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WO2001068641A1 - 6-aminoalkyle-dihydropirimidines et utilisation en tant qu'agents pharmaceutiques contre des maladies virales - Google Patents

6-aminoalkyle-dihydropirimidines et utilisation en tant qu'agents pharmaceutiques contre des maladies virales Download PDF

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Publication number
WO2001068641A1
WO2001068641A1 PCT/EP2001/002443 EP0102443W WO0168641A1 WO 2001068641 A1 WO2001068641 A1 WO 2001068641A1 EP 0102443 W EP0102443 W EP 0102443W WO 0168641 A1 WO0168641 A1 WO 0168641A1
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alkyl
substituted
halogen
cio
formula
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English (en)
Inventor
Siegfried Goldmann
Jürgen Stoltefuss
Ulrich Niewöhner
Karl-Heinz Schlemmer
Jörg Keldenich
Arnold Paessens
Erwin Graef
Olaf Weber
Karl Deres
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Bayer AG
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero 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
    • C07D491/08—Bridged systems
    • 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 new 6-aminoalkyl-dihydropyrimidines, processes for their preparation and their use as medicaments, in particular for the treatment and prophylaxis of hepatitis B virus infections.
  • the invention also relates to combinations of these dihydropyrimidines with other antiviral agents and, if appropriate, immunomodulators and medicaments containing these combinations, in particular for the treatment and prophylaxis of HBV infections such as hepatitis B.
  • the hepatitis B virus belongs to the Hepadna virus family. It causes an acute and / or a persistent-progressive, chronic illness. A wide variety of other clinical manifestations in the clinical picture are also caused by the hepatitis B virus - in particular chronic inflammation of the liver, liver zinosis and hepatocellular carcinoma. Furthermore, coinfection with the hepatitis delta virus can have a negative impact on the course of the disease.
  • interferon The only agents approved for the treatment of chronic hepatitis are interferon and lamivudine.
  • interferon is only moderately effective and has undesirable side effects;
  • lamivudine works well, resistance develops quickly during treatment, and rebound occurs in most cases after therapy is discontinued.
  • WO 99/1438 relates to dihydropyrimidines which are said to be suitable for the treatment of cerebrovascular ischemia and pain.
  • WO 99/54312, 99/54326 and 99/54329 relate to dihydropyrimidines which are suitable for the treatment and prophylaxis of hepatitis.
  • the present invention relates to compounds of the formula
  • R 1 pyridyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl, where these radicals can be substituted up to three times by halogen and / or -CC 6 alkyl,
  • R 2 C 6 -C ⁇ aryl or 5- to 10-membered heteroaryl, these aryl or heteroaryl radicals each having one to three substituents from the group d- C 6 alkyl, -CC 6 alkoxycarbonyl, halogen, nitro , Polyfluoro-C 4 alkyl may be substituted,
  • R 6 and R 7 independently of one another are hydrogen, C 1 -C 6 -alkoxycarbonyl or a straight-chain, branched or cyclic, saturated or unsaturated C 1 -C 8 -hydrocarbon group which is optionally substituted by di- C] -C 6 -alkylamino, or together with the nitrogen atom to which they are attached form a 3- to 8-membered ring which can be mono- to trisubstituted by C 1 -C 6 -alkyl and can contain one or two further heteroatoms from the series nitrogen, oxygen, sulfur ;
  • R 4 -C-C ⁇ o-alkyl the halogen, hydroxy, aminocarbonyl, 5- to
  • 10-membered heteroaryl and or 5- to 10-membered heterocyclyl may be substituted and the carbon chain of which may be interrupted by -O-, -S-, -SO 2 - and / or - (-C-C 6 -alkyl) N-, or C 6 -C ⁇ o aryl or 5- to 10-membered heteroaryl or 5- to 10- membered heterocyclyl, the halogen-C ⁇ -C 6 turn respectively - alkoxy and / or C ⁇ -C 6 - may be substituted alkyl,
  • R 5 is hydrogen or Cj-do-alkyl, which may be substituted by halogen, hydroxy or phenyl and the carbon chain of which may be interrupted by -O-, -S-, -SO - and / or - (-C-C 6 -alkyl) N- can, or C 6 -C] o-aryl or 5- to 10-membered heteroaryl, which in turn can be substituted by halogen, dC 6 alkoxy and / or C 1 -C 6 alkyl,
