WO2001068642A1 - Dihydropirimidines et leur utilisation en tant qu'agents pharmaceutiques destines au traitement de l'hepatite b - Google Patents

Dihydropirimidines et leur utilisation en tant qu'agents pharmaceutiques destines au traitement de l'hepatite b Download PDF

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WO2001068642A1
WO2001068642A1 PCT/EP2001/002444 EP0102444W WO0168642A1 WO 2001068642 A1 WO2001068642 A1 WO 2001068642A1 EP 0102444 W EP0102444 W EP 0102444W WO 0168642 A1 WO0168642 A1 WO 0168642A1
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alkyl
substituted
alkoxy
phenyl
formula
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PCT/EP2001/002444
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German (de)
English (en)
Inventor
Siegfried Goldmann
Jürgen Stoltefuss
Ulrich Niewöhner
Karl-Heinz Schlemmer
Thomas Krämer
Arnold Paessens
Erwin Graef
Olaf Weber
Karl Deres
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Bayer Aktiengesellschaft
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Priority to AU56185/01A priority Critical patent/AU5618501A/en
Publication of WO2001068642A1 publication Critical patent/WO2001068642A1/fr

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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
    • C07D401/02—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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • the present invention relates to new dihydropyrimidines, processes for their preparation and medicaments containing these dihydropyrimidines, 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, cirrhosis of the liver 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.
  • EP-PS 103 796 dihydropyrimidines are known, to which an effect influencing the circulation is attributed.
  • EP-A 169 712 describes substituted dihydropyrimidines as intermediates which can be oxidized to the corresponding pyrimidines.
  • 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 dihydropyrimidines of the formula
  • R phenyl, furyl or thienyl, where these ring systems can be substituted, independently of one another, one or more times by substituents selected from the group halogen, nitro, cyano, hydroxy, alkyl, trifluoromethyl, alkoxy, trifluoromethoxy,
  • R is hydrogen, a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical which optionally contains one or two identical or different hetero chain links from the group -O-, -CO-, -NH-, -N (CpC - alkyl) -, -S - or -SO 2 - and which is optionally substituted by halogen, nitro, cyano, hydroxy, aryl, aralkyl, heteroaryl or the group -NR 6 R 7 ,
  • R 6 and R 7 independently of one another are hydrogen, benzyl or alkyl or together with the nitrogen atom to which they are attached stand, form a 5- to 6-membered ring which optionally contains oxygen,
  • R is a double-bonded linear, branched or cyclic, saturated or unsaturated hydrocarbon radical which is optionally mono- or polysubstituted, identically or differently by halogen, optionally substituted aryl, azido, cyano, hydroxy, carbonyl, carboxyl, alkoxycarbonyl, optionally substituted heteroaryl, alkoxy or alkylthio is substituted,
  • R 9 is hydrogen, optionally substituted aryl, optionally substituted heteroaryl or a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical which is optionally interrupted one to three times by oxygen and which is optionally one or more times, identical or different, by aryl, aryloxy, Azido, cyano, hydroxy, carboxyl, alkoxycarbonyl,
  • R 11 and R 12 independently of one another denote hydrogen, aryl, aralkyl or denote alkyl, which is optionally by Alkoxycarbonyl, hydroxyl, phenyl or benzyl is substituted, phenyl or benzyl optionally being substituted one or more times, identically or differently by hydroxy, carboxyl, alkyl or alkoxy, or alkyl optionally by -NH- CO-CH 3 or -NH-CO -CF 3 is substituted,
  • R 11 and R 12 together with the nitrogen atom on which they are located form a morpholinyl, piperidinyl or pyrrolidinyl ring,
  • n zero or 1
  • R 3 contains either a) at least one hydroxyl group and at least one ether oxygen atom or b) at least two ether oxygen atoms,
  • R 4 is hydrogen, alkyl, alkenyl, benzoyl or acyl
  • R pyridyl which is identical or different up to three times by halogen, hydroxy, cyano, alkyl, trifluoromethyl, alkoxy, alkylthio, carbalkoxy, acyloxy,
  • Amino, nitro, mono- or di alkylamino can be substituted, or thiazolyl, thienyl or furyl, which can be identical or different up to two times by halogen, hydroxy, cyano, alkyl, trifluoromethyl, alkoxy, alkylthio, carbalkoxy, acyloxy, amino, nitro, Mono- or dialkylamino can be substituted, mean and their salts.
