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WO2008099022A1 - 10-sulfonyl-dibenzodiazépinones utiles comme inhibiteurs du virus de l'hépatite c - Google Patents

10-sulfonyl-dibenzodiazépinones utiles comme inhibiteurs du virus de l'hépatite c Download PDF

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Publication number
WO2008099022A1
WO2008099022A1 PCT/EP2008/051905 EP2008051905W WO2008099022A1 WO 2008099022 A1 WO2008099022 A1 WO 2008099022A1 EP 2008051905 W EP2008051905 W EP 2008051905W WO 2008099022 A1 WO2008099022 A1 WO 2008099022A1
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het
optionally substituted
alkyl
group
aryl
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Pierre Jean-Marie Bernard Raboisson
Sandrine Marie Helene Vendeville
Jean-François BONFANTI
David Mc Gowan
Koen Vandyck
Frédéric Marc Maurice DOUBLET
Lili Hu
Origène NYANGUILE
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Janssen R&D Ireland ULC
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Tibotec Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention is concerned with 10-sulfonyl-dibenzodiazepinones having inhibitory activity on the replication of the hepatitis C virus (HCV). It further concerns compositions comprising these compounds as active ingredients as well as processes for preparing these compounds and compositions.
  • HCV hepatitis C virus
  • Hepatitis C virus is the leading cause of chronic liver disease worldwide and has become a focus of considerable medical research.
  • HCV is a member of the Flaviviridae family of viruses in the hepacivirus genus, and is closely related to the flavivirus genus, which includes a number of viruses implicated in human disease, such as dengue virus and yellow fever virus, and to the animal pestivirus family, which includes bovine viral diarrhoea virus (BVDV).
  • BVDV bovine viral diarrhoea virus
  • HCV is a positive-sense, single- stranded RNA virus, with a genome of around 9,600 bases.
  • the genome comprises both 5 ' and 3 ' untranslated regions that adopt RNA secondary structures, and a central open reading frame that encodes a single polyprotein of around 3,010-3,030 amino acids.
  • the polyprotein encodes ten gene products, which are generated from the precursor polyprotein by an orchestrated series of co- and posttranslational endoproteolytic cleavages mediated by both host and viral proteases.
  • the viral structural proteins include the core nucleocapsid protein, and two envelope glycoproteins El and E2.
  • the non- structural (NS) proteins encode some essential viral enzymatic functions (helicase, polymerase, protease), as well as proteins of unknown function.
  • Replication of the viral genome is mediated by an RNA-dependent RNA polymerase, encoded by non-structural protein 5b (NS5B).
  • NS5B non-structural protein 5b
  • the viral helicase and protease functions both encoded in the bifunctional NS3 protein, have been shown to be essential for replication of HCV RNA.
  • HCV also encodes a metalloproteinase in the NS2 region.
  • HCV replicates preferentially in hepatocytes but is not directly cytopathic, leading to persistent infection. In particular, the lack of a vigorous T-lymphocyte response and the high propensity of the virus to mutate appear to promote a high rate of chronic infection.
  • HCV type 1 is the predominant genotype in the US and Europe. For instance, HCV type 1 accounts for 70 to 75 percent of all HCV infections in the United States.
  • the extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, perhaps explaining difficulties in vaccine development and the lack of response to therapy. An estimated 170 million persons worldwide are infected with hepatitis C virus (HCV).
  • HCV hepatitis C virus
  • liver fibrosis leading to cirrhosis, end-stage liver disease, and HCC hepatocellular carcinoma
  • HCC hepatocellular carcinoma
  • Liver cirrhosis due to HCV infection is responsible for about 10,000 deaths per year in the U.S.A. alone, and is the leading cause for liver transplantations.
  • Transmission of HCV can occur through contact with contaminated blood or blood products, for example following blood transfusion or intravenous drug use.
  • the introduction of diagnostic tests used in blood screening has led to a downward trend in post-transfusion HCV incidence.
  • the existing infections will continue to present a serious medical and economic burden for decades (Kim, W.R. Hepatology, 36, 5 Suppl. S30-S34, 2002).
  • HCV therapies are based on (pegylated) interferon-alpha (IFN- ⁇ ) in combination with ribavirin.
  • This combination therapy yields a sustained viro logic response in more than 40% of patients infected by genotype 1 viruses and about 80% of those infected by genotypes 2 and 3.
  • combination therapy has significant side effects and is poorly tolerated in many patients. For instance, in registration trials of pegylated interferon and ribavirin, significant side effects resulted in discontinuation of treatment in approximately 10 to 14 percent of patients.
  • Major side effects of combination therapy include influenza- like symptoms, hematologic abnormalities, and neuropsychiatric symptoms.
  • the development of more effective, convenient and tolerated treatments is a major public health objective. Thus, the treatment of this chronic disease is an unmet clinical need, since current therapy is only partially effective and limited by undesirable side effects.