  • the linkage can take place via the same carbon atom (spiro), via two directly adjacent carbon atoms (fused) or via two non-adjacent carbon atoms (bridged) and the bicyclus optionally comprises up to 3 identical or different substituents in the row above,
  • Ci-Cio-alkyl or C 3 -C ⁇ o-cycloalkyl which can each be substituted by hydroxy and / or phenyl, or C] -C 6 -acyl, benzoyl, C 6 -C ⁇ o-aryl or 5- to 10-membered heteroaryl, where the aryl and heteroaryl radicals are each halogen, -C-C 6 alkoxy and / or Ci-C ö -Alkyl can be substituted, and
  • R ' hydrogen or C, -C 6 alkyl
  • Preferred compounds (I) and (Ia) are those in which
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated mono- or bicyclic ring with bis
  • Form 10 carbon atoms of whose carbon ring members up to 3 may be replaced identically or differently by -O-, -NR 8 -, -S-, and in the case of a monocyclic ring this contains at least one substituent which, if attached to a C -Atom is out of line
  • Ci-Cio-alkyl Ci-Cio-alkoxy, hydroxy-dC 6 -alkyl, mono- and di-C ⁇ -C 6 -alkylamino-C ⁇ -C 6 -alkyl, Ci-C ö - Alkoxycarbonylamino is selected
  • Alkoxy and / or -CC 6 - alkyl can be substituted
  • the linkage can take place via the same carbon atom (spiro), via two directly adjacent carbon atoms (fused) or via two non-adjacent carbon atoms (bridged) and the bicyclus can optionally contain up to 3 identical or different substituents from the above Row carries,
  • acyl and the acyl part of acyloxy mean a linear or branched acyl radical having 1 to 6, preferably 1 to 4, carbon atoms, such as e.g. Acetyl and propionyl.
  • alkyl represents a linear or branched AUcyhest having 1 to 6 carbon atoms, such as Methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • a linear or branched AUcyhest with up to is preferred
  • Cycloalkyl in the context of the invention stands for cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopentyl or cyclohexyl.
  • alkenyl represents a linear or branched alkenyl radical having 2 to 5, preferably 3 to 5, carbon atoms, such as, for example, Ethenyl, propenyl, allyl, n-pentenyl and n-hexenyl.
  • alkoxy represents a linear or branched alkoxy radical having 1 to 6, preferably 1 to 4, carbon atoms, such as e.g. Methoxy, ethoxy and
  • alkoxycarbonyl represents a linear or branched alkoxycarbonyl radical having 1 to 6, preferably 1 to 4, carbon atoms, such as e.g. Methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.
  • a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical generally contains 1 to 12, preferably 1 to 10 and in particular 1 to 8 carbon atoms and includes, for example, the alkyl, alkynyl and cycloalkyl radicals described above, preferably dC 6 -alkyl radicals, on.
  • Aryl and the aryl part of aryloxy generally mean an aromatic radical having 6 to 10 carbon atoms, preferably phenyl and naphthyl.
  • aralkyl stands for aralkyl with preferably 6 to 10, in particular 6, carbon atoms in the aryl part (preferably phenyl or naphthyl, in particular phenyl) and preferably 1 to 4, in particular 1 or 2, carbon atoms in the alkyl part, where the alkyl part can be linear or branched , Preferred aralkyl radicals are benzyl and phenethyl.
  • Heteroaryl in the context of the invention represents 5- to 7-membered rings with preferably 1 to 3, in particular 1 or 2 identical or different heteroatoms from the series oxygen, sulfur and nitrogen.
  • Preferred examples include furyl, thienyl, pyrazolyl, imidazolyl, 1.2.3- and 1.2.4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pynolyl, pyridyl, pyrimidinyl and pyrazinyl.
  • 5- to 10-membered heterocycle stands for 5- to 10-membered rings, preferably bonded via a nitrogen atom, with preferably 1 to 3, in particular 1 or 2 identical or different heteroatoms from the series oxygen, sulfur, nitrogen.
  • Preferred examples include, for example
  • the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
  • the invention relates to both
  • Enantiomers or diastereomers and their respective mixtures can be separated into the stereoisomerically uniform constituents in a manner known per se.
  • the compounds according to the invention include the isomers of the formulas (I) and (I a) and mixtures thereof.
  • the compounds according to the invention can also be present as salts. Physiologically acceptable salts are preferred in the context of the invention.
