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WO2009120783A1 - Inhibiteurs à haute affinité de protéase ns3/4a du virus de l'hépatite c - Google Patents

Inhibiteurs à haute affinité de protéase ns3/4a du virus de l'hépatite c Download PDF

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Publication number
WO2009120783A1
WO2009120783A1 PCT/US2009/038253 US2009038253W WO2009120783A1 WO 2009120783 A1 WO2009120783 A1 WO 2009120783A1 US 2009038253 W US2009038253 W US 2009038253W WO 2009120783 A1 WO2009120783 A1 WO 2009120783A1
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compound according
formula
hcv
group
compound
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Ernesto Freire
Rogelio Siles
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Johns Hopkins University
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Johns Hopkins University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom

Definitions

  • the present invention relates to the hepatitis C virus and more particularly to methods and compositions that inhibit the hepatitis C virus (HCV) life cycle such as low molecular weight compounds that inhibit the HCV NS3/4A protease.
  • HCV hepatitis C virus
  • HCV infection represents an increasingly important global health-problem.
  • HCV infection is responsible for ⁇ 65% of all cases ' of liver cancer and accounts for ⁇ 70% of all liver transplants.
  • Genotype 1 is the most prevalent and most difficult to treat viral strain in Europe and North America, and represents the greatest unmet treatment need.
  • Genotypes 2 and 3 appear to be more prevalent in the Far East.
  • genotype 4 is common in Africa and the Middle East, whereas genotypes 5 and 6 are predominant in South Africa and South-East Asia, respectively.
  • HCV HCV
  • STAT-C specifically targeted antiviral therapy for HCV
  • Potential processes for viral inhibition include virus entry into the host cell, proteolytic processing, RNA replication, and the assembly and release of the new virions.
  • protease and polymerase inhibitors are the most promising new agents in development.
  • HCV NS3/4A protease consists of the protease domain of the viral NS3 protein which gets activated when bound to the NS4A polypeptide.
  • the structure of the protease is shown in panel B of Fig. 1.
  • the active NS3/4A is a serine protease that plays an essential role in the processing and maturation of the non- structural proteins in the virus, and is an important target for drug therapy.
  • NS indicates non-structural proteins
  • S represents structural proteins
  • items 1, 2, 3, and 4 represent places of cleavage promoted by the NS3 protease.
  • HCV NS3/4A protease is one of the most important targets for drug development against HCV. Pharmaceutical companies are spending significant efforts in developing potent HCV NS3/4A protease inhibitors which can be administered alone, in combination with NS5B polymerase inhibitors, other antivirals, or other pharmaceutical or medical modality.
  • the non-structural protein NS3 possesses a protease domain that is responsible for polyprotein processing and is a potential target for antiviral intervention.
  • a protease domain that is responsible for polyprotein processing and is a potential target for antiviral intervention.
  • the catalytic site being a shallow and largely hydrophobic groove, making it difficult to target, several compound inhibitors of the NS3 protease have been designed, for example, TelaprevirTM (VX-950), BoceprevirTM (SCH 503034), BIl 2202, MK-7009, TMC435350 and 1TMN-191.
  • telaprevirTM VX-950
  • BoceprevirTM SCH 503034
  • ITMN-191TM from Intermune/Roche are undergoing clinical trials.
  • the structures of these three HCV NS3/4A protease inhibitors are shown in Fig. 2.
  • the proof-of principle for this class of HCV NS3/4A protease inhibitor compounds was provided by BILN 2061.
  • BILN 2061 provides at least a 2-3 Iogio decrease in HCV load within 48 hours.
  • the structure of BILN 2061 is set forth in Fig. 2. However, the clinical development of BILN 2061 was stopped owing to significant side effects. .
  • This invention relates to inhibitors of the HCV NS3/4A protease.
  • these inhibitors are used in therapies that are specific and effective against HCV disease; these therapies may have low side effect and toxicity profiles.
  • Embodiments include compounds of Formula I, shown below, that inhibit the HCV NS3/4A protease (NS3/4A inhibitors).
  • X is Ar o CH Ar, wherein Ar is aryl or heteroaryl, either of which may be further substituted by one or more wherein is independently selected from the group consisting of ( alkyl, )alkoxy, haloalkyl, )hydroxyalkyl, halogen, and - are each independently hydrogen or (Ci-C 6 )alkyl; and R 1 5 is -CN or -
  • compositions comprising these compounds and one or more pharmaceutical excipients.
  • compositions comprising a compound of
  • compositions or agents to a subject that is infected with HCV.
  • the HCV-infectcd subject thereby achieves a therapeutic benefit.
  • the compositions or agents may be administered orally.
  • HCV NS3/4A protease consists of the protease domain of the viral NS3 protein which gets activated when bound to the NS4A polypeptide.
  • Figure 2 Structures of HCV NS3/4A protease inhibitors BILN-2061 ; telaprevir; boceprevir; and ITMN-191.
  • Figure 3 Exemplary compounds according to Formula VH.
  • Figure 4 Exemplary compounds according to Formulas X and XI.
  • Figure 5 Diagramatic scheme for chemical synthesis of compounds according to
  • Figure 6 Diagramatic scheme for chemical synthesis of exemplary compound RS-
  • Figure 7 Diagramatic scheme for chemical synthesis of compounds according to
  • Figure 8 Diagramatic scheme for chemical synthesis of compounds according to
  • Figure 10 Chemical structure of exemplary compound RS-2-19.
  • agent is a non-peptide, small molecule compound according to the invention.
  • analog is meant an agent having structural or functional homology to a reference agent.
  • cell substrate is meant the cellular or acellular material (e.g., extracellular matrix, polypeptides, peptides, or other molecular components) that is in contact with the cell.
  • cellular or acellular material e.g., extracellular matrix, polypeptides, peptides, or other molecular components
  • control is meant a standard or reference condition.
  • disease is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, organ or subject.
  • effective amount is meant the amount of an agent required to ameliorate the symptoms of a disease relative to an untreated subject.
  • the effective amount of an active therapeutic agent for the treatment of a disease or injury varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending clinician will decide the appropriate amount and dosage regimen.
  • modifies is meant alters.
  • an agent that modifies a cell, substrate, or cellular environment produces a biochemical alteration in a component (e.g., polypeptide, nucleotide, or molecular component) of the cell, substrate, or cellular environment.
  • a component e.g., polypeptide, nucleotide, or molecular component
  • the terms "prevent,” “preventing,” “prevention,” “prophylactic treatment” and the like refer to reducing the probability of developing a disorder or condition in a subject, who does not have, but is at risk of or susceptible to developing a disorder or condition.
  • a “prodrug” is a pharmacologically inactive compound that is converted into a pharmacologically active agent by a metabolic transformation.
  • subject is meant a mammal, including, but not limited to, