USRE45004E1 - Bromo-phenyl substituted thiazolyl dihydropyrimidines - Google Patents

Bromo-phenyl substituted thiazolyl dihydropyrimidines Download PDF

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USRE45004E1
USRE45004E1 US13/869,947 US200813869947A USRE45004E US RE45004 E1 USRE45004 E1 US RE45004E1 US 200813869947 A US200813869947 A US 200813869947A US RE45004 E USRE45004 E US RE45004E
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formula
hepatitis
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Siegfried Goldmann
Jing Li
Yi Song Liu
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Sunshine Lake Pharma Co Ltd
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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 invention relates to a new bromo-phenyl substituted thiazolyl dihydropyrimidine, its preparation method and use as a medicament especially for treating and preventing hepatitis B infections.
  • the invention also relates to a composition comprising the dihydropyrimidine, other antiviral agent and, when appropriate, an immunomodulator and a medicament comprising the composition especially for treating and preventing HBV infections such as hepatitis B infections.
  • the hepatitis B virus belongs to the family of hepadna viruses. It can cause acute and/or persistent or progressive chronic diseases. Many other clinical manifestations in the pathological state are also caused by the hepatitis B virus—in particular chronic inflammation of the liver, cirrhosis of the liver and hepatocellular carcinoma. In addition, coinfection with the hepatitis delta virus may have adverse effects on the progress of the disease.
  • the interferon and lamivudine are conventional medicaments approved to be used for treating chronic hepatitis.
  • the interferon has just moderate activity but has an adverse side reaction.
  • lamivudine has good activity, its resistance develops rapidly during the treatment and relapse effects often appear after the treatment is stopped.
  • the IC 50 value of lamivudine (3-TC) is 300 nM (Science, 299 (2003), 893-896).
  • U.S. Pat. No. 7,074,784 discloses 6-amidoalkyldihydropyrimidine and its use as a medicament especially for treating and preventing hepatitis B infection.
  • R 1 is o-chlorine
  • R 2 is p-chlorine
  • R 6 is 3,5-difluoropyridin-2-yl
  • X is —CH 2 —
  • Z is morpholinyl.
  • the compound can inhibit the growth of hepatitis B virus during cell culturing.
  • the IC 50 value is 2 nM (tested by themselves).
  • U.S. Pat. No. 7,074,784 B2 also discloses an example, wherein a difluoro residue is substituted for thiazol-2-yl (described in Example 45 of the patent).
  • the derivative has a similar IC 50 value (2 nM) (see Table 1).
  • This invention relates to a compound having formula (I) and its isomer (Ia),
  • R 1 is o-bromine
  • R 2 is p-fluorine
  • R 3 is C 1 -C 4 alkyl
  • R 6 is thiazol-2-yl
  • X is methylene
  • Z is morpholinyl.
  • R 1 of the compound of the invention having formula (I) and (Ia) is o-bromine
  • R 2 is p-fluorine
  • R 3 is methyl or ethyl
  • R 6 is thiazol-2-yl
  • X is methylene
  • Z is morpholinyl.
  • This invention also relates to an enantiomer of the compound disclosed herein and a mixture thereof.
  • the racemate can be separated by a known method, and fundamentally it is a homogeneous component in a stereoisomer mixture.
  • the compounds of the invention comprise an isomer having formula (I) and (Ia) and a mixture thereof.
  • the compound of the invention can also be in a form of a salt, preferably a physiologically acceptable salt.
  • the physiologically acceptable salt can be an inorganic acid salt or organic acid salt.
  • it is an inorganic acid salt such as chloride, bromide, phosphate or sulfate, etc., or a carboxylate or a sulfonate, such as acetate, maleate, fumarate, malate, citrate, tartarate, lactate, benzoate or methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate or naphthalenedisulfonate, etc.
  • the physiologically acceptable salt can also be a metal salt or an ammonium salt of the compound of the invention.
  • it is a sodium salt, potassium salt, magnesium salt or calcium salt, and an ammonium salt produced by ammonia or organic amine such as ethylamine, diethylamine or triethylamine, diethanolamine or triethanolamine, dicyclohexylamine, dimethylaminoethyl alcohol, arginine, lysine, ethylenediamine or 2-phenylethylamine, etc.
