EP2054053A1 - Acides spirotétroniques à substitution biphényle et leur utilisation pour le traitement de maladies rétrovirales - Google Patents

Acides spirotétroniques à substitution biphényle et leur utilisation pour le traitement de maladies rétrovirales

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Publication number
EP2054053A1
EP2054053A1 EP07801624A EP07801624A EP2054053A1 EP 2054053 A1 EP2054053 A1 EP 2054053A1 EP 07801624 A EP07801624 A EP 07801624A EP 07801624 A EP07801624 A EP 07801624A EP 2054053 A1 EP2054053 A1 EP 2054053A1
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EP
European Patent Office
Prior art keywords
alkyl
phenyl
substituents
alkoxy
halogen
Prior art date
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Application number
EP07801624A
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German (de)
English (en)
Inventor
Dirk Heimbach
Adrian Tersteegen
Kai Thede
Reinhold Welker
Beate Fast
Arnold Paessens
Frank Dittmer
Rudolf Schohe-Loop
Axel Harrenga
Alexander Hillisch
Kerstin Henninger
Walter Hübsch
Marcus Bauser
Daniela Paulsen
Alexander Birkmann
Thomas Bretschneider
Reiner Fischer
Susanne Greschat
Andreas Urban
Steffen Wildum
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Aicuris GmbH and Co KG
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Aicuris GmbH and Co KG
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Publication of EP2054053A1 publication Critical patent/EP2054053A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

Definitions

  • the present invention relates to novel substituted spirotetronic acids, processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the production of medicaments for the treatment and / or prophylaxis of diseases, in particular of retroviral diseases, in humans and / or animals.
  • HIV human immunodeficiency virus
  • ABDS Advanced Immunodeficiency Syndrome
  • RT inhibitors There are two classes of RT inhibitors: Nucleosidic RT inhibitors (NRTIs) act by competitive inhibition or chain termination in DNA polymerization.
  • NRTIs Nucleosidic RT inhibitors
  • NRTI Non-nucleoside RT inhibitors
  • PI protease inhibitors
  • WO 99/55673, DE 4014420 and WO 2006/000355 describe, inter alia, spirotetronic acids as pesticides and herbicides.
  • WO 96/29333 and WO 95/07901 describe tetronic acids for the treatment of HTV.
  • the invention relates to compounds of the formula
  • R 1 and R 2 together with the carbon atom to which they are attached are a group of the formula
  • X is an oxygen atom, a sulfur atom or NR 14 ,
  • R 14 is C r C 6 alkyl, C 2 -C 4 alkenyl, C r C 4 alkylsulfonyl, benzylsulfonyl, - (CH 2 ) O COR 16 , - (CH 2 ) p CONR 17 R 18 , - (CH 2 ) q is NR 24 COR 25 or - (CH 2 ) V NR 26 SO 2 R 27 ,
  • alkyl, alkenyl and alkylsulfonyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, hydroxycarbonyl, aminosulfonyl, QC 4 - alkoxy, Ci-C 4 -alkoxycarbonyl , Ci-C4 -AIlCy laminocarbonyl, Ci-C 4 - alkylaminosulfonyl, benzylaminosulfonyl, C 3 -C 7 cycloalkyl, phenyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, and -
  • phenyl, heterocyclyl and heteroaryl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, C] -C 4 - Alkyl, dC 4 alkoxy, -C 4 alkylamino, C r C 4 alkylsulfonyl and Ci-C4-alkoxycarbonyl,
  • alkoxy may be substituted with a substituent
  • phenyl, heterocyclyl and heteroaryl may in turn be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, cyano,
  • phenyl, heterocyclyl and heteroaryl in turn may be substituted with 1 to 3 substituents, wherein the substituents are independently selected
  • 25 are selected from the group consisting of halogen, cyano,
  • o is a number 0, 1, 2 or 3
  • p is a number 0, 1, 2 or 3,
  • q is a number 2 or 3
  • v is a number 2 or 3
  • R 16 is Ci-Q-alkyl, C 2 -C 4 alkenyl, C r C 6 alkoxy, phenyl, benzyloxy or 5- to 10-membered heterocyclyl,
  • alkyl and alkenyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl,
  • Cycloalkyl phenyl, phenoxy, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl and 5- or 6-membered heteroarylcarbonyl,
  • substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulphonyl, C r Q-alkyl, C r C 4 alkoxy, C r C 4 - alkylamino, C r C 4 - 20 alkylsulfonyl and Ci-C4-alkoxycarbonyl,
  • R 17 is hydrogen, C r C 4 alkyl or phenyl
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of methoxy, C 3 -C 7 cycloalkyl, phenyl, 5- to 10-membered heterocyclyl and 5- or 6-membered heteroaryl,
  • phenyl, heterocyclyl and heteroaryl may in turn be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, cyano,
  • R 18 is hydrogen or C r C 4 alkyl
  • R 24 is hydrogen or C 1 -C 4 -alkyl
  • R 25 is Ci-Ce-alkyl, C 2 -C 4 alkenyl, C r C 6 alkoxy, phenyl, benzyloxy or 5- to 10-membered heterocyclyl,
  • alkyl and alkenyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl,
  • Cycloalkyl phenyl, phenoxy, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl and 5- or 6-membered heteroarylcarbonyl,
  • substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulphonyl, Cp C4 alkyl, C, -C 4 alkoxy, C, -C 4 alkylamino, QC 4 - 20 alkylsulfonyl and Ci-C4-alkoxycarbonyl,
  • R 26 is hydrogen or C 1 -C 4 -alkyl
  • R 27 is C r C 6 alkyl, C 2 -C 4 -alkenyl, phenyl or 5- to 10-membered heterocyclyl,
  • alkyl and alkenyl may be substituted with a
  • R 15 is Ci-C 6 alkyl, C 2 -C 4 alkenyl, C r C 4 alkylsulfonyl, benzylsulfonyl, -
  • alkyl, alkenyl and alkylsulfonyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano,
  • phenyl, heterocyclyl and heteroaryl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, C] -C 4 -
  • alkoxy may be substituted with a substituent selected from the group consisting of halogen, cyano,
  • substituents 5 may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, hydroxy-carbonyl, hydroxysulfonyl, C r C 4 alkyl, C r C 4 - Alkoxy, C 1 -C 4 -
  • R 23 is C 3 -C 7 -cycloalkyl, phenyl, 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl,
  • phenyl, heterocyclyl and heteroaryl in turn may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, hydroxy-carbonyl,
  • 25 r stands for a number 0, 1, 2 or 3,
  • s stands for a number 0, 1, 2 or 3,
  • t is a number 2 or 3
  • R 19 is C 1 -C 6 -alkyl, C 2 -C 4 -alkenyl, C 1 -C 6 -alkoxy, phenyl, benzyloxy or 5- to 10-membered heterocyclyl,
  • alkyl and alkenyl may be substituted with a substituent, wherein the substituent is selected from
  • phenyl, phenoxy and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, Q-
  • R 20 is hydrogen, C r C 4 alkyl or phenyl
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of
  • phenyl, heterocyclyl and heteroaryl in turn may be substituted with 1 to 3 substituents, wherein the substituents are independently selected
  • 25 are selected from the group consisting of halogen, cyano,
  • R 21 is hydrogen or C r C 4 alkyl
  • R 28 is hydrogen or C r C 4 alkyl
  • R 29 is C 1 -C 6 -alkyl, C 2 -C 4 -alkenyl, C 1 -C 6 -alkoxy, phenyl, benzyloxy or 5- to 10-membered heterocyclyl,
  • alkyl and alkenyl may be substituted with a substituent, wherein the substituent is selected from
  • phenyl, phenoxy and heteroaryl may be substituted by 1 to 3 substituents, the substituents being independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, C 1 -
  • R 30 is hydrogen or C 1 -C 4 -alkyl
  • R 31 is C 1 -C 6 -alkyl, C 2 -C 4 -alkenyl, phenyl or 5- to 10-membered heterocyclyl,
  • alkyl and alkenyl may be substituted with a
  • Substituent wherein the substituent is selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, hydroxycarbonyl, aminosulfonyl, Ci-C 4 alkoxycarbonyl, C 3 -C 7 - cycloalkyl, phenyl, phenoxy, 5- to 10-membered heterocyclyl , 5-
  • phenyl, phenoxy and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from
  • R 8 represents hydrogen, oxo, trifluoromethyl, trifluoromethoxy, C r C 4 alkyl, C, -C 4 alkoxy or C r C 4 alkylthio,
  • R 9 is hydrogen, C r C 4 alkyl or C r C 4 alkoxy
  • R 10 is hydrogen or C r C 4 alkyl
  • R 11 is hydrogen or C r C 4 alkyl
  • R 12 is hydrogen or C 1 -C 4 -alkyl
  • R 13 is hydrogen or C 1 -C 4 -alkyl
  • R 3 is hydrogen, halogen, cyano, methyl, ethyl, methoxy, ethoxy or phenoxy,
  • R 4 is hydrogen, halogen, methyl, ethyl, methoxy or ethoxy,
  • R 5 is hydrogen, halogen, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, hydroxymethyl, aminomethyl, Ci-C4-alkyl, Ci-C 4 - alkoxy, Ci-C 4 alkylamino, C r C 4 alkylthio, C r C 4 alkylcarbonyl, C r C 4 - alkylaminocarbonyl, C 3 -C 6 cycloalkylaminocarbonyl, Ci-C4-alkylcarbonylamino, QC 4 -
  • Ci-C 4 alkylsulfonyl Ci-C4 alkylsulfonylamino, C 2 -Q- Alkenylsulfonylamino, Ci-C4-alkylsulfonyl (Ci-C 4 alkyl) amino, benzylsulfonylamino, 5- or 6-membered or 5 Heteroarylsulfonylamino - to 7-membered heterocyclyl,
  • alkylaminocarbonyl, alkylcarbonylamino and alkylsulfonylamino may be substituted by a substituent, the substituent being selected from the group consisting of cyano, hydroxy, amino, hydroxycarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, morpholinyl, piperidinyl, Pyrrolidinyl and benzylamino,
  • R 6 is hydrogen, halogen, C r C 4 alkyl or C r C 4 alkoxy
  • R 7 is hydrogen, halogen, C, -C 4 alkyl or C r C 4 alkoxy
  • R 5 and R 6 are attached to adjacent carbon atoms and together with the carbon atoms to which they are attached form a 1,3-dioxolane,
  • Compounds of the invention are the compounds of formula (I) and their salts, solvates and solvates of the salts; the compounds of the formula (I) below and the salts, solvates and solvates of the salts thereof and the compounds of formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the of formula (I), compounds mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • the present invention encompasses all tautomeric forms.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Physiologically acceptable salts of the compounds of the present invention also include salts of conventional bases such as, by way of example and by way of example, alkali metal salts (e.g., sodium and potassium salts), alkaline earth salts (e.g., calcium and magnesium salts), and ammonium salts derived from alkali metal salts (e.g., sodium and potassium salts), alkaline earth salts (e.g., calcium and magnesium salts), and ammonium salts derived from any suitable bases.
  • Ammonia or organic amines having 1 to 16 carbon atoms as exemplified and preferably Ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.
  • Alkyl and the alkyl moieties in alkoxy Alkylamino, alkylthio.
  • Alkylcarbonyl Alkylsulfonyl.
  • Alkoxycarbonyh Alkylaminocarbonyl, Alkylaminosulfonyl.
  • Alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino and alkylsulfone vKQ-Gi-alkyDamino represents straight-chain or branched alkyl and, unless stated otherwise, comprises C 1 -C 6 -alkyl, in particular C 1 -C 4 -alkyl, such as, for example, methyl, ethyl, propyl, isopropyl, Butyl, isobutyl.
  • Alkenyl represents a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms. Preferred is a straight-chain alkenyl radical having 2 to 3 carbon atoms.
  • vinyl, allyl, n-prop-1-en-1-yl and n-but-2-en-1-yl By way of example and by way of preference: vinyl, allyl, n-prop-1-en-1-yl and n-but-2-en-1-yl.
  • 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. Preference is given to a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.
  • Alkylamino in the context of the invention represents an amino group having one or two (independently selected) straight-chain or branched alkyl substituents, which preferably have 1 to 6, 1 to 4 or 1 to 2 carbon atoms.
  • C 1 -C 3 -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • Alkylthio is exemplified and preferably methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.
  • Alkylcarbonyl is exemplified and preferably methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl and tert-butylcarbonyl.
  • Alkylsulfonyl is, by way of example and by way of preference, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.
  • Alkoxycarbonyl is exemplified and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • Alkylaminocarbonyl in the context of the invention represents an aminocarbonyl group having one or two (independently selected) straight-chain or branched alkyl substituents, which preferably have 1 to 6, 1 to 4 or 1 to 2 carbon atoms.
  • C 1 -C 3 -alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • Alkylaminosulfonyl in the context of the invention is an aminosulfonyl group having one or two (independently selected) straight-chain or branched alkyl substituents which preferably have 1 to 6, 1 to 4 or 1 to 2 carbon atoms.
  • C 1 -C 3 -alkylaminosulfonyl is, for example, a monoalkylaminosulfonyl radical having 1 to 3 carbon atoms or a dialkylaminosulfonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • Alkylcarbonylamino is, by way of example and by way of preference, methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino and tert-butylcarbonylamino.
  • Alkoxycarbonylamino is exemplified and preferably methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, t-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonylamino.
  • Alkylsulfonylamino is by way of example and preferably methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino and n-hexylsulfonylamino.
  • Alkenylsulfonylamino is, by way of example and by way of preference, vinylsulfonylamino, amylsulfonylamino, n-prop-1-en-1-ylsulfonylamino and n-but-2-en-1-ylsulfonylamino.
  • Cycloalkyl represents a cycloalkyl group having usually 3 to 7 carbon atoms, by way of example and preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Cycloalkylaminocarbonyl is by way of example and preferably cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl and cycloheptylaminocarbonyl.
  • Heterocyclyl is a mono- or bicyclic, heterocyclic radical having usually 3 to 10, preferably 5 to 8 ring atoms and up to 3, preferably up to 2 heteroatoms and / or
  • hetero groups from the series N, O, S, SO, SO 2 where a nitrogen atom can also form an N-oxide.
  • the heterocyclyl radicals may be saturated or partially unsaturated. Preference is given to 5- to 8-membered monocyclic saturated heterocyclyl radicals having up to two heteroatoms from
  • Heteroaryl represents a 5- to 10-membered aromatic mono- or bicyclic heterocycle, preferably a 5- or 6-membered aromatic monocyclic heterocycle having up to 3 heteroatoms from the series S, O and / or N, wherein the heterocycle also in Form of the N-oxide, for example indolyl, 1H-indazolyl, 1H-1,2,3-benzotriazolyl, 1H-benzimidazolyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, pyrazolyl, thiadiazolyl, N-triazolyl, Isoxazolyl, oxazolyl or imidazolyl. Preference is given to pyridyl, thienyl, furyl and thiazolyl.
  • Halogen is fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred unless otherwise specified.
  • the abovementioned general or preferred radical definitions 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.
  • radical definitions given in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of other combinations, irrespective of the particular combinations of the radicals indicated.
  • the invention also relates to compounds of the formula (I) in which
  • R 1 and R 2 together with the carbon atom to which they are attached are a group of the formula
  • n is the number 2
  • X is an oxygen atom, a sulfur atom or NR 14 ,
  • R 14 is Ci-C 6 alkyl, C 2 -C 4 alkenyl, C r C 4 alkylsulfonyl, benzylsulfonyl, - (CH 2) O COR 16 or - (CH 2) P CONR 17 R 18,
  • alkyl, alkenyl and alkylsulfonyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano,
  • phenyl, heterocyclyl and heteroaryl may be substituted with "1 to 3 substituents wherein the substituents C 1 -C 4 -alkoxy, Ci-C alkyl, 4 alkylamino, C, -C 4 - are independently selected from the group consisting of halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, Ci-C 4 Alkylsulfonyl and C 1 -C 4 -alkoxycarbonyl,
  • o is a number 0, 1, 2 or 3,
  • p is a number 0, 1, 2 or 3,
  • R 16 is C 1 -C 6 -alkyl, C 2 -C 4 -alkenyl, C 1 -C 6 -alkoxy, phenyl, benzyloxy or 5- to 10-membered heterocyclyl,
  • alkyl and alkenyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl,
  • Cycloalkyl phenyl, phenoxy, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl and 5- or 6-membered heteroarylcarbonyl,
  • substituents 20 can be substituted with 1 to 3 substituents wherein the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, C 1 - Q alkyl, C r C 4 alkoxy, C r C 4 -Alkylamino, C 1 -C 4 -alkylsulfonyl and QQ-alkoxycarbonyl,
  • R 17 is hydrogen, C r C 4 alkyl or phenyl
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of methoxy, C 3 -C 7 -Cycolalkyl, phenyl, 5- to 10-membered heterocyclyl and 5- or 6-membered heteroaryl, in which phenyl and heteroaryl may in turn be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy and Q-Gralkyl,
  • R 18 is hydrogen or C r C 4 alkyl
  • R 8 represents hydrogen, oxo, trifluoromethyl, trifluoromethoxy, Ci-C 4 alkyl, Ci-C 4 -alkoxy or C r C 4 alkylthio,
  • R 9 is hydrogen, C r C 4 alkyl or QC 4 -alkoxy
  • R 10 is hydrogen
  • R 1 ' is hydrogen
  • R 3 is hydrogen, halogen, methyl, ethyl, methoxy, ethoxy or phenoxy,
  • R 4 is hydrogen, halogen, methyl, ethyl, methoxy or ethoxy,
  • R 5 is hydrogen, halogen, cyano, nitro, hydroxyl, amino, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, hydroxymethyl, aminomethyl, C t -C 4 -alkyl, C 1 -C 4 -
  • alkylaminocarbonyl, alkylcarbonylamino and alkylsulfonylamino may be substituted with a substituent wherein the substituent is selected from the group consisting of cyano, hydroxy, amino, hydroxycarbonyl, C r C 4 alkoxy, C r C 4 alkylamino, morpholinyl, piperidinyl, pyrrolidinyl and benzylamino,
  • R 6 is C 4 alkyl or C, -C 4 alkoxy, hydrogen, halogen, C r,
  • R 7 is hydrogen
  • R 5 and R 6 are attached to adjacent carbon atoms and together with the carbon atoms to which they are attached form a 1,3-dioxolane,
  • the invention also relates to compounds of the formula (I) in which
  • R 1 and R 2 together with the carbon atom to which they are attached are a group of the formula
  • X stands for NR 14 .
  • R 14 is C r C 4 alkyl, C 2 -C 4 alkenyl, benzylsulfonyl, - (CH 2 ) O COR 16 or
  • alkyl and alkenyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, hydroxycarbonyl, aminosulfonyl, Ci-C 4 - alkoxy, Ci-C 4 alkoxycarbonyl , C 3 -C 7 -cycloalkyl, phenyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl,
  • phenyl, heterocyclyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulphonyl, C r C 4 - alkyl, -C 4 alkoxy, Ci-C 4 alkylamino, C r C 4 alkylsulfonyl and C r C 4 alkoxycarbonyl,
  • o is a number 1 or 2
  • p is a number 1 or 2
  • R 16 is C r C 4 alkyl, C r C 4 alkoxy, phenyl or benzyloxy,
  • R 17 is hydrogen, C r C 4 alkyl or phenyl
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of methoxy, phenyl and 5- or 6-membered heteroaryl,
  • phenyl may in turn be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy and Q-Q-alkyl,
  • R 18 is hydrogen
  • R 8 is hydrogen, Ci-Q-alkyl or C r Q-alkoxy
  • R 9 is hydrogen or C r C 4 -Alky 1
  • R 10 is hydrogen
  • R 11 represents hydrogen
  • R 3 is hydrogen, halogen, methyl, ethoxy or phenoxy
  • R 4 is hydrogen, halogen or methyl
  • R 5 is hydrogen, halogen, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, hydroxymethyl
  • alkylaminocarbonyl, alkylcarbonylamino and alkylsulfonylamino may be substituted by a substituent, wherein the substituent is selected from the group consisting of amino, C 1 -C 4 -alkylamino, morpholinyl and pyrrolidinyl,
  • R 6 is hydrogen, halogen, Ci-C 4 alkyl or C r C 4 alkoxy
  • R 7 is hydrogen
  • the invention furthermore relates to compounds of the formula (I) in which
  • R 1 and R 2 together with the carbon atom to which they are attached are a group of the formula
  • n is the number 1, 2 or 3, represents an oxygen atom, a sulfur atom or NR 14 ,
  • R 14 is C 1 -C 6 -alkyl, C 2 -C 4 -alkenyl, C 1 -C 4 -alkylsulfonyl, benzylsulfonyl, - (CH 2 ) O, COR 16 , - (CH 2 ) p CONR 17 R 18 , - (CH 2 ) q NR 24 COR 25 or - (CH 2 ) V NR 26 SO 2 R 27 ,
  • alkyl, alkenyl and alkylsulfonyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, hydroxycarbonyl, aminosulfonyl, Ci-C 4 - alkoxy, C r C 4 alkoxycarbonyl, C r C 4 alkylaminocarbonyl, C r C 4 -
  • phenyl, heterocyclyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, Ci-C 4 - alkyl, C r C 4 alkoxy, C r C 4 alkylamino, C r C 4 alkylsulfonyl and Ci-Q-alkoxycarbonyl,
  • alkoxy may be substituted by a substituent selected from the group consisting of halogen, cyano, trifluoromethyl, hydroxy, hydroxy-carbonyl, aminocarbonyl, aminosulfonyl, C 1 -C 4 -alkoxy, CpQ-alkoxycarbonyl, CpC 4 -
  • phenyl, heterocyclyl and heteroaryl may in turn be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, cyano, Oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulphonyl, C r C 4 alkyl, C r C 4 alkoxy, C 1 -C 4 - alkylamino, C r C 4 alkylsulfonyl and C 1 -C 4 - alkoxycarbonyl,
  • R 22 is C 3 -C r cycloalkyl, phenyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl,
  • phenyl, heterocyclyl and heteroaryl in turn may be substituted with 1 to 3 substituents, wherein
  • the substituents are independently selected from the group consisting of halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, QQ-AIkyl, C r C 4 alkoxy, CpC 4 - alkylamino, Ci-C 4 -Alskylsulfonyl and C 1 -C 4 -
  • o is a number 0, 1, 2 or 3,
  • p is a number 0, 1, 2 or 3,
  • v is a number 2 or 3
  • R 16 is C r C 6 alkyl, C 2 -C 4 alkenyl, C r C 6 alkoxy, phenyl, benzyloxy or 5- to 10-membered heterocyclyl,
  • alkyl and alkenyl may be substituted with a
  • phenyl, phenoxy and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents
  • R 17 is hydrogen, C r C 4 alkyl or phenyl
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of methoxy, C 3 -C 7 cycloalkyl, phenyl, 5- to 10-membered heterocyclyl and 5- or 6-membered heteroaryl,
  • phenyl, heterocyclyl and heteroaryl may in turn be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl,
  • R 18 is hydrogen or C r C 4 alkyl
  • R 24 C 4 -alkyl, hydrogen or C r
  • R 25 is C 1 -C 6 -alkyl-CyI, C 2 -C 4 alkenyl, C, -C 6 alkoxy, phenyl, benzyloxy or 5- to 10-membered heterocyclyl,
  • alkyl and alkenyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl,
  • Cycloalkyl phenyl, phenoxy, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl and 5- or 6-membered heteroarylcarbonyl,
  • phenyl, phenoxy and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from
  • R 26 is hydrogen or C r C 4 alkyl
  • R 27 is C r C 6 alkyl, C 2 -C 4 -alkenyl, phenyl or 5- to 10-membered heterocyclyl,
  • alkyl and alkenyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl,
  • phenyl, phenoxy and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, Q-C 4 alkyl, C r C 4 Alkoxy, QG t -alkylamino, C r C 4 -
  • R15 is d-C ⁇ -alkyl, C 2 -C 4 alkenyl, C r C 4 alkylsulfonyl, benzylsulfonyl, - (CH 2 XCOR 19, - (CH 2) S CONR 20 R 21, - (CH 2) t NR 28 COR 29 or
  • alkyl, alkenyl and alkylsulfonyl may be substituted by 1 to 2 substituents, where the substituents are independently selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, hydroxycarbonyl, aminosulfonyl, Ci-C 4 -
  • substituents are independently selected from the group consisting of halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, C 1 -C 4 - alkyl, C 1 -C 4 -alkoxy, C r C 4 alkylamino, C r C 4 alkylsulfonyl and 15 C] -C 4 alkoxycarbonyl,
  • alkoxy may be substituted with a substituent selected from the group consisting of halogen, cyano, trifluoromethyl, hydroxy, hydroxy-carbonyl, aminocarbonyl,
  • substituents 25 may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, C r C 4 alkyl, C r C 4 alkoxy, C r C 4 -
  • R 23 is C 3 -C 7 -cycloalkyl, phenyl, 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl,
  • PhenyJ, heterocyclyl and heteroaryl in turn may be substituted with 1 to 3 substituents, wherein
  • the substituents are independently selected from the group consisting of halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulphonyl, dC 4 alkyl, C r C 4 alkoxy, C 1 -C 4 - alkylamino, Ci-C 4 Alkylsulfonyl and Ci-C 4 - 10 alkoxycarbonyl,
  • r is a number 0, 1, 2 or 3,
  • s stands for a number 0, 1, 2 or 3,
  • w is a number 2 or 3
  • R 19 is C 1 -C 6 -alkyl, C 2 -C 4 -alkenyl, C 1 -C 6 -alkoxy, phenyl, benzyloxy or 5- to 10-membered heterocyclyl,
  • alkyl and alkenyl may be substituted with a
  • phenyl, phenoxy and heteroaryl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, C 1 - C 4 alkyl, C, -C 4 alkoxy, C r C 4 alkylamino, C 1 -C 4 - alkylsulfonyl, and Ci-C 4 alkoxycarbonyl,
  • R 20 is hydrogen, C 1 -C 4 -alkyl or phenyl
  • alkyl may be substituted with a substituent
  • phenyl, heterocyclyl and heteroaryl in turn may be substituted with 1 to 3 substituents, wherein
  • the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, C, -C 4 alkyl, C r C 4 alkoxy, C r C 4 - alkylamino, C r C 4 Alkylsulfonyl and Ci-C 4 -
  • R 21 is hydrogen or C r C 4 alkyl
  • R 28 is hydrogen or C r C 4 alkyl
  • R 29 4 alkenyl, C stands for C r C 6 alkyl, C 2 -C 6 alkoxy, phenyl, benzyloxy or 5- to 10-membered heterocyclyl,
  • alkyl and alkenyl may be substituted with a
  • Substituents where the substituent is selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, hydroxycarbonyl, aminosulfonyl, QQ-alkoxycarbonyl, C 3 -C 7 -cycloalkyl, phenyl, phenoxy, 5- to 10-membered heterocyclyl, 5-
  • phenyl, phenoxy and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from
  • R 30 is hydrogen or Ci-Q-alkyl
  • R 31 is C 1 -C 6 -alkyl, C 2 -C 4 -alkenyl, phenyl or 5- to 10-membered heterocyclyl,
  • alkyl and alkenyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, hydroxycarbonyl, aminosulfonyl, C] -C 4 alkoxycarbonyl, C 3 -C 7 cycloalkyl, phenyl , Phenoxy, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl and 5- or 6-membered heteroarylcarbonyl,
  • phenyl, phenoxy and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from
  • R 8 is C 4 alkoxy or C r C 4 alkylthio stands for hydrogen, oxo, trifluoromethyl, trifluoromethoxy, C r C 4 alkyl, C r,
  • R 9 is hydrogen, C r C 4 alkyl or C r C 4 alkoxy
  • R 10 is hydrogen or C r C 4 alkyl
  • R 1 ' is hydrogen or C 1 -C 4 -alkyl
  • R 12 is hydrogen or C 1 -C 4 -alkyl
  • R 13 is hydrogen or C r C 4 alkyl
  • R 3 is hydrogen, halogen, cyano, methyl, ethyl, methoxy, ethoxy or phenoxy,
  • R 4 is hydrogen, halogen, methyl, ethyl, methoxy or ethoxy
  • R 5 is hydroxy, amino, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, hydroxymethyl, aminomethyl
  • alkylaminocarbonyl, alkylcarbonylamino and alkylsulfonylamino may be substituted with a substituent, whereby the substituent is selected from the group consisting of cyano, hydroxy, amino, hydroxycarbonyl, C r C 4 alkoxy, Ci-C4-alkylamino, morpholinyl, piperidinyl,
  • R 6 is C 4 alkyl or C, -C 4 alkoxy, hydrogen, halogen, C r,
  • R 7 is hydrogen, halogen, C r C 4 alkyl or C r C 4 alkoxy
  • R 5 and R 6 are attached to adjacent carbon atoms and together with the carbon atoms to which they are attached form a 1,3-dioxolane,
  • the invention also relates to compounds of the formula (I) in which
  • R 1 and R 2 together with the carbon atom to which they are attached are a group of the formula
  • n is the number 2, represents an oxygen atom, a sulfur atom or NR 14 ,
  • R 14 is Ci-C 6 alkyl, C 2 -C 4 alkenyl, C r C 4 alkylsulfonyl, benzylsulfonyl, - (CH 2) O COR 16 or - (CH 2) P CONR 17 R 18,
  • alkyl, alkenyl and alkylsulfonyl may be substituted with 1 to
  • substituents wherein the substituents are independently selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, hydroxycarbonyl, aminosulfonyl, Ci-C 4 - alkoxy, C r C 4 alkoxycarbonyl, C 3 -C 7 cycloalkyl, phenyl , 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl,
  • phenyl, heterocyclyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, Ci-C 4 -
  • o is a number 0, 1, 2 or 3,
  • p is a number 0, 1, 2 or 3,
  • R 16 is Ci-C 6 alkyl, C 2 -C 4 alkenyl, C r C 6 alkoxy, phenyl, benzyloxy or 5- to 10-membered heterocyclyl,
  • alkyl and alkenyl may be substituted with a substituent, wherein the substituent is selected from
  • R 17 is hydrogen, C r C 4 alkyl or phenyl
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of
  • phenyl and heteroaryl in turn may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from
  • R 18 is hydrogen or C r C 4 alkyl
  • R 8 is C 4 alkoxy or C r C 4 alkylthio stands for hydrogen, oxo, trifluoromethyl, trifluoromethoxy, C r C 4 alkyl, C r,
  • R 9 is hydrogen, C r C 4 alkyl or C r C 4 alkoxy
  • R 10 is hydrogen
  • R 1 ' is hydrogen
  • R 3 is hydrogen, halogen, methyl, ethyl, methoxy, ethoxy or phenoxy,
  • R 4 is hydrogen, halogen, methyl, ethyl, methoxy or ethoxy,