  • Preferred compounds of the formulas (I) or (I a) according to the invention are those in which
  • R 1 is phenyl, furyl or thienyl, it being possible for these ring systems to be substituted one or two times identically or differently by substituents from the group halogen, hydroxyl, methyl, C 1 -C 4 -alkoxy, trifluoromethoxy,
  • R 2 is hydrogen, C 3 -C 4 alkenyl or C ö alkyl optionally substituted by halogen, hydroxy, C ⁇ -C 2 - alkoxy, pyridyl, cyano, phenoxy or benzyl,
  • R 3 the group -CH 2 -R 8 m -XR 9 ,
  • R -C-C 6 alkylene which is optionally substituted by halogen, -C-C 4 - (alkoxy) - carbonyl, hydroxy, phenyl or heteroaryl, which in turn is up to twice by halogen, hydroxy, -C-C 2 alkyl, Ci - C 2 alkoxy or -CC 3 - (alkoxy) carbonyl may be substituted,
  • R 9 is hydrogen, phenyl or heteroaryl or a -CC-alkyl radical, which is optionally interrupted one to three times by oxygen, phenyl or heteroaryl optionally by halogen, hydroxyl, -CC 2 -alkyl, C 1 -C -alkoxy or C ⁇ -C - (alkoxy) carbonyl are substituted and the C ⁇ -C ⁇ o-alkyl radical is optionally substituted by halogen, hydroxy, C ⁇ -C - alkoxy, alkoxycarbonyl or by phenyl, which in turn is up to twice by halogen, Hydroxy, CrC 2 - alkyl, C] -C 4 alkoxy or -CC 4 alkoxycarbonyl may be substituted,
  • n zero or 1
  • R contains either a) at least one hydroxyl group and 1 to 4 ether oxygen atoms or b) at least 2 to 4 ether oxygen atoms,
  • R 5 pyridyl or thiazolyl, which can be substituted up to twice in the same or different way by fluorine, chlorine, bromine, alkyl or alkoxy,
  • R 1 phenyl which is optionally substituted up to twice, identically or differently, by substituents from the group fluorine, chlorine, bromine, iodine, hydroxyl, methyl, methoxy, trifluoromethoxy,
  • R 2 is hydrogen or C r C 4 alkyl
  • R 3 the group -CH 2 -R 8 m -XR 9
  • R C-C 4 alkylene optionally by fluorine, chlorine, hydroxy, Ci
  • R 9 is hydrogen, -CC 8 - alkyl, optionally up to twice
  • Oxygen is interrupted, phenyl or 5- to 6-membered heteroaryl, alkyl, phenyl and heteroaryl optionally being substituted by halogen, hydroxy, methyl or -Cs-alkoxy,
  • n zero or 1
  • R 3 contains either a) at least one hydroxyl group and 1 to 3 ether oxygen atoms or b) 2 to 3 ether oxygen atoms,
  • R 5 pyridyl or thiazolyl, which can be substituted up to twice the same or different by fluorine, chlorine, bromine, C 1 -C 3 -alkyl or -Cj- alkoxy,
  • R phenyl optionally up to twice the same or different
  • R linear or branched C 1 -C 4 alkyl
  • R 3 is the group -CH 2 -R 8 m -XR 9 , wherein
  • R Cj-C -alkylene which can be substituted by fluorine, chlorine, hydroxy or phenyl, where the phenyl radical is optionally substituted by fluorine, chlorine, hydroxy, methyl or methoxy,
  • R 9 is hydrogen, Ci-C ö -alkyl which is optionally interrupted once by oxygen, fluorine, chlorine, hydroxyl or methoxy substituted phenyl or 5- to 6-membered heteroaryl, wherein alkyl, phenyl and heteroaryl are optionally substituted by;
  • n zero or 1
  • R 3 contains either a) a hydroxyl group and one or two ether oxygen atoms or b) 2 ether oxygen atoms, R 4 is hydrogen
  • R 5 pyridyl or thiazolyl, which can be substituted up to twice, identically or differently, by fluorine, chlorine or bromine,
  • R 5 represents 2-pyridyl, which can be substituted by 1 to 2 fluorine atoms, or represents thiazolyl.
  • 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 alkyl radical having 1 to 6 carbon atoms, e.g. Methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • a linear or branched alkyl radical having up to 4 carbon atoms is preferred.
  • Cyclic saturated hydrocarbon radical 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 and n-pentenyl.
  • alkoxy represents a linear or branched alkoxy radical having 1 to 6, preferably 1 to 4, carbon atoms, such as, for example, methoxy, ethoxy and propoxy.
  • Alkoxycarbonyl stands for a linear or branched in the context of the invention
  • Alkoxycarbonyl radical having 1 to 6, preferably 1 to 4 carbon atoms in the alkoxy radical, 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
  • 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, the alkyl part being linear or branched can be.
  • aryl part preferably phenyl or naphthyl, in particular phenyl
  • 1 to 4 in particular 1 or 2
  • 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
  • the compounds of the invention can be in stereoisomeric forms, which are either like image and mirror image (enantiomers), or which are not like image and
  • the invention relates to both Enantiomers or diastereomers and their respective mixtures. Like the diastereomers, the racemic forms 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. If R 4 is hydrogen, the isomers (I) and (la) are in tautomeric equilibrium:
  • 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 acids. Salts of inorganic acids such as, for example, are preferred.
  • Hydrochloric acid hydrobromic acid, phosphoric acid or sulfuric acid, or salts of organic carboxylic or sulfonic acids such as, for example, 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 naphthalenedisulfonic acid.
  • organic carboxylic or sulfonic acids such as, for example, 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 naphthalenedisulfonic acid.
  • Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention.
  • Z are particularly preferred.
  • the compounds (I) according to the invention can be prepared by
  • R 1 has the meaning given above
  • salts e.g. hydrochlorides or acetates
  • R 1 has the meaning given above
  • amidines of the formula (III) or with their salts such as hydrochlorides or acetates
  • base or acid preferably at temperatures of 20 to 150 ° C, optionally in the presence of inert organic solvents or
  • R. 13 represents C 1 -C 4 -alkyl
  • a strong base preferably at temperatures of 20 to 150 ° C, optionally in the presence of inert organic solvents.
  • 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 Dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine and hexamethylphosphoric triamide.
  • reaction temperatures can be varied over a wide range. In general, temperatures from 20 to 150 ° C, but preferably at the boiling point of the solvent.
  • the reaction can be carried out at normal pressure, but also at elevated pressure. Generally one works under normal pressure.
  • reaction can be carried out with or without addition of base or acid; however, it is advisable to implement in the presence of weaker acids, such as. B. acetic acid or formic acid.
  • 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, 2 401 665, Mijano et al., Chem. Abstr. 59, 13 929 c (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)].
  • the ylidene- ⁇ -keto esters (V) used as starting materials can be prepared by methods known from the literature [cf. G. Jones, "The Knoevenagel Condition” in Organic Reactions, Vol. XV, 204 ff. (1967)].
  • enaminocarboxylic acid esters (VI) and the imino ethers (VII) used as starting materials are known or can be prepared by methods known from the literature [cf. S.A. Glickman and A.C. Cope, J. Am. Chem. Soc. 67, 1017 (1945)].
  • ß-ketocarboxylic acid esters (IV) used as starting materials are known or can be prepared by methods known from the literature [e.g. BD Borrmann, "Implementation of Diketene with Alcohols, Phenols and Mercaptans” in “Methods of Organic Chemistry” (Houben-Weyl), Vol. VII / 4, 230 ff (1968); Y. Oikawa, K. Sugano and O. Yonemitsu, J. Org. Chem. 43, 2087 (1978)].
  • BD Borrmann "Implementation of Diketene with Alcohols, Phenols and Mercaptans” in “Methods of Organic Chemistry” (Houben-Weyl), Vol. VII / 4, 230 ff (1968); Y. Oikawa, K. Sugano and O. Yonemitsu, J. Org. Chem. 43, 2087 (1978)].
  • the compounds according to the invention show a valuable, unforeseeable activity against viruses. Surprisingly, they are antiviral against hepatitis BV viruses (HBV) by causing an extremely strong reduction in the DNA of intra- and extracellular hepatitis B viruses.
  • 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 cirrhosis of the liver and / or hepatocellular carcinoma.
  • 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.
  • One embodiment of the invention relates to combinations of A) above dihydropyrimidines (I) or (Ia) and B) at least one HBV antiviral agent different from A.
  • a particular embodiment of the invention relates to combinations of A) the above dihydropyrimidines (I) or (Ia), B) HBV polymerase inhibitors and, if appropriate, C) immunomodulators.
  • 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 a maximum of 50% of the activity of the zero value results:
  • HBV virions from culture supernatants incorporate nucleoside 5'-triphosphates into the plus strand of HBV DNA in vitro.
  • nucleoside 5'-triphosphates Using agarose gel electrophoresis, the incorporation of [- P] deoxynucleoside 5'-triphosphate into the 3.2 kb viral DNA product in the presence and absence of a substance with potential HBV-
  • HBV virions are obtained from the cell culture supernatant of HepG2.2.15 cells by precipitation with polyethylene glycol and concentrated. 1 volume of clarified cell culture supernatant is mixed with V mit volume of an aqueous solution containing 50% by weight of 8000 polyethylene glycol and 0.6 M sodium chloride. The virions are centrifuged at
  • each reaction mixture (100 ⁇ l) contains at least 10 5 HBV virions; 50 mM Tris-HCl (p H 7.5); 300mM potassium chloride; 50mM magnesium chloride; 0.1% ®Nonident
  • Solution (containing 10 g SDS per 90 ml water) is made up to a final concentration of 1 vol .-% (based on total volume), and Proteinase K is added to a final concentration of 1 mg / ml. After incubation at 37 ° C for one hour, samples are extracted with the same volume of phenol / chloroform / isoamyl alcohol (volume ratio 25: 24: 1) and the DNA is precipitated from the aqueous phase with ethanol. The DNA pellet is dissolved in 10 ⁇ l gel buffer (solution of
  • HBV polymerase inhibitor is present when a maximum of 50% of the activity of the negative control is present.
  • 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) the 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 - 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, -CC alkyl, optionally substituted C] -C - alkoxy, nitro, cyano or trifluoromethyl,
  • R 13 is hydrogen, -CC 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 ((55 xx 1100 44 ZZeelllleenn // mmll)) iinn WWaacchhssttuummssmmeeddiiuumm pplluuss 22 GGeeww ..-- %% föföttaalles calf serum.
  • the test mixture was incubated for 4 days at 37 ° C. and 5% CO 2 (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 as changes in cell morphology by light microscopy. Such substance-induced changes in the HepG2.2.15 cells compared to untreated cells were 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
  • Nylon filters were typically labeled with non-radioactive, digoxigenin Hepatitis B-specific DNA probes carried out, which were labeled with digoxigenin, purified and used for hybridization according to the manufacturer's instructions.
  • the prehybridization and hybridization took place 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).
  • the half-maximum inhibitory concentration (IC 0 , inhibitory concentration 50%) was determined as the concentration at which the intra- or extracellular hepatitis B -specific band was reduced by 50% compared to an untreated sample by the compound according to the invention.
  • 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 ingredients (I) or (Ia) or consist of a combination according to the invention.
  • the active ingredients (I) or (Ia) in the pharmaceutical preparations listed above should be in a concentration of about 0.1 to 99.5% by weight, preferably about
  • 0.5 to 95 wt .-% of the total mixture may be present.
  • 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; preferably it is 5 to 500 mg A / 10 to 1000 mg B, in particular 10 to 200 mg A / 20 to 400 mg B.
  • Component C which is optionally to be used, can be used in amounts of preferably 1 to 10 million, in particular 2 to 7 million I.U. (international units), applied approximately 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) in general, it has proven to be advantageous in both human and veterinary medicine to add the active ingredient (s) according to the invention in a total amount of from about 0.5 to about 500, preferably from 1 to 100 mg / kg of body weight per 24 Hours, if necessary in the form of several single doses, 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 body weight.
  • the invention therefore furthermore relates to the compounds and
  • 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 furthermore 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 were combined under nitrogen and stirred at 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.
  • This compound was prepared in analogy to Example VII starting from 2-bromo-4-fluoro-benzaldehyde and methyl acetoacetate.

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Abstract

L'invention concerne les dihydropyrimidines de formule générale (I) ou leur forme isomère (Ia), R?1, R2, R3, R4 et R5¿ ayant la signification donnée dans le descriptif, ainsi que leurs combinaisons avec d'autres agents antiviraux, lesdites dihydropyrimidines et leurs combinaisons servant à la lutte contre des infections par HBV.
PCT/EP2001/002444 2000-03-16 2001-03-05 Dihydropirimidines et leur utilisation en tant qu'agents pharmaceutiques destines au traitement de l'hepatite b WO2001068642A1 (fr)

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DE10012824A DE10012824A1 (de) 2000-03-16 2000-03-16 Arzneimittel gegen virale Erkrankungen

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WO2008154818A1 (fr) * 2007-06-18 2008-12-24 Zhang, Zhongneng Thiazolyl-dihydropyrimidines à substitution fluorophényle
WO2008154820A1 (fr) * 2007-06-18 2008-12-24 Zhang, Zhongneng Thiazolyl-dihydropyrimidines à substitution carbéthoxy
WO2008154819A1 (fr) * 2007-06-18 2008-12-24 Zhang, Zhongneng Thiazolyl-dihydropyrimidines à substitution carbéthoxy
EP2119708A1 (fr) * 2007-01-16 2009-11-18 Beijing Molecule Science and Technology Co., Ltd. Composés de tétrahydroquinazoline et leur utilisation dans la préparation de médicaments destinés au traitement et à la prévention de viroses
US8236797B2 (en) 2007-06-18 2012-08-07 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
WO2013102655A1 (fr) 2012-01-06 2013-07-11 Janssen R&D Ireland 1,4-dihydropyrimidines 4,4-disubstituées et leur utilisation en tant que médicaments pour le traitement de l'hépatite b
WO2014029193A1 (fr) 2012-08-24 2014-02-27 Sunshine Lake Pharma Co., Ltd. Composés de dihydropyrimidine et leur application dans des produits pharmaceutiques
CN103664897A (zh) * 2012-09-01 2014-03-26 广东东阳光药业有限公司 二氢嘧啶类化合物及其在药物中的应用
JP2015511614A (ja) * 2012-03-31 2015-04-20 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ｂ型肝炎ウイルス感染の治療および予防のための新規４−メチル−ジヒドロピリミジン
US9447086B2 (en) 2012-09-10 2016-09-20 Hoffmann-La Roche Inc. 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection
US9498479B2 (en) 2013-11-19 2016-11-22 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
US9573941B2 (en) 2013-11-27 2017-02-21 Sunshine Lake Pharma Co., Ltd. Processes for preparing dihydropyrimidine derivatives and intermediates thereof
US9771358B2 (en) 2014-03-28 2017-09-26 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
US9856247B2 (en) 2012-03-31 2018-01-02 Hoffmann-La Roche Inc. 4-methyl-dihydropyrimidines for the treatment and prophylaxis of Hepatitis B virus infection
US10081627B2 (en) 2014-03-07 2018-09-25 Hoffmann-La Roche Inc. 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection
US10098889B2 (en) 2015-02-07 2018-10-16 Sunshine Lake Pharma Co., Ltd. Complexes and salts of dihydropyrimidine derivatives and their application in pharmaceuticals
WO2019020070A1 (fr) 2017-07-27 2019-01-31 江苏恒瑞医药股份有限公司 Dérivé de pipérazine hétéroaryle, son procédé de préparation et son utilisation en médecine
US11337982B2 (en) 2016-09-13 2022-05-24 Hoffmann-La Roche, Inc. Combined treatment with a TLR7 agonist and an HBV capsid assembly inhibitor
US11771699B2 (en) 2015-03-16 2023-10-03 Hoffmann-La Roche Inc. Combined treatment with a TLR7 agonist and an HBV capsid assembly inhibitor
US11873302B2 (en) 2019-03-25 2024-01-16 Hoffmann-La Roche Inc. Solid forms of a compound of HBV core protein allosteric modifier

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CN101225084A (zh) * 2007-01-16 2008-07-23 北京摩力克科技有限公司 二氢嘧啶类化合物及其用于制备治疗和预防病毒性疾病的药物的用途

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WO1999001438A1 (fr) * 1997-07-02 1999-01-14 Astra Aktiebolag (Publ) Nouveaux composes
WO1999054329A1 (fr) * 1998-04-18 1999-10-28 Bayer Aktiengesellschaft Nouvelles dihydropyrimidines a substitution 2-heterocyclique
WO1999054312A1 (fr) * 1998-04-18 1999-10-28 Bayer Aktiengesellschaft Utilisation de dihydropyrimidines comme medicaments, et nouvelles substances

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WO1999001438A1 (fr) * 1997-07-02 1999-01-14 Astra Aktiebolag (Publ) Nouveaux composes
WO1999054329A1 (fr) * 1998-04-18 1999-10-28 Bayer Aktiengesellschaft Nouvelles dihydropyrimidines a substitution 2-heterocyclique
WO1999054312A1 (fr) * 1998-04-18 1999-10-28 Bayer Aktiengesellschaft Utilisation de dihydropyrimidines comme medicaments, et nouvelles substances

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US8188091B2 (en) 2007-01-16 2012-05-29 Beijing Molecule Science And Technology Co., Ltd. Tetrahydroquinazoline compounds and their use in preparing medicaments for treating and preventing virosis
JP2010515763A (ja) * 2007-01-16 2010-05-13 ベイジン・モレキュール・サイエンス・アンド・テクノロジー・カンパニー・リミテッド テトラヒドロキナゾリン化合物、ならびに、ウィルス疾病を処置および予防するための薬を調製することにおけるその使用
EP2119708A4 (fr) * 2007-01-16 2011-07-06 Beijing Molecule Science And Technology Co Ltd Composés de tétrahydroquinazoline et leur utilisation dans la préparation de médicaments destinés au traitement et à la prévention de viroses
EP2119708A1 (fr) * 2007-01-16 2009-11-18 Beijing Molecule Science and Technology Co., Ltd. Composés de tétrahydroquinazoline et leur utilisation dans la préparation de médicaments destinés au traitement et à la prévention de viroses
US8343969B2 (en) 2007-06-18 2013-01-01 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
WO2008154819A1 (fr) * 2007-06-18 2008-12-24 Zhang, Zhongneng Thiazolyl-dihydropyrimidines à substitution carbéthoxy
WO2008154820A1 (fr) * 2007-06-18 2008-12-24 Zhang, Zhongneng Thiazolyl-dihydropyrimidines à substitution carbéthoxy