  • the compound (I) of the invention can be prepared by the following methods:
  • R 1 , R 2 , R 3 , X and Z are as defined herein, and then the benzylidene compound reacts with an amidine having formula (V) or a salt thereof (such as hydrochloride or acetate) with or without the addition of an alkali or an acid, and, when appropriate, in the presence of an inert organic solvent:
  • R 6 is as defined herein; or [B] the ⁇ -ketoester having formula (III) reacts with the benzaldehyde having formula (II) and the amidine having formula (V) or a salt thereof (such as hydrochloride or acetate) with or without the addition of an alkali or an acid, and, when appropriate, in the presence of an inert organic solvent in one step; or [C] if X in formula (I) is methylene, a compound having formula (VI) reacts with morpholine having formula (VII) with or without the addition of an alkali, and, when appropriate, in the presence of an inert organic solvent,
  • R 1 , R 2 , R 3 and R 6 are as defined herein and Y is a nucleophilic substituent, such as chloro, bromo, iodo, methylsulfonyl or toluenesulfonyl; or [D] the benzaldehyde having formula (II) reacts with a compound having formula (X) and the amidine having formula (V) with or without the addition of an alkali and, when appropriate, in an inert organic solvent,
  • R 3 , X and Z are as defined herein.
  • Compound of formula (VI) can be prepared by, for example, reacting a compound having formula (VIII)
  • R 1 , R 2 , R 3 and R 6 are as defined herein, with a brominating agent such as N-bromosuccinimide, preferably in an inert organic solution, to produce a compound having formula (IX):
  • R 3 is as defined herein.
  • ⁇ -keto carboxylate (III) is well-known, or can be prepared by known methods published in the literature [for example, D. Baumann, “Um GmbH von Diketen mit mecanicen, Phenolen und Mercaptanen”, in “Methoden der organischen Chemie” (Houben-Weyl), vol. VII/4, 230 ff (1968); Y. Oikawa, K. Sugano und O. Yonemitsu, J. Org. Chem. 43, 2087 (1978)].
  • the compound (V) is known and can be prepared according to the descriptions of WO-A-99/54326 and WO-A-99/54329.
  • Morpholine (VII) is commercially available.
  • the inert organic solvent is preferably an alcohol such as methanol, ethanol and isopropyl alcohol, an ether such as dioxane, diethyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, a carboxylic acid such as acetic acid, dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine or hexamethyl phosphoric triamide.
  • an alcohol such as methanol, ethanol and isopropyl alcohol
  • an ether such as dioxane, diethyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, a carboxylic acid such as acetic acid, dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine or hexamethyl phosphoric triamide.
  • the reaction temperature can be varied within quite a wide range. Usually the temperature is between 20° C. and 150° C. Preferably, the temperature is the boiling temperature of the selected solvent.
  • the reaction can be carried out under the atmospheric pressure or under a high pressure. It is usually carried out under the atmospheric pressure.
  • the reaction can be carried out with or without an acid or alkali. It is preferable to carry out the reaction in the presence of a weak acid such as acetic acid, formic acid or the like.
  • a weak acid such as acetic acid, formic acid or the like.
  • An embodiment of the invention relates to a composition
  • a composition comprising A) at least one of the above dihydropyrimidines and B) at least one of other antiviral agents different from A).
  • a certain embodiment of the invention relates to a composition
  • a composition comprising A) the above dihydropyrimidine, B) an HBV polymerase inhibitor and, when appropriate, C) an immunomodulator.
  • the immunomodulator C) is selected from, for example, all the interferons such as ⁇ -interferon, ⁇ -interferon and ⁇ -interferon, especially ⁇ -2a-interferon and ⁇ -2b-interferon, an interleukin such as interleukin-2, a polypeptide such as thymosin- ⁇ -1 and a thymoctonan, an imidazoquinoline derivative such as levamisole, an immunoglobulin and a therapeutic vaccine.
  • interferons such as ⁇ -interferon, ⁇ -interferon and ⁇ -interferon, especially ⁇ -2a-interferon and ⁇ -2b-interferon, an interleukin such as interleukin-2, a polypeptide such as thymosin- ⁇ -1 and a thymoctonan, an imidazoquinoline derivative such as levamisole, an immunoglobulin and a therapeutic vaccine.
  • this invention also relates to a composition for treating and preventing HBV infections and its use for treating diseases induced by HBV.
  • the use of the combinations of the invention provides valuable advantages for the treatment of HBV-induced diseases compared with monotherapy with the individual compounds, namely principally a synergistic antiviral activity, but also good tolerability of the combinations of the invention in Tox-50 (the range of toxicity at which 50% of the cells survive).