  • NIs nucleoside inhibitors
  • NNIs non-nucleoside inhibitors
  • the present invention concerns inhibitors of HCV replication, which can be represented by formula (I):
  • each X and Y is, independently, CH or N;
  • R 1 is hydrogen, amino, or hydroxy;
  • R 3 is Ci_ 6 alkyl optionally substituted with C 3 _ 7 Cycloalkyl, aryl, or Het; C 3 _ 7 Cycloalkyl; aryl; or Het; each R 4a and R 4b is, independently, C 1-6 alkyl, or both R 4a and R 4b together with the carbon atom of the tricyclic ring to which they are attached may form a C 3 _ 7 Cycloalkyl;
  • R 7 is d- ⁇ alkyl, C3 -7 cycloalkyl, di(Ci_3alkyl)amino, or aryl;
  • R 3 is Ci_ 6 alkyl optionally substituted with C 3 - 7 cycloalkyl, aryl, or Het; C 3 - 7 cycloalkyl; aryl; or Het; each R 4a and R 4b is, independently, C 1-6 alkyl, or both R 4a and R 4b together with the carbon atom of the tricyclic ring to which they are attached may form a C 3 - 7 cycloalkyl;
  • R 7 is d- ⁇ alkyl, C3-7cycloalkyl, di(Ci_3alkyl)amino, or aryl;
  • R 8 is hydrogen; Ci_ 6 alkyl optionally substituted with Ci_ 6 alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, nitro, or amino; or phenyl optionally substituted with one or two substituents selected from halo, amino, nitro, d ⁇ alkyl, and phenyl; aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro- naphthyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, polyhaloCi- ⁇ alkyl, cyano, d_ 6 alkyl, polyhaloCi_ 6 alkoxy
  • the invention further relates to methods for the preparation of the compounds of formula (I), the iV-oxides, quaternary amines, salts, hydrates, solvates, metal complexes, prodrugs, and stereochemically isomeric forms thereof, their intermediates, and the use of the intermediates in the preparation of the compounds of formula (I).
  • the invention relates to the compounds of formula (I) per se, the iV-oxides, salts, hydrates, solvates, quaternary amines, metal complexes, prodrugs, and stereochemically isomeric forms thereof, for use as a medicament.
  • the invention relates to the compounds of formula (J) per se, the iV-oxides, salts, hydrates, solvates, quaternary amines, metal complexes, prodrugs, and stereochemically isomeric forms thereof, for treating hepatitis C.
  • the invention further relates to pharmaceutical compositions comprising a carrier and an anti-virally effective amount of a compound of formula (I) as specified herein.
  • the pharmaceutical compositions may comprise combinations of the aforementioned compounds with other anti-HCV agents.
  • the pharmaceutical compositions may comprise combinations of the aforementioned compounds with anti-HIV agents.
  • the invention further relates to the aforementioned pharmaceutical compositions for administration to a subject suffering from HCV infection.
  • the invention also relates to the use of a compound of formula (I), or a JV-oxide, salt, hydrate, solvate, quaternary amine, metal complex, prodrug, or stereochemically isomeric forms thereof, for the manufacture of a medicament for inhibiting HCV replication.
  • the invention relates to a method of inhibiting HCV replication in a warm-blooded animal said method comprising the administration of an effective amount of a compound of formula (I), or a prodrug, JV-oxide, salt, hydrate, solvate, quaternary amine, metal complex, or stereochemically isomeric forms thereof.
  • halo is generic to fluoro, chloro, bromo and iodo.
  • Ci_ 4 alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as for example methyl, ethyl, prop-1-yl, prop-2-yl, but-l-yl, but-2-yl, isobutyl, 2-methyl- prop-1-yl;
  • Ci_3alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as for example methyl, ethyl, prop-1-yl, prop-2-yl;
  • Ci_ 6 alkyl encompasses Ci_ 3 alkyl and Ci_ 4 alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pent-1-yl, pent-2-yl, pent-3-yl, hex-l-yl, hex-2-yl, 2-methylbut-l-y
  • C2-6alkenyl refers to an unsaturated hydrocarbyl group, which may be linear, or branched, comprising one or more carbon- carbon double bonds.
  • Examples of C 2 - 6 alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and the like.
  • polyhaloCi- ⁇ alkyl refers to a Ci_ 6 alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with one or more halogens as defined above.
  • Non- limiting examples of such polyhalo- C i_ 6 alkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl.
  • Cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Ci_6alkoxy or "Ci_6alkyloxy” as a group or part of a group refers to a radical having the Formula -OR a wherein R a is Ci_ 6 alkyl as defined above.
  • suitable Ci_6alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • Suitable Ci_4alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, and tert-butoxy.
  • polyhaloCi- ⁇ alkoxy refers to a Ci_6alkoxy radical having the meaning as defined above wherein one or more hydrogens are replaced with one or more halogens as defined above.
  • Non- limiting examples of such polyhaloCi- ⁇ alkoxy radicals include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 1,1,1-trifluoroethoxy.
  • the carbon atom to which the oxo is linked is a saturated carbon.
  • Ci_ 6 alkylsulfonyl refers to a group of Formula -S ⁇ 2-R b wherein R b is Ci_6alkyl as defined herein.
  • Non-limiting examples of Ci_ 6 alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, butylsulfonyl, prop- 1-ylsulfonyl, n-pentylsulfonyl, and hexylsulfonyl.
  • Ci_6alkylthio refers to a group consisting of a sulfur atom attached to a Ci_6alkyl group.
  • Non- limiting examples of Ci_6alkylthio groups include methylthio (SCH3), ethylthio (SCH2CH3), n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, te/t-butylthio, and the like.
  • radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable.
  • piperidinyl includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl
  • pentyl includes pent-1-yl, pent-2-yl and pent-3-yl.
  • each definition is independent.
  • One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the JV-oxides, salts, as the possible stereoisomeric forms thereof.
  • Another embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the salts as the possible stereoisomeric forms thereof.
