WO2008154819A1 - Thiazolyl-dihydropyrimidines à substitution carbéthoxy - Google Patents

Thiazolyl-dihydropyrimidines à substitution carbéthoxy Download PDF

Info

Publication number
WO2008154819A1
WO2008154819A1 PCT/CN2008/001189 CN2008001189W WO2008154819A1 WO 2008154819 A1 WO2008154819 A1 WO 2008154819A1 CN 2008001189 W CN2008001189 W CN 2008001189W WO 2008154819 A1 WO2008154819 A1 WO 2008154819A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
composition
salt
hepatitis
Prior art date
Application number
PCT/CN2008/001189
Other languages
English (en)
Chinese (zh)
Inventor
Goldmann Siegfried
Jing Li
Yisong Liu
Original Assignee
Zhang, Zhongneng
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhang, Zhongneng filed Critical Zhang, Zhongneng
Publication of WO2008154819A1 publication Critical patent/WO2008154819A1/fr

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel ethoxycarbonyl-substituted thiazolyl dihydropyrimidine, a process for the preparation thereof and its use as a medicament, especially as a medicament for the treatment and prevention of hepatitis B virus infection.
  • the invention further relates to compositions of these dihydropyrimidines with other antiviral agents and, where appropriate, immunomodulators, and medicaments containing such compositions, especially compositions for the treatment and prevention of HBV infections such as hepatitis B. Background technique
  • Hepatitis B virus belongs to the family of hepatic viruses. It can cause acute and/or persistent/progressive chronic conditions. Hepatitis B virus also causes many other clinical signs in pathological morphology - especially chronic inflammation of the liver, cirrhosis of the liver and carcinogenesis of hepatocytes. In addition, co-infection with hepatitis D can have an adverse effect in the development of the disease.
  • Interferon and lamivudine are conventional drugs approved for the treatment of chronic hepatitis. However, interferon is only moderately active and has harmful side effects; although lamivudine has good activity, its resistance develops rapidly during treatment and often has a rebound effect after stopping treatment. Lamivudine (3-butyl 0> has an IC 5 Q value of 300 nM (Science, 299 (2003), 893-896).
  • No. 7,074,784 discloses 6-aminoalkyldihydropyrimidines and their use as medicaments, especially for the treatment and prevention of hepatitis B virus infection.
  • This patent discloses 54 different examples, and almost all of them (50) are compounds having a fluorine-substituted 2-pyridine residue at the position of R6.
  • R3 is a methyl group.
  • the present invention relates to a compound represented by the formula (I) and an isomer thereof (la)
  • R 1 is o-chloro
  • R 2 is p-chloro
  • R 3 is C 2 -C 3 alkyl
  • R 6 is thiazol-2-yl
  • X is methylene
  • Z is morpholinyl.
  • R 1 is o-chloro
  • R 2 is p-chloro
  • R 3 is ethyl
  • R 6 is thiazol-2-yl
  • X is methylene
  • Z is morpholinyl.
  • the invention also relates to enantiomers of the above compounds and to their respective mixtures.
  • the racemic form can be separated by known means, which is essentially a homogeneous component of the stereoisomer.
  • the compounds of the invention comprise isomers of the formulae (I) and (la) and mixtures thereof.
  • the compounds of the invention may also be in the form of a salt.
  • a physiologically acceptable salt is preferred.
  • the physiologically acceptable salt may be a mineral acid salt or an organic acid salt.
  • the physiologically acceptable salt may also be a metal or ammonium salt of a compound of the invention.
  • Particularly preferred examples are sodium, potassium, magnesium, or calcium salts, and from ammonia or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, An ammonium salt formed by arginine, lysine, ethylenediamine, or 2-phenylethylamine.
  • the compound (I) of the present invention can be produced by the following method:
  • R 6 means as described above, or
  • RR 2 , R 3 and R 6 have the same meanings as defined above, and Y is a nucleophilic substituent such as chloride, bromide, iodide, methanesulfonyl or tosyl, and morpholine (VII)
  • the reaction is carried out with or without the addition of a base, as appropriate, in the presence of an inert solvent.
  • a base as appropriate, in the presence of an inert solvent.
  • the compound (VI) can be produced, for example, by using the compound of the formula (VIII)
  • R 1 , R 2 , R 3 and R 6 have the same meanings as defined above, and a brominating agent such as N-bromosuccinate; imine, preferably in an inert solution, to give a compound of the formula (IX)
