Classifications

• • 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
  • 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
• • 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

Definitions

• the present invention relates to novel substituted aminofuranones, processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular retroviral diseases, in humans and / or animals.
• HTV Human Immunodeficiency Virus
• AIDS Acquired Immunodeficiency Syndrome
• RT inhibitors Two classes of RT inhibitors exist: ⁇ ucleosidic RT inhibitors ( ⁇ RTI) act by competitive inhibition or chain termination during D ⁇ A polymerization.
• Non-nucleoside RT inhibitors ( ⁇ RTI) bind allosterically to a hydrophobic pocket near the active site of the RT and mediate a conformational change of the enzyme.
• PI protease inhibitors
• 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
• n is the number 1, 2 or 3
• X is 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 I7 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) -C 4 alkoxycarbonyl, Ci-C ⁇ alkylaminocarbonyl, Ci-C ⁇ - 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, where the substituents are independently selected from the group consisting of halogen, cyano, nitro, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, C r C 4 - Alkyl, C, -C 4 alkoxy, C, -C 4 alkylamino, Ci-C 4 alkylsulfonyl, Ci-C 4 alkoxycarbonyl and benzyl,
• 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 stands for C r C 6 alkyl, C 2 -C 4 alkenyl, C, -C 6 alkoxy, phenyl, benzyloxy or 5- to 10-membered heterocyclyl,
• alkyl, alkenyl and alkoxy may be substituted with a substituent, wherein the substituent is selected from the group consisting of halogen, cyano, hydroxy,
• substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulphonyl, Cr C 4 alkyl, C r C 4 alkoxy, C r C 4 - alkylamino, C, -C 4 - 20 alkylsulfonyl and Ci-C4-alkoxycarbonyl,
• R 17 is hydrogen, C 1 -C 4 -alkyl or phenyl
• alkyl may be substituted with a substituent wherein the substituent is selected from the group consisting of methoxy, methoxycarbonyl, C 3 -C 7 cycloalkyl, phenyl, 5-10- to 25-membered heterocyclyl, and 5- to 10-membered heteroaryl,
• cycloalkyl, phenyl, heterocyclyl and heteroaryl in turn may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting
• R 18 is hydrogen or C 1 -C 4 -alkyl
• R 24 is hydrogen or C 1 -C 4 -alkyl
• R 25 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, Ci -
• R 26 is hydrogen or C r C 4 alkyl
• R 27 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-
• heteroarylcarbonyl in which 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, Ci -
• R 15 is C r C 6 alkyl, C 2 -C 4 alkenyl, Ci-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, where the substituents are independently selected from the group consisting of halogen, cyano, nitro, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, Ci-C 4 -
• alkoxy may be substituted with a substituent selected from the group consisting of halogen, cyano,
• substituents are independently selected from the group consisting of halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulfonyl, C 1 -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, hydroxycarbonyl,
• 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, alkenyl and alkoxy 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, d-
• R 20 is hydrogen, C 1 -C 4 -alkyl or phenyl
• alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of
• cycloalkyl, phenyl, heterocyclyl and heteroaryl in turn may be substituted with 1 to 3 substituents, wherein the substituents independently
• 25 are selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulphonyl, Q- C4 alkyl, C, -C 4 alkoxy, C r C 4 alkylamino, C, -C 4 Alkylsulfonyl, C 1 -C 4 -alkylsulfonylamino and CpC 4 -
• R 21 is hydrogen or C 1 -C 4 -alkyl
• R 28 is hydrogen or C 1 -C 4 -alkyl
• R 29 is C-C ⁇ 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
• 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 30 is hydrogen or C 1 -C 4 -alkyl
• R 31 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, 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 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, -C 4 alkyl or C r C 4 alkoxy
• R 10 is hydrogen or C 1 -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 1 -C 4 -alkyl
• R 3 is hydrogen, halogen, cyano, methyl, methoxy, ethoxy or phenoxy,
• R 4 is hydrogen, halogen, methyl, methoxy or ethoxy
• R 5 is hydrogen, halogen, cyano, nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, hydroxymethyl, aminomethyl, C r C 4 alkyl, Ci-C 4 - alkoxy, C r C 4 alkylamino, Ci C 4 alkylthio, Ci-C4-alkylcarbonyl, C] -C 4 alkoxycarbonyl, Ci-Ci-alkylaminocarbonyl, Ca-C ö cycloalkylaminocarbonyl, C] -C 4 alkylcarbonylamino,
• Ci-C4-alkoxycarbonylamino Ci-C 4 alkylsulfonyl, C] -C 4 alkylsulfonylamino, C 2 -C 4 - Alkenylsulfonylamino, C r C 4 alkylsulfonyl (Ci-C 4 alkyl) amino, benzylsulfonylamino, 5- or 6-membered heteroarylsulfonylamino or 5- 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 represents hydrogen, halogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy
• R 5 and R 6 are bonded to adjacent carbon atoms and form, together with the carbon atoms to which they are attached, 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 according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from 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.
• customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammoni
• solvates 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.
• Alkoxycarbonylamino, alkylsulfonylamino and AlkylsulfonylfC ⁇ -Cj-alkyPamino represents straight-chain or branched alkyl and comprises, unless indicated otherwise, Ci-C 6 alkyl, especially Ci-C 4 - alkyl, such as 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
• 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 preferably vinylsulfonylamino, allylsulfonylamino, 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.
• Heterocvclyl 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, lH-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 preferably 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 is an oxygen atom, a sulfur atom or NR 14 ,
• R 14 is C, -C 6 alkyl, C 2 -C 4 alkenyl, C r C 4 alkylsulfonyl, benzylsulfonyl, - (CH 2) O COR 16 or - (CH 2) P CONR I7 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, 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 with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, hydroxysulphonyl, C] -C 4 - alkyl, Ci-C 4 -alkoxy, Ci-C 4 alkylamino, 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 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 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, Cp C 4 alkyl, C, -C 4 alkoxy, C, -C 4 alkylamino, C, -C 4 - 25 alkylsulfonyl and Ci-C4-alkoxycarbonyl,
• R 17 is hydrogen, C 1 -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, 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 C 1 -C 4 -alkyl,
• R 18 is hydrogen or C 1 -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 1 -C 4 -alkyl or C, -C 4 alkoxy,
• R 10 is hydrogen
• R 1 ' is hydrogen
• R 3 is hydrogen, halogen, methyl, methoxy, ethoxy or phenoxy
• R 4 is hydrogen, halogen, methyl, methoxy or ethoxy
• R 5 is hydrogen, halogen, cyano, nitro, hydroxyl, amino, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, hydroxymethyl, aminomethyl, C 1 -C 4 -alkyl, C r C 4 -
• Alkenylsulfonylamino C
• alkylaminocarbonyl, alkylcarbonylamino and alkylsulfonylamino may be substituted with a substituent, wherein the substituent is selected from the group consisting of cyano, hydroxy, amino, hydroxycarbonyl, Ci-C 4 alkoxy, Ci-C 4 alkylamino, morpholinyl, piperidinyl, pyrrolidinyl and benzylamino,
• R 6 is 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 preferably also compounds of 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 stands for NR 14 .
• 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 are independently selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, hydroxycarbonyl, aminosulfonyl, Ci-C 4 - alkoxy, Qd-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, C 1 -C 4 - Alkyl, C r C 4 alkoxy, Ci-C 4 alkylamino, C, -C 4 alkylsulfonyl and C i -C 4 -Alkoxycarbony 1,
• o is a number 1 or 2
• p is a number 1 or 2
• R 16 is C r C 4 alkyl, C, -C 4 alkoxy, phenyl or benzyloxy,
• R 17 is hydrogen, C 1 -C 4 -alkyl or phenyl
• alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of
• phenyl may in turn be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy and
• R 18 is hydrogen
• R 8 is hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy
• R 9 is hydrogen or C 1 -C 4 -alkyl
• R 10 is hydrogen
• R 1 ' is hydrogen
• R 3 is hydrogen, halogen, methyl, ethoxy or phenoxy
• R 4 is hydrogen, halogen or methyl
• R 5 represents hydrogen, halogen, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, hydroxymethyl, C) -C 4 -alkyl, C r C 4 -alkoxy, C 1 -C 4 -
• 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, C, -C 4 alkyl or C r C 4 alkoxy
• R 7 is hydrogen
• the invention also preferably relates to compounds of the formula (I) in which R 1 and R 2 together with the carbon atom to which they are attached form a group of the formula
• the invention preferably also compounds of formula (T), in which R 3 is hydrogen, halogen or methyl.