  • the compounds of formula (I) may have one or more centers of chirality and may exist as stereochemically isomeric forms.
  • stereochemically isomeric forms as used herein defines all the possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures, which the compounds of formula (I) may possess.
  • the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms, which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form or mixed with each other are intended to be embraced within the scope of the present invention.
  • stereoisomerically pure concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e.
  • Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures.
  • enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the diastereomeric racemates of the compounds of formula (I) can be obtained separately by conventional methods.
  • Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography.
  • the absolute stereochemical configuration was not experimentally determined.
  • a person skilled in the art is able to determine the absolute configuration of such compounds using art-known methods such as, for example, X-ray diffraction.
  • the present invention encompasses compounds of Formula (II) and (III).
  • preferred configuration has Formula (II).
  • R 1 , R 2 , R 3 , R 4a and R 4b have the same meaning as that defined herein.
  • the present invention is also intended to include all isotopes of atoms occurring on the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • Isotopes of carbon include C- 13 and C- 14.
  • prodrug as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I).
  • the reference by Goodman and Gilman The Pharmacological Basis of Therapeutics, 8 th ed, McGraw-Hill, Int. Ed.
  • Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
  • Prodrugs of a compound of the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound.
  • ester prodrugs that are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy or a carboxyl group.
  • An in vivo hydrolysable ester is an ester, which is hydro lyzed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include Ci_6alkoxymethyl esters for example methoxy- methyl, Ci_ 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 _ 8 CycloalkoxycarbonyloxyCi_ 6 alkyl esters for example 1-cyclohexylcarbonyl- oxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen- 2-onylmethyl; and Ci_ 6 alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyl- oxyethyl which may be formed at any carboxy group in the compounds of this invention.
  • An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxy- methoxy and 2,2-dimethylpropionyloxy-methoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and ⁇ /-(dialkylaminoethyl)- ⁇ /-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.
  • salts of the compounds of formula (I) are those wherein the counter-ion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable acid and base salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • butanedioic acid maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, /?-toluenesulfonic, cyclamic, salicylic, / ⁇ -aminosalicylic, pamoic and the like acids.
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • the compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, JV-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • quaternary amine as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates.
  • a quaternary amine has a positively charged nitrogen.
  • Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
  • iV-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called iV-oxide.
  • the compounds of formula (I) may have metal binding, chelating, complex forming properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.
  • One embodiment of the present invention concerns compounds of formula (I) or any subgroup thereof, wherein
  • each R 6a and R 6b is, independently, hydrogen;
  • Ci_6alkyl optionally substituted with one or two substituents selected from -OR 8 ;
  • each R 6a and R 6b is, independently, hydrogen; Ci_ 6 alkyl optionally substituted with one or two substituents selected from -OR 8 ; aryl; or Het;
  • R 7 is d- ⁇ alkyl, C3-7cycloalkyl, di(Ci_3alkyl)amino, or aryl; preferably R 7 is d- ⁇ alkyl,
  • R 7 is d- ⁇ alkyl
  • R 8 is hydrogen
  • One embodiment of the present invention concerns compounds of formula (I) or any subgroup thereof, wherein each X and Y is, independently, CH or N; R 1 is hydrogen, amino, or hydroxy;
  • R is Ci_ 6 alkyl optionally substituted with C 3 _ 7 Cycloalkyl, aryl, or Het; C 3 _ 7 Cycloalkyl; aryl; or Het; each R 4a and R 4b is, independently, C 1-6 alkyl, or both R 4a and R 4b together with the carbon atom of the tricyclic ring to which they are attached may form a Cs-ycycloalkyl;
  • each R 6a and R 6b is, independently, hydrogen;
  • R 7 is Ci_ 6 alkyl, C 3 _ 7 Cycloalkyl, di(Ci_ 3 alkyl)amino, or aryl;
  • R 8 is hydrogen; Ci_ 6 alkyl optionally substituted with Ci_ 6 alkoxy, phenyl, or Het, wherein the Ci_6alkoxy may optionally be substituted with
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein each X and Y is, independently, CH or N;
  • R 1 is hydrogen, amino, or hydroxy
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein each X and Y is, independently, CH or N;
  • R 1 is hydrogen, amino, or hydroxy
  • R 3 is Ci_ 6 alkyl; C 3 - 7 cycloalkyl; aryl; or Het; each R 4a and R 4b is, independently, Ci_ 6 alkyl; preferably each R 4a and R 4b is, independently, Ci_ 4 alkyl; more preferably each R 4a and R 4b is, independently, methyl, ethyl, n-propyl, or isopropyl,
  • R 5 is hydrogen; Ci_ 6 alkyl optionally substituted with -OR 8 , aryl, or Het; each R 6a and R 6b is, independently, hydrogen; Ci_ 6 alkyl optionally substituted with one or two substituents selected from -OR 8 ; C 2 _ 6 alkenyl; C 3-7 Cy cloalkyl; aryl; or Het;
  • R 7 is Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, or aryl;
  • Ci_ 6 alkylcarbonyl, Ci_ 6 alkylthio, Ci_ 6 alkylsulfonyl, -S( O) 2 NH 2 , and pyrrolyl;
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein each X and Y is, independently, CH or N;
  • R 1 is hydrogen or hydroxy
  • Het as a group or part of a group is a 5 to 6 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one benzene ring, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, oxo, or Ci_ 6 alkyl.
