WO2001068639A1 - Esters d'acide carboxylique-5-dihydropyrimidine et leur utilisation en tant qu'agent pharmaceutique contre des maladies virales - Google Patents

Esters d'acide carboxylique-5-dihydropyrimidine et leur utilisation en tant qu'agent pharmaceutique contre des maladies virales Download PDF

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WO2001068639A1
WO2001068639A1 PCT/EP2001/002441 EP0102441W WO0168639A1 WO 2001068639 A1 WO2001068639 A1 WO 2001068639A1 EP 0102441 W EP0102441 W EP 0102441W WO 0168639 A1 WO0168639 A1 WO 0168639A1
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formula
compounds
zero
salts
methyl
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PCT/EP2001/002441
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German (de)
English (en)
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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 AU2001240674A priority Critical patent/AU2001240674A1/en
Publication of WO2001068639A1 publication Critical patent/WO2001068639A1/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
    • 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

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 HBN infections such as hepatitis B.
  • the hepatitis B virus belongs to the Hepadna family. It causes an acute and / or a persistent-progressive, chronic illness. A 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 effect 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 2 is methyl or ethyl
  • R 3 is a group of the formula -CH 2 -R 8 m -X n -R 9 ,
  • R 8 the group -CR 10 R n -
  • R 9 optionally branched C ! -C 4 alkyl, which may be substituted by azido,
  • R 10 is hydrogen, hydroxyl or methyl
  • R 11 is hydrogen or methyl
  • R 4 is hydrogen
  • R 5 pyridyl, which is substituted up to twice identical or different by halogen, or thiazolyl,
  • n zero or 1
  • Preferred compounds of the formulas (I) or (I a) according to the invention are those in which
  • R 2 is methyl or ethyl
  • R is a group of the formula -CH 2 -R m-Xn-R, wherein
  • R 9 is methyl, ethyl, n- or i-propyl, which can each be substituted by azido,
  • R 4 is hydrogen
  • R 5 pyrid-2-yl which is substituted in the 2-position by halogen or in the 2,4-position is identical or differently substituted by halogen, or thiazolyl,
  • n zero or 1
  • R 1 is phenyl which is disubstituted by fluorine, chlorine or bromine in the 2.4 or 3.4 position, identically or differently,
  • R 2 is methyl or ethyl
  • R 3 is a group of the formula -CH 2 -R 8 m -X n -R 9 , embedded image in which
  • R 9 is methyl, ethyl, n-propyl, i-propyl or -C 2 H -azido,
  • R 5 pyrid-2-yl which is monosubstituted by fluorine or chlorine in the 2-position or is identical or different in the 2.4-position, or thiazolyl,
  • n zero or 1
  • R 3 contains at least one oxygen atom
  • R 1 is phenyl which is identical or different in the 2.4 position by fluorine, chlorine or
  • Bromine or in the 3.4 position is disubstituted by fluorine, R 2 is methyl or ethyl,
  • R 4 is hydrogen
  • R 5 is pyrid-2-yl which is monosubstituted by fluorine or chlorine in the 2-position or is disubstituted by fluorine in the 2.4-position, or thiazolyl, and
  • n zero or 1
  • 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 the 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 (Ia) 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
  • Salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts of organic carboxylic or sulfonic acids such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or toluenesulfonic acid or toluenesulfonic acid or toluenesulfonic acid
  • Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention.
  • Z are particularly preferred.
  • the compounds of formula (I) according to the invention can be prepared by: [A] aldehydes of the formula
  • R 1 has the meaning given above
  • R 1 has the meaning given above
  • R »2 and ⁇ , ⁇ R, 3 have the meanings given above, and amidines of the formula (III) or with their salts (such as hydrochlorides or acetates)
  • R ) 5 has the meaning given above and
  • R. 1 1 3 J represents CrC 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.
  • the reaction can be carried out with or without addition of base or acid; however, it is advisable to carry out the reaction in the presence of weaker acids, e.g. Acetic acid or formic acid.
  • weaker acids e.g. Acetic acid or formic acid.
  • 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 (TV) 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 (VIII) are new; the invention therefore also relates to compounds of the formula (VIII).
  • 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.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the formulas (I), (I a) or the example table or which consist of a or several active ingredients of the formulas (I) and (I a), and processes for the preparation of these preparations.
  • the active compounds of the formulas (I) and (I a) should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95,% by weight of the preparations his.
  • the pharmaceutical preparations listed above can also contain other active pharmaceutical ingredients.
  • One embodiment of the invention relates to combinations of A) at least one of the dihydropyrimidines defined above, B) at least one other antiviral agent other than A.
  • a particular embodiment of the invention relates to combinations A) above
  • Dihydropyrimidines B) HBV polymerase inhibitors and optionally C) immunomodulators.
  • Preferred immunomodulators C) include, for example, all interferons such as ⁇ , ⁇ and ⁇ interferons, in particular also ⁇ -2a and ⁇ -2b interferons, interleukins such as interleukin-2, polypeptides such as thymosin- ⁇ -1 and thymoctonan, imidazoquinoline, derivatives such as ®Levamisole, immunoglobulins and therapeutic vaccines.