  • HBV polymerase inhibitors B for the purposes of the invention are those which, in the endogenous polymerase assay which was published by Ph. A. Furman et al. in Antimicrobial Agents and Chemotherapy, Vol. 36 (No. 12), 2688 (1992) and which is described hereinafter, lead to an inhibition of the formation of an HBV DNA double strand, so as to result in a maximum of 50% of the activity of the zero value.
  • HBV polymerase inhibitors B for use in the invention are the substances disclosed in the endogenous polymerase experiment published in “Antimicrobial Agents and Chemotherapy” Vol. 36 (No. 12), 2688 (1992) by Ph. A. Furman, and the substances described below for inhibiting the formation of double-stranded HBV DNA thereby resulting in the maximum 50% activity value to be zero.
  • HBV virions from culture supernatants incorporate nucleoside 5′-triphosphates into the plus strand of the HBV DNA in vitro.
  • agarose gel electrophoresis By using agarose gel electrophoresis, the incorporation of [ ⁇ - 32 P]-deoxynucleoside 5′-triphosphate into the viral 3.2 kb DNA product is observed in the presence and absence of a substance potentially having HBV polymerase-inhibiting properties.
  • HBV virions are obtained from the cell culture supernatant of HepG2.2.15 cells by precipitation with polyethyleneglycol and are concentrated. One part by volume of clarified cell culture supernatant is mixed with 1 ⁇ 4 by volume of an aqueous solution containing 50% by weight polyethylene glycol 8000 and 0.6 M sodium chloride.
  • the virions are sedimented by centrifugation at 2500 ⁇ g/15 minutes.
  • the sediments are resuspended in 2 ml of buffer containing 0.05 M tris-HCl (pH 7.5) and dialyzed against the same buffer containing 100 mM potassium chloride.
  • the samples can be frozen at ⁇ 80° C.
  • Each reaction mixture (100 ⁇ l) contains at least 105 HBV virions; 50 mM tris-HCl (pH 7.5); 300 mM potassium chloride; 50 mM magnesium chloride; 0.1% Nonident® P-40 (nonionic detergent from Boehringer Mannheim); 10 ⁇ M dATP, 10 ⁇ M dGTP, 10 ⁇ M dTTP; 10 ⁇ Ci [ 32 P]dCTP (3000 Ci/mmol; final concentration 33 nM) and 1 ⁇ M of the potential polymerase inhibitor in its triphosphorylated form.
  • the samples are incubated at 37° C. for one hour and then the reaction is stopped by adding 50 mM EDTA.
  • a 10% weight/volume SDS solution (containing 10 g of SDS per 90 ml of water) is added to a final concentration of 1% by volume (based on the 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 (ratio 25:24:1 by volume), and the DNA is precipitated from the aqueous phase with ethanol.
  • Adefovir dipivoxil 9- ⁇ 2-[[bis[(pivaloyloxy)-methoxy]-phosphinyl]-methoxy]-ethyl ⁇ -a-denine, cf.
  • Abacavir ( ⁇ )-(1S-cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, cf.
  • FTC (2R-cis)-4-amino-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-pyrimidin-2(1H)-one, cf.
  • ⁇ -L-FDDC 5-(6-amino-2-fluoro-9H-purin-9-yl)-tetrahydro-2-furanmethanol, cf.
  • L-FMAU 1-(2-deoxy-2-fluoro- ⁇ -L-arabinofuranosyl)-5-methyl-pyrimidine-2,4(1H,3H)-dione, cf. WO 99/05157, WO 99/05158 and U.S. Pat. No. 5,753,789.
  • a further preferred embodiment of the invention relates to a composition
  • a composition comprising A) the above dihydropyrimidines having formula (I) and (Ia); and B) lamivudine.
  • HBV antiviral agents B comprise, for example, phenylpropenamides of the following formula:
  • R 1 and R 2 are, each independently, C 1-4 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 are each independently hydrogen, halogen, C 1-4 alkyl, optionally substituted C 1-4 alkoxy, nitro, cyano or trifluoromethyl;
  • R 13 is hydrogen, C 1-4 alkyl, C 1-7 acyl or aralkyl and X is halogen or optionally substituted C 1-4 alkyl.
  • AT-61 is the compound
  • Preferred immunomodulators C) comprise, for example, all interferons such as ⁇ -, ⁇ - and ⁇ -interferons, in particular also ⁇ -2a- and ⁇ -2b-interferons, interleukins such as interleukin-2, polypeptides such asthymosin- ⁇ -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 asthymosin- ⁇ -1 and thymoctonan, imidazoquinoline derivatives such as Levamisole®, immunoglobulins and therapeutic vaccines.