  • R 5 is hydroxy, amino, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, hydroxymethyl, aminomethyl, C r C 4 alkylamino, Ci-C4-alkylcarbonyl, CpC 4 - alkylaminocarbonyl, C3-C6 cycloalkylaminocarbonyl, Ci-C 4 - alkylcarbonylamino, Ci-C 4 - alkoxycarbonylamino, Ci-C4 alkylsulfonylamino, C 2 -C 4 -Alkenylsulfonylamino, Ci-C 4 - Alkylsulfonyl (Ci-Gralkyl) amino, benzylsulfonylamino, 5- or 6-membered heteroarylsulfonylamino or 5- to 7-membered heterocyclyl,
  • alkylaminocarbonyl, alkylcarbonylamino and alkylsulfonylamino may be substituted with a substituent, wherein the substituent is selected from the group consisting of cyano, hydroxy, amino, hydroxycarbonyl, C r C 4 alkoxy, C r C 4 alkylamino, Mo ⁇ holinyl, piperidinyl, pyrrolidinyl and benzylamino,
  • R 6 represents hydrogen, halogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy
  • R 7 is hydrogen
  • R 5 and R 6 are attached to adjacent carbon atoms and together with the carbon atoms to which they are attached form a 1,3-dioxolane,
  • the invention also relates to compounds of the formula (I) in which
  • R 1 and R 2 together with the carbon atom to which they are attached are a group of the formula
  • R 14 is C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, benzylsulfonyl, - (CH 2 ) O, COR 16 or - (CH 2 ) p CONR 17 R 18 ,
  • alkyl and alkenyl may be substituted with 1 to 2 substituents, wherein the substituents independently
  • 10 may be selected from the group consisting of halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulphonyl, Cj-C 4 with 1 to 3 substituents, whereby the substituents are independently selected from - alkyl, C r C 4 alkoxy, C r C 4 alkylamino, C r C 4 alkylsulfonyl and 15 Ci-C 4 alkoxycarbonyl,
  • o is a number 1 or 2
  • p is a number 1 or 2
  • R 16 is C, -C 4 alkyl, C r C 4 alkoxy, phenyl or benzyloxy,
  • R 17 is hydrogen, C r C 4 alkyl or phenyl
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of methoxy, phenyl and 5- or 6-membered heteroaryl,
  • phenyl may in turn be substituted with 1 to 3
  • R 8 is hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy
  • R 9 is hydrogen or C r C 4 alkyl
  • R 10 is hydrogen
  • R 11 is hydrogen
  • R 3 is hydrogen, halogen, methyl, ethoxy or phenoxy
  • R 4 is hydrogen, halogen or methyl
  • R 5 is hydroxy, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl,
  • Ci-C 4 alkylaminocarbonyl C 3 -C 6 cycloalkylaminocarbonyl, C r C 4 - alkylcarbonylamino, Ci-Q-alkoxycarbonylamino, Ci-C4 alkylsulfonylamino, C 2 -Q-
  • alkylaminocarbonyl, alkylcarbonylamino and alkylsulfonylamino may be substituted by a substituent, wherein the substituent is selected from the group consisting of amino, C 1 -C 4 -alkylamino,
  • R 6 is hydrogen, halogen, C r C 4 alkyl or C r C 4 alkoxy
  • R 7 is hydrogen
  • the invention also relates to compounds of the formula (I) in which R 5 is hydroxyl, amino, hydroxycarbonyl, aminocarbonyl, hydroxymethyl, aminomethyl, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkylaminocarbonyl, C 3 -C 6 cycloalkylaminocarbonyl, C r C 4 - alkylcarbonylamino, Ci-C 4 alkoxycarbonylamino, C r C 4 alkylsulfonylamino, C 2 -Q- Alkenylsulfonylamino, Ci-C4-alkylsulfonyl (Ci-C 4 alkyl) amino, benzylsulfonylamino, 5- or 6-membered heteroarylsulfonylamino or 5-7-membered heterocyclyl,
  • alkylaminocarbonyl, alkylcarbonylamino and alkylsulfonylamino may be substituted with a substituent, wherein the substituent is selected from the group consisting of cyano, hydroxy, amino, hydroxycarbonyl, C r C 4 alkoxy, C 1 -C 4 - alkylamino, morpholinyl, piperidinyl, pyrrolidinyl, and benzylamino.
  • the invention also relates to compounds of the formula (I) in which R 5 is CpC 4 -alkylcarbonylamino or C 1 -C 4 -alkylsulfonylamino,
  • alkylcarbonylamino and alkylsulfonylamino may be substituted with one
  • Substituent wherein the substituent is selected from the group consisting of cyano, hydroxy, amino, hydroxycarbonyl, C r C 4 alkoxy, C r C 4 alkylamino, morpholinyl, piperidinyl, pyrrolidinyl and benzylamino.
  • the invention also provides compounds of the formula (I) in which R 5 is CpC 4 -alkylsulfonylamino,
  • alkylsulfonylamino may be substituted with a substituent, wherein the substituent is selected from the group consisting of cyano, hydroxy, amino, hydroxycarbonyl, CpC 4 -alkoxy, Ci-C 4 alkylamino, morpholinyl, piperidinyl, pyrrolidinyl and benzylamino.
  • the invention also provides compounds of the formula (I) in which R 5 is CpC 4 -alkylsulfonylamino,
  • alkylsulfonylamino may be substituted with a substituent, wherein the substituent is selected from the group consisting of amino, CpC 4 alkylamino, morpholinyl and pyrrolidinyl.
  • the invention also relates to compounds of the formula (I) in which R 5 is CpC 4 -alkylsulfonyl.
  • the invention further provides a process for the preparation of the compounds of the formula (I), wherein the process
  • R> 1, r R> 2 , D R3, T R> 4 , DR 5 , DR 6 . and & DJJ 7 have the abovementioned meaning
  • R is methyl or ethyl
  • R 1 , R 2 , R 3 and R 4 have the abovementioned meaning
  • R 5 , R 6 and R 7 have the abovementioned meaning
  • Q is -B (OFT) 2 , a boronic acid ester, preferably boronic acid pinacol ester, or -BF 3 TC + ,
  • reaction according to process [A] is generally carried out in inert solvents, preferably in a temperature range from room temperature to reflux of the solvent at normal pressure.
  • Inert solvents are, for example, hydrocarbons such as toluene or benzene, or other solvents such as dioxane, dimethylformamide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred is dimethylformamide.
  • bases examples include potassium tert-butoxide, sodium hydride, lithium diisopropylamide, sodium, potassium or lithium hexamethyldisilylamide. Particularly preferred is potassium tert-butoxide.
  • reaction according to process [B] is generally carried out in inert solvents, in the presence of a catalyst, if appropriate in the presence of an additional reagent, preferably in a temperature range from room temperature to 130 ° C. under normal pressure.
  • catalysts are conventional palladium catalysts for Suzuki reaction conditions, preferably catalysts such as e.g. Dichlorobis (triphenylphosphine) palladium, tetrakistriphenylphosphinepalladium (O), palladium (II) acetate, palladium (IT) acetate / triscyclohexylphosphine or bis (diphenylphosphaneferrocenyl) palladium (I [) chloride or palladium (IT) acetate with a Ligands such as dicyclohexyl- (2 ', 4', 6'-triisopropyl-biphenyl-2-yl) -phosphine.
  • catalysts such as e.g. Dichlorobis (triphenylphosphine) palladium, tetrakistriphenylphosphinepalladium (O), palladium (II) acetate, palladium (IT) acetate /
  • Additional reagents are, for example, potassium acetate, cesium, potassium or sodium carbonate, potassium tert-butoxide, cesium fluoride or potassium phosphate, preference is given to addition reagents, such as, for example, Potassium acetate and / or aqueous sodium carbonate solution.
  • Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons, such as benzene, xylene or toluene, or carboxamides, such as dimethylformamide or dimethylacetamide, alkylsulfoxides, such as dimethyl sulfoxide, or N-methylpyrrolidone, or mixtures of the solvents with alcohols, such as methanol or ethanol and / or water, preferred is 1,2-dimethoxyethane.
  • ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • hydrocarbons such as benzene, xylene or toluene
  • carboxamides such as dimethylformamide or dimethylacetamide
  • alkylsulfoxides such as dimethyl sulfoxide, or N-methylpyrrolidone
  • alcohols such as m
  • the compounds of the formula (III) can be synthesized from the corresponding starting materials by process [A].
  • the compounds of the formula (IV) are known or can be synthesized by known processes from the corresponding starting materials.
  • the compounds of the formula (II) are known or can be prepared by reacting the compounds of the formula
  • R 3 , R 4 , R 5 , R 6 and R 7 have the abovementioned meaning
  • R 1 , R 2 and R 32 have the abovementioned meaning
  • reaction of the compound of the formula (V) with thionyl chloride or oxalic acid dichloride in the first stage is generally carried out in inert solvent, preferably in a temperature range from room temperature to reflux of the solvent at atmospheric pressure.
  • Inert solvents are, for example, halohydrocarbons such as dichloromethane or dichloroethane, hydrocarbons such as benzene, xylene or toluene, or other solvents such as chlorobenzene, toluene is preferred.
  • halohydrocarbons such as dichloromethane or dichloroethane
  • hydrocarbons such as benzene, xylene or toluene
  • other solvents such as chlorobenzene, toluene is preferred.
  • reaction of the resulting carboxylic acid chloride in the second stage with a compound of formula (VI) is generally carried out in inert solvent, preferably in a temperature range of 50 0 C to the reflux of the solvent at atmospheric pressure.
  • Inert solvents are, for example, hydrocarbons such as benzene, xylene or toluene, or other solvents such as chlorobenzene, toluene is preferred.
  • hydrocarbons such as benzene, xylene or toluene
  • other solvents such as chlorobenzene, toluene is preferred.
