WO2001045712A1 - Combinaison de medicaments pour lutter contre des maladies virales - Google Patents

Combinaison de medicaments pour lutter contre des maladies virales Download PDF

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Publication number
WO2001045712A1
WO2001045712A1 PCT/EP2000/012570 EP0012570W WO0145712A1 WO 2001045712 A1 WO2001045712 A1 WO 2001045712A1 EP 0012570 W EP0012570 W EP 0012570W WO 0145712 A1 WO0145712 A1 WO 0145712A1
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Prior art keywords
alkyl
substituted
hydrogen
phenyl
optionally
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PCT/EP2000/012570
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German (de)
English (en)
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WO2001045712A8 (fr
Inventor
Arnold Paessens
Karl Deres
Olaf Weber
Erwin Graef
Siegfried Goldmann
Thomas Krämer
Ulrich Niewöhner
Karl-Heinz Schlemmer
Jürgen Stoltefuss
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Bayer Aktiengesellschaft
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Priority claimed from DE1999162010 external-priority patent/DE19962010A1/de
Priority claimed from DE2000112259 external-priority patent/DE10012259A1/de
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to AU30098/01A priority Critical patent/AU3009801A/en
Publication of WO2001045712A1 publication Critical patent/WO2001045712A1/fr
Publication of WO2001045712A8 publication Critical patent/WO2001045712A8/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • 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
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the invention relates to combinations of A) non-nucleoside inhibitors, e.g. Dihydropyrimidines, B) other antiviral agents and optionally C)
  • Immunomodulators a process for their preparation and their use as medicines, in particular for the treatment and prophylaxis of HBV infections.
  • “Combinations” in the sense of the invention are understood not only to be dosage forms which contain all components (so-called fixed combinations) and combination packs which contain the components separately from one another, but also components which are applied simultaneously or at different times, provided that they are used for treatment or prophylaxis of the same disease.
  • the hepatitis B virus belongs to the Hepadna virus family. It causes an acute and / or a persistent-progressive, chronic illness. Various other clinical manifestations in the clinical picture are also caused by the hepatitis B virus - in particular chronic liver inflammation, cirrhosis and hepatocellular carcinoma. Furthermore, co-infection with the hepatitis delta virus can have a negative impact on the course of the disease.
  • the polymerase is one of the essential and essential enzymatic activities of the HBV virus in the propagation cycle; see. Radziwill et al., J. Virol. 64: 613-620 (1990). Analogs of the natural substrates - mostly after phosphorylation by the host's own enzymes - inhibit the viral polymerase complex Polymerase activity and thus the replication of HBV in vitro and in vivo; see. e.g. Chang et al., J. Biol. Chem. 267, 13938 -13942 (1992).
  • Lamivudine has recently been used to treat patients with chronic HBV infection. However, it shows a high rebound effect after stopping the therapy and leads to resistance during long-term therapy.
  • BMS 200475 Adefovir Dipivoxil, BMS 200475 and the other inhibitors mentioned above, there is as yet no generally accessible clinical experience.
  • interferon Treatment of chronic hepatitis by interferon; however, it is only moderately effective and has undesirable side effects. Combinations of interferon with lamivudine are not synergistically effective.
  • AT-61 N - [(1E) - 2-chloro-2-phenyl-l- (l-piperidinylcarbonyl) ethenyl] benzamide, which apparently interferes with the process of packaging the pregenomic RNA into the unfinished core particles; see. King et al., Antimicrob. Agents and chemother. 42, 3179-3186 (1998). Even if the mechanism has not yet been fully elucidated, the authors seem to rule out an effect on the core protein. The in vitro combination of AT-61 and lamivudine is described as being synergistically effective.
  • the invention therefore relates to combinations A) of at least one dihydropyrimidine, B) at least one HBV-antiviral agent different from A, preferably an HBV polymerase inhibitor, and optionally C) at least one immunomodulator.
  • the invention thus relates to combinations of nucleoside and non-nucleoside inhibitors and, if appropriate, immunomodulators for the treatment and prophylaxis of HBV infections and the use of these combinations for the treatment of HB V-induced diseases.
  • the combinations according to the invention unpredictably inhibit the multiplication of the HBV virus significantly better than the agents known from the prior art or their known combinations.
  • the use of the combinations according to the invention offers valuable treatments for HBV-induced diseases
  • Preferred dihydropyrimidines A correspond, for example, to the formula
  • R phenyl, furyl, thienyl, triazolyl, pyridyl, cycloalkyl having 3 to 6 carbon atoms or radicals of the formulas
  • R 6 optionally halogen-substituted phenyl
  • R to R are independently hydrogen, phenyl, hydroxy-substituted phenyl, hydroxy, QC ö acyl or Ci-C ⁇ -alkyl, where the alkyl radical for its part substituted hydroxy-substituted by hydroxy, dC ö alkoxycarbonyl, phenyl or phenyl may be substituted .