  • a further preferred embodiment of the invention relates to combinations of A) above dihydropyrimidines (I) and (Ia), B) lamivudine and, where appropriate, C) an interferon.
  • the antiviral action of the compounds of the invention on hepatitis B virus is investigated by methods based on those described by M. A. Sells et al., Proc. Natl. Acad. Sci., 84, 1005-1009 (1987) and B. E. Korba et al., Antiviral Research 19, 55-70 (1992).
  • the antiviral tests are carried out in 96-well microtiter plates.
  • the first vertical row of the plate receives only growth medium and HepG2.2.15 cells. It serves as virus control.
  • test compounds 50 mM
  • DMSO dimethyl methoxysulfoxide
  • test concentration 100 ⁇ M (1st test concentration) in each case into the second vertical test row of the microtiter plate and subsequently diluted in twofold steps 210 times in growth medium plus 2% by weight of fetal calf serum (volume 25 ⁇ l)
  • Each well of the microtiter plate then contains 225 ⁇ l of HepG2.2.15 cell suspension (5 ⁇ 104 cells/ml) in growth medium plus 2% by weight of fetal calf serum.
  • the test mixture is incubated at 37° C. and 5% CO2 (v/v) for 4 days.
  • the supernatant is then aspirated off and discarded, and the wells receive 225 ⁇ l of freshly prepared growth medium.
  • the compounds according to the invention are each added anew as 10-fold concentrated solution in a volume of 25 ⁇ l. The mixtures are incubated for a further 4 days
  • the HepG2.2.15 cells are examined under the light microscope or by means of biochemical detection methods (for example Alamar Blue stain or Trypan Blue stain) for cytotoxic changes
  • the supernatant and/or cells are then harvested and sucked by means of a vacuum onto 96-well dot-blot chambers covered with a nylon membrane (in accordance with the manufacturer's information).
  • Substance-induced cytotoxic or cytostatic changes in the HepG2.2.15 cells are detected, for example, under the light microscope as changes in cell morphology. Such substance-induced changes in the HepG2.2.15 cells compare with untreated cells are visible, for example, as cytolysis, vacuolation or altered cell morphology.
  • a 50% cytotoxicity (Tox.-50) means that 50% of the cells show a morphology comparable to the corresponding cell control.
  • the tolerability of some of the compounds according to the invention is additionally tested on other host cells such as, for example, HeLa cells, primary human peripheral blood cells or transformed cell lines such as H-9 cells.
  • the intra- or extracellular supernatants of the HepG2.2.15 cells are denatured (1.5 M NaCl/0.5 N NaOH), neutralized (3 M NaCl/0.5M Tris HCl, pH 7.5) and washed (2 ⁇ SSC).
  • the DNA is then baked onto the membrane by incubating the filters at 120° C. for 2-4 hours.
  • Detection of the viral DNA from the treated HepG2.2.15 cells on the nylon filters is usually carried out with nonradioactive, digoxigenin-labeled hepatitis B-specific DNA probes, each of which is labeled with digoxigenin, purified and employed for the hybridization in accordance with the manufacturer's information.
  • the prehybridization and hybridization take place in 5 ⁇ SSC, 1 ⁇ blocking reagent, 0.1% by weight N-lauroylsarcosine, 0.02% by weight SDS and 100 ⁇ g of herring sperm DNA.
  • the prehybridization takes place at 60° C. for 30 minutes, and the specific hybridization takes place with 20 to 40 ng/ml of the digoxigenized, denatured HBV-specific DNA (14 hours, 60° C.). The filters are then washed.
  • the filters were washed and prehybridized in a blocking reagent (in accordance with the manufacturer's information). Hybridization was then carried out with an anti-DIG antibody coupled to alkaline phosphatase for 30 minutes. After a washing step, the substrate of alkaline phosphatase, CSPD, was added, incubated with the filters for 5 minutes, then packed in plastic film 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 50 , 50% inhibitory concentration) was determined as the concentration at which the intra- or extracellular hepatitis B-specific band was reduced by the compound according to the invention by 50% compared with an untreated sample.
  • the compound of the invention exhibits an effective antiviral effect with an IC 50 less than 1 nM. Therefore, the compound of the invention is suitable for use in treating the diseases induced by viruses, especially acute and chronic persistent HBV infections.
  • Chronic viral diseases induced by HBV can worsen the morbidity and the chronic hepatitis B virus infection can cause liver cirrhosis and/or hepatocellular carcinoma in many cases.
  • Areas of indication which may be mentioned for the compounds of the invention are, for example: the treatment of acute and chronic viral infections which may lead to infectious hepatitis, for example infections with hepatitis B viruses.