  • Physiologically acceptable salts can be salts of inorganic or organic
  • Salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts of organic carboxylic or sulfonic acids such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or toluenesulfonic acid or toluenesulfonic acid or toluenesulfonic acid
  • Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention.
  • Z are particularly preferred.
  • the compounds according to the invention can be produced by:
  • R 1 has the meaning given above
  • Y represents a nucleophilically exchangeable group such as chloride, bromide, iodide, mesylate or tosylate, with compounds of the formula
  • the compounds (VI) can be prepared, for example, by using compounds of the formula
  • brominating agent e.g. N-bromosuccinimide
  • amidines (V) or their salts such as hydrochlorides or acetates
  • bases or acids if appropriate in the presence of inert organic solvents.
  • aldehydes (II) used as starting materials are known or can be prepared by methods known from the literature [cf. T. D. Harris and G.P. Roth, J. Org. Chem. 44, 146 (1979); DE-OS 2 165 260 and 2 401 665 ,; Mijano et al., Chem. Abstr. 59, 13,929c (1963); E. Adler and H.-D. Becker, Chem. Scand. 15, 849 (1961); E.P. Papadopoulos, M. Mardin and Ch. Issidoridis, J. Org. Chem. Soc. 78, 2543 (1956)].
  • ß-ketocarboxylic acid esters (III) used as starting materials are known in some cases or can be prepared analogously to methods known from the literature [e.g. B. D. Borrmann, "Reaction of Diketene with Alcohols, Phenols and Mercaptans", in “Methods of Organic Chemistry” (Houben-Weyl), Vol. VIL / 4, 230 ff (1968);
  • Some of the compounds (V) are known or can be prepared as described in WO-A-99/54326 and WO-A-99/54329.
  • the compounds (VIII) and (X) can be prepared in accordance with process variants [A] or [B] as described in WO-A-99/54326.
  • the compounds (VII) and (XI) are known or can be prepared by customary methods.
  • solvents are suitable as solvents.
  • solvents preferably include alcohols such as methanol, ethanol, isopropanol, ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether, glycol dimethyl ether, carboxylic acids such as glacial acetic acid, or
  • reaction temperatures can be varied over a wide range. In general, you work between 20 and 150 ° C, but preferably at
  • the reaction can be carried out at normal pressure, but also at elevated pressure. Generally one works under normal pressure.
  • the reaction can be carried out with or without addition of base or acid; however, it is advisable to carry out the reaction in the presence of weaker acids, e.g. Acetic acid or formic acid.
  • weaker acids e.g. Acetic acid or formic acid.
  • Areas of indication for the compounds according to the invention include: The treatment of acute and chronic viral infections that can lead to infectious hepatitis, for example infections with hepatitis B viruses.
  • the compounds according to the invention are particularly suitable for the treatment of chronic hepatitis B infections and the treatment of acute and chronic hepatitis B virus infections.
  • An embodiment of the invention relates to combinations of A) at least one of the dihydropyrimidines defined above (without taking into account the provisions (1) and (2)), B) at least one other antiviral agent other than A.
  • a particular embodiment of the invention relates to combinations A) of the above dihydropyrimidines (without taking into account the provisions (1) and (2)), B) HBV polymerase inhibitors and, if appropriate, C) immunomodulators.
  • Preferred immunomodulators C) include, for example, all interferons such as ⁇ , ⁇ and ⁇ interferons, in particular also ⁇ -2a and ⁇ -2b interferons, interleukins such as interleukin-2, polypeptides such as thymosin- ⁇ -1 and thymoctonan, imidazoquinoline, derivatives such as ®Levamisole, immunoglobulins and therapeutic vaccines.
  • interferons such as ⁇ , ⁇ and ⁇ interferons, in particular also ⁇ -2a and ⁇ -2b interferons, interleukins such as interleukin-2, polypeptides such as thymosin- ⁇ -1 and thymoctonan, imidazoquinoline, derivatives such as ®Levamisole, immunoglobulins and therapeutic vaccines.
  • the invention therefore also relates to these combinations for the treatment and prophylaxis of HBV infections and their use for the treatment of HBV-induced diseases.