WO2008154818A1 (fr) * 2007-06-18 2008-12-24 Zhang, Zhongneng Thiazolyl-dihydropyrimidines à substitution fluorophényle
US8236797B2 (en) 2007-06-18 2012-08-07 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
USRE44987E1 (en) 2007-06-18 2014-07-01 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
US9233933B2 (en) 2012-01-06 2016-01-12 Janssen Sciences Ireland Uc 4,4-disubstituted-1,4-dihydropyrimidines and the use thereof as medicaments for the treatment of hepatitis B
WO2013102655A1 (fr) 2012-01-06 2013-07-11 Janssen R&D Ireland 1,4-dihydropyrimidines 4,4-disubstituées et leur utilisation en tant que médicaments pour le traitement de l'hépatite b
US9856247B2 (en) 2012-03-31 2018-01-02 Hoffmann-La Roche Inc. 4-methyl-dihydropyrimidines for the treatment and prophylaxis of Hepatitis B virus infection
JP2015511614A (ja) * 2012-03-31 2015-04-20 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ｂ型肝炎ウイルス感染の治療および予防のための新規４−メチル−ジヒドロピリミジン
RU2655914C2 (ru) * 2012-08-24 2018-05-30 Саншайн Лейк Фарма Ко., Лтд. Соединения дигидропиримидина и их применение в фармацевтических препаратах
RU2655914C9 (ru) * 2012-08-24 2018-07-24 Саншайн Лейк Фарма Ко., Лтд. Соединения дигидропиримидина и их применение в фармацевтических препаратах
US9340538B2 (en) 2012-08-24 2016-05-17 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
WO2014029193A1 (fr) 2012-08-24 2014-02-27 Sunshine Lake Pharma Co., Ltd. Composés de dihydropyrimidine et leur application dans des produits pharmaceutiques
CN103664897A (zh) * 2012-09-01 2014-03-26 广东东阳光药业有限公司 二氢嘧啶类化合物及其在药物中的应用
CN103664897B (zh) * 2012-09-01 2018-04-03 广东东阳光药业有限公司 二氢嘧啶类化合物及其在药物中的应用
US9447086B2 (en) 2012-09-10 2016-09-20 Hoffmann-La Roche Inc. 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection
US9498479B2 (en) 2013-11-19 2016-11-22 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
US9617252B2 (en) 2013-11-27 2017-04-11 Sunshine Lake Pharma Co., Ltd. Processes for preparing dihydropyrimidine derivatives and intermediates thereof
US9643962B2 (en) 2013-11-27 2017-05-09 Sunshine Lake Pharma Co., Ltd. Processes for preparing dihydropyrimidine derivatives and intermediates thereof
US9573941B2 (en) 2013-11-27 2017-02-21 Sunshine Lake Pharma Co., Ltd. Processes for preparing dihydropyrimidine derivatives and intermediates thereof
US10081627B2 (en) 2014-03-07 2018-09-25 Hoffmann-La Roche Inc. 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection
US10428069B2 (en) 2014-03-07 2019-10-01 Hoffmann-La Roche Inc. 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection
US9771358B2 (en) 2014-03-28 2017-09-26 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
US10098889B2 (en) 2015-02-07 2018-10-16 Sunshine Lake Pharma Co., Ltd. Complexes and salts of dihydropyrimidine derivatives and their application in pharmaceuticals
US11771699B2 (en) 2015-03-16 2023-10-03 Hoffmann-La Roche Inc. Combined treatment with a TLR7 agonist and an HBV capsid assembly inhibitor
US11337982B2 (en) 2016-09-13 2022-05-24 Hoffmann-La Roche, Inc. Combined treatment with a TLR7 agonist and an HBV capsid assembly inhibitor
WO2019020070A1 (fr) 2017-07-27 2019-01-31 江苏恒瑞医药股份有限公司 Dérivé de pipérazine hétéroaryle, son procédé de préparation et son utilisation en médecine
US11247998B2 (en) 2017-07-27 2022-02-15 Jiangsu Hengrui Medicine Co., Ltd. Piperazine heteroaryl derivative, preparation method therefor and use of same in medicine
US11873302B2 (en) 2019-03-25 2024-01-16 Hoffmann-La Roche Inc. Solid forms of a compound of HBV core protein allosteric modifier

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