WO2006033995A2 - Thiazolidine-4-ones possedant une activite antihepatite b - Google Patents

Thiazolidine-4-ones possedant une activite antihepatite b Download PDF

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Publication number
WO2006033995A2
WO2006033995A2 PCT/US2005/033038 US2005033038W WO2006033995A2 WO 2006033995 A2 WO2006033995 A2 WO 2006033995A2 US 2005033038 W US2005033038 W US 2005033038W WO 2006033995 A2 WO2006033995 A2 WO 2006033995A2
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Prior art keywords
phenyl
substituted
branched alkyl
alkyl
optionally substituted
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PCT/US2005/033038
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WO2006033995A3 (fr
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Robert K. Hamatake
Huanming Chen
Anneke Raney
Matthew J. Allan
Stanley Lang
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Valeant Research And Development
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Publication of WO2006033995A3 publication Critical patent/WO2006033995A3/fr

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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
    • C07D417/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to compounds, compositions and method of treatment for viral infections and the diseases associated therewith, particularly those infections and associated diseases caused by viruses in the hepadnavirus family, particularly the hepatitis B virus (HBV).
  • viruses in the hepadnavirus family particularly the hepatitis B virus (HBV).
  • HBV hepatitis B virus
  • interferon alpha has been widely used for the treatment of chronic HBV infection for a number of years.
  • interferon is effective only in certain subpopulations of chronic hepatitis B patients and is poorly tolerated.
  • lamivudine (3'-thia-2',3'-dideoxycytidine), a particularly strong inhibitor of HBV replication, is used to treat HBV infection.
  • resistance against this nucleoside analog is increasingly common, and has limited its efficacy in a high proportion of patients.
  • adefovir dipivoxil (9-(2-((-bis((pivaloyloxy)methoxy)phosphinyl)methoxy)ethyl)adenine), and while this nucleoside analog is active against the lamivudine-resistant viruses, the sustained viral response rate is below 20%, and nephrotoxicity typically limits the maximum tolerated dose and/or treatment duration.
  • HBV high-deoxy-beta-L-arabinofuranosyluracil
  • Gilead 2'-deoxy-5-fluoro- 3'-thiacytidine
  • Idenix 2'-deoxy-L-thymidine
  • Idenix 2'-deoxy-L-cytidine
  • carbocyclic nucleoside analogs (2-amino-l,9-dihydro-9-((lS,3R,4S)-4- hydroxy-3 -(hydroxymethyty-Z-methylenecyclopentyl- ⁇ H-purin- ⁇ -one monohydrate ; Bristol-Myers Squibb)
  • acyclic nucleoside analogs with liver targeting properties were reported as having anti-HBV activity in clinical trials.
  • the present invention provides a compound and composition for preventing and treating HBV infections in mammals and for preventing and treating diseases associated with HBV infection.
  • the compounds of the invention have the following structure:
  • R 1 represents a substituent selected from alkyl and branched alkyl of 1-8 carbons optionally substituted with phenyl and substituted phenyl, heterocyclic and substituted heterocyclic moieties and fused aryl and heteroaryl which can contain functionalities such as halogen, alkyl, alkoxy, cyano, nitro, CF 3 , and NR 7 R 8 , wherein R 7 and R 8 can be the same or different and are H, C]-C 8 alkyl and branched alkyl which can be optionally substituted with OR 7 and NR 7 R 8 .
  • R 1 can also be phenyl and substituted phenyl, heterocyclic and substituted heterocyclic moieties and fused aryl and heteroaryl which can contain functionalities such as halogen, alkyl, alkoxy, cyano, nitro, CF 3 , and NR 7 R 8 wherein R 7 and R 8 can be the same or different and are H, C 1 - C 8 alkyl and branched alkyl which can be optionally substituted with OR 7 and NR 7 R 8 .
  • At least one of R 2 and R 3 is H, and the other may be H or a Ci-C 8 linear or branched alkyl which can be optionally substituted with OR 7 and NR 7 R 8 .