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein one or more of the following restrictions apply: (a) each X and Y is, independently, CH or N;
  • R 1 is hydrogen, amino, or hydroxy
  • R 3 is Ci_ 6 alkyl optionally substituted with C 3 _ 7 Cycloalkyl, aryl, or Het; C 3 _ 7 Cyclo-alkyl; aryl; or Het;
  • each R 4a and R 4b is, independently, Ci_ 6 alkyl
  • each R 6a and R 6b is, independently, hydrogen; Ci_ 6 alkyl optionally substituted with one or two substituents selected from -OR 8 , mono- or diCi_6alkylamino,
  • R 7 is Ci_ 6 alkyl, C 3 - 7 cycloalkyl, di(Ci_ 3 alkyl)amino, or aryl;
  • R 8 is hydrogen; Ci_ 6 alkyl optionally substituted with Ci_ 6 alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, nitro, or amino; or phenyl optionally substituted with one or two substituents
  • each X and Y is, independently, CH or N;
  • R 1 is hydrogen, amino, or hydroxy;
  • R is Ci_ 6 alkyl; C 3 _ 7 Cycloalkyl; aryl; or Het;
  • each R 4a and R 4b is, independently, Ci_ 6 alkyl;
  • R 5 is hydrogen; Ci_6alkyl optionally substituted with -OR 8 , aryl, or Het;
  • each R 6a and R 6b is, independently, hydrogen; Ci_ 6 alkyl; C 2 - 6 alkenyl; C 3 - 7 cycloalkyl; aryl; or Het;
  • R 7 is d- ⁇ alkyl, C 3 - 7 cycloalkyl, or aryl;
  • Ci_6alkylcarbonyl, Ci_6alkylthio, Ci_6alkylsulfonyl, -S( O) 2 NH 2 , and pyrrolyl;
  • Het as a group or part of a group is a 5 to 6 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one benzene ring, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, oxo, -OR 8 , -CN, C ⁇ aUcyl, or -C(O)-NH 2 .
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein one or more of the following restrictions apply:
  • each X and Y is, independently, CH or N;
  • R 1 is hydrogen or hydroxy
  • R 3 is aryl
  • each R 4a and R 4b is, independently, C h alky!;
  • R 5 is hydrogen or Ci_ 6 alkyl;
  • each R 6a and R 6b is, independently, hydrogen, aryl, or Het;
  • R 7 is Ci_ 6 alkyl;
  • R 8 is Ci_ 6 alkyl optionally substituted with phenyl; or phenyl optionally substituted with one or two halo;
  • aryl as a group or part of a group is phenyl optionally substituted with one or two halo, Ci_ 6 alkyl, -OR 8 ;
  • Het as a group or part of a group is a 5 to 6 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur.
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein (a) each X and Y is, independently, CH or N; (b) R 1 is hydrogen or hydroxy;
  • R 3 is aryl
  • each R 4a and R 4b is, independently, Ci_ 6 alkyl; preferably Ci_ 4 alkyl, preferably, methyl, ethyl, or n-propyl;
  • R 5 is hydrogen or Ci_ 6 alkyl;
  • each R 6a and R 6b is, independently, hydrogen, aryl, or Het;
  • R 7 is Ci_ 6 alkyl
  • R 8 is Ci_ 6 alkyl optionally substituted with phenyl; or phenyl optionally substituted with one or two halo;
  • aryl as a group or part of a group is phenyl optionally substituted with one or two halo, Ci_ 6 alkyl, -OR 8 ;
  • Het is pyridinyl.
  • the present invention encompasses compounds of Formula (II-a) and (III-a).
  • preferred configuration has Formula (II-a),
  • the present invention encompasses compounds of Formula (II -b) and (III-b).
  • preferred configuration has Formula (II-b),
  • the present invention encompasses compounds of Formula (II-c) and (III-c).
  • preferred configuration has Formula (II-c),
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof wherein each X and Y is, independently, CH or N;
  • R 1 is hydrogen or hydroxy
  • R 3 is aryl; each R 4a and R 4b is, independently, Ci_ 6 alkyl; preferably each R 4a and R 4b is, independently, Ci_ 4 alkyl; more preferably each R 4a and R 4b is, independently,
  • R 5 is hydrogen or Ci_ 6 alkyl; preferably R 5 is hydrogen or Ci_ 4 alkyl; each R 6a and R 6b is, independently, hydrogen; Ci_ 6 alkyl optionally substituted with one or two substituents selected from -OR 8 ; aryl; or Het; R 7 is C i - 6 alkyl; preferably R 7 is C i _ 4 alkyl;
  • Het is a group selected from tetrazolyl, pyridinyl, imidazolyl, benzo[d]isoxazolyl, oxazolyl, isoxazolyl, thiophenyl, tetrahydrothiophenyl, imidazolyl, thiazolyl, isothiazolyl, tetrahydrothieno[3,4-d]-2-oxo-imidazolyl, or imidazo[l,2-b]isothiazolyl, each group being optionally substituted with one or two substituents each independently selected from the group consisting of halo, oxo, cyano, or Ci_ 6 alkyl.
  • compounds of Formula I or any subgroup thereof that in the inhibition assays described below have an inhibition value of less than 100 ⁇ M, preferably less than 50 ⁇ M, more preferably less than 10 ⁇ M, preferably less than 5 ⁇ M, even more preferably less than l ⁇ M preferably less than 100 nM, and in particular less than 10 nM, as determined by a suitable assay, such as the assays used in the Examples below.