  • A is a radical -O-, -S-, -SO- or -SO 2 -,
  • R is substituted and phenyl which is optionally monosubstituted to polysubstituted by identical or different substituents selected from the group halogen, nitro, trifluoromethyl, QC ö alkyl and C ⁇ -C 6 -alkoxy, mean
  • X is a single bond or oxygen
  • R 12 is hydrogen, straight-chain or branched CrC ⁇ alkoxycarbonyl, a straight-chain, branched or cyclic, saturated or unsaturated C j -C 8 hydrocarbon radical, which may be a or two identical or different hetero chain links from the group -O-, -CO-, -NH-, -N- (dC 4 -alkyl) -,
  • R 15 and R 16 independently of one another are hydrogen, benzyl or dC 6 -alkyl
  • R 13 and R 14 independently of one another are hydrogen, C 1 -C 6 -alkyl or cycloalkyl having 3 to 6 carbon atoms,
  • R> 3 is hydrogen, amino or a radical of the formula
  • R 17 and R 18 independently of one another are hydrogen or aryl having 6 to 10 carbon atoms, aralkyl having 6 to 10 carbon atoms or C 1 -C 6 -alkyl, which are optionally substituted by -CC 6 -alkoxycarbonyl, amino, hydroxyl, phenyl or benzyl wherein phenyl and benzyl are optionally mono- or polysubstituted, identically or differently by hydroxyl, carboxyl, C ⁇ -C6 alkyl or C ⁇ -C substituted 6 alkoxy and / or C ⁇ -C6 alkyl optionally substituted by -NH-CO- CH 3 or -NH-CO-CF 3 is substituted,
  • R 17 and R 18 together with the nitrogen atom on which they stand mean a morpholinyl, piperidinyl or pyrrolidinyl ring,
  • R optionally methoxy-substituted phenyl
  • R and R together form a radical of the formula R is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, benzoyl or acyl having 2 to 6 carbon atoms, preferably hydrogen, methyl, benzoyl or C 2 -C 6 acyl, and
  • R 5 pyridyl, pyrimidyl or pyrazinyl, each up to 3 times, the same or different by halogen, hydroxy, cyano, trifluoromethyl, Ci-C ö alkoxy, Ci-C 6 alkyl, dC 6 alkylthio, carbalkoxy, dC 6 -acyloxy, amino, nitro, mono- or di-C 6 -C 6 -alkylamino can be substituted,
  • the compounds I and Ia include the isomers of the formulas (I) and (Ia) and mixtures thereof.
  • R 4 is hydrogen
  • the isomers (I) and (la) are in tautomeric equilibrium:
  • Preferred compounds of the formulas (I) and (Ia) are those in which
  • R 1 is phenyl, furyl, thienyl, triazolyl, pyridyl, cyclopentyl, cyclohexyl or
  • X is a single bond or an oxygen atom
  • R 12 is hydrogen, C 2 -C 4 -alkenyl, dC -alkoxycarbonyl or dC 4 -alkyl, where the alkyl radical is optionally substituted by pyridyl, cyano, phenoxy, benzyl or by a radical of the formula -NR 15 R 16 , in which
  • R 5 and R 6 are independently hydrogen, benzyl or -CC 4 alkyl
  • R 13 and R 14 independently of one another denote hydrogen, -CC alkyl or cyclopropyl, R 3 is hydrogen, amino or a radical of the formula
  • Formyl, cyano, hydroxy-substituted C 1 -C 4 alkylthio, trifluoromethyl, cyclopropyl, pyridyl or C -C alkyl means, where the alkyl radical optionally by halogen, dC 4 alkoxycarbonyl, hydroxy and / or by the group - (CO ) a-NR 17 R 18 is substituted, wherein
  • R 17 and R 18 independently of one another are hydrogen, phenyl, benzyl or Ci
  • C 4 alkyl which are optionally substituted by C 3 -C 3 -alkoxycarbonyl, amino, hydroxyl, phenyl or benzyl, phenyl and benzyl independently of one another optionally optionally one or two times, identically or differently, by hydroxyl, carboxy, Ci-d- Alkyl or -CC 3 alkoxy are substituted and dC 3 alkyl is optionally substituted by radicals of the formulas -NH-CO-CH 3 or -NH-CO-CF 3 , phenyl or
  • R 17 and R 18 together with the nitrogen atom on which they stand mean a morpholinyl, piperidinyl or pyrrolidinyl ring,
  • R 5 is pyridyl, pyrimidyl or pyrazinyl, and their salts.
  • R 1 is phenyl, furyl, thienyl, triazolyl, pyridyl, cyclopentyl, cyclohexyl or
  • the above-mentioned ring systems optionally up to two, identical or different by substituents selected from the group fluorine, chlorine, bromine, iodine, hydroxy, trifluoromethyl, nitro, -SO 2 -CF 3 , Methyl, cyano, trifluoromethoxy, carboxyl, methoxycarbonyl or residues of the formulas -CO-NH-CH 2 -C (CH 3 ) 3 , -CO-NH (CH 2 ) 2 OH, -CO-NH-CH 2 - C 6 H 5 , -CO-NH-C 6 H 5 , -CO-NH-OHj-C ö E, -O-CH 2 -C 6 H 5 or -S-pCl- C ⁇ i are substituted,
  • R 2 is a radical of the formulas -XR 12 or -NR 13 R 14 , in which
  • X is a single bond or an oxygen atom
  • R 12 is hydrogen, C 2 -C 3 alkenyl, dC 4 alkoxycarbonyl or dC 4 alkyl, in which the alkyl radical is optionally substituted by pyridyl, cyano, phenoxy, benzyl or by a radical of the formula -NR 15 R 16 , in which
  • R 15 and R 16 independently of one another are hydrogen or methyl
  • R 13 and R 14 independently of one another are hydrogen, C 3 -C 3 -alkyl or cyclopropyl
  • R 3 is hydrogen, amino or a radical of the formula
  • Formyl, cyano, trifluoromethyl, cyclopropyl, pyridyl or dC ⁇ alkyl means, where the alkyl radical is optionally substituted by fluorine, chlorine, -C-C 3 - alkoxycarbonyl or hydroxy, or R 3 optionally methoxy-substituted phenyl or
  • R 2 and R 3 together represent a radical of the formula
  • R 4 is hydrogen, methyl, vinyl or acetyl
  • R 5 is pyridyl, pyrimidyl or pyrazinyl, and their salts.
