of MEM, 10% fetal calf serum, 10% DMSO. The evaluation is carried out after serial dilution of the virus-infected cells in steps of ten by titer determination on 24-well plates of confluent NHDF cells after vital staining with neutral red. The number of infectious virus particles after substance treatment compared to the placebo-treated control group is determined.
  • the new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, ie in amounts which are sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, if appropriate using emulsifiers and / or dispersants, it being possible, for example if organic solvents to be used as diluents, to use organic solvents as auxiliary solvents.
  • the application is carried out in the usual way, preferably orally, parenterally or topically, in particular perlingually or intravenously.
  • TIPS Triisopropylsilyl titr. titrated
  • Example 8A 4- (4-Chl ⁇ henyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester
  • the ester to be saponified is dissolved in a THF / methanol mixture (1: 1) and the solution is cooled to 0 ° C. At this temperature 2 eq. 1 N sodium hydroxide solution slowly added dropwise. After the reaction has ended (reaction control by TLC), equal proportions of an IN sodium hydroxide solution and dichloromethane are added in each case. The organic phase is extracted twice with 1 N sodium hydroxide solution. The combined aqueous phases are then acidified with concentrated hydrochloric acid and the product extracted three times with dichloromethane. After drying over sodium sulfate, filtration and evaporation of the solvent, the product is obtained and used for the next synthesis step without further purification.
  • the reflux condenser was added and 1,2-dichloroethane was added at RT (20 ml per g of aluminum trichloride).
  • the suspension is cooled to 0 ° C. with an ice bath and then the anhydride (1.05 eq.) Is added in portions.
  • stirring is continued for 5 min, and then benzene (1.0 eq.) Is slowly added dropwise.
  • the mixture is slowly warmed to room temperature overnight, then poured onto ice and the precipitate is redissolved with 1N hydrochloric acid.
  • the aqueous phase is extracted twice with dichloromethane, the combined organic phases washed twice with water, dried over sodium sulfate and the solvent removed in vacuo. The substance is used as a crude product in subsequent reactions.
  • fuming nitric acid is cooled in a flask to -15 ° C and the aromatic is added in portions at this temperature in counter-argon (300 mg per 1 ml nitric acid). After 30 min the mixture is poured onto ice, and
  • nitro compound (1.0 eq.) And hydrazine monohydrate (20.0 eq.) are placed in ethanol at RT (0.1 M solution), then 10% by weight of palladium-carbon (10% by weight) are added and the mixture is heated under reflux overnight. Then the
  • the catalyst is filtered off, washed with ethanol and then the solvent is removed in vacuo.
  • the product is purified by repeated recrystallization from ethanol or by column chromatography (silica gel for separating the o-isomer, preparative HPLC (method 12) for separating the p-isomer).
  • the target compound is obtained quantitatively as a crude product, which is reacted without further purification.
  • example 44A is also prepared from 4- (2-hydroxy-5-nitrophenyl) -3,3-dimethyl-4-oxobutanoic acid (example 42A) according to the same synthesis instructions.
  • 3-bromophenyl isocyanate is stirred overnight at room temperature. A white solid precipitates out. Filtration gives 48.4 mg (84% of theory) of product as a white solid.
  • the target compound is prepared as a racemate from the corresponding educts and then separated from the other enantiomer by an HPLC method (Method 9) developed specifically for this enantiomer separation.
  • the target compound is prepared as a racemate from the corresponding educts and then separated from the other enantiomer by an HPLC method (Method 9) developed specifically for this enantiomer separation.
  • Example 61 The examples in Table 1 can be obtained according to the general working procedure [H].
  • Example 61 The examples in Table 1 can be obtained according to the general working procedure [H].
  • N-methacrylacyl-L-leucine-dicyclopropylmethylamide flow 15 ml / min eluent: iso-hexane / ethyl acetate 20:80

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Abstract

La présente invention concerne de nouveaux composés, des procédés de production desdits composés et leur utilisation comme médicaments, notamment comme agents antiviraux, en particulier contre des cytomégalovirus.
EP02740725A 2001-06-28 2002-06-17 Pyridazinones Withdrawn EP1404657A1 (fr)

Applications Claiming Priority (3)

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DE10131133 2001-06-28
DE10131133A DE10131133A1 (de) 2001-06-28 2001-06-28 Pyridazinone
PCT/EP2002/006641 WO2003002541A1 (fr) 2001-06-28 2002-06-17 Pyridazinones

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MXPA05005409A (es) 2002-11-21 2005-08-03 Neurosearch As Derivados de arilureido y su uso medico.
DE10300109A1 (de) * 2003-01-07 2004-07-15 Bayer Healthcare Ag Methode zur Inhibition der Replikation von Herpesviren
DE102005033103A1 (de) * 2005-07-15 2007-01-25 Bayer Healthcare Ag Heterocyclylamid-substituierte Thiazole, Pyrrole und Thiophene

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DE1670043C3 (de) * 1966-01-07 1975-05-22 Basf Ag, 6700 Ludwigshafen Verfahren zur Herstellung von 3-(Aminophenyl)-pyridazon-(6)-derivaten
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