  • interferons such as ⁇ , ⁇ and ⁇ interferons, in particular also ⁇ -2a and ⁇ -2b interferons, interleukins such as interleukin-2, polypeptides such as thymosin- ⁇ -1 and thymoctonan, imidazoquinoline, derivatives such as ®Levamisole, immunoglobulins and therapeutic vaccines.
  • the invention therefore also relates to these combinations for the treatment and prophylaxis of HBV infections and their use for the treatment of HBV-induced
  • HBV-induced diseases have valuable advantages compared to monotherapy with the individual compounds, namely mainly a synergistic antiviral
  • 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 into the plus strand of HBV DNA in vitro.
  • agarose gel electrophoresis the incorporation of [ ⁇ - 32 P] deoxynucleoside 5'-triphosphate into the 3.2 kb viral DNA product is observed in the presence and absence of a substance with potentially HBV polymerase-inhibiting properties , HBV virions are derived from the
  • Cell culture supernatant from HepG2.2.15 cells obtained 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 sedimented by centrifugation at 2,500 x g / 15 minutes. The sediments are contained in 2 ml of buffer
  • Tris-HCl H 7.5
  • the samples can be frozen at -80 ° C.
  • Each reaction mixture 100 ⁇ l contains at least 10 5 HBV virions; 50 rnM 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 nmM 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 added to a final concentration of 1 mg / ml.
  • 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.
  • An 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) above dihydropyrimidines (I) or (Ia) and B) lamivudine.
  • HBV antiviral agents B include, for example, phenylpropenamides of the formula
  • R 1 and R 2 independently of one another are C 1 -C 4 -alkyl or, together with the nitrogen atom on which they are located, form a ring having 5 to 6 ring atoms which comprise carbon and / or oxygen,
  • R 3 to R 12 independently of one another are hydrogen, halogen, -CC 4 -alkyl, optionally substituted Cr -alkoxy, nitro, cyano or trifluoromethyl,
  • R 13 is hydrogen, CC 4 alkyl, -CC 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.
  • 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 pipetted into the second vertical test series of the microtiter plate in a test concentration of 100 ⁇ M (1st test concentration) and then diluted 2 ⁇ 10 -fold in wax medium plus 2% by weight fetal calf serum (volume 25 ⁇ l ).
  • Each well of the microtiter plate then received 225 ⁇ l of a HepG2.2.15 cell suspension (5 ⁇ 10 4 cells / ml) in growth medium plus 2% by weight of fetal calf serum.
  • 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 (e.g. Alamar blue staining or trypan blue staining).
  • the supernatants and / or cells were then harvested and sucked by means of a vacuum onto 96-well dot-blot chamber 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 changed 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, primary peripheral blood cells of the
  • Human or transformed cell lines such as H-9 cells.
  • the intra- or extracellular supernatants of the He ⁇ G2.2.15 cells were denatured (1.5 M NaCl 0.5 N NaOH), neutralized (3 M NaCl / 0.5 M Tris HC1, pH 7.5) and washed (2 x SSC). Then the
  • 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 hepatitis B-specific DNA signals were visualized by exposing the filters to an X-ray film (incubation depending on signal strength: 10 minutes to 2 hours).
  • IC 50 inhibitory concentration 50%
  • the compounds according to the invention show an unforeseeable activity against viruses. Surprisingly, they have antiviral activity against hepatitis B (HBV) and are therefore suitable for the treatment of virus-induced diseases, in particular acute and chronic persistent viral infections of HBV.
  • HBV hepatitis B
  • 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 present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds (I) or (Ia) or a combination according to the invention, or which consist of one or more active compounds (I) or (Ia) or consist of a combination according to the invention.
  • the active ingredients (I) or (Ia) should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight, of the total mixture his.
  • the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.
  • the quantitative ratio of components A, B and optionally C of the combinations according to the invention can vary within wide limits; 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 total amounts of from about 0.5 to about 500, preferably from 1 to 100 mg / kg of body weight per 24 hours, if appropriate in Form of multiple doses to be administered to achieve the desired results.
  • a single dose contains the active ingredient (s) preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg body weight.
  • the invention therefore furthermore relates to the compounds and combinations defined above for combating diseases.
  • the invention further relates to medicaments containing at least one of the compounds or combinations defined above and optionally one or more further pharmaceutical active ingredient (s).
  • the invention further relates to the use of the compounds and combinations defined above in the manufacture of a medicament for the treatment and prophylaxis of the diseases described above, preferably viral diseases, in particular hepatitis B.
  • Analog Troschuetz, R. et al., J. Heterocycl. Chem. 33, 1815-1821 (1996) 150 ml of diethylene glycol dimethyl ether, 47.68 g (0.261 mol) of 2,3,5-trichloropyridine, 2.0 g (0.005 mol) of tetraphenylphosphonium bromide, 4.0 g (0.024 mol) are finely powdered Potassium iodide and 75.0 g (0.838 mol) of copper (I) cyanide combined under nitrogen and stirred 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-fluorobenzaldehyde and methyl acetoacetate.
  • Example 1 4- (2-chloro-4-fluorophene) -2- (3,5-difluoro-2-pyridinyl) -6- (isopropoxy-methyl) - 1,4-dihy dropyrimidine-5-carboxylic acid methyl ester