  • R 1 is phenyl or triazolyl, which are optionally substituted up to twice, identically or differently, by fluorine, chlorine, bromine or iodine,
  • R 2 straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms
  • R 3 is methyl, ethyl or cyclopropyl or
  • R 2 and R 3 together represent a radical of the formula
  • R 4 is hydrogen, vinyl or acetyl
  • R 5 is pyridyl. Particularly preferred dihydropyrimidines A are listed in Table A.
  • the dihydropyrimidines A listed in Table B are very particularly preferred.
  • Particularly preferred dihydropyrimidines A are the above compounds 24, 25 and 41 to 44 of Table B.
  • the following compounds are very particularly preferred: their isomeric forms and their salts.
  • R has the meaning given above, with or without addition of base or acid, if appropriate in the presence of inert organic solvents, preferably at temperatures from 20 to 150 ° C., or
  • R 1 has the meaning given above
  • R 5 has the meaning given above and R 1 represents (dC 4 ) alkyl
  • inert organic solvents are suitable as solvents for process variants A, B, C and D.
  • These preferably include alcohols such as ethanol, methanol, isopropanol, ethers such as diethyl ether, tetrahydrofuran, dioxane,
  • Glycol monomethyl ether glycol dimethyl ether, carboxylic acids such as glacial acetic acid, or dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine and
  • reaction temperatures can be varied within a wide range. In general, the process is carried out in the range from 20 to 150 ° C., but preferably at the boiling point of the particular solvent.
  • 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; the presence of weaker acids such as acetic acid or formic acid is preferred.
  • the aldehydes (II) used as starting materials are known or can be prepared by methods known from the literature [cf. TD Harris and GP Roth, J. Org. Chem. 44, 146 (1979), DE-OS 2 165 260 and 2 401 665, Mijano et al., Chem. Abstr. 59, (1963), 13 929 c, E. Adler and H.-D. Becker, Chem. Scand. 15, 849
  • ⁇ -ketocarboxylic acid esters (TV) used as starting materials are known or can be prepared by methods known from the literature [e.g. D. Borrmann,
  • the ylidene- ⁇ -keto esters (V) used as starting materials can be prepared by methods known from the literature [cf. G. Jones, "The Knoevenagel Condensation” 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)].
  • the compounds (E) can be prepared by using compounds of the formula
  • R 5 has the meaning given above, as usual via the imino ethers and finally reacted with ammonium chloride in methanol [cf. see WK Fife, Heterocycles 22, 93-96 (1984); T. Sakamoto, S. Kaneda, S. Nishimura, H. Yamanaka, Chem. Pharm. Bull. 33, 565, 571 (1986)] or other methods known from the literature, such as, for example, Garigipati, Tetrahedron Lett. 1990, 1969-1972, Boere et al, J. Organomet. Chem. 1987, 331, 161, or Caton et al., J. Chem. Soc. 1967, 1204.
  • All process steps can be carried out at normal pressure and in a temperature range from 0 to 130 ° C., preferably from 20 to 100 ° C.
  • the compounds (VIII) are known or can be prepared by processes known per se, for example by using pyridines of the formula
  • TMSCN trimethylsilyl cyanide
  • Y and Z represent the substitution radicals of the pyridyl ring indicated under R, with the help of cyanides, such as potassium cyanide or copper cyanide, which exchanges chlorine for cyanide,
  • Y 'and Z' independently of one another are chlorine or bromine
  • alkali metal or ammonium fluorides preferably potassium fluoride
  • polar solvents such as, for example, polyglycols, polyglycol ethers, DMSO or sulfolane, optionally with the addition of phase transfer catalysts, in the sense of a halogen / fluorine exchange reaction.
  • R 1 is phenyl, furyl, thienyl, pyridyl, cycloalkyl having 3 to 6 carbon atoms or a radical of the formulas
  • Carboxyl, hydroxyl, -CC 6 alkoxy, d-C ⁇ -alkoxycarbonyl and Ci-C ⁇ -alkyl, are substituted, the alkyl radical in turn by aryl with 6 to 10th
  • Carbon atoms or halogen can be substituted, and / or the listed ring systems optionally by groups of
  • R 1 6 optionally halogen-substituted phenyl
  • R 7 to R 10 independently of one another are hydrogen, phenyl, hydroxy-substituted phenyl, hydroxy, dC 6 -acyl or dC 6 -alkyl, where the The alkyl radical in turn can be substituted by hydroxy, dC 6 -alkoxycarbonyl, phenyl or hydroxy-substituted phenyl,
  • A is a radical -O-, -S-, -SO- or -SO 2 -,
  • R 11 is phenyl which is optionally substituted one or more times, identically or differently, by substituents selected from the group consisting of halogen, nitro, trifluoromethyl, Ci-Cö-alkyl and d-Cö-alkoxy,
  • R 2 is a radical of the formulas -OR 12 or -NR 13 R 14 , wherein
  • R 12 is hydrogen, dC 6 -alkoxycarbonyl or a straight-chain, branched or cyclic, saturated or unsaturated C j -C 8 -hydrocarbon radical, which optionally contains one or two identical or different hetero-chain links from the group -O-, -CO- , -NH-, -N- (dC 4 alkyl) -, -S- and -SO 2 - and optionally by halogen, nitro, cyano, hydroxy, aryl with 6 to 10 carbon atoms or aralkyl with 6 to 10 carbon atoms .