  • the compounds of formulas (V) and (VI) are known or can be synthesized by known methods from the corresponding starting materials.
  • reaction of the compounds of the formula (V) with compounds of the formula (VI) can also be carried out via the thiocarbonic acid esters of the compounds of the formula (V).
  • the compounds of the invention show an unpredictable, valuable spectrum of pharmacological activity.
  • the compounds of the present invention are characterized in particular by a favorable anti-retroviral spectrum of activity.
  • Another object of the present invention is the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases caused by retroviruses, in particular of HI viruses.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using a therapeutically effective amount of the compounds of the invention.
  • Examples of indications in human medicine include: 1.) The treatment and prophylaxis of human retrovirus infections
  • HIV I human immunodeficiency virus, formerly called HTLV m / LAV
  • HTV ⁇ caused infections and diseases
  • AIDS AIDS related complex
  • LAS Lymphadenopathy Syndrome
  • Resistant HIV viruses means e.g. Viruses with resistance to nucleoside inhibitors (RTI), non-nucleoside inhibitors (NNRTI) or protease inhibitors (PI) or viruses with resistance to other principles of action, e.g. T20 (fusion inhibitors).
  • RTI nucleoside inhibitors
  • NRTI non-nucleoside inhibitors
  • PI protease inhibitors
  • Examples of indications in veterinary medicine include:
  • Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention and at least one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • the compounds according to the invention can also be used to advantage, in particular in points 2, 3 and 4 above, as constituents of a combination therapy with one or more other compounds active in these areas of application.
  • these compounds can be used in combination with effective doses of antivirally active substances based on the principles of action listed below:
  • Inhibitors of HTV protease examples include: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, tipranavir;
  • Nucleosic and non-nucleosidic inhibitors of HTV reverse transcriptase examples include: zidovudine, lamivudine, didanosine, citalitabine, stavudine, abacavir, tenofovir, adefovir, nevirapine, delavirdine, efavirenz, emtricitabine, etravirine, rilpivirine;
  • Inhibitors of HTV integrase by way of example may be mentioned: S 1360, L870810;
  • Inhibitors of HTV fusion may be mentioned by way of example: Pentafuside, T 1249.
  • Inhibitors of cytochrome P450 monooxygenase by way of example: ritonavir.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicines including powder inhalers, nebulizers
  • nasal drops solutions, sprays
  • lingual, sublingual or buccal tablets to be applied
  • films / wafers or capsules to be applied
  • suppositories ear or eye preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (such as patches)
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • These adjuvants include, among others. Carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (eg antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides), and flavor and / or odor remedies.
  • Carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents eg liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents for example sodium dodecyl
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the active ingredient (s) according to the invention in total amounts of 0.1 to 200 mg / kg, preferably 1 to 100 mg / kg body weight per 24 hours, optionally in the form of several Single doses to give the desired result.
  • the active substance (s) preferably in amounts of 1 to 80 mg / kg, in particular 1 to 30 mg / kg of body weight.
  • Method 1 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - »2.5 min 30% A -» 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 5O 0 C; UV detection: 208-400 nm.
  • Method 2 Device Type MS: Micromass ZQ; Device type HPLC: Waters AHiance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A -> 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • Method 3 Device Type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - »2.5 min 30% A -» 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min. 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • Method 4 Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3 ⁇ 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A - »0.2 min 100% A -> 2.9 min 30% A -» 3.1 min 10% A - * 5.5 min 10% A; Oven: 50 ° C .; Flow: 0.8 ml / min; UV detection: 210 nm.
  • Method 5 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Onyx Monolithic C18, 100 mm x 3 mm.
  • Eluent A 1 l of water + 0.5 ml of 50% formic acid
  • eluent B 1 l of acetonitrile + 0.5 ml of 50% formic acid
  • Flow 2 ml / min
  • Oven 40 ° C
  • UV detection 208-400 nm.
  • Method 6 Device Type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Gemini 3 ⁇ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A - »3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min. 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • Method 7 Device Type MS: Waters ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Onyx Monolithic C18, 100 mm x 3 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2 min 65% A - »4.5 min 5% A -» 6 min 5% A; Flow: 2 ml / min; Oven: 40 ° C; UV detection: 210 nm.
  • Method 1 Instrument: Micromass GCT, GC6890; Column: Restek RTX-35MS, 30 m ⁇ 250 ⁇ m ⁇ 0.25 ⁇ m; constant flow with helium: 0.88 ml / min; Oven: 60 ° C; Inlet: 250 ° C; Gradient: 60 0 C (0.30 min hold), (1.7 min hold) 50 ° C / min ⁇ 120 0 C, 16 ° C / min ⁇ 250 0 C, 30 ° C / min ⁇ 300 0C.
  • the phenylacetic acid is initially charged in toluene, treated with thionyl chloride (3 eq) and stirred at 80 ° C until the evolution of hydrogen chloride. After cooling, the mixture is concentrated and the resulting acid chloride in toluene heated together with the hydroxycarboxylic acid ester for two days under reflux. It is concentrated and optionally purified or separated diastereomers by flash chromatography (mobile phase: cyclohexane / ethyl acetate gradient).
  • the purification or diastereomer separation can be carried out by column chromatography on silica gel 60 (mobile phase: cyclohexane / ethyl acetate gradient) or by preparative HPLC (RP 18 column, mobile phase: acetonitrile-water gradient, 0.1% formic acid).
  • the phenylacetic acid is initially charged in toluene, admixed with oxalic acid dichloride (5 eq.) And stirred at 80 ° C. until the evolution of hydrogen chloride has ended. After cooling, the mixture is concentrated and the resulting acid chloride is heated in toluene together with the hydroxycarboxylic acid ester overnight at 140 ° C. It is concentrated and, if appropriate, purified or separated by flash chromatography (mobile phase: cyclohexane / ethyl acetate gradient).
  • the purification or diastereomer separation can be carried out by column chromatography on silica gel 60 (mobile phase: cyclohexane / ethyl acetate gradient) or by preparative HPLC (RP 18 column, mobile phase: acetonitrile-water gradient, 0.1% formic acid).
  • Example 6A Analogously to Example 6A, the respective AAV and the general information on the preparation, the following compounds are prepared.
  • the phenylacetic acids are known in some cases from WO 97/01535 or WO 99/55673 or are prepared analogously thereto, the hydroxy carboxylic acid esters are obtainable from the corresponding cyanohydrins according to T. Bretschneider, J. Benet-Buchholz, R. Fischer, R. Nauen , Chimia 2003, 57, 697-701.
  • the purification or diastereomer separation can be carried out by column chromatography on silica gel 60 (mobile phase: cyclohexane / ethyl acetate gradient) or by flash chromatography (mobile phase: cyclohexane / ethyl acetate gradient).
  • the aqueous solution may alternatively be extracted with ethyl acetate.
  • the combined organic phases are dried over sodium sulfate, filtered, concentrated and purified as described.
  • Example 36A Analogously to Example 36A, the AAV 3 and the general information on the preparation of the following compounds are prepared. Some of the products are obtained after chromatographic separation of the diastereomer or the enantiomer mixtures.
  • Example 36A Analogously to Example 36A, the AAV 3 and the general information on the preparation of the following compounds are prepared.
  • Example 36A Analogously to Example 36A, the AAV 3 and the general information on the preparation of the following compounds are prepared.
  • the aryl halide (1.0 eq), the boronic acid (1.1 eq), the catalyst palladium (II) acetate (0.03 eq), the ligand dicyclohexyl- (2 ', 4', 6'-triisopropyl-biphenyl-2-yl) -phosphine (0.07 eq) and the base
  • Cesium carbonate (3 eq) are combined. It is degassed and aerated twice with argon, DME is added, degassed and aerated twice with argon and heated overnight at 50 ° C. After cooling, the reaction mixture is poured into 1 N hydrochloric acid solution, the aqueous phase is extracted with DCM, the dried combined organic phases over sodium sulfate, filtered and concentrated. It is purified by preparative HPLC (RP18 column, eluent: acetonitrile).