  • interesting compounds according to the present invention are compound nr. 20 , compound nr. 21 , compound nr. 14 , compound nr. 13 , compound nr. 11 , compound nr. 19 , compound nr. 22 , compound nr. 23 .
  • the amino nitroaryl (1-1) which is commercially available or can be synthesized following art-known procedures, is submitted to a hydrogenation to reduce the nitro moiety to amino.
  • the hydrogenation is carried out with a suitable catalyst, and in a solvent.
  • the nitro group of 2-amino-3-nitrophenol (1-1) is reduced by a metal such as Iron and the like in presence of a source of hydrogen such as an ammonium, and acid or an alcohol.
  • the catalyst may be selected from palladium on charcoal, palladium acetate, palladium chloride, palladium hydroxide, or palladium hydroxide on charcoal.
  • the solvent may be selected from tetrahydrofuran (THF), methyltetrahydrofuran (MeTHF), (methyl)(isobutyl)ketone, Ci-4alcohol, dimethylformamide (DMF), methyl t-butylether (MTBE), toluene, or any mixture thereof.
  • Intermediate (1-4) may then be reacted with an aldehyde of formula R 3 -CHO (1-6). Such reaction occurs in the presence of an acid, such as acetic acid, and in an appropriate solvent.
  • an acid such as acetic acid
  • Step 1-8 -> 1-9 Protection of the hydroxyl group of compound of formula (1-8) may be performed in order to introduce the R 2 -sulfonyl substituent, thereby yielding intermediate (1-9) wherein PG represents a protecting group.
  • Protection of the hydroxy group may be performed with benzyl or substituted benzyl ethers, e.g. 4-methoxybenzyl ether, benzoyl or substituted benzoyl esters, e.g. 4-nitrobenzoyl ester, or with trialkylsilyl groups (e.g. trimethylsilyl or tert-butyi- dimethylsilyl).
  • benzyl or substituted benzyl ethers e.g. 4-methoxybenzyl ether
  • benzoyl or substituted benzoyl esters e.g. 4-nitrobenzoyl ester
  • trialkylsilyl groups e.g. trimethylsilyl or tert-butyi- dimethylsilyl
  • a base such as an alkali or alkaline metal hydride such as LiH or sodium hydride, or alkali metal alkoxide such as sodium or potassium methoxide or ethoxide, potassium te/t-butoxide, optionally in an inert solvent like a dipolar aprotic solvent, e.g. DMA, DMF, THF, and the like.
  • Intermediate (I- 11) is further reacted with an alkali metal hydroxide (LiOH, NaOH, KOH), in an aqueous medium comprising water and a water-soluble organic solvent such as an alkanol (methanol, ethanol) and THF.
  • an alkali metal hydroxide LiOH, NaOH, KOH
  • an aqueous medium comprising water and a water-soluble organic solvent such as an alkanol (methanol, ethanol) and THF.
  • a water-soluble organic solvent such as an alkanol (methanol, ethanol) and THF.
  • the compounds of formula (I) may be converted to the corresponding JV-oxide forms following art-known procedures for converting a trivalent nitrogen into its iV-oxide form.
  • Said JV-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide.
  • Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide;
  • appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarbo- peroxoic acid or halo substituted benzenecarboperoxoic acid, e.g.
  • Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
  • Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g., counter-current distribution, liquid chromatography and the like.
  • the compounds of formula (I) may be obtained as racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
  • the racemic compounds of formula (I), which are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid.
  • An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemical ⁇ isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • said compound may be synthesized by stereospecific methods of preparation. These methods may advantageously employ enantiomerically pure starting materials.
  • the present invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as specified herein, or a compound of any of the subgroups of compounds of formula (I) as specified herein, and a pharmaceutically acceptable carrier.
  • a therapeutically effective amount in this context is an amount sufficient to prophylactically act against, to stabilize or to reduce viral infection, and in particular HCV viral infection, in infected subjects or subjects being at risk of being infected.
  • this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of formula (I), as specified herein, or of a compound of any of the subgroups of compounds of formula (I) as specified herein.
  • compositions of the present invention may be formulated into various pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of the particular compound, optionally in salt form or metal complex, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
  • the compounds of the present invention may also be administered via oral inhalation or insufflation by means of methods and formulations employed in the art for administration via this way.
  • the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder, a solution being preferred. Any system developed for the delivery of solutions, suspensions or dry powders via oral inhalation or insufflation are suitable for the administration of the present compounds.
  • the present invention also provides a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
  • the compounds of the present invention are administered via inhalation of a solution in nebulized or aerosolized doses.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • Viral infections and their associated diseases treatable using the compounds and methods of the present invention include those infections brought on by HCV and other pathogenic flaviviruses such as Yellow fever, Dengue fever (types 1-4), St. Louis encephalitis, Japanese encephalitis, Murray valley encephalitis, West Nile virus and Kunjin virus.
  • the diseases associated with HCV include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and HCC; and for the other pathogenic flaviviruses the diseases include yellow fever, dengue fever, hemorrhagic fever and encephalitis.
  • the compounds of formula (I) or any subgroup thereof, their prodrugs, //-oxides, salts, quaternary amines, metal complexes and stereochemically isomeric forms are useful in the treatment of individuals experiencing a viral infection, particularly a HCV infection, and for the prophylaxis of these infections.
  • the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses, in particular flaviviruses such as HCV.
  • the compounds of the present invention or any subgroup thereof may therefore be used as medicines.