  • Heteroaryl or a group of the formula -NR 15 R 16 is substituted, in which R 15 and R 16 independently of one another are hydrogen, benzyl or dC 6 -alkyl,
  • R 13 and R 14 independently of one another hydrogen, -CC 6 alkyl or
  • R, 3 is hydrogen, amino or a radical of the formula
  • R 17 and R 18 independently of one another are hydrogen or aryl, aralkyl having 6 to
  • Ci-Ce- alkyl 10 carbon atoms or Ci-Ce- alkyl, which are optionally substituted by dC 6 - alkoxycarbonyl, amino, hydroxyl, phenyl or benzyl, phenyl and benzyl optionally one or more times, identically or differently, by hydroxyl, carboxyl, C 1 -C 6 Alkyl or dC 6 -alkoxy are substituted and or d-C ⁇ -alkyl is optionally substituted by -NH-CO-CH 3 or -NH-CO-CF 3 ,
  • R 17 and R 18 together with the nitrogen atom on which they stand mean a morpholinyl, piperidinyl or pyrrolidinyl ring,
  • D is an oxygen or sulfur atom
  • R 5 is hydrogen, halogen or straight-chain or branched alkyl having up to 6 carbon atoms, and their salts.
  • R 1 is phenyl, furyl, thienyl, pyridyl, cyclopentyl or cyclohexyl, these ring systems optionally one or two times, identical or different by substituents, selected from the group halogen, trifluoromethyl, nitro, -SO 2 -CF 3 , methyl, cyano, Trifluoromethoxy, carboxyl, methoxycarbonyl or residues of the formulas -CO-NH-CH 2 -C (CH 3 ) 3 , -CO-NH (CH 2 ) 2 OH, - CO-NH-CH 2 -C 6 H 5 , -CO -NH-C 6 H 5 , -CO-NH- (pOH) -C 6 H 4 , -O-CH 2 -C 6 H 5 or -S-pCl-dEL; are substituted,
  • R 2 represents a radical of the formulas -OR 12 or -NR 13 R 14 , in which
  • R 12 is hydrogen, C 2 -C 4 alkenyl or dC 4 alkyl, the alkyl radical in turn optionally being substituted by pyridyl, cyano, phenoxy, benzyl or by a radical of the formula -NR 15 R 16 , in which R 15 and R l ⁇ are independently hydrogen, methyl or ethyl,
  • R 13 and R 14 independently of one another are hydrogen, methyl, ethyl or cyclopropyl
  • R 3 is hydrogen or a radical of the formula
  • Formyl, cyano, trifluoromethyl, cyclopropyl or dC 4 -alkyl means, the alkyl radical in turn optionally being represented by radicals of the formulas
  • R and R independently of one another are hydrogen, phenyl, benzyl or Ci
  • C 4 alkyl which are optionally substituted by dC 3 - alkoxycarbonyl, amino, hydroxyl, phenyl or benzyl, phenyl and benzyl independently of one another optionally optionally one or two times, identically or differently, by hydroxyl, carboxy, C 1 -C 3 - Alkyl or dC 3 -alkoxy are substituted and dC -alkyl is optionally substituted by radicals of the formulas -NH-CO-CH 3 or -NH-CO-CF 3 , phenyl or
  • R 4 is hydrogen, methyl, ethyl or acetyl
  • D is an oxygen or sulfur atom
  • R 5 is hydrogen, halogen or C ⁇ . -C 4 alkyl, and their salts.
  • R 1 is phenyl or thienyl, these ring systems optionally being substituted up to twice, identically or differently, by substituents selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl and nitro,
  • R 2 is a radical of the formulas -OR 12 or -NR 13 R 14 , wherein
  • R 12 is hydrogen or d-alkyl
  • R 13 and R 14 independently of one another denote hydrogen or methyl
  • R 3 denotes hydrogen or formyl, cyano, trifluoromethyl, cyclopropyl or dC 3 alkyl which is optionally substituted by fluorine, chlorine or hydroxyl and which in turn can be substituted up to 3 times by dC 3 alkoxycarbonyl,
  • R 4 is hydrogen or methyl
  • D is an oxygen or sulfur atom
  • R 5 is hydrogen, fluorine, chlorine or -CC 3 alkyl, and their salts.
  • R 1 is phenyl or thienyl, which are optionally substituted up to twice, identically or differently, by fluorine or chlorine,
  • R 4 is hydrogen
  • D is an oxygen or sulfur atom
  • R 5 is hydrogen, fluorine or chlorine, and their salts.
  • Preferred such 2-heterocyclically substituted dydropyrimidines include, for example, the compounds in the following table.
  • the Rr values were determined in cyclohexane / ethyl acetate (7: 3 parts by volume).