  • R 4 and R 5 can be aryl such as phenyl and substituted phenyl, heterocyclic and substituted heterocyclic which can contain functionalities such as halogen, alkyl, alkoxy, cyano, nitro, CF 3 , and NR 7 R 8 wherein R 7 and R 8 can be the same or different and are H, C 1 -C 8 alkyl and branched alkyl which can be optionally substituted with OR 7 and NR 7 R 8 ; R 6 can be H, halogen, Ci-C 8 alkyl and branched alkyl, R 4 and R 5 can optionally be Ci-C 8 alkyl and branched alkyl, R 4 and R 5 can also be alkyl and branched alkyl of 1-8 carbons optionally substituted with phenyl and substituted phenyl, heterocyclic and substituted heterocyclic moieties and fused aryl and heteroaryl which can contain functionalities such as halogen, alkyl, alkoxy, cyano
  • R 4 can be halogen, CF 3 , alkyl and branched alkyl, cycloalkyl, alkenyl and alkynyl and substituted alkyl, branched alkyl, cycloalkyl, alkenyl and alkynyl. These may also be substituted with O, N, or S atoms and these may contain alkyl and branched alkyl, cycloalkyl, alkenyl and alkynyl and substituted alkyl, branched alkyl, cycloalkyl, alkenyl and alkynyl, aryl and substituted aryl, heteroaryl and substituted heteroaryl, heterocyclic and substituted heterocyclic.
  • W is selected from O, N and substituted N, and S;
  • X' can be N, C double- bonded to X, or CR 9 , where R 9 can be lower alkyl, lower cycloalkyl, aryl, substituted aryl, CF 3 , heteroaryl CF 3 CF 2 , CF 3 CH 2 , or CH 3 CF 2 ; and Y and Z are the same or different and can be CR or N.
  • the present invention provides a compound and composition for preventing and treating HBV infections in mammals and for preventing and treating diseases associated with HBV infection.
  • These compounds of the invention have the following structure:
  • R represents a substituent selected from linear or branched alkyl of 1-8 carbons optionally substituted with phenyl, substituted phenyl, heterocyclic, substituted heterocyclic, fused aryl and fused heteroaryl moieties which can contain functionalities such as halogen, alkyl, alkoxy, cyano, nitro, CF 3 , and NR 7 R 8 , wherein R 7 and R 8 can be the same or different, and are H, Ci-C 8 linear or branched alkyl which can be optionally substituted with OR 7 and NR 7 R 8 ; R 1 can also be phenyl, substituted phenyl, heterocyclic, substituted heterocyclic, fused aryl or fused heteroaryl, which can contain functionalities such as halogen, alkyl, alkoxy, cyano, nitro, CF 3 , and NR 7 R 8 wherein R 7 and R 8 can be the same or different and are H or Ci-C 8 linear or branched alkyl
  • R 2 and R 3 is H, and the other can be H, or Ci-C 8 linear or branched alkyl which can be optionally substituted with OR 7 and NR 7 R 8 .
  • R 4 and R 5 can be aryl such as phenyl and substituted phenyl, heterocyclic and substituted heterocyclic which can contain functionalities such as halogen, alkyl, alkoxy, cyano, nitro, CF 3 , and NR R wherein R and R can be the same or different and are H, Ci-C 8 alkyl and branched alkyl which can be optionally substituted with OR 7 and NR 7 R 8 ;
  • R 6 can be H, halogen, Ci-C 8 alkyl and branched alkyl, R 4 and R 5 can optionally be Ci-C 8 alkyl and branched alkyl, R 4 and R 5 can also be alkyl and branched alkyl of 1-8 carbons optionally substituted with phenyl and substituted phenyl,
  • X is S, O, or N, provided that when X is N X' is C and is double bonded to X.
  • X' is N, C double-bonded to X, or CR 9 , where R 9 is H, lower alkyl, lower cycloalkyl, aryl, substituted aryl, CF 3 , heteroaryl CF 3 CF 2 , CF 3 CH 2 , or CH 3 CF 2 ;
  • X is S
  • X' is CH
  • R 4 and R 5 are aryl or heteroaryl.
  • X is S
  • X' is CH
  • R 2 and R 6 are H
  • R 4 and R 5 are aryl or heteroaryl.
  • X is S, X' is CH, R 2 and R 6 are H; and R 4 and R 5 are independently selected from the group consisting of phenyl, pyridyl, pyrazinyl, and pyrimidinyl and are unsubstituted or independently substituted with one or more halogen or methyl groups.
  • X is S, X' is CH, R 2 and R 6 are H; R 4 and R 5 are aryl or heteroaryl; and R 1 is chosen from the group consisting of phenyl, benzyl, 2-phenethyl, tetrahydro-2-furfuryl, 5-methyl-2-furfuryl, 2-thienylethyl, 3,3- dimethylbutyl, 3-isopropyloxypropyl, beta-hydroxy-2-phenethyl, isobutyl, 3- methoxypropyl, piperonyl, and 2,2-dimethyl-3-hydroxypropyl.
  • W X is S, X' is CH, R 2 and R 6 are H; R 4 and R 5 are independently selected from the group consisting of phenyl, pyridyl, pyrazinyl, and pyrimidinyl and are unsubstituted or independently substituted with one or more halogen or methyl groups; and R 1 is chosen from the group consisting of phenyl, benzyl, 2-phenethyl, tetrahydro-2-furfuryl, 5-methyl-2-furfuryl, 2-thienylethyl, 3,3-dimethylbutyl, 3-isopropyloxypropyl, beta-hydroxy-2-phenethyl, isobutyl, 3- methoxypropyl, piperonyl, and 2,2-dimethyl-3-hydroxypropyl.
  • one or more carbon atoms may present an asymmetric center.
  • the invention encompasses isolated enantiomers and diastereomers as well as racemic and non-racemic mixtures thereof, which may readily be prepared, for example by the use of appropriately chiral starting materials.
  • the compounds of the invention are included in a pharmaceutical composition that is formulated with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
  • parenteral administration refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intra-articular injection and infusion.
  • compositions for parenteral injection preferably comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • Contemplated compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming unitary or microparticulate matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drag release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration • through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, cetyl alcohol and glycerol monostearate
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, water or other solvents, solubilizing agents and emulsifiers such as ethyl
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi ⁇ lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non ⁇ toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used.
  • the present compositions in liposome form may contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y. (1976), p. 33 et seq.
  • the compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • pharmaceutically acceptable salt is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq.
  • the salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid.
  • Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecano
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • Preferred salts of the compounds of the invention include phosphate, TRIS, and acetate.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • dosage levels of about 1 to about 500, more preferably of about 5 to about 50 mg of an active compound per kilogram of body weight per day are administered orally to a mammalian patient.
  • the effective daily dose may be divided into multiple doses for purposes of administration, e.g., two to four separate doses per day.
  • the invention also provides methods for the treatment of HBV viral infection in a mammal by administration of the compounds of the invention, pharmaceutical compositions comprising one or more compounds of the invention, a method of inhibiting replication of HBV comprising contacting a compound of the invention with the replicating HBV, and the use of compounds of the invention for the preparation of a pharmaceutical composition for treatment of HBV.
  • the invention also provides a method of treating a patient suffering from a hepatitis B viral infection, comprising administering to the patient a therapeutically effective amount of a compound of the invention.
  • HepG2 cells are transduced using a baculovirus to deliver the HBV genome essentially as previously described (Delaney, W.E., and Isom, H.C. Hepatitis B virus replication in human HepG2 cells mediated by hepatitis B virus recombinant baculovirus. Hepatology 1998; 28: 1134-1146.).
  • Transduced cells are cultured in supplemented EMEM media with 10% fetal bovine serum in a 5% CO 2 incubator at 37°C for three days in the presence of test compounds. The cells are lysed in a buffer containing 0.5% NP-40 and 500 microgram/ml proteinase K.
  • a solid-phase hybridization is performed to capture the viral DNA and to label the target DNA with Digoxigenin-labeled DNA probes.