• the invention also preferably relates to compounds of the formula (I) in which R 4 is hydrogen, halogen or methyl.
• the invention relates preferably to compounds of formula (I) in which R 5 is hydroxy, amino, hydroxycarbonyl, aminocarbonyl, hydroxymethyl, aminomethyl, CpC 4 - alkylamino, C r C 4 alkylcarbonyl, Ci-C 4 alkylaminocarbonyl, C 3 -C 6 cycloalkylaminocarbonyl, C i -C 4 - alkylcarbonylamino, C
• alkylaminocarbonyl, alkylcarbonylamino and alkylsulfonylamino may be substituted with a substituent, wherein the substituent is selected from the group consisting of cyano, hydroxy, amino, hydroxycarbonyl, Ci-C 4 alkoxy, Ci-C 4 - alkylamino, morpholinyl, piperidinyl, pyrrolidinyl, and benzylamino.
• the invention also provides compounds of formula (I) in which R represents Cp G t alkylcarbonylamino or C are preferably 4 alkylsulphonylamino,
• alkylcarbonylamino and alkylsulfonylamino may be substituted with one
• Substituent wherein the substituent is selected from the group consisting of cyano, hydroxy, amino, hydroxycarbonyl, C] -C 4 alkoxy, Ci-C 4 alkylamino, morpholinyl, piperidinyl, pyrrolidinyl and benzylamino.
• the invention preferably also compounds of formula (I), in which R 5 is C r Gt-alkylsulfbnylamino,
• alkylsulfonylamino may be substituted with a substituent, wherein the substituent is selected from the group consisting of cyano, hydroxy, amino, hydroxycarbonyl, QQ-alkoxy, Ci-C 4 alkylamino, morpholinyl, piperidinyl, pyrrolidinyl and benzylamino.
• the invention also preferably relates to compounds of the formula (I) in which R 5 is C r C 4 -alkylsulfonylamino,
• alkylsulfonylamino may be substituted with a substituent, wherein the substituent is selected from the group consisting of amino, Ci-C 4 alkylamino, morpholinyl and pyrrolidinyl.
• the invention also preferably relates to compounds of the formula (I) in which R 5 is C 1 -C 4 -alkylsulfonyl.
• the invention preferably also compounds of formula (I), in which R 6 and R 7 are hydrogen.
• the invention further provides a process for the preparation of the compounds of the formula (I), wherein the process
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the abovementioned meaning
• 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 (OH) 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, acetonitrile or dichloromethane. It is likewise possible to use mixtures of the solvents. Particularly preferred is dimethylformamide or dichloromethane.
• bases examples include potassium tert-butylate, sodium hydride, lithium diisopropylamide, sodium, potassium or lithium hexamethyldisilylamide or 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,2,2-diazaphosphorin (BEMP).
• bases particularly preferred is potassium tert-butoxide or 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,2,2-diazaphosphorin (BEMP).
• 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 13O 0 C at atmospheric 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 (II) acetate / triscyclohexylphosphine or bis (diphenylphosphanferrocenyl) palladium ( ⁇ ) chloride or palladium (II) acetate with a ligand 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 (II) 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 or a mixture of 1, 2-dimethoxyethane with ethanol and water.
• 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 and R 2 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.
• the 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 from 50 ° C to 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.
• reaction of compounds of formula (V) with compounds of formula (VI) may also be via the thiocarbonic acid esters of compounds of formula (V) in the presence of bases such as dimethylaminopyridine.
• 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 of 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:
• HIV I human immunodeficiency virus, formerly called HTLV DI / LAV
• HIV II infections and diseases (AIDS) and the associated stages such as ARC (AIDS related complex) and LAS (lymphadenopathy Syndrome) as well as the immunodeficiency and encephalopathy caused by this virus.
• HIV I human immunodeficiency virus, formerly called HTLV DI / LAV
• HIV II infections and diseases (AIDS) and the associated stages such as ARC (AIDS related complex) and LAS (lymphadenopathy Syndrome) as well as the immunodeficiency and encephalopathy caused by this virus.
• 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 the HIV protease examples include: saquinavir, indinavir, ritonavir, nelf ⁇ navir, 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 HIV integrase may be mentioned by way of example: S 1360, L870810;
• Inhibitors of HIV fusion examples include: Pentafuside, Tl 249.
• Inhibitors of cytochrome P450 monooxygenase by way of example: ritonavir. This selection is intended to illustrate the combination options, but not to limit the examples listed here; In principle, any combination of the compounds according to the invention with antivirally active substances should be considered within the scope of the invention.
• 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, conjunctival, 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)
• excipients include, but are not limited to, excipients (e.g., microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitanoleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin). , Stabilizers (eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) and flavor and / or odoriferous agents.
• excipients e.g., microcrystalline cellulose, lactose, mannitol
• solvents eg, liquid polyethylene glycols
• emulsifiers and dispersing or wetting agents e.g., sodium dodecyl sulfate, polyoxysorbitanole
• 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 one or more active compounds 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.
• a single dose preferably contains the active substance (s) 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: 50 ° C .; UV detection: 208-400 nm.
• Method 2 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 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 1 100; 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 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: 6O 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.
• Method 6 (preparative RP-HPLC): column: Grom-Sil 120 ODS-4HE, 10 ⁇ m, SNr. 3355, 250 mm x 30 mm. Eluent A: water + 0.1% hydrochloric acid, eluent B: acetonitrile. Flow: 50 ml / min. Program: 0-4 min: 10% B; 4.01-33 min: gradient to 90% B.
• Method 7 (Preparative RP-HPLC): Column: Grom-Sil Cl 8, 10 ⁇ m, 250 mm ⁇ 30 mm. Eluent A: water + 0.1% formic acid, eluent B: acetonitrile. Flow: 50 ml / min. Program: 0-5 min: 10% B; 5-38 min: gradient to 95% B.
• Method 8 (LC-MS): Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Onyx Monolithic Cl 8, 100 mm x 3 mm.
• Method 9 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 11 Instrument MS: Micromass TOF (LCT); Instrument HPLC: Waters 2690; Autosampler: Waters 2700, column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 ⁇ m; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A -> 0.2 min 95% A - »1.8 min 25% A -> 1.9 min 10% A -> 2.0 min 5% A -» 3.2 min 5% A -> 3.21 min 100% A - > 3.35 min 100% A; Oven: 40 ° C; Flow: 3.0 ml / min; UV detection: 210 nm.
• Method 12 Instrument MS: Waters ZQ 2000; Instrument HPLC: Agilent 1100, 2-column circuit, Autosampler: HTC PAL; Column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 ⁇ m; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A -> 0.2 min 95% A - »1.8 min 25% A -» 1.9 min 10% A -> 2.0 min 5% A - »3.2 min 5% A ⁇ » 3.21 min 100% A - > 3.35 min 100% A; Oven: 40 ° C; Flow: 3.0 ml / min; UV detection: 210 nm.
• reaction mixture is stirred vigorously with 6000 ml of 20% hydrochloric acid for 10 min, then extracted several times with tert-butyl methyl ether, the Washed combined organic phases with 20% hydrochloric acid, dried over sodium sulfate, filtered and the solvent removed on a rotary evaporator.
• a rotary evaporator After purification of the residue on silica gel 60 by means of reduced pressure column chromatography (eluent: cyclohexane), 235 g (83% of theory) of product are obtained.
• the crude product is reacted further without further purification.