  • Cycloalkyl having 3 to 6 carbon atoms in the context of the invention represents cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, preferably cyclopentyl and cyclohexyl.
  • Aryl generally represents 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.
  • 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, thiophenyl, pyrazolyl, imidazolyl, 1.2.3- and 1.2.4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1.2.3-, 1.3.4-, 1.2.4- and 1.2.5-oxadiazolyl , Pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, 1.3.5-, 1.2.4- and 1.2.3-triazinyl, 1.2.4-, 1.3.2-, 1.3.6- and
  • acyl represents a straight-chain or branched acyl radical having 1 to 6, preferably 1 to 4, carbon atoms, such as, for example, acetyl and propionyl.
  • alkyl represents a straight-chain or branched alkyl radical having 1 to 6, preferably 1 to 4, carbon atoms, such as e.g. Methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6, preferably 3 to 5, carbon atoms, such as, for example, ethenyl,
  • alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6, preferably 1 to 4, carbon atoms, such as e.g. Methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • alkylthio represents a straight-chain or branched alkylthio radical having 1 to 6, preferably 1 to 4, carbon atoms, such as, for example, methylthio, ethylthio and propylthio.
  • alkoxycarbonyl represents a straight-chain or branched alkoxycarbonyl radical having 1 to 6, preferably 1 to 4, carbon atoms, such as, for example, Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • Halogen in the context of the invention represents fluorine, chlorine, bromine or iodine.
  • the compounds I and Ia can be in stereoisomeric forms, which are either like
  • the compounds I and Ia thus include both the enantiomers and the diastereomers and their respective Mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
  • the compounds I and Ia can also be present as salts.
  • physiologically acceptable salts are preferred.
  • Physiologically acceptable salts can be salts of the compounds I or Ia with inorganic or organic acids.
  • Salts of inorganic acids such as, for example, 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.
  • Physiologically acceptable salts can also be metal or ammonium salts
  • Compounds I or Ia For example, particular preference is given to Sodium, potassium, magnesium or calcium salts and ammonium salts derived from ammonia or organic amines, such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2- Phenylethylamine.
  • ammonia or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2- Phenylethylamine.
  • the compounds (I) or (Ia) can be prepared by
  • R 1 has the meaning given above
  • amidines of the formula wherein R • 5 and D have the meanings given above, with or without addition of base or acid, preferably at temperatures of 20 to 150 ° C, optionally in the presence of inert organic solvents, or
  • R 1 has the meaning given above
  • R - C C - CO-R 2
  • solvents are suitable as solvents.
  • solvents preferably include alcohols such as ethanol, methanol, 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 acid triamide.
  • reaction temperatures can be varied within a wide range; generally one works in a range of 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.
  • the reaction can be carried out with or without addition of base or acid, preferably in the presence of weaker acids, such as, for example, acetic acid or formic acid.
  • weaker acids such as, for example, acetic acid or formic acid.
  • the aldehydes (II) used as starting materials are known or can be prepared by methods known from the literature [cf. TD Harris and GP Roth, J. Org. Chem. 44, 146 (1979), DE-OS 2 165 260 and 2 401 665, Mijano et al., Chem. Abstr. 59, (1963), 13 929 c, E. Adler and H.-D. Becker, Chem. Scand. 15, 849 (1961), EP Papadopoulos, M. Mardin and Ch. Issidoridis, J. Org. Chem. Soc. 78
  • amidines (III) used as starting materials are known or can be prepared by methods known from the literature [cf. "Methods of Organic Chemistry” (Houben-Weyl), Vol. 11/2, page 38 ff (1958); R.L. Shoiner and F.W.
  • ⁇ -ketocarboxylic acid esters (IV) used as starting materials are known or can be prepared by methods known from the literature [e.g. D. Borrmann, "Reaction 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 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)].
  • enammocarboxylic acid esters (VI) used as starting materials are known or can be prepared by methods known from the literature [cf. A.C. Cope, J. Am. Chem. Soc. 67, 1017 (1945)].
  • the dihydropyrimidines A act as HBV core protein inhibitors. Combinations are therefore a further subject of the invention.
  • HBV core protein inhibitors in the sense of the invention are those non-nucleoside inhibitors which in the cell (i) at least halve the half-life of the HBV core protein or (ii) pass the binding test described below.
  • the synthesis rate and the stability of the HBV core protein can be measured by pulse chase labeling of HepG2.2.15 cells and subsequent immunoprecipitation of the HBV core protein.
  • the half-life of the core protein is used as a measure of the stability.
  • the amount of protein correlates with the built-in radioactivity and consequently that
  • Blackening of an X-ray film or the radiation intensity that can be made visible by a phosphor imager Blackening of an X-ray film or the radiation intensity that can be made visible by a phosphor imager.
  • the HepG2.2.15 cells are used in cell culture bottles (75 cm 2 ; Costar) with a density of 6 ⁇ 10 6 cells per bottle in HepG2 cell culture medium (Biochrom KG, Berlin). 100 liters of this medium consist of 74.8 liters of ®seromed RPMI 1640 medium and 14.4 liters of ⁇ seromed Medium 199 with Earle's
  • FCS fetal calf serum
  • test substance is prepared as a 50 mM stock solution in dimethyl sulfoxide (DMSO; Sigma, Kunststoff). It is diluted in HepG2 cell culture medium and adjusted to 100 times the IC 50 concentration. 1 ml of this test substance solution is added to 19 ml of HepG2 cell culture medium. The test substance is added with the sowing in graduated dilution steps. The cells are incubated at 37 ° C and 5% CO 2 (v / v) in the incubator.