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Abstract

L'invention concerne de nouvelles dihydropyrimidines de la formule (I) ou de sa forme isomère (Ia), R1 représentant du dihalogénophényle, R2 représentant du méthyle ou de l'éthyle, R3 représentant un groupe de la formule -CH¿2-R?8m-Xn-R9, R4 représentant de l'hydrogène, et R5 représentant du pyridyle substitué jusqu'à deux fois de manière identique ou différente par de l'halogène, ou du thiazolyle, et leurs combinaisons avec d'autres agents pharmaceutiques, lesdites dihydropyrimidines et leurs combinaisons servant à la lutte contre les infections par HBV.
PCT/EP2001/002441 2000-03-17 2001-03-05 Esters d'acide carboxylique-5-dihydropyrimidine et leur utilisation en tant qu'agent pharmaceutique contre des maladies virales WO2001068639A1 (fr)

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AU2001240674A AU2001240674A1 (en) 2000-03-17 2001-03-05 Dihydropyrimidine-5-carboxylic acid esters and use thereof as medicaments against viral diseases

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DE10013125A DE10013125A1 (de) 2000-03-17 2000-03-17 Arzneimittel gegen virale Erkrankungen
DE10013125.5 2000-03-17

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WO2008154819A1 (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
WO2008154820A1 (fr) * 2007-06-18 2008-12-24 Zhang, Zhongneng Thiazolyl-dihydropyrimidines à substitution carbéthoxy
US8236797B2 (en) 2007-06-18 2012-08-07 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
JP2012530726A (ja) * 2009-06-25 2012-12-06 中国人民解放▲軍▼▲軍▼事医学科学院毒物▲薬▼物研究所 ジヒドロピリミジン化合物及び合成方法、医薬組成物及びその使用
US9340538B2 (en) 2012-08-24 2016-05-17 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
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
US10098889B2 (en) 2015-02-07 2018-10-16 Sunshine Lake Pharma Co., Ltd. Complexes and salts of dihydropyrimidine derivatives and their application in pharmaceuticals

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USRE45004E1 (en) 2007-06-18 2014-07-08 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
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
US8236797B2 (en) 2007-06-18 2012-08-07 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
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
US8802669B2 (en) 2009-06-25 2014-08-12 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences, P.L.A. China Dihydropyrimidine compounds and preparation methods, pharmaceutical compositions and uses thereof
JP2012530726A (ja) * 2009-06-25 2012-12-06 中国人民解放▲軍▼▲軍▼事医学科学院毒物▲薬▼物研究所 ジヒドロピリミジン化合物及び合成方法、医薬組成物及びその使用
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
US9340538B2 (en) 2012-08-24 2016-05-17 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
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
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
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

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