  • the captured viral DNA is detected by ELISA using horseradish peroxidase-conjugated anti-digoxigenin antibodies.
  • the EC 50 values are determined using ExcelFit software from the inhibition values of a titration curve for each compound.
  • the test compounds are co-cultured with non- transduced HepG2 for three days under the conditions described above.
  • the Promega CellTiter 96 AQ ueous One Solution Cell Proliferation Assay is used to measure cell proliferation/viability.
  • the CC50 values are determined using ExcelFitTM software from the inhibition values of the titration curve for each compound.
  • Table 1 below lists selected compounds with their structures and corresponding antiviral activity (CC50 values in ⁇ M; A, EC50 ⁇ 1.0 ⁇ M; B, 1.0 ⁇ M ⁇ EC50 ⁇ 10 ⁇ M; C, EC50 > 10 ⁇ M). Antiviral activity was determined using assay systems as described above. All compounds were tested for a CC50 value. ND means not determined. Further examples are provided in Table 2.
  • POCl 3 (3.0ml, 33mmol) was slowly added to anhydrous DMF (7.65ml, 66mmol) at 0 0 C (ice-bath) with stirring. After stirring for 5 min, the semicarbazone was added portionwise to the above mixture with well-stirring. The mixture was heated to 60 0 C for 5 hours and poured onto 2Og of ice. It was neutralized with NaOH (6g in 24 ml of water) and heated at 60 0 C for 20 min, then cooled to room temperature and neutralized with ION HCl to pH 6. The resulting white precipitates were filtered and washed with water. After drying in vacuo at 60 0 C, 2.35 g (82%) of the aldehyde as white solid was obtained.
  • the solution was then slowly poured into 225ml of 4N HCl, the resulting solution warming to 26°C, before cooling back down.
  • the aqueous layer was then isolated and diluted with 500 ml of water.
  • the aqueous solution was extracted with 3x150ml portions of ethyl acetate.
  • the combined organic layer were washed with water, then saturated NaHCO 3 , dried over anhydrous Na 2 SO 4 , filtered and evaporated to yield 1.8 g of off-white solid.
  • the aqueous layer was allowed to stand for 18h, then re-extracted with 3x250ml portions of ethyl acetate.
  • the organic phase was washed with water, saturated NaHCO 3 , dried over anhydrous Na 2 SO 4 , filtered and evaporated to yield 4.4g of a yellow solid and combined 54% yield.

Abstract

L'invention concerne des composés (I) possédant une structure générale dans laquelle X représente S, O, ou N et X' représente N ou C. Ces composés sont utiles dans la prévention et le traitement d'infections par le virus de l'hépatite B (HBV) chez des mammifères, et dans la prévention et le traitement de maladies associées à cette infection.
PCT/US2005/033038 2004-09-16 2005-09-16 Thiazolidine-4-ones possedant une activite antihepatite b WO2006033995A2 (fr)

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WO2013144129A1 (fr) 2012-03-31 2013-10-03 F. Hoffmann-La Roche Ag Nouveaux 4-méthyl-dihydropyrimidines pour le traitement et la prophylaxie du virus de l'hépatite b
CN103664916A (zh) * 2012-09-12 2014-03-26 中国科学院化学研究所 基于联噻吩亚二吡咯及其衍生物的共轭小分子材料及其制备方法与应用
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
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US9045455B2 (en) 2013-03-14 2015-06-02 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9120757B2 (en) 2013-03-14 2015-09-01 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
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US9233978B2 (en) 2014-03-07 2016-01-12 Hoffmann-La Roche Inc. 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection
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US9394258B2 (en) 2013-03-14 2016-07-19 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9447079B2 (en) 2013-03-14 2016-09-20 Epizyme, Inc. PRMT1 inhibitors and uses thereof
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
WO2016202721A1 (fr) 2015-06-16 2016-12-22 F. Hoffmann-La Roche Ag Sels d'acide (s)-4-[(r)-6-(2-chloro-4-fluoro-phényl)-5-méthoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylméthyl]-morpholine-3-carboxylique, agent salifiant et leurs procédés de préparation et d'utilisation
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