• the solvent is removed completely on a rotary evaporator, the residue is treated with water, extracted several times with tert-butyl methyl ether, the aqueous phase is acidified with concentrated hydrochloric acid, the precipitated crystals are separated by filtration, the filter residue washed with n-heptane and dried after drying Solid under high vacuum 141.5 g (75% of theory) of product.
• reaction solution is treated with dichloromethane and washed with 1N hydrochloric acid, 1N sodium hydroxide solution and saturated sodium chloride solution. After this Drying (sodium sulfate) and evaporation in vacuo, the residue is purified by preparative RP-HPLC. 2.53 g (68% of theory) of product are obtained.
• the crude product (130 mg oil, 81% content by LC-MS) contains about 16% of N- [4 '- (4-amino-2-oxo-1-oxaspiro [4.5] dec-3-ene-3 as a minor component -yl) -2'-chloro-5'-methylbiphenyl-3-yl] -3-chloropropane-1-sulfonamide and is reacted without further purification.
• Example 9A Analogously to the procedure for Example 9A, the title compound is prepared from 5.6 g of the compound from Example 13. It is purified by silica gel chromatography, eluent dichloromethane, dichloromethane / methanol (50: 1). There are obtained 4.52 g (quantitative) of the product as a solid.
• the suspension is treated with 17.5 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) under argon, the reaction is heated to 50 0 C and stirred overnight at this temperature.
• the solvent is completely removed on a rotary evaporator and after purification via preparative RP-HPLC (Method 6) 34 mg (38% of theory) of the target compound are obtained.
• the aryl halide 120 mg, 0.22 mmol is dissolved in 3 ml dimethoxyethane, 2 ml water and 1 ml ethanol, the solution is degassed with argon and then 3-methylsulfonylphenylboronic acid (50 mg, 0.25 mmol), tetrakis (triphenylphosphine) palladium (0 ) (10 mg, 0.01 mmol) and cesium carbonate (218 mg, 0.67 mmol). The reaction is stirred for 12-18 hours at 50 0 C under argon atmosphere.
• Examples 2 to 14 are prepared according to general procedure 1 or 2.
• Deviation AAV 2D solvent of dioxane / water, Base: sodium carbonate, temp .: 80 0 C, purification: HPLC (Method 13) directly from the reaction solution by filtration.
• Examples 36 to 47 of the Table are prepared in an analogous manner according to the following general procedure: 0.1 mmol of the compound from Example 12A dissolved in DMF and 0.1 mmol of the corresponding reagents dissolved in DMSO are shaken with 0.2 mmol of potassium carbonate Id at RT, filtered and purified by preparative HPLC.
• 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, Il 5V, Ll 91, 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 ( M 1865 from Bachern, Bubendorf, Switzerland; Matayoshi et al., Science 1990, 247, 954-8) in Buffer
• the assembly assay relieves the late phase of HFV 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 virus 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
• HIV-susceptible, permanent H9 cells are used instead of normal human blood lymphocytes 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 the microtiter plate receives only HTV-infected cells (virus control) in growth medium.
• the remaining wells contain compounds of the invention in different concentrations, starting from the wells of the 3rd vertical row of the microtiter plate, from which the test substances are diluted in steps of 2. 2 10 -fold.
• supernatant infections are performed (see above), in which the cells are seeded in 96-well plates.
• the HIV virus is then added in a volume of 50 ⁇ l.
• test mixtures are incubated at 37 ° C. until the syncytia formation typical for HFV 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. Accordingly, 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 evaluation of the Alamar Blue treated cells show extinctions smaller 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 in
• the treated cell cultures are also with regard to cytotoxic, cytostatic or cytological changes as well as in terms of
• the compounds of the invention protect HFV-infected cells from virus-induced cell destruction.
• the antiviral activity of a substance ie the ability to reduce the human immunodeficiency virus (HIV) titer, is tested in the murine HTV model.
• HIV human immunodeficiency virus
• Human cells are infected with HIV in vitro. After incubation the infected cells are on a collagen sponge (gelfoam ®) transferred and transplanted subcutaneously on the back immundefizi enter mice.
• In the in vivo assay at least three groups of 5 to 10 animals each are used. One group is the negative control 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. For each additional test batch, 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.
• compositions are 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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