  • the compounds of the invention are particularly suitable for the treatment of chronic hepatitis B infections and the treatment of acute and chronic hepatitis B viral infections.
  • the present invention includes pharmaceutical preparations which, besides nontoxic, inert pharmaceutically suitable carriers, comprise one or more compounds (I) or (Ia) or a combination of the invention or which consist of one or more active ingredients (I) or (Ia) or of a combination of the invention.
  • the active ingredients (I) and (Ia) are intended to be present in the pharmaceutical preparations mentioned above in a concentration of about 0.1 to 99.5% by weight, preferably of about 0.5 to 95% by weight, of the complete mixture.
  • compositions mentioned above may also comprise other active pharmaceutical ingredients apart from the compounds (I) and (Ia).
  • the ratio of the amounts of the components A, B and, where appropriate, C in the compositions of the invention may vary within wide limits; it is preferably 5 to 500 mg of A/10 to 1000 mg of B, in particular 10 to 200 mg of A/20 to 400 mg of B.
  • Component C which is also to be used where appropriate, may be used in amounts of, preferably, 1 to 10 million, in particular 2 to 7 million, I.U. (international units), about three times a week over a period of up to one year.
  • the compounds or compositions of the invention are intended to be present in the pharmaceutical preparations mentioned above in general in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95, % by weight of the complete mixture.
  • the pharmaceutical preparations mentioned above can be produced in a conventional way by known methods, for example by mixing the active ingredient(s) with the carrier(s).
  • a single dose contains the active ingredient(s) preferably in amounts of about 1 to about 80, in particular 1 to 30 mg/kg of body weight.
  • the invention therefore relates further to the compounds and compositions defined above for controlling diseases.
  • the invention further relates to medicaments comprising at least one of the compounds or compositions defined above and, where appropriate, one or more other active pharmaceutical ingredient(s).
  • the invention further relates to the use of the compounds and compositions defined above for producing a medicament for the treatment and prophylaxis of the diseases described above, preferably of viral diseases, in particular of hepatitis B.
  • the percentage data in the following examples relate in each case to weight unless indicated otherwise.
  • the ratios of solvents in solvent mixtures are in each case based on volume.
  • the anti-HBV active compounds in the two examples are enantiomers having a relatively long retention time.
  • the treatment of the hepatitis B virus-producing HepG2.2.15 cells with the compounds of the invention can lead to a reduction in intra- and/or extracellular viral DNA.
  • the compounds disclosed herein exhibit an effective antiviral effect with the IC 50 less than 1 nM. Therefore, the compounds can be used for the treatment of a disease induced by viruses, especially acute and chronic persistent HBV infections according to the methods of the invention or any method known to a person skilled in the art.

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US13/869,947 2007-06-18 2008-06-18 Bromo-phenyl substituted thiazolyl dihydropyrimidines Active 2028-12-24 USRE45004E1 (en)

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CN200710119019 2007-06-18
CN200710119019 2007-06-18
US13/869,947 USRE45004E1 (en) 2007-06-18 2008-06-18 Bromo-phenyl substituted thiazolyl dihydropyrimidines
PCT/CN2008/001187 WO2008154817A1 (fr) 2007-06-18 2008-06-18 Thiazolyl-dihydropyrimidines à substitution bromo-phényle
US12/664,392 US8236797B2 (en) 2007-06-18 2008-06-18 Bromo-phenyl substituted thiazolyl dihydropyrimidines

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Families Citing this family (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2514750B1 (en) * 2007-06-18 2013-11-20 Sunshine Lake Pharma Co., Ltd Bromo-phenyl substituted thiazolyl dihydropyrimidines
WO2010069147A1 (zh) * 2008-12-17 2010-06-24 张中能 二氢嘧啶类化合物、其组合物及其应用
CN101744823B (zh) * 2008-12-17 2013-06-19 广东东阳光药业有限公司 一种二氢嘧啶类化合物的固体分散体及其药用制剂
CN101575318B (zh) 2009-06-25 2012-02-08 中国人民解放军军事医学科学院毒物药物研究所 二氢嘧啶类化合物及其用于制备治疗和/或预防病毒性疾病的药物的用途
CN104302626B (zh) * 2012-01-06 2016-09-07 爱尔兰詹森科学公司 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
US20130267517A1 (en) 2012-03-31 2013-10-10 Hoffmann-La Roche Inc. Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
ES2640049T3 (es) * 2012-08-24 2017-10-31 Sunshine Lake Pharma Co., Ltd. Derivados de 3,6-dihidropirimidina 2,4,5,6-sustituidos como inhibidores de la polimerasa del virus de la hepatitis B (VHB) para el tratamiento de, por ejemplo, la hepatitis crónica
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
CN103664925B (zh) * 2012-09-07 2018-01-23 广东东阳光药业有限公司 杂芳基取代的二氢嘧啶类化合物及其在药物中的应用
MA37942B1 (fr) 2012-09-10 2020-01-31 Hoffmann La Roche Hétéroaryldihydropyrimidines d'acide 6-aminé pour le traitement et la prophylaxie d'une infection par le virus de l'hépatite b
CN103664899B (zh) * 2012-09-11 2017-06-16 广东东阳光药业有限公司 杂芳基取代的二氢嘧啶类化合物及其在药物中的应用
CN103724339B (zh) * 2012-09-27 2015-10-14 广东东阳光药业有限公司 二氢嘧啶衍生物的晶型
AU2014235957A1 (en) * 2013-03-20 2015-10-01 Indiana University Research And Technology Corporation Fluorescent-HAP: a diagnostic stain for HBV cores in cells
MX2016006564A (es) 2013-11-19 2017-09-12 Sunshine Lake Pharma Co Ltd Compuestos dihidropirimidina y su aplicacion en productos farmaceuticos.