  • HBV polymerase inhibitors B for the purposes of the invention are substances which are described in the endogenous polymerase assay described below, which was described by Ph. A. Furman et al. in Antimicrobial Agents and Chemotherapy, Vol. 36 (No. 12), 2688 (1992), lead to an inhibition of the formation of an HBV-DNA double strand in such a way that there is a maximum of 50% of the activity of the zero value:
  • HBV virions from culture supernatants incorporate nucleoside 5'-triphosphates into the plus strand of HBV DNA in vitro.
  • nucleoside 5'-triphosphates into the plus strand of HBV DNA in vitro.
  • HBV virions are obtained from the cell culture supernatant of HepG2.2.15 cells by precipitation with polyethylene glycol and concentrated. 1 part by volume of clarified cell culture is obtained with part by volume of an aqueous solution containing 50% by weight of polyethylene glycol
  • HCl p H 7.5
  • 300mM potassium chloride 50mM magnesium chloride; 0.1% ®Nonident P-40 (non-ionic detergent from Boehringer Mannheim); 10 ⁇ M each of dATP, dGTP and dTTP; 10 ⁇ Ci [ 32 P] dCTP (3000 Ci / mmol; final concentration 33 nM) and 1 ⁇ M of the potential polymerase inhibitor in its triphosphorylated form.
  • the samples are incubated at 37 ° C for one hour and then the reaction is stopped by adding 50 mM EDTA.
  • Preferred HBV polymerase inhibitors B) include, for example
  • L-FMAU 1- (2-deoxy-2-fluoro-ß-L-arabinofuranosyl) -5-methyl-pyrimidine-2.4 (1H, 3H) -dione, cf. WO 99/05157, WO 99/05158 and US Pat. No. 5,753,789.
  • Another preferred embodiment of the invention relates to combinations of A) above dihydropyrimidines (I) or (Ia) and B) lamivudine.
  • HBV antiviral agents B include e.g. Phenylpropenamides of the formula
  • R 1 and R 2 independently of one another are C 1 -C 4 -alkyl or, together with the nitrogen atom on which they are located, form a ring having 5 to 6 ring atoms which comprise carbon and / or oxygen,
  • R 3 to R 12 independently of one another are hydrogen, halogen, C 1 -C 4 -alkyl, optionally substituted C 1 -C 4 alkoxy, nitro, cyano or trifluoromethyl,
  • R 13 is hydrogen, C, -C 4 alkyl, -C-C 7 acyl or aralkyl and
  • AT-61 is the compound of the above formula wherein X is chlorine, A 1 -piperidinyl and Y and Z are each phenyl.
  • Preferred immunomodulators C) include, for example, all interferons such as ⁇ , ⁇ and ⁇ interferons, in particular also ⁇ -2a and ⁇ -2b interferons, interleukins such as interleukin-2, polypeptides such as thymosin- ⁇ -1 and thymoctonan, imidazoquinoline, derivatives such as ®Levamisole, immunoglobulins and therapeutic vaccines.
  • interferons such as ⁇ , ⁇ and ⁇ interferons, in particular also ⁇ -2a and ⁇ -2b interferons, interleukins such as interleukin-2, polypeptides such as thymosin- ⁇ -1 and thymoctonan, imidazoquinoline, derivatives such as ®Levamisole, immunoglobulins and therapeutic vaccines.
  • Another preferred embodiment of the invention relates to combinations of A) above dihydropyrimidines (I) or (Ia), B) lamivudine and optionally C) interferon.
  • the antiviral activity of the compounds according to the invention against the hepatitis B virus was based on that of M.A. Seils et al., Proc. Natl. Acad. Be. 84, 1005-1009 (1987) and B.E. Korba et al., Antiviral Research 19, 55-70 (1992).
  • the antiviral tests were carried out in 96-well microtiter plates.
  • the first vertical row of the plate received only growth medium and HepG2.2.15 cells. It served as a virus control.
  • test compounds 50 mM were first dissolved in DMSO, further dilutions were made in the growth medium of HepG2.2.15.
  • the compounds according to the invention were generally in a test concentration of 100 ⁇ M (1st test concentration) in each case in the second vertical test series of the test compounds
  • Each well of the microtiter plate then received 225 ⁇ l of a HepG2.2.15 cell suspension (5 ⁇ 10 4 cells / ml) in growth medium plus 2% by weight of fetal calf serum.
  • a HepG2.2.15 cell suspension (5 ⁇ 10 4 cells / ml) in growth medium plus 2% by weight of fetal calf serum.
  • Test mixture was incubated for 4 days at 37 ° C and 5% CO (v / v).
  • the supernatant was then aspirated and discarded, and the wells received 225 ⁇ l of freshly prepared growth medium.
  • the compounds according to the invention were each added again as a 10-fold concentrated solution in a volume of 25 ⁇ l. The batches were incubated for a further 4 days.
  • the HepG2.2.15 cells were examined for cytotoxic changes by light microscopy or by means of biochemical detection methods (eg Alamar blue staining or trypan blue staining). The supernatants and / or cells were then harvested and sucked by means of vacuum onto 96-well dot-blot chambers covered with nylon membrane (according to the manufacturer's instructions).
  • Substance-induced cytotoxic or cytostatic changes in the HepG2.2.15 cells were e.g. determined by means of light microscopy as changes in cell morphology. Such substance-induced changes in the HepG2.2.15 cells in the
  • Comparison to untreated cells was e.g. visible as cell lysis, vacuolization or altered cell morphology.
  • 50% cytotoxicity (Tox.-50) means that 50% of the cells have a morphology comparable to the corresponding cell control.
  • the tolerance of some of the compounds according to the invention was additionally tested on other host cells such as e.g. HeLa cells, human primary peripheral blood cells or transformed cell lines such as H-9 cells.
  • the intra- or extracellular supernatants of the HepG2.2.15 cells were denatured (1.5 M NaCl / 0.5 N NaOH), neutralized (3 M NaCl / 0.5 M Tris HCl, pH 7.5) and washed (2 x SSC ). The DNA was then baked on the membrane by incubating the filters at 120 ° C. for 2-4 hours. Hybridization of the DNA
  • the detection of the viral DNA from the treated HepG2.2.15 cells on the nylon filters was generally carried out using non-radioactive, digoxigenin-labeled hepatitis B-specific DNA probes, which were labeled with digoxigenin according to the manufacturer's instructions, purified and used for hybridization ,
  • the prehybridization and hybridization were carried out in 5 x SSC, 1 x blocking reagent, 0.1% by weight N-lauroylsarcosine, 0.02% by weight SDS and 100 ⁇ g sperm DNA of the herring.
  • the pre-hybridization took place at 60 ° C for 30 minutes, the specific hybridization with 20 to 40 ng / ml of the digoxigenized, denatured HBV-specific DNA (14 hours, 60 ° C). The filters were then washed.
  • the filters were washed and prehybridized in a blocking reagent (according to the manufacturer's instructions). The mixture was then hybridized for 30 minutes with an anti-DIG antibody which was coupled with alkaline phosphatase. After a washing step, the substrate of the alkaline phosphatase, CSPD, was added, incubated with the filters for 5 minutes, then wrapped in plastic wrap and incubated at 37 ° C. for a further 15 minutes. The chemiluminescence of the hepatitis B-specific DNA signals was visualized by exposing the filters to an X-ray film (incubation depending on signal strength: 10 minutes to 2 hours).
  • IC 50 inhibitory concentration 50%
  • the compounds according to the invention show an unforeseeable and valuable activity against viruses. They are surprisingly antiviral to hepatitis B
  • Viruses are effective by causing an extremely large reduction in intra- and / or extracellular HBV DNA.
  • the compounds according to the invention are therefore suitable for the treatment of virus-induced diseases, in particular acute and chronic persistent viral infections of HBV.
  • a chronic viral disease caused by HBV can lead to different severity of the clinical picture; As is well known, chronic hepatitis B virus infection in many cases leads to liver zinosis and / or hepatocellular carcinoma.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds (I) or (Ia) or a combination according to the invention or which consist of one or more active compounds (I) or (Ia) or consist of a combination according to the invention.
  • the active ingredients (I) or (Ia) should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight, of the total mixture his.
  • the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.
  • the quantitative ratio of components A, B and optionally C of the combinations according to the invention can vary within wide limits; it is preferably 5 to 500 mg A / 10 to 1000 mg B, in particular 10 to 200 mg A / 20 to
  • Component C which may also be used, can be used in amounts of preferably 1 to 10 million, in particular 2 to 7 million IU (international units), about three times a week over a period of up to one year.
  • the compounds or combinations according to the invention should generally be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95,% by weight of the total mixture.
  • the preparation of the pharmaceutical preparations listed above can be carried out in a conventional manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.
  • the active ingredient (s) according to the invention in total amounts of from about 0.5 to about 500, preferably from 1 to 100 mg / kg of body weight per 24 hours, if appropriate in Form of multiple doses to be administered to achieve the desired results.