  • DMSO dimethyl sulfoxide
  • the culture medium is discarded and replaced by 20 ml of a medium from which the amino acids methionine and cystine are removed ("starvation medium").
  • MEM minimum essential medium with Earle's salts; Gibco 51091-015 - the composition is described before the examples
  • the incubation with hunger medium is carried out in the presence of the test substance (concentration as above).
  • the cells are incubated for 45 minutes at 37 ° C. and 5% CO 2 (v / v) in the incubator.
  • 16 ml of hunger medium are removed and the remaining medium is mixed with 25 ⁇ l of 35 S-Redivue Promix (2.5 mCi / 175 ⁇ l) (Amersham, AGQ 0080).
  • the cells are incubated for a further 10 minutes at 37 ° C. and 5% CO 2 (v / v) in the incubator (“pulse”).
  • the marking solution is then removed and fed with starving medium plus aqueous L-cystine solution (up to a cystine concentration of the total solution of 1 mM) and aqueous L-methionine solution (up to a methionine concentration of the total solution of 1 mM) ) ("Labelstopmedium”) replaced. This stops the marking. Incubation with label stop medium is also carried out in the presence of the test substance (concentration as above). The total volume is 20 ml per bottle. The cultures are at
  • the medium is removed and the cells are washed once with PBS (phosphate-buffered saline without Ca / Mg **) (biochrome No. L1825).
  • the cell lawn is then washed with 1 ml of lysis buffer ⁇ 10 mM Tris-HCl pH 7.5; 1% (v / v) of the nonionic detergent ⁇ Triton X-100 [trademark of Rohm & Haas, 4- (1.1.3.3-tetramethylbutyl) -phenol-polyethoxyethanol]; 140 mM NaCl ⁇ lysed.
  • Tris stands for 2-amino-2- (hydroxymethyl) -1,3-propanediol.
  • Precipitation of the HBV core protein by specific immunoprecipitation To the lysate are added 10 ul Kanichen normal serum (Sigma 7523) and 200 ul Sepharose beads suspended in PBS (Protein-A-Sepharose C1-4B; Pharmacia, 17-0780-01) (Alternatively, the complex of beads and antibodies are preformed). This is followed by incubation for 2 hours at 4 ° C on the rotary wheel. The immunoprecipitates are separated by centrifugation (2 minutes; 1000 rpm) and stored at 4 ° C. The supernatant is transferred to a new Eppendorf tube.
  • the beads are washed three times with NET buffer [50 mM Tris-HCl pH 7.4; 0.5% (v / v) of the nonionic detergent ⁇ Nonident NP-40 (Boehringer Mannheim); 150 mM NaCl; 5 mM EDTA (ethylenediaminetetraacetic acid)], i.e. alternately suspended and centrifuged (2 minutes at 1000 rpm).
  • NET buffer 50 mM Tris-HCl pH 7.4; 0.5% (v / v) of the nonionic detergent ⁇ Nonident NP-40 (Boehringer Mannheim); 150 mM NaCl; 5 mM EDTA (ethylenediaminetetraacetic acid)], i.e. alternately suspended and centrifuged (2 minutes at 1000 rpm).
  • NET buffer 50 mM Tris-HCl pH 7.4; 0.5% (v / v) of the nonionic detergent ⁇ Nonident NP-40 (Boehringer Mannheim); 150 mM
  • the gel is immersed three times for 5 minutes in fixing solution (70 vol.% Ethanol; 10 vol.% Acetic acid; 20 vol.% Water). The gel is then bathed in an enhancer (Enlightning Rapid Autoradiography Enhancer NEN Research Products No. NEF-974) for 20 minutes. The gel is placed on filter paper (BioRad No. 165-0921) and covered with cellophane (BioRad No. 165-0922). This arrangement is dried for 50 minutes with the BioRad gel dryer.
  • the dried gel is placed on an X-ray film (Hyperfilm MP; Amersham RPN 2115H) and developed after an appropriate exposure period.
  • the dried gel can be analyzed on a phosphor imager (Fujix BAS 100). The evaluation compares the half-lives of the HBV core protein in the presence and absence of the test substance.
  • chromatographic behavior of a protein or one of its naturally occurring forms of aggregation (dimers, multimers) during gel permeation chromatography depends on the choice of the gel material used.
  • the gel material used in desalination columns e.g. Sephadex G-25; Pharmacia
  • Molecular weight is 5000 daltons; ie all proteins with a molecular weight greater than 5000 Da are eluted in the exclusion volume.
  • a globular protein that has a molecular weight below 5000 Da penetrates the separation material and is retained on the column.
  • the rule of thumb is: the lower the molecular weight of a molecule, the longer it will take the way through the gel bed and the later the molecule is eluted.
  • This basic test arrangement can be used for a binding test. The binding test is used to examine whether a test substance binds to a protein of interest.
  • the material is applied to the column and eluted with an elution buffer (eg 10 mM Tris pH 7.4 and 1 mM EDTA).
  • an elution buffer eg 10 mM Tris pH 7.4 and 1 mM EDTA.
  • the labeled test substance like the free protein, is eluted in the exclusion volume.
  • a non-binding test substance or the excess of the test substance is eluted in the late elution volume.