  • R 3 , X and Z have the same meanings as defined above, and the oxime represented by the formula (V) has or does not carry a base adduct.
  • R 3 has the same meaning as described above.
  • Compound (V) is known and can be prepared as described in WO-A-99/54326 and WO-A-99/54329.
  • Morpholine (VII) is commercially available.
  • inert organic solvents are suitable for the eight, B, C and D steps.
  • Preferred among them are alcohols such as methanol, ethanol, isopropanol, ethers such as dioxins, diethyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, carboxylic acids such as glacial acetic acid, or dimethyl.
  • Alcohols such as methanol, ethanol, isopropanol
  • ethers such as dioxins, diethyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, carboxylic acids such as glacial acetic acid, or dimethyl.
  • the reaction temperature can be varied within a relatively wide range.
  • a temperature between 20 and 150 ° C is usually used, but is preferably at the boiling temperature of the selected solvent.
  • the reaction can be carried out under atmospheric pressure or under high pressure. It is usually carried out under atmospheric pressure.
  • the reaction can be carried out in the presence or absence of an acid or a base; however, it is preferred to carry out the reaction in the presence of a weak acid such as acetic acid or formic acid.
  • a weak acid such as acetic acid or formic acid.
  • One embodiment of the invention relates to the use of A) at least one of the above-described dihydropyrimidines,
  • a detailed embodiment of the invention relates to a composition
  • a composition comprising A) a dihydropyrimidine, a B) HBV polymerase inhibitor and, if appropriate, a C) immunomodulator.
  • Preferred immunomodulators C) include, for example, all interferons such as alpha-, beta- and gamma-interferons, especially a-2a- and a-2b-interferon, interleukins such as interleukin-2 Polypeptides such as thymosin-ct-1 and thymoctonan, imidazoquinoline derivatives such as 8 levamisole, immunoglobulins and therapeutic vaccines. .
  • the present invention also relates to such compositions for the treatment and prevention of HBV infection and their use in the treatment of diseases caused by HBV.
  • compositions of the invention are beneficial for the treatment of HBV-induced diseases, primarily synergistic antiviral activity, and Tox-50 relative to a single component (50% cell viability toxicity) relative to a single treatment of a single compound. Scope)
  • the compositions of the invention are well tolerated.
  • HBV polymerase inhibitors used to achieve the objects of the present invention are in Ph. A. Furman et al., Antimicrobial Agents and Chemotherapy Vol. 36 (No. 12), 2688 (1992). Those materials disclosed in the endogenous polymerase experiments, as well as those described below, inhibit the formation of HBV DNA duplexes, resulting in a maximum of 50% of the activity values of zero.
  • HBV virions from culture suspensions integrate nucleoside 5'-triphosphate in vitro
  • the DNA of HBV is in the positive strand.
  • agarose gel electrophoresis the product in which [ ⁇ - 32 P]-deoxynucleoside 5'-triphosphate was incorporated into the virus 3.2 kb DNA was found, and there was no potential HBV polymerase-inhibiting property. substance.
  • One part by volume of the clarified cell culture suspension was mixed with 1/4 part by volume of an aqueous solution containing 50% by weight of polyethylene glycol 8000 and 0.6 M of sodium chloride.
  • the pellet was centrifuged at 2500 x g for 15 minutes, and the precipitate was resuspended in 2 ml of a buffer containing 0.05 M tris-HCl M (H 7.5), and dialyzed against the buffer containing 100 mM potassium chloride.
  • the sample was frozen at -80 Torr.
  • Each reaction mixture (100 ⁇ ) contains at least 10 5 HBV virions, 50 mM tris-HCl (p.sub.H 7.5), 300 mM potassium chloride, 50 mM magnesium chloride, 0.1%® Nonident P-40 (non-ion Type of washing, Boehringer Mannheim) > ⁇ ⁇ ⁇ , 10 ⁇ dGTP , 10 ⁇ dTTP; 10 ⁇ [ 32 P]dCTP (3000 Ci/mmol; final concentration 33 nM) and 1 ⁇ triphosphate form of polymerase potential inhibition Agent.
  • the samples were incubated at 37 C for one hour and then stopped by the addition of 50 mM EDTA.
  • the gel therein is dried or transformed into a membrane using Southern transformation techniques.
  • a maximum 50% concentration of the control group indicates the presence of an HBV polymerase inhibitor.