  • Said use as a medicine or method of treatment comprises the systemic administration to virally infected subjects or to subjects susceptible to viral infections of an amount effective to combat the conditions associated with the viral infection, in particular the HCV infection.
  • the present invention also relates to the use of the present compounds or any subgroup thereof in the manufacture of a medicament for the treatment or the prevention of viral infections, particularly HCV infection.
  • the present invention furthermore relates to a method of treating a warm-blooded animal infected by a virus, or being at risk of infection by a virus, in particular by HCV, said method comprising the administration of an anti- virally effective amount of a compound of formula (I), as specified herein, or of a compound of any of the subgroups of compounds of formula (I), as specified herein.
  • the present invention also concerns combinations of a compound of formula (I) or any subgroup thereof, as specified herein with other anti-HCV agents.
  • the invention concerns combination of a compound of Formula (I) or any subgroup thereof with at least one anti-HCV agent.
  • the invention concerns combination of a compound of Formula (I) or any subgroup thereof with at least two anti-HCV agents.
  • the invention concerns combination of a compound of Formula (I) or any subgroup thereof with at least three anti-HCV agents.
  • the invention concerns combination of a compound of Formula (I) or any subgroup thereof with at least four anti-HCV agents.
  • combination of previously known anti-HCV compound such as, for instance, interferon- ⁇ (IFN- ⁇ ), pegylated interferon- ⁇ , ribavirin or a combination thereof, and a compound of formula (I) can be used as a medicine in a combination therapy.
  • the term "combination therapy” relates to a product containing mandatory (a) a compound of formula (I), and (b) at least one other anti-HCV compound, as a combined preparation for simultaneous, separate or sequential use in treatment of HCV infections, in particular, in the treatment of infections with HCV.
  • Anti-HCV compounds encompass agents selected from HCV polymerase inhibitors, R-7128, MK-0608, VCH759, PF-868554, GS9190, NM283, valopicitabine, PSI-6130, XTL-2125, NM-107, R7128 (R4048), GSK625433, R803, R-1626, BILB-1941, HCV- 796, JTK-109 and JTK-003, benzimidazole derivatives, benzo-l,2,4-thiadiazine derivatives, phenylalanine derivatives, A-831 and A-689; HCV proteases (NS2-NS3 and NS3-NS4A) inhibitors, the compounds of WO02/18369 (see, e.g., page 273, lines 9-22 and page 274, line 4 to page 276, line 11), BI-1335, TMC435350, MK70009, ITMN-191, BILN-2061, VX-950, BILN-2065, BMS
  • VX-944 drugs for treating HCV such as zadaxin, nitazoxanide, BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA-971, NOV-205, tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab, and Oglufanide; or combinations of any of the above.
  • drugs for treating HCV such as zadaxin, nitazoxanide, BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA-971, NOV-205, tarvacin, E
  • the compounds of formula (I) may be co-administered in combination with for instance, interferon- ⁇ (IFN- ⁇ ), pegylated interferon- ⁇ , ribavirin or a combination thereof, as well as therapeutics based on antibodies targeted against HCV epitopes, small interfering RNA (si RNA), ribozymes, DNAzymes, antisense RNA, small molecule antagonists of for instance NS3 protease, NS3 helicase and NS5B polymerase.
  • IFN- ⁇ interferon- ⁇
  • pegylated interferon- ⁇ ribavirin or a combination thereof
  • therapeutics based on antibodies targeted against HCV epitopes small interfering RNA (si RNA), ribozymes, DNAzymes, antisense RNA, small molecule antagonists of for instance NS3 protease, NS3 helicase and NS5B polymerase.
  • si RNA small interfering RNA
  • the combinations of the present invention may be used as medicaments. Accordingly, the present invention relates to the use of a compound of formula (I) or any subgroup thereof as defined above for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV viruses, wherein said medicament is used in a combination therapy, said combination therapy preferably comprising a compound of formula (I) and at least one other HCV inhibitory compound, e.g. IFN- ⁇ , pegylated IFN- ⁇ , ribavirin or a combination thereof.
  • a compound of formula (I) or any subgroup thereof as defined above for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV viruses, wherein said medicament is used in a combination therapy, said combination therapy preferably comprising a compound of formula (I) and at least one other HCV inhibitory compound, e.g. IFN- ⁇ , pegylated IFN- ⁇ , ribavirin or a combination thereof.
  • HIV infection appears to adversely affect all stages of HCV infection, leading to increased viral persistence and accelerated progression of HCV-related liver disease.
  • HCV infection may affect the management of HIV infection, increasing the incidence of liver toxicity caused by antiviral medications.
  • the present invention therefore also concerns combinations of a compound of Formula (I) or any subgroup thereof with anti-HIV agents. Also, the combination of one or more additional anti-HIV compounds and a compound of Formula (I) can be used as a medicine.
  • combination therapy also encompasses a product comprising (a) a compound of Formula (I) or any subgroup thereof, and (b) at least one anti-HIV compound, and (c) optionally at least one other anti-HCV compound, as a combined preparation for simultaneous, separate or sequential use in treatment of HCV and HIV infections, in particular, in the treatment of infections with HCV and HIV.
  • the present invention also relates to a product containing (a) at least one compound of Formula (I) or any subgroup thereof, and (b) one or more additional anti- HIV compounds, as a combined preparation for simultaneous, separate or sequential use in anti-HCV and anti-HIV treatment.