  • individual fractions are collected and the radioactivity is determined in the scintillation counter (or by another suitable detection method).
  • this method is carried out as a variant of the binding test in such a way that, for example, a labeled substance that binds to the HBV core protein (“labeled substance”) is used to find further core protein binders: the labeled one Substance is directly displaced by a test substance ("displacing substance”) (competition for the same binding site) or the
  • Test substance modifies the protein (or one of its aggregate forms) in such a way that the labeled substance can no longer bind (modification of the binding site).
  • the Sephadex G-25 column (height of the column: 5 cm, diameter of the column: 1.5 cm) is cast according to standard procedures (manufacturer's instructions) or obtained from a manufacturer (e.g. PDIO desalting columns from Phamacia).
  • the column is equilibrated in the desired buffer (10 mM Tris pH 7.4 and 1 mM EDTA).
  • test substance displaces labeled substance, less activity is measured in the fractions containing the exclusion volume than in fractions in which no test substance was present (zero value).
  • An HBV core protein inhibitor is present when a maximum of 50% of the activity of the zero value is present.
  • the half-life test (i) described above usually gives the more accurate values; however, it is time consuming. If many substances are to be tested, the binding test (ii) will be chosen because of the higher test speed; it is also suitable for screening, which can then be followed by a half-life test (i) for selected compounds.
  • HBV core protein inhibitors in the sense of the invention are those which pass at least the half-life test (i) described above.
  • 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 in the sense 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.
  • 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 1 volume of an aqueous solution containing 50% by weight of 8000 polyethylene glycol and 0.6 M sodium chloride. The virions are sedimented by centrifugation at 2,500 xg / 15 minutes. The sediments are contained in 2 ml of buffer
  • Tris-HCl P H 7.5
  • the samples can be frozen at -80 ° C.
  • 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 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.
  • samples are incubated at 37 ° C for one hour and then the reaction is stopped by adding 50 mM EDTA.
  • a 10% weight volume SDS solution (containing 10 g SDS per 90 ml water) is added to a final concentration of 1% by volume (based on total volume) and Proteinase K is added to a final concentration of 1 mg / ml added.
  • 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
  • FTC (2R-cis) -4-amino-5-fluoro-l- [2- (hydroxymethyl) -1.3-oxathiolan-5-yl] pyrimidine -
  • 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. Phenylpropenamide the
  • R 1 and R 2 independently of one another denote dC -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 -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, -CC 4 alkyl, -C 7 -acyl or aralkyl and X is halogen or optionally substituted dC 4 alkyl, and their salts.
  • AT-61 is the compound of the above formula wherein X is chlorine, A 1-piperidinyl and Y and Z are each phenyl. Our own studies have shown that AT-61 is not an HBV core protein inhibitor in the sense of this invention (test see above).
  • 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 present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more combinations according to the invention or which consist of a combination according to the invention, and methods for producing these preparations.
  • 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 400 mg B.
  • Component C which may optionally be used, can be used in amounts of preferably 1 to 10 million, in particular 2 to 7 million IE (international units), applied approximately three times a week over a period of up to one year.
  • the 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 pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.
  • compositions listed above can be prepared in a customary manner by known methods, e.g. by mixing the active ingredient or ingredients with the carrier (s).
  • a single dose contains the active ingredient or active ingredients preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg body weight.
  • the doses mentioned may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or Interval within which the administration takes place.
  • the combinations according to the invention are antiviral against hepatitis B viruses
  • HBV virus-induced diseases
  • a chronic viral disease caused by HBV can lead to different degrees of severity Cause clinical pictures;
  • chronic hepatitis B virus infection in many cases leads to cirrhosis of the liver and / or hepatocellular carcinoma.
  • the indication areas for the combinations according to the invention include:
  • prophylactic / therapeutic treatment for transplants such as Liver transplants.
  • the invention therefore also relates to the combinations defined above for combating diseases.
  • the invention further relates to medicaments containing at least one of the combinations defined above and optionally further pharmaceuticals
  • Another object of the invention is the use of the combinations defined above for the manufacture of a medicament for the treatment and prophylaxis of the diseases described above, preferably viral diseases, in particular hepatitis B.
  • the antiviral effect of the combinations according to the invention 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 combinatorial test of the test substances was carried out by means of checkerboard titration.
  • the antiviral tests were carried out in 96 well microtiter plates.
  • the first vertical row of the plate only received HepG2.2.15 cells in growth medium. It served as a virus cone.
  • test compounds 50 mM were first dissolved in DMSO; further dilutions were made in growth medium. The remaining wells contained the combinations according to the invention or their individual components in the test concentrations of e.g. 5 ⁇ M to 0.01 ⁇ M, starting from A2 to Hl 1 der
  • test mixture was incubated for 8 days at 37 ° Celsius and 5% CO 2 (v / v). On day 4, the medium was replaced by fresh inhibitor-containing medium.
  • the HepG2.2.15 cells were examined for light-microscopic changes or by means of biochemical detection methods (e.g. Alamar blue staining or trypan blue staining) for cytotoxic changes.
  • biochemical detection methods e.g. Alamar blue staining or trypan blue staining
  • Substance-induced cytotoxic or cytostatic changes in the HepG2.2.15 cells were e.g. determined by light microscopy as changes in cell morphology. 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 nucleic acids contained therein 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 onto the membrane by incubating the filters at 120 ° C. for 2-4 hours.