  • Abacavir (-)-(lS-cis)-4-[ 2 -amino-6-(cyclopropylamine)-9H-indol-9-yl]-2-yl-cyclopentene- 1-methanol, cf.
  • FTC (2R-cis)-4-amino-5-fluoro-l-[2-(hydroxymethyl)-1.3-oxothio-5-yl]-p-pyrimidine-2(1H)-one, Cf.
  • WO 92/14743 US Pat. Nos. 5,204,466; 5,210,085; 5,539,116; 5,700,937; 5,728,575; 5,814,639; 5,827,727; 5,852,027; 5,892,025; 5,914,331; 5,914,400) and WO 92/18517;
  • a more preferred embodiment of the invention relates to a composition comprising the above dihydropyrimidines (I) and (la) and B) lamivudine.
  • Another preferred HBV antiviral agent B contains, for example, phenylacrylamide represented by the following formula
  • R 1 and R 2 independently of each other, d- -fluorenyl or, together with the nitrogen atom at the position thereof, form a ring having 5 to 6 ring atoms including carbon and/or oxygen atoms.
  • R 3 to R 12 are independently hydrogen, cyano, C r C 4 -alkyl, optionally substituted for C r C 4 -nonyloxy, nitro, cyano or trifluoromethyl.
  • R 13 is hydrogen, C r C 4 -alkyl, dC 7 -acyl or aralkyl, and X is halogen or an optionally substituted C r C 4 -fluorenyl group.
  • AT-61 is a compound
  • Preferred immunomodulators C) include, for example, all interfering agents such as ⁇ -, ⁇ - and ⁇ -interferons, in particular a-2a- and a-2b-interfering, interleukins such as interleukin-2 , polypeptides such as thymosin-ot-1 and thymoctonan, imidazoquinoline derivatives such as 8 levamisole, immunoglobulins and therapeutic vaccines.
  • interfering agents such as ⁇ -, ⁇ - and ⁇ -interferons, in particular a-2a- and a-2b-interfering, interleukins such as interleukin-2 , polypeptides such as thymosin-ot-1 and thymoctonan, imidazoquinoline derivatives such as 8 levamisole, immunoglobulins and therapeutic vaccines.
  • Another preferred embodiment of the invention relates to a composition
  • a composition comprising A) the above-described dihydropyrimidines (I) and (la); B) lamivudine; and, where appropriate, C) interferon.
  • Antiviral testing was performed on 96-well microtiter plates. The first column only received medium and HepG2.2.15 cells as a virus control.
  • the mother liquor of the test compound (50 mM) was first dissolved in DMSO and then diluted with HepG2.2.15 medium. Typically, a 100 ⁇ test concentration (1 st test concentration) of the compound of the invention is pipetted into the second test column of the microtiter plate each time, and then added to the medium in which 2% by weight fetal calf serum (25 ⁇ l in volume) is added. Diluted 2 1Q times in two steps.
  • Each well of the microtiter plate containing 2% by weight of fetal bovine serum contained 225 l of HepG 2.2.15 cell suspension (5 x 10 4 cdls/ml). The test mixture was incubated for 4 days at 37 ° C, 5% C0 2 (v/v).
  • the surface suspension was then aspirated and discarded, and 225 ⁇ M of freshly prepared medium was added to the wells. A 25 ⁇ volume of a 1/10 concentration solution of the compound of the invention was added. The mixture was continued for 4 days.
  • cytotoxic or cytotoxic changes induced by substances in HepG2.2.15 cells for example, changes in cell morphology under a light microscope. Changes in these substances in HepG2.2.15 cells are evident compared to untreated cells, such as cytolysis, vacuoles, or changes in cell morphology.
  • 50% toxicity (TOX.-50) means that 50% of the cells exhibit a morphology compared to the corresponding control cells.
  • the tolerance of some of the compounds of the invention is tested by other host cells such as, for example, HeLa cells, primary human peripheral hematopoietic cells or transformed cell lines such as H-9 cells. No change in cytotoxin was detected at concentrations of the compounds of the invention > 10 ⁇ 1 . Determination of antiviral effect
  • the intracellular or extracellular suspension of HepG2.2.15 cells was denatured (1.5 M NaCl/0.5 N NaOH), neutralized ( 3 M NaCl/0.5 M Tris HCl, pH 7.5), then rinse (2xSSC) o
  • the DNA was dried onto the membrane by incubating the filter at 120 °C for 2-4 hours.
  • Viral DNA from treated HepG2.2.15 cells on nylon filters is typically detected by a non-radioactive, digoxin-labeled hepatitis B-specific DNA probe, labeled with digoxin, and according to the manufacturer Instructions for purification and hybridization.
  • Pre-hybridization is at 60. C was run for 30 minutes and then specifically hybridized with 20 to 40 ng/ml of digoxin-labeled, denatured HBV-specific DNA (14 hours, 60 °C). Wash the filter. Detection of HBV-DNA with digoxin antibody