  • the different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
  • Said other anti- HIV compounds may be any known antiretroviral compounds such as suramine, pentamidine, thymopentin, castanospermine, dextran (dextran sulfate), foscarnet- sodium (trisodium phosphono formate); nucleoside reverse transcriptase inhibitors (NRTIs), e.g.
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • NcRTIs nucleotide-competing reverse transcriptase inhibitors
  • TAT-inhibitors e.g. RO-5-3335, BI-201, and the like
  • REV inhibitors e.g. RO-5-3335, BI-201, and the like
  • protease inhibitors e.g.
  • RTV ritonavir
  • SQV saquinavir
  • ABT-378 or LPV lopinavir
  • IDV indinavir
  • amprenavir VX-478
  • TMC126 nelfmavir
  • BMS 232,632 darunavir
  • TMC 114 fosamprenavir
  • entry inhibitors which comprise fusion inhibitors (e.g. enfuvirtide (T-20)), attachment inhibitors and co-receptor inhibitors, the latter comprise the CCR5 antagonists (e.g. ancriviroc, CCR5mAb004, maraviroc (UK-427,857), PRO-140, TAK-220, TAK-652, vicriviroc (SCH-D, SCH-417,690)) and CXR4 antagonists (e.g.
  • entry inhibitors are PRO-542, TNX-355, BMS-488,043, BlockAide/CRTM, FP 21399, hNMOl, nonakine, VGV-I; a maturation inhibitor for example is PA-457; inhibitors of the viral integrase e.g. raltegravir (MK-0518), elvitegravir (JTK-303, GS-9137), BMS-538,158; ribozymes; immunomodulators; monoclonal antibodies; gene therapy; vaccines; siRNAs; antisense RNAs; microbicides; Zinc-finger inhibitors.
  • compositions may be formulated into suitable pharmaceutical dosage forms such as the dosage forms described above.
  • Each of the active ingredients may be formulated separately and the formulations may be co-administered or one formulation containing both and if desired further active ingredients may be provided.
  • composition is intended to encompass a product comprising the specified ingredients, as well as any product that results, directly or indirectly, from the combination of the specified ingredients.
  • therapeutically effective amount means that amount of active compound or component or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought, in the light of the present invention, by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated. Since the instant invention refers as well to combinations comprising two or more agents, the "therapeutically effective amount” in the context of combinations is also that amount of the agents taken together so that the combined effect elicits the desired biological or medicinal response.
  • the therapeutically effective amount of a composition comprising (a) the compound of formula (I) and (b) another anti-HCV agent, would be the amount of the compound of formula (I) and the amount of the other anti-HCV agent that when taken together have a combined effect that is therapeutically effective.
  • an antiviral effective daily amount would be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
  • the exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.
  • an article of manufacture comprising a composition effective to treat an HCV infection or to inhibit the NS5B polymerase of HCV; and packaging material comprising a label which indicates that the composition can be used to treat infection by the hepatitis C virus; wherein the composition comprises a compound of the formula (I) or any subgroup thereof, or the combination as described herein.
  • kits or containers comprising a compound of the formula (I) or any subgroup thereof, in an amount effective for use as a standard or reagent in a test or assay for determining the ability of potential pharmaceuticals to inhibit HCV NS5B polymerase, HCV growth, or both.
  • This aspect of the invention may find its use in pharmaceutical research programs.
  • the compounds and combinations of the present invention can be used in high- throughput target-analyte assays such as those for measuring the efficacy of said combination in HCV treatment.
  • Example 1 ./V-(Yl l-(4-(benzyloxy)-2-chloro-phenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo
  • Step 5 Synthesis of l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzo[ ⁇ ,e][l,4]diazepin-l-one (8).
  • Example 2 [1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor&, el [1, 41 diazepine-10-sulfonvH acetic acid (13).
  • Example 4 2-[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1 ,2,3 ,4,5 , 11 -hexahydro-dibenzo
  • Example 5 3-[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[ ⁇ ,el[l,41diazepine-10-sulfonyl1propionic acid methyl ester (17).
  • Example 6 propane-2-sulfonic acid ⁇ 2-[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy- 3,3-dimethyl-l-oxo-l,2,3,4,5,l l-hexahvdrodibenzor ⁇ ,eiri,41diazepine-10-sulfonyll- acetyll amide (18) and l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-10-methane- sulfonyl-3, 3-dimethyl-2, 3,4,5, 10,11-hexahvdrodibenzor ⁇ , el [l,41diazepin-l -one (19).
  • CDI l,l'-carbonyldiimidazole; 54 mg, 0.335 mmol
  • isopropyl- sulfonamide 55 mg, 0.447 mmol
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene; 67 ⁇ L, 0.447 mmol
  • the compounds of formula (I) were examined for inhibitory activity of HCV RNA replication in a cellular assay.
  • the assay demonstrated that the compounds of formula (I) inhibited a HCV functional cellular replicating cell line, also known as HCV replicons.
  • the cellular assay was based on a bicistronic expression construct, as described by Lohmann et al. (1999) Science vol. 285 pp. 110-113 with the modifications described by Krieger et al. (2001) Journal of Virology 75: 4614-4624, in a multi-target screening strategy. In essence, the method was as follows: The assay utilized the stably transfected cell line Huh-7 luc/neo (hereafter referred to as Huh-Luc).