  • a single dose contains the active ingredient (s) preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg
  • the invention therefore furthermore relates to the compounds and combinations defined above for combating diseases.
  • the invention further relates to medicaments containing at least one of the compounds or combinations defined above and optionally one or more further pharmaceutical active ingredient (s).
  • the invention further relates to the use of the compounds and combinations defined above in the manufacture of a medicament for the treatment and prophylaxis of the diseases described above, preferably viral diseases, in particular hepatitis B.
  • Methanol is mixed with a sodium methylate solution consisting of 0.40 g (17.391 mmol) sodium and 65 ml methanol and stirred at 20 ° C. for 72 hours. 5.44 g (101.682 mmol) ammonium chloride (powdered) and 17.39 mmol (1.04 ml) acetic acid are added, the mixture is stirred at 40 ° C. for 28 hours and cooled. It is suctioned off from the insoluble salt (1.78 g), concentrated, concentrated with acetone, then stirred with acetone, suction filtered and washed. Yield: 10.6 g Mp .: «150 ° C dec.
  • Analog Troschuetz, R. et al., J. Heterocycl. Chem. 33, 1815-1821 (1996) 150 ml of diethylene glycol dimethyl ether, 47.68 g (0.261 mol) of 2,3,5-trichloropyridine, 2.0 g (0.005 mol) of tetraphenylphosphonium bromide, 4.0 g (0.024 mol) are finely powdered Potassium iodide and 75.0 g (0.838 mol) of copper (I) cyanide combined under nitrogen and stirred under reflux for 24 hours.
  • Potassium fluoride and 10 g of polyethylene glycol 8000 are mixed with 125 ml of DMSO and heated to 160 ° C. for 30 minutes. After cooling, the product is distilled off together with the DMSO under high vacuum, the distillate is added to water, extracted with toluene and dried over sodium sulfate. The product is further implemented as a toluene solution.
  • the ethyl acetate phase is extracted once with 30 ml of 1 N hydrochloric acid.
  • the combined aqueous phases are extracted three times with 10 ml of diethyl ether.
  • the aqueous phase is made alkaline with sodium hydroxide solution and extracted with ethyl acetate.
  • the organic phases are dried over sodium sulfate and concentrated. 7.4 g (80%) of product, mp: 126 ° C., are obtained

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Abstract

L'invention concerne de nouvelles dihydropyrimidines (I) ou leurs formes isomères (Ia), avec R<1> = pyridyle, pyrimidinyle, pyrazinyle, thiazolyle ou oxazolyle, ces restes pouvant être substitués jusqu'à trois fois par de l'halogène ou C1-C6-alkyle ; R<2> = C6-C10-aryle ou hétéroaryle ayant 5 à 10 éléments, ces restes aryle ou hétéroaryle pouvant être substitués respectivement par un à trois substituants du groupe C1-C6-alkyle, C1-C6-alkoxycarbonyle, halogène, nitro, polyfluor-C1-C4-alkyle ; R<3> = C1-C14-alkyle, un à deux atomes de carbone pouvant être remplacés par de l'hydrogène ou du soufre dans cette chaîne, et/ou le reste C1-C14-alkyle pouvant être substitué par un à trois substituants du groupe hydroxy, cyano, NR<6>R<7>, C1-C6-alkoxycarbonyle, C6-C10-aryle, et hétéroaryle ayant 5 à 10 éléments, et C6-C10-aryle et hétéroaryle avec 5 à 10 éléments pouvant à leur tour être substitués par un à trois substituants du groupe hydroxy, C1-C6-alkyle, C1-C6-alkoxy, C1-C6-alkoxycarbonyle, halogène, et C1-C6-alkyle halogène ; X = C1-C3-alcoylène pouvant être interrompu par de l'oxygène et/ou substitué par C1-C6-alkyle. Lesdites dihydropyrimidines et leurs combinaisons avec d'autres agents antiviraux servent à la lutte contre des infections par HBV.
PCT/EP2001/002443 2000-03-17 2001-03-05 6-aminoalkyle-dihydropirimidines et utilisation en tant qu'agents pharmaceutiques contre des maladies virales Ceased WO2001068641A1 (fr)

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DE10013126A DE10013126A1 (de) 2000-03-17 2000-03-17 Arzneimittel gegen virale Erkrankungen
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