MY172391A (en) 2013-11-27 2019-11-22 Sunshine Lake Pharma Co Ltd Processes for preparing dihydropyrimidine derivatives and intermediates thereof
MY196243A (en) 2014-03-28 2023-03-24 Sunshine Lake Pharma Co Ltd Dihydropyrimidine Compounds and Their Application In Pharmaceuticals
CA2948580A1 (en) * 2014-05-09 2015-11-12 Adam Zlotnick Methods and compositions for treating hepatitis b virus infections
CN105859708B (zh) 2015-02-07 2020-01-21 广东东阳光药业有限公司 二氢嘧啶衍生物的盐及其在药物中的应用
EP3370759A1 (en) 2015-11-03 2018-09-12 H. Hoffnabb-La Roche Ag Combination therapy of an hbv capsid assembly inhibitor and an interferon
CN109689059A (zh) 2016-08-24 2019-04-26 豪夫迈·罗氏有限公司 Hbv衣壳组装抑制剂和核苷或核苷酸类似物的组合疗法
EP3587420B1 (en) 2017-02-23 2021-03-31 Fujian Cosunter Pharmaceutical Co., Ltd. Tri-cycle compound and applications thereof
CA3058111A1 (en) 2017-03-31 2018-10-04 Fujifilm Corporation 4-pyridone compound or salt thereof, and pharmaceutical composition and formulation including same
AU2018291688B2 (en) 2017-06-27 2022-02-03 Janssen Pharmaceutica Nv Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis B infections
CN107501257B (zh) * 2017-08-17 2020-05-29 山东大学 二氢嘧啶-三氮唑类衍生物及其制备方法与应用
EP3805223A4 (en) 2018-05-25 2021-12-22 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. 2,3-DIHYDRO-1H-PYRROLIZIN-7-FORMAMIDE DERIVATIVE AND USE OF IT
US11053235B2 (en) 2018-08-09 2021-07-06 Janssen Sciences Ireland Unlimited Company Substituted 1,4-dihydropyrimidines for the treatment of HBV infection or HBV-induced diseases
US11952388B2 (en) 2018-08-23 2024-04-09 Fujian Akeylink Biotechnology Co., Ltd. Crystal form of tri-cycle compound and application thereof
WO2020255016A1 (en) 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combination of hepatitis b virus (hbv) vaccines and dihydropyrimidine derivatives as capsid assembly modulators
US20230026869A1 (en) 2019-11-22 2023-01-26 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Crystal form of nucleoprotein inhibitor and use thereof
JP2024505709A (ja) 2021-02-05 2024-02-07 ヘパジーン セラピューティクス（エイチケー）リミティド フェニルジヒドロピリミジン系化合物及びその使用
WO2022268154A1 (zh) * 2021-06-24 2022-12-29 上海齐鲁制药研究中心有限公司 新型抗乙肝化合物

Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4822798A (en) 1982-09-18 1989-04-18 Bayer Aktiengesellschaft Circulation-active 4-phenyl-6-substituted dihydropyrimidines
WO2000058302A1 (de) 1999-03-25 2000-10-05 Bayer Aktiengesellschaft Dihydropyrimidine und ihre verwendung zur behandlung von hepatitis b
WO2001045712A1 (de) 1999-12-22 2001-06-28 Bayer Aktiengesellschaft Arzneimittelkombinationen gegen virale erkrankungen
WO2001068641A1 (de) 2000-03-17 2001-09-20 Bayer Aktiengesellschaft 6-aminoalkyl-dihydroppyrimidine und ihre verwendung als arzneimittel gegen virale erkrankungen
WO2001068647A1 (de) 2000-03-15 2001-09-20 Bayer Aktiengesellschaft Arzneimittel gegen virale erkrankungen
WO2001068639A1 (de) 2000-03-17 2001-09-20 Bayer Aktiengesellschaft Dihydropyrimidin-5-carbonsäureester und ihre verwendung als arzneimittel gegen virale erkrankungen
WO2001088642A1 (en) 2000-05-18 2001-11-22 Inovacor Ab Computer based system adapted to create a representation of the pumping action of a heart
US6436943B1 (en) 1998-04-18 2002-08-20 Bayer Aktiengesellschaft Use of dihydropyrimidines as medicaments, and novel substances
US6503913B1 (en) 1998-04-18 2003-01-07 Bayer Aktiengesellschaft 2-heterocyclically substituted dihydropyrimidines