  • 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 hybidization ,
  • the prehybidization and hybidization were carried out in 5 x SSC, 1 x blocking reagent, 0.1% N-lauroylsarcosine, 0.02% 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 - 40 ng / ml of the digoxigenized, denatured HBV-specific DNA (14 hours, 60 ° C). The filters were then washed.
  • the digoxigenin-labeled DNA was detected immunologically according to the manufacturer's instructions.
  • 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 alkaline phosphatase, CSPD, was added, 5
  • the treatment of HBV with the combinations according to the invention has an antiviral effect better than the individual treatment; the treatment of the HepGits 2.2 virus-producing HepG2.2.15 cells with the combinations according to the invention led to a greater reduction in the intracellular viral DNA; the combination treatment is synergistically effective.

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Abstract

L'invention concerne des combinaisons de dihydropyrimidines, lamivudine et éventuellement d'interféron, qui inhibent la multiplication de virus HBV, de façon améliorée par rapport aux agents connus.
PCT/EP2000/012570 1999-12-22 2000-12-12 Combinaison de medicaments pour lutter contre des maladies virales WO2001045712A1 (fr)

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DE1999162010 DE19962010A1 (de) 1999-12-22 1999-12-22 Arzneimittelkombinationen gegen virale Erkrankungen
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US8236797B2 (en) 2007-06-18 2012-08-07 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
CN104302626A (zh) * 2012-01-06 2015-01-21 爱尔兰詹森研发公司 4,4-二取代的-1,4-二氢嘧啶及其作为治疗乙型肝炎的药物的用途
WO2015180631A1 (fr) * 2014-05-30 2015-12-03 南京明德新药研发股份有限公司 Dérivé de boucle dihydropyrimido à titre d'inhibiteur du vhb
CN105153164A (zh) * 2014-05-30 2015-12-16 南京明德新药研发股份有限公司 作为hbv抑制剂的二氢嘧啶并环衍生物
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
WO2017076791A1 (fr) * 2015-11-03 2017-05-11 F. Hoffmann-La Roche Ag Polythérapie au moyen d'un inhibiteur d'ensemble capside hbv et d'un interféron
WO2017108630A1 (fr) * 2015-12-21 2017-06-29 F. Hoffmann-La Roche Ag Polythérapie à inhibiteur hbsag et inhibiteur d'assemblage de capside du vhb
EP3102225A4 (fr) * 2014-02-05 2017-11-01 Novira Therapeutics Inc. Polythérapie pour le traitement d'infections par le vhb
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
WO2019086141A1 (fr) 2017-11-02 2019-05-09 Aicuris Gmbh & Co. Kg Nouveaux indole-2-carboxamides à substitution amino-thiazole hautement actifs agissant contre le virus de l'hépatite b (vhb)
WO2019086142A1 (fr) 2017-11-02 2019-05-09 Aicuris Gmbh & Co. Kg Nouveaux indole-2-carboxamides à substitution pyrazolo-pipéridine hautement actifs agissant contre le virus de l'hépatite b (vhb)
WO2019214610A1 (fr) * 2018-05-08 2019-11-14 Janssen Sciences Ireland Unlimited Company Dérivés de dihydropyrimidine et leurs utilisations dans le traitement d'une infection par le virus de l'hépatite b ou de maladies induites par le virus de l'hépatite b
WO2020089460A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Nouvelles urée-6,7-dihydro-4 h-thiazolo[5,4-c]pyridines actives contre le virus de l'hépatite b (vhb)
WO2020089453A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Nouveaux 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine indole-2-carboxamides actifs contre le virus de l'hépatite b (vhb)
WO2020089455A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg 6,7-dihydro-4 h-pyrazolo[1,5-a]pyrazine indole-2-carboxamides actifs contre le virus de l'hépatite b (vhb)
WO2020089452A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Nouvelles 6,7-dihydro-4h-pyrazolo[4,3-c]pyridines d'urée actives contre le virus de l'hépatite b (vhb)
WO2020089456A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Nouvelles 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazines d'urée actives contre le virus de l'hépatite b (vhb)
WO2020089459A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Nouvelles 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazines d'urée actives contre le virus de l'hépatite b (vhb)
WO2020221826A1 (fr) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Nouveaux indole-2-carboxamides actifs contre le virus de l'hépatite b (vhb)
WO2020221816A1 (fr) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Nouvelles urées de phényle et de pyridyle actives contre le virus de l'hépatite b (vhb)
WO2020221824A1 (fr) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Nouveaux indolizine-2-carboxamides actifs contre le virus de l'hépatite b (vhb)
WO2020221811A1 (fr) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Nouvelles oxalyl pipérazines actives contre le virus de l'hépatite b (vhb)
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US8343969B2 (en) 2007-06-18 2013-01-01 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
USRE45004E1 (en) 2007-06-18 2014-07-08 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
US8236797B2 (en) 2007-06-18 2012-08-07 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
CN104302626A (zh) * 2012-01-06 2015-01-21 爱尔兰詹森研发公司 4,4-二取代的-1,4-二氢嘧啶及其作为治疗乙型肝炎的药物的用途
JP2015508402A (ja) * 2012-01-06 2015-03-19 ヤンセン サイエンシズ アイルランド ユーシー ４，４−二置換−１，４−ジヒドロピリミジン、及びｂ型肝炎の処置のための医薬としてのその使用
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