  • the aryl halide (1.0 eq), the boronic acid (1.1 eq) and DME are combined and degassed three times and aerated with argon.
  • the catalyst is added tetrakis (triphenylphosphine) palladium (O) (0.06 eq) and a degassed 20% aqueous sodium carbonate solution (10 eq) and heated overnight at 80 0 C. After cooling, the reaction mixture is poured into In aqueous hydrochloric acid, the aqueous phase is extracted with DCM, the combined organic phases are dried over sodium sulfate, filtered and concentrated. It is purified by preparative HPLC (RP18 column, mobile phase: acetonitrile-water gradient, 0.1% formic acid).
  • the purification can be carried out by column chromatography on silica gel 60 (mobile phase: cyclohexane / ethyl acetate gradient) or by flash chromatography (mobile phase: cyclohexane / ethyl acetate gradient).
  • toluene and ethanol may also be used as the solvent and heated under reflux.
  • the aryl halide (1.0 eq) and boronic acid (1.1 eq) are combined in DME, water and ethanol (3: 2: 1), degassed three times, and vented with argon.
  • the catalyst is added tetrakis (triphenylphosphine) palladium (0) (0.04 eq) and cesium carbonate (3eq.) And heated overnight at 50 0 C. After cooling, the reaction mixture is poured into 1 molar aqueous hydrochloric acid, the aqueous phase is extracted DCM, the combined organic phases are dried over sodium sulfate, filtered and concentrated. It is purified by preparative HPLC (RP18 column, mobile phase: acetonitrile-water gradient, 0.1% formic acid).
  • the purification can be carried out by column chromatography on silica gel 60 (mobile phase: cyclohexane / ethyl acetate gradient) or by flash chromatography (mobile phase: cyclohexane / ethyl acetate gradient).
  • Example 176 Analogously to Example 176 and the respective AAV 13 and AAV 14, the following compounds are prepared:
  • Example 17 Analogously to Example 17, the respective AAV and the general information on the preparation, the following compounds are prepared: Analogously to Example 176 and AAV 15, the following compounds are prepared:
  • Test substances are resolved to determine their in vitro effect on HIV protease in DMSO and serially diluted. In each case 0.5 .mu.l dilution of substance, 20 .mu.l 0.2 - 1 nM HIV-I protease wild type or mutant protein (eg multi-resistant isolate "35513": LlOI, I15V, L19I, K20R, E35D, M36I, R41K, I54V, L63P, H69K, A71V , T74P, I84V, L89M, L90M, I93L, AscoProt Biotech, Praha, Czech Republic) in buffer 1 (50 mM sodium acetate pH 4.9, 0.02% BSA, 0.1 mM EDTA, 0.5 mM DTT) and 20 ⁇ l of 8 ⁇ M substrate (M1865 of Bachern, Bubendorf, Switzerland; Matayoshi et al., Science 1990, 247, 954-8) in buffer 1 are
  • All embodiments have an IC 50 value less than 10,000 nM in this assay for HIV-I protease wild-type protein.
  • the examples of Table 1 have an IC 50 value less than or equal to 10 o nM.
  • the Assembly Assay seizes the late phase of HTV replication.
  • the transfected cells are adjusted to 3 ⁇ 10 5 cells / ml with fresh medium and seeded 40 ⁇ l of the cell suspension per well on a white 384 MTP (Greiner), which is already filled with 10 ⁇ l / well test substance solution (substances to be tested in medium without pen / Strep ) is occupied.
  • HEK293T cells of a logarithmically growing culture are adjusted with medium to a concentration of 3.5 ⁇ 10 5 cells / ml and 40 ⁇ l per well of this cell suspension are spread on a white 384 MTP and incubated overnight in a cell culture incubator.
  • the CC 50 value of a test substance results from the luciferase activity of the treated transfected cells compared to the untreated control cells.
  • the EC 50 value of a test substance results from the luciferase activity of the infected cells compared to uninfected control cells.
  • PBLs Primary human blood lymphocytes
  • RPMI 1640 medium from Gibco, Invitrogen Corporation, Düsseldorf, Germany
  • 20% fetal calf serum with phyto-agglutinin 90 ⁇ g / ml
  • interleukin-2 40 U / ml
  • PBLs are pelleted and the cell pellet is subsequently suspended in 1 ml of a suitably diluted HTV viral adsorption solution and incubated for 1 hour at 37 ° C. (pellet infection). Unabsorbed virus is then removed by centrifugation, and the infected cells are transferred to test plates (e.g., 96-well microtiter plates) containing the test substances in appropriate dilution.
  • test plates e.g., 96-well microtiter plates
  • HTV susceptible, permanent H9 cells instead of normal human blood lymphocytes used to test the antiviral effects of the compounds of the invention.
  • Infected H9 cells are cultured for testing in RPMI 1640 medium, 2% and / or 20% fetal calf serum.
  • the virus adsorption solution is centrifuged and the infected cell pellet is taken up in growth medium so that 1 ⁇ 10 5 cells per ml are set.
  • the cells thus infected are pipetted approximately 1 ⁇ 10 4 cells / well into the wells of 96-well microtiter plates (pellet infection).
  • the HTV is pipetted in separately after preparation of the substance dilutions in the microtiter plates and after addition of the cells (supernatant infection).
  • the first vertical row of the microtiter plate contains only growth medium and cells that are not infected but otherwise treated the same way as described above (cell control).
  • the second vertical row of Mikrotite ⁇ latte receives only HTV-infected cells (virus control) in growth medium.
  • the remaining wells contain the compounds of the invention in different concentrations, starting from the wells of the third vertical row of Mikrotite ⁇ latte, of which the test substances in 2-step 2 are diluted 10 -fold.
  • test mixtures are incubated at 37 ° C. until the syncytia formation typical for HTV occurs in the untreated virus control (between day 3 and 6 after infection), which is then either microscopically or via p24 ELISA detection method (Vironostika, BioMerieux, The Netherlands). or evaluated by means of Alamar Blue indicator dye photometrically or fluorimetrically.
  • the untreated virus control about 20-100 syncytia result under these test conditions, while the untreated cell control has no syncytia.
  • the ELISA test shows values less than 0.1 for the cell controls and values between 0.1 and 2.9 for the virus controls.
  • the photometric analysis of the Alamar Blue-treated cells shows extinctions of less than 0.1 for the cell controls, while the virus controls have values between 0.1 and 3 at corresponding wavelengths.
  • the IC 50 values are determined as the concentration of the treated and infected cells at which 50% (about 20-100 syncytia) of the virus-induced syncytia are suppressed by the treatment with the compound according to the invention. Accordingly, the cut-off values are set in the ELISA test and in the photometric or fluorometric determination using Alamar Blue. In addition to the determination of antiviral effects, the treated cell cultures are also examined microscopically for cytotoxic, cytostatic or cytological changes as well as for solubility. Active compounds which show cell-altering, cytotoxic findings in the concentration range of action are not evaluated in their antiviral activity.
  • the antiviral activity of a substance ie the ability to reduce the human immunodeficiency virus (HTV) titer, is tested in the murine HIV model.
  • HTV human immunodeficiency virus
  • Human cells are infected with HTV in vitro. After incubation the infected cells are on a collagen sponge (gelfoam ®) transferred and transplanted subcutaneously on the back of immunodeficient mice.
  • In the in vivo assay at least three groups of 5 to 10 animals each are used. One group is the negative contraceptive group (placebo). One group is treated with a known antiviral substance (eg Sustiva) and serves as a positive control group. In other groups, the substance is tested with unknown effect.
  • a group of 5-10 animals each is added. The animals are treated for several days (eg 4 days) in different ways (eg orally twice a day). Subsequently, the animals are killed.
  • Blood or tissue samples for further analyzes can be taken.
  • the collagen sponge is removed and enzymatically digested so that the cells remain. From these cells RNA or DNA is isolated and the viral load z. B. determined by quantitative PCR.
  • the antiviral efficacy of a substance is determined relative to the action in the placebo or in the postive control with the aid of statistical methods.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • Example 1 100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
  • the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
  • the compound according to the invention is used in a concentration below the saturation solubility in a physiologically tolerated solvent (eg isotonic saline, glucose solution 5%, PEG 400 solution 30%).
  • a physiologically tolerated solvent eg isotonic saline, glucose solution 5%, PEG 400 solution 30%.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