  • This cell line harbors an RNA encoding a bi-cistronic expression construct comprising the wild type NS3-NS5B regions of HCV type Ib translated from an Internal Ribosome Entry Site (IRES) from encephalomyocarditis virus (EMCV), preceded by a reporter portion (FfL- luciferase), and a selectable marker portion (neo R , neomycine phosphotransferase). The construct is bordered by 5' and 3' NTRs (non-translated regions) from HCV type Ib.
  • G418 neo R
  • the stably transfected replicon cells that express HCV RNA which replicates autonomously and to high levels, encoding inter alia luciferase, are used for screening the antiviral compounds.
  • the replicon cells were plated in 384-well plates in the presence of the test and control compounds which were added in increasing concentrations. Following an incubation of three days, HCV replication was measured by assaying luciferase activity (using standard luciferase assay substrates and reagents and a Perkin Elmer ViewLuxTM ultraHTS microplate imager). Replicon cells in the control cultures have high luciferase expression in the absence of any inhibitor. The inhibitory activity of the compounds was monitored on the Huh-Luc cells, enabling a dose-response curve to be generated for each test compound. EC50 values were then calculated, which value represents the amount of the compound required to decrease by 50% the level of detected luciferase activity, or more specifically, the ability of the genetically linked HCV replicon RNA to replicate.
  • NS5B amino acid 1-570 (HC-J4, genotype Ib, pCV-J4L6S, genebank accession number AF054247) was subcloned into the Nhe I and Xho I restriction sites of pET-21b. Expression of the subsequent His-tagged C-terminal 21 amino acid deleted NS5B was performed as follows:
  • the NS5B expression construct was transformed into E. coli BL21(DE3) (Novagen, Madison, WI). Five milliliter of LB-medium supplemented with ampicillin (50 ⁇ g/mL) was inoculated with one colony. When the pre-culture reached an optical density of 0.6 measured at 600 nm, it was transferred to fresh LB-medium supplemented with ampicillin, at a ratio of 1 :200.
  • Cells were grown to an optical density at 600 nm of 0.6, after which the expression cultures were shifted to a growth temperature of 20 0 C following induction with ispopropyl-1-thio- ⁇ -D-galactopyranoside and MgCl 2 at a final concentration of 0.4 mM and 10 ⁇ M, respectively. After ten hours of induction, cells were harvested by centrifugation and resuspended in 20 mM Tris-HCl, pH 7.5, 300 mM NaCl, 10% glycerol, 0.1% NP40, 4 mM MgCl 2 , 5 mM DTT supplemented with EDTA-free Complete Protease Inhibitor (Roche, Basel, Switzerland).
  • HCV NS5B polymerization activity was performed by evaluating the amount of radiolabeled GTP incorporated by the enzyme in a newly synthesized RNA using heteropolymeric RNA template/primer.
  • the RdRp assay was carried out in 384-well plates using 50 nM enzyme, 300 nM 5'-biotinylated oligo(rGi3)/poly(rC) primer-template, 600 nM of GTP, and 0.1 ⁇ Ci of [ 3 H]GTP in 25 mM Tris-HCl, pH 7.5, 5 mM MgCl 2 , 25 mM KCl, 17 mM NaCl and 3 mM of DTT. Test compounds were dissolved in DMSO.
  • test compounds were added to the preformed polymerase- template complex, and incubated at room temperature for 15 min before the addition of NTPs.
  • the 30 ⁇ l reaction was terminated after 2h at 25°C upon addition of 30 ⁇ l streptavidin-coated SPA beads (GE Heathcare, Uppsala, Sweden 5 mg/ml in 0.5 M EDTA).
  • streptavidin-coated SPA beads GE Heathcare, Uppsala, Sweden 5 mg/ml in 0.5 M EDTA.
  • the plate was counted using a Packard TopCount microplate reader (30 sec/well, 1 min count delay) and IC50 values were calculated.
  • IC50 values represent the concentration of compound required to decrease by 50% the amount of RNA produced which is measured by the detection of incorporated radiolabeled GTP.
  • Table 1 lists compounds that were prepared according to any one of the above examples. The activities of the compounds tested are also depicted in Table 1. Table 1

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Abstract

L'invention porte sur des inhibiteurs de réplication du VHC de formule (I) et les stéréoisomères, les promédicaments, les tautomères, les racémiques, les sels, les hydrates ou les solvates de ceux-ci. Dans la formule, X, Y, R1 ; R2 ; R3 ; R4a et R4b ont la signification définie dans les revendications. La présente invention porte également sur des procédés de préparation desdits composés, sur des compositions pharmaceutiques les contenant et sur leur utilisation en thérapie du VHC.
PCT/EP2008/051905 2007-02-16 2008-02-15 10-sulfonyl-dibenzodiazépinones utiles comme inhibiteurs du virus de l'hépatite c Ceased WO2008099022A1 (fr)

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US9044482B2 (en) 2012-08-15 2015-06-02 Asana Biosciences, Llc Use of aminoindane compounds in treating overactive bladder and interstitial cystitis

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8865741B2 (en) 2011-02-18 2014-10-21 Asana Biosciences, Llc Aminoindane compounds and use thereof in treating pain
US9044482B2 (en) 2012-08-15 2015-06-02 Asana Biosciences, Llc Use of aminoindane compounds in treating overactive bladder and interstitial cystitis
US9375423B2 (en) 2012-08-15 2016-06-28 Asana Biosciences, Llc Use of aminoindane compounds in treating overactive bladder and interstitial cystitis

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