US6696451B1 (en) 1998-04-18 2004-02-24 Bayer Aktiengesellschaft Dihydropyrimidines
US7074784B2 (en) 2000-03-16 2006-07-11 Siegfried Goldmann Medicaments against viral diseases
WO2008009209A1 (fr) 2006-07-10 2008-01-24 Beijing Molecule Science And Technology Co., Ltd Composés de dihydropyrimidine et leurs utilisations dans la préparation de médicaments pour traiter et prévenir des maladies antivirales
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
WO2008154819A1 (fr) 2007-06-18 2008-12-24 Zhang, Zhongneng Thiazolyl-dihydropyrimidines à substitution carbéthoxy
US20100004268A1 (en) 2006-07-10 2010-01-07 Song Li Optically Pure Dihydropyrimidine Compounds and Their Uses for the Preparation of a Medicament for Treatment and Prevention of Viral Diseases
US20100010013A1 (en) 2007-01-16 2010-01-14 Beijing Molecule Science And Technology Co., Ltd. Dihydropyrimidine compounds and their uses in manufacture of a medicament for treatment and prevention of viral diseases
US8236797B2 (en) 2007-06-18 2012-08-07 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines

Family Cites Families (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6458772B1 (en) 1909-10-07 2002-10-01 Medivir Ab Prodrugs
CS263952B1 (en) 1985-04-25 1989-05-12 Holy Antonin Remedy with antiviral effect
CS263951B1 (en) 1985-04-25 1989-05-12 Antonin Holy 9-(phosponylmethoxyalkyl)adenines and method of their preparation
US5047407A (en) 1989-02-08 1991-09-10 Iaf Biochem International, Inc. 2-substituted-5-substituted-1,3-oxathiolanes with antiviral properties
GB8815265D0 (en) 1988-06-27 1988-08-03 Wellcome Found Therapeutic nucleosides
MY104575A (en) 1989-12-22 1994-04-30 The Wellcome Foundation Ltd Therapeutic nucleosides.
US6642245B1 (en) 1990-02-01 2003-11-04 Emory University Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane
US5276151A (en) 1990-02-01 1994-01-04 Emory University Method of synthesis of 1,3-dioxolane nucleosides
US5204466A (en) 1990-02-01 1993-04-20 Emory University Method and compositions for the synthesis of bch-189 and related compounds
US5728575A (en) 1990-02-01 1998-03-17 Emory University Method of resolution of 1,3-oxathiolane nucleoside enantiomers
US5700937A (en) 1990-02-01 1997-12-23 Emory University Method for the synthesis, compositions and use of 2'-deoxy-5-fluoro-3'-thiacytidine and related compounds
EP0481214B1 (en) 1990-09-14 1998-06-24 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Prodrugs of phosphonates
US5340816A (en) 1990-10-18 1994-08-23 E. R. Squibb & Sons, Inc. Hydroxymethyl(methylenecyclopentyl) purines and pyrimidines
US5206244A (en) 1990-10-18 1993-04-27 E. R. Squibb & Sons, Inc. Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines
NZ250842A (en) 1991-02-22 1996-03-26 Univ Emory Resolution of a racemic mixture of nucleoside enantiomers such as 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (ftc)
WO1992018517A1 (en) 1991-04-17 1992-10-29 Yale University Method of treating or preventing hepatitis b virus
TW374087B (en) 1993-05-25 1999-11-11 Univ Yale L-2',3'-dideoxy nucleotide analogs as anti-hepatitis B(HBV) and anti-HIV agents
US5627160A (en) 1993-05-25 1997-05-06 Yale University L-2',3'-dideoxy nucleoside analogs as anti-hepatitis B (HBV) and anti-HIV agents
US5753789A (en) 1996-07-26 1998-05-19 Yale University Oligonucleotides containing L-nucleosides