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Abstract

La présente invention concerne de nouveaux acides spirotétroniques substitués de formule (I) dans laquelle R1 et R2 forment ensemble avec l'atome de carbone auquel ils sont rattachés un groupe de la formule (1), (2), (3) ou (4), * désignant l'atome de carbone auquel R1 et R2 sont rattachés; des procédés pour les préparer; leur utilisation pour le traitement et/ou la prophylaxie de maladies ainsi que leur utilisation dans la préparation de médicaments destinés au traitement et/ou à la prophylaxie de maladies, en particulier de maladies rétrovirales, chez l'homme et/ou l'animal.
EP07801624A 2006-08-25 2007-08-13 Acides spirotétroniques à substitution biphényle et leur utilisation pour le traitement de maladies rétrovirales Withdrawn EP2054053A1 (fr)

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DE102006039912A DE102006039912A1 (de) 2006-08-25 2006-08-25 Substituierte Spirotetronsäuren und ihre Verwendung
PCT/EP2007/007130 WO2008022725A1 (fr) 2006-08-25 2007-08-13 Acides spirotétroniques à substitution biphényle et leur utilisation pour le traitement de maladies rétrovirales

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DE102006059319A1 (de) * 2006-12-15 2008-06-19 Bayer Healthcare Ag Substituierte Aminofuranone und ihre Verwendung
KR20110083733A (ko) * 2008-11-10 2011-07-20 화이자 리미티드 피롤리딘
EP2435440A4 (fr) * 2009-05-26 2013-01-02 Syngenta Participations Ag Nouveaux dérivés spirohétérocycliques de furane- et thiofuranedione
DE102010008644A1 (de) 2010-02-15 2011-08-18 Bayer Schering Pharma Aktiengesellschaft, 13353 Zyklische Ketoenole zur Therapie
DE102011080405A1 (de) 2011-08-04 2013-02-07 Bayer Pharma AG Substituierte 3-(Biphenyl-3-yl)-8,8-difluor-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one zur Therapie
WO2012110519A1 (fr) 2011-02-17 2012-08-23 Bayer Cropscience Ag 3-(biphényle-3-yl)-8,8-difluoro-4-hydroxy-1-azaspiro[4,5]dec-3-en-2-ones substituées pour la thérapie et des cétoénols spirocycliques substitués par des halogènes
DE102011080406A1 (de) 2011-08-04 2013-02-07 Bayer Pharma AG Substituierte 3-(Biphenyl-3-yl)-4-hydroxy-8-methoxy-1-azaspiro8[4.5]dec-3-en-2-one

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DE4014420A1 (de) * 1989-09-23 1991-04-04 Bayer Ag 5h-furan-2-on-derivate
US5207817A (en) * 1989-09-23 1993-05-04 Bayer Aktiengesellschaft Herbicidal 5H-furan-2-one derivatives
EP0720607A1 (fr) * 1993-09-17 1996-07-10 PHARMACIA & UPJOHN COMPANY Acides tetroniques substitues utiles dans le traitement du vih et d'autres retrovirus
DE69626276T2 (de) * 1995-03-20 2003-11-13 Upjohn Co Tetronsäurederivate zur behandlung von hiv- und anderen retroviruserkrankungen
IT1276167B1 (it) * 1995-11-24 1997-10-27 Foscama Biomed Chim Farma Imidazo(1,2-alfa)chinossalin-4-ammine attivi come antagonisti adenosinici,procedimento per la loro preparazione e loro composizioni
DE19808261A1 (de) * 1998-02-27 1999-10-28 Bayer Ag Arylphenylsubstituierte cyclische Ketoenole
DE19818732A1 (de) * 1998-04-27 1999-10-28 Bayer Ag Arylphenylsubstituierte cyclische Ketoenole
DE102004030753A1 (de) * 2004-06-25 2006-01-19 Bayer Cropscience Ag 3'-Alkoxy spirocyclische Tetram- und Tretronsäuren

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Inventor name: BRETSCHNEIDER, THOMAS

Inventor name: BIRKMANN, ALEXANDER

Inventor name: PAULSEN, DANIELA

Inventor name: BAUSER, MARCUS

Inventor name: HUEBSCH, WALTER

Inventor name: HENNINGER, KERSTIN

Inventor name: HILLISCH, ALEXANDER

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Inventor name: PAESSENS, ARNOLD

Inventor name: FAST, BEATE

Inventor name: WELKER, REINHOLD

Inventor name: THEDE, KAI

Inventor name: TERSTEEGEN, ADRIAN

Inventor name: HEIMBACH, DIRK

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Inventor name: WILDUM, STEFFEN

Inventor name: URBAN, ANDREAS

Inventor name: GRESCHAT, SUSANNE

Inventor name: FISCHER, REINER

Inventor name: BRETSCHNEIDER, THOMAS

Inventor name: BIRKMANN, ALEXANDER

Inventor name: PAULSEN, DANIELA

Inventor name: BAUSER, MARCUS

Inventor name: HUEBSCH, WALTER

Inventor name: HENNINGER, KERSTIN

Inventor name: HILLISCH, ALEXANDER

Inventor name: HARRENGA, AXEL

Inventor name: SCHOHE-LOOP, RUDOLF

Inventor name: DITTMER, FRANK

Inventor name: PAESSENS, ARNOLD

Inventor name: FAST, BEATE

Inventor name: WELKER, REINHOLD

Inventor name: THEDE, KAI

Inventor name: TERSTEEGEN, ADRIAN

Inventor name: HEIMBACH, DIRK

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