  • Immunodetection of digoxin-labeled DNA was performed according to the manufacturer's instructions: The wash filter was hybridized in a blocking reagent (according to the manufacturer's instructions). Hybridization was then carried out using an anti-DIG antibody coupled to alkaline phosphatase for 30 minutes. After the washing step, the substrate of alkaline phosphatase, CSPD, was incubated with the filter for 5 minutes, then coated with a plastic film, and for another 15 minutes at 37 ° C. The filter was exposed to the X-ray layer.
  • HBV DNA was seen emission signal (incubation depending on signal strength: 10 to 2 minutes) at half maximum inhibitory concentration (IC 5 o, 50% inhibitory concentration) of a 50% reduction compared to the compounds of the present invention and an untreated sample.
  • IC 5 o half maximum inhibitory concentration
  • the compounds of the present invention exhibited an effective antiviral effect of IC 5 () below 1 nM, which was unexpected.
  • the compounds of the invention are useful in the treatment of viral-induced diseases, particularly acute and chronic persistent HBV viral infections.
  • Chronic viral disease caused by HBV It can lead to serious morbidity, and chronic hepatitis B virus infection can lead to cirrhosis and/or hepatocellular carcinogenesis in many cases.
  • the indicated regions that may be mentioned are, for example, the treatment of acute and chronic viral infections that may result in infectious hepatitis, for example, hepatitis B virus infection.
  • the compounds of the invention are especially suitable for the treatment of chronic hepatitis B infection and acute and chronic hepatitis B virus infection.
  • the invention includes a pharmaceutical preparation comprising, in addition to a non-toxic, inert, pharmaceutically suitable carrier, one or more compounds (I) or (la) or compositions of the invention or one or more activities Ingredient (I) or (la) or a composition of the invention.
  • the active ingredients (I) and (Ia) used in the above pharmaceutical preparations have a concentration of from about 0.1 to 99.5% by weight, preferably from about 0.5 to 95% by weight, based on the whole of the mixture.
  • the above pharmaceutical preparations may also contain other active pharmaceutical ingredients other than the compounds (I) and (la).
  • the content ratio of components A, B and suitable C in the composition of the invention may vary within wide limits, preferably from 5 to 500 mg of A/10 to 1000 mg of B, especially from 10 to 200 mg. A/20-400 mg of B.
  • Component C if appropriate, can also be used, preferably in an amount of from 1 to 10 million, more preferably from 2 to 7 million, I.U. (international unit), three times a week for a period of more than one year.
  • the compound or composition of the present invention for use in the above pharmaceutical preparations is usually present in a concentration of from about 0.1% to about 99.5%, preferably from about 0.5% to about 95%, by weight based on the total of the mixture.
  • the above pharmaceutical preparations can be prepared by a known conventional method, for example, by mixing the active ingredient with a carrier.
  • a total dose of from about 0.05 to about 500, preferably from 0.1 to 100 mg/kg body weight per 24 hours, whether in humans or veterinary, for a single dose of multiple doses.
  • the active ingredient contained in a single dose is preferably in a total amount of from about 0.1 to about 80, preferably from 0.1 to 30 mg/kg of body weight. No It is necessary to vary the above dosage, especially depending on the type and weight of the subject to be treated, the nature and severity of the condition, the type of preparation, the manner in which the medicine is administered, and the time or interval at which the medicine is administered.
  • the present invention also relates to the above compounds and compositions for use in the control of diseases.
  • the invention further relates to a medicament comprising at least one of the above compounds or compositions and, where appropriate, one or more other active pharmaceutical ingredients.
  • the invention further relates to the use of the above compounds and compositions for the preparation of a medicament for the treatment and prevention of the above mentioned diseases, in particular viral diseases, in particular hepatitis B.
  • the anti-HBV active compounds of Example 3 were all enantiomers with a longer retention time.
  • the activity data for the compounds of the invention are listed below:

Abstract

L'invention concerne des nouvelles thiazolyl-dihydropyrimidines à substitution carbéthoxy et des compositions de celles-ci avec d'autres agents antiviraux, qui sont utilisées pour combattre des infections par le virus de l'hépatite B (VHB).
PCT/CN2008/001189 2007-06-18 2008-06-18 Thiazolyl-dihydropyrimidines à substitution carbéthoxy WO2008154819A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200710119017 2007-06-18
CN200710119017.9 2007-06-18

Publications (1)

Publication Number Publication Date
WO2008154819A1 true WO2008154819A1 (fr) 2008-12-24

Family

ID=40155888

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2008/001189 WO2008154819A1 (fr) 2007-06-18 2008-06-18 Thiazolyl-dihydropyrimidines à substitution carbéthoxy

Country Status (2)

Country Link
CN (1) CN101328169B (fr)
WO (1) WO2008154819A1 (fr)

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010069147A1 (fr) * 2008-12-17 2010-06-24 张中能 Derives de la dihydropyrimidine, leurs compositions et leur utilisation
US8236797B2 (en) 2007-06-18 2012-08-07 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
WO2014029193A1 (fr) 2012-08-24 2014-02-27 Sunshine Lake Pharma Co., Ltd. Composés de dihydropyrimidine et leur application dans des produits pharmaceutiques
JP2015531354A (ja) * 2012-09-27 2015-11-02 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． ジヒドロピリミジン誘導体の結晶形
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
US9873671B2 (en) 2014-01-16 2018-01-23 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
WO2018036941A1 (fr) 2016-08-24 2018-03-01 F. Hoffmann-La Roche Ag Thérapie de combinaison d'un inhibiteur d'ensemble capside du vhb et d'un analogue de nucléotide/nucléoside
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
US10098889B2 (en) 2015-02-07 2018-10-16 Sunshine Lake Pharma Co., Ltd. Complexes and salts of dihydropyrimidine derivatives and their application in pharmaceuticals
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10160743B2 (en) 2013-05-17 2018-12-25 Janssen Sciences Ireland Uc Sulphamoylthiophenamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10196376B2 (en) 2011-12-21 2019-02-05 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US10213420B2 (en) 2014-02-05 2019-02-26 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10537580B2 (en) 2015-03-19 2020-01-21 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US10596173B2 (en) 2015-11-03 2020-03-24 Hoffmann-La Roche Inc. Combination therapy of an HBV capsid assembly inhibitor and an interferon
WO2020087107A1 (fr) 2018-10-31 2020-05-07 The University Of Sydney Compositions et méthodes de traitement d'infections virales
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2014184328A1 (fr) * 2013-05-17 2014-11-20 F. Hoffmann-La Roche Ag Héteroaryldihydropyrimidines pontées en position 6 pour le traitement et la prophylaxie d'une infection par le virus de l'hépatite b

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068641A1 (fr) * 2000-03-17 2001-09-20 Bayer Aktiengesellschaft 6-aminoalkyle-dihydropirimidines et utilisation en tant qu'agents pharmaceutiques contre des maladies virales
WO2001068642A1 (fr) * 2000-03-16 2001-09-20 Bayer Aktiengesellschaft Dihydropirimidines et leur utilisation en tant qu'agents pharmaceutiques destines au traitement de l'hepatite b
WO2001068639A1 (fr) * 2000-03-17 2001-09-20 Bayer Aktiengesellschaft Esters d'acide carboxylique-5-dihydropyrimidine et leur utilisation en tant qu'agent pharmaceutique contre des maladies virales
WO2001068640A1 (fr) * 2000-03-16 2001-09-20 Bayer Aktiengesellschaft Agents pharmaceutiques contre des maladies virales

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068642A1 (fr) * 2000-03-16 2001-09-20 Bayer Aktiengesellschaft Dihydropirimidines et leur utilisation en tant qu'agents pharmaceutiques destines au traitement de l'hepatite b
WO2001068640A1 (fr) * 2000-03-16 2001-09-20 Bayer Aktiengesellschaft Agents pharmaceutiques contre des maladies virales
WO2001068641A1 (fr) * 2000-03-17 2001-09-20 Bayer Aktiengesellschaft 6-aminoalkyle-dihydropirimidines et utilisation en tant qu'agents pharmaceutiques contre des maladies virales
WO2001068639A1 (fr) * 2000-03-17 2001-09-20 Bayer Aktiengesellschaft Esters d'acide carboxylique-5-dihydropyrimidine et leur utilisation en tant qu'agent pharmaceutique contre des maladies virales

Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
WO2010069147A1 (fr) * 2008-12-17 2010-06-24 张中能 Derives de la dihydropyrimidine, leurs compositions et leur utilisation
US10196376B2 (en) 2011-12-21 2019-02-05 Novira Therapeutics, Inc. Hepatitis B antiviral agents
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
EP2888241A4 (fr) * 2012-08-24 2016-05-25 Sunshine Lake Pharma Co Ltd Composés de dihydropyrimidine et leur application dans des produits pharmaceutiques
WO2014029193A1 (fr) 2012-08-24 2014-02-27 Sunshine Lake Pharma Co., Ltd. Composés de dihydropyrimidine et leur application dans des produits pharmaceutiques
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10995064B2 (en) 2012-08-28 2021-05-04 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
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
JP2015531354A (ja) * 2012-09-27 2015-11-02 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． ジヒドロピリミジン誘導体の結晶形
US9403814B2 (en) 2012-09-27 2016-08-02 Sunshine Lake Pharma Co., Ltd. Crystalline forms of dihydropyrimidine derivatives
US10941113B2 (en) 2013-02-28 2021-03-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10398677B2 (en) 2013-04-03 2019-09-03 Janssen Sciences Ireland Uc N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10457638B2 (en) 2013-05-17 2019-10-29 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10160743B2 (en) 2013-05-17 2018-12-25 Janssen Sciences Ireland Uc Sulphamoylthiophenamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10377709B2 (en) 2013-10-23 2019-08-13 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9498479B2 (en) 2013-11-19 2016-11-22 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
US9617252B2 (en) 2013-11-27 2017-04-11 Sunshine Lake Pharma Co., Ltd. Processes for preparing dihydropyrimidine derivatives and intermediates thereof
US9643962B2 (en) 2013-11-27 2017-05-09 Sunshine Lake Pharma Co., Ltd. Processes for preparing dihydropyrimidine derivatives and intermediates thereof
US9573941B2 (en) 2013-11-27 2017-02-21 Sunshine Lake Pharma Co., Ltd. Processes for preparing dihydropyrimidine derivatives and intermediates thereof
US9873671B2 (en) 2014-01-16 2018-01-23 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10632112B2 (en) 2014-02-05 2020-04-28 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US10213420B2 (en) 2014-02-05 2019-02-26 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
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
US10537580B2 (en) 2015-03-19 2020-01-21 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
US10596173B2 (en) 2015-11-03 2020-03-24 Hoffmann-La Roche Inc. Combination therapy of an HBV capsid assembly inhibitor and an interferon
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US11129834B2 (en) 2016-04-15 2021-09-28 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
WO2018036941A1 (fr) 2016-08-24 2018-03-01 F. Hoffmann-La Roche Ag Thérapie de combinaison d'un inhibiteur d'ensemble capside du vhb et d'un analogue de nucléotide/nucléoside
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
WO2020087107A1 (fr) 2018-10-31 2020-05-07 The University Of Sydney Compositions et méthodes de traitement d'infections virales
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases

Also Published As

Publication number Publication date
CN101328169B (zh) 2011-05-25
CN101328169A (zh) 2008-12-24

Similar Documents

Publication Publication Date Title
WO2008154819A1 (fr) Thiazolyl-dihydropyrimidines à substitution carbéthoxy
JP5970421B2 (ja) ブロモフェニル置換チアゾリルジヒドロピリミジン
WO2008154818A1 (fr) Thiazolyl-dihydropyrimidines à substitution fluorophényle
WO2008154820A1 (fr) Thiazolyl-dihydropyrimidines à substitution carbéthoxy
US7074784B2 (en) Medicaments against viral diseases
US6503913B1 (en) 2-heterocyclically substituted dihydropyrimidines
WO2010069147A1 (fr) Derives de la dihydropyrimidine, leurs compositions et leur utilisation
JP2002512233A (ja) 薬剤としてのジヒドロピリミジン類の使用及び新規な物質
WO2008009209A1 (fr) Composés de dihydropyrimidine et leurs utilisations dans la préparation de médicaments pour traiter et prévenir des maladies antivirales
WO2008009210A1 (fr) Composés de dihydropyrimidine optiquement purs et leurs utilisations dans la fabrication d'un médicament pour traiter ou prévenir des viroses
WO2001068639A1 (fr) Esters d'acide carboxylique-5-dihydropyrimidine et leur utilisation en tant qu'agent pharmaceutique contre des maladies virales
HU219299B (en) Oxathiolanes, method for their preparation and pharmaceutical compositions contating same
JP2003514896A (ja) 新規な５−ピリミジンカルボキサミド誘導体及び該誘導体を含む製薬組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08757465

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08757465

Country of ref document: EP

Kind code of ref document: A1