WO1998009964A1 (en) 1996-09-03 1998-03-12 Bristol-Myers Squibb Company IMPROVED PROCESS FOR PREPARING THE ANTIVIRAL AGENT [1S-(1α, 3α, 4β)]-2-AMINO-1,9-DIHYDRO-9-[4-HYDROXY-3-(HYDROXYMETHYL)-2-METHYLENECYCLOPENTYL]-6H-PURIN-6-ONE
WO1998033501A1 (en) 1997-01-31 1998-08-06 Avid Therapeutics Inc. 2-benzoylamino-3-phenylpropenamide derivatives and methods of using the same
TW434252B (en) 1997-07-23 2001-05-16 Univ Georgia Res Found Process for the preparation of 2'-fluoro-5-methyl-β-L-arabino-furanosyluridine
US6636943B1 (en) * 1999-07-30 2003-10-21 Hewlett-Packard Development Company, L.P. Method for detecting continuity modules in a direct Rambus DRAM subsystem
DE10012824A1 (de) 2000-03-16 2001-09-20 Bayer Ag Arzneimittel gegen virale Erkrankungen
TWI332091B (en) 2003-07-22 2010-10-21 Univ Tokyo Nat Univ Corp Polarized plate of reflection type,laminated optical device and liquid display device

Patent Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4822798A (en) 1982-09-18 1989-04-18 Bayer Aktiengesellschaft Circulation-active 4-phenyl-6-substituted dihydropyrimidines
US6436943B1 (en) 1998-04-18 2002-08-20 Bayer Aktiengesellschaft Use of dihydropyrimidines as medicaments, and novel substances
US6696451B1 (en) 1998-04-18 2004-02-24 Bayer Aktiengesellschaft Dihydropyrimidines
US6503913B1 (en) 1998-04-18 2003-01-07 Bayer Aktiengesellschaft 2-heterocyclically substituted dihydropyrimidines
WO2000058302A1 (de) 1999-03-25 2000-10-05 Bayer Aktiengesellschaft Dihydropyrimidine und ihre verwendung zur behandlung von hepatitis b
WO2001045712A1 (de) 1999-12-22 2001-06-28 Bayer Aktiengesellschaft Arzneimittelkombinationen gegen virale erkrankungen
WO2001068647A1 (de) 2000-03-15 2001-09-20 Bayer Aktiengesellschaft Arzneimittel gegen virale erkrankungen
US7074784B2 (en) 2000-03-16 2006-07-11 Siegfried Goldmann Medicaments against viral diseases
WO2001068639A1 (de) 2000-03-17 2001-09-20 Bayer Aktiengesellschaft Dihydropyrimidin-5-carbonsäureester und ihre verwendung als arzneimittel gegen virale erkrankungen
WO2001068641A1 (de) 2000-03-17 2001-09-20 Bayer Aktiengesellschaft 6-aminoalkyl-dihydroppyrimidine und ihre verwendung als arzneimittel gegen virale erkrankungen
WO2001088642A1 (en) 2000-05-18 2001-11-22 Inovacor Ab Computer based system adapted to create a representation of the pumping action of a heart
WO2008009209A1 (fr) 2006-07-10 2008-01-24 Beijing Molecule Science And Technology Co., Ltd Composés de dihydropyrimidine et leurs utilisations dans la préparation de médicaments pour traiter et prévenir des maladies antivirales
US20100004268A1 (en) 2006-07-10 2010-01-07 Song Li Optically Pure Dihydropyrimidine Compounds and Their Uses for the Preparation of a Medicament for Treatment and Prevention of Viral Diseases
US20100010013A1 (en) 2007-01-16 2010-01-14 Beijing Molecule Science And Technology Co., Ltd. Dihydropyrimidine compounds and their uses in manufacture of a medicament for treatment and prevention of viral diseases
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
WO2008154819A1 (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
US8343969B2 (en) 2007-06-18 2013-01-01 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Huff, Joel R., "HIV Protease: A Novel Chemotherapeutic Target for AIDS," Journal of Medicinal Chemistry, Aug. 1991, pp. 2305-2314, vol. 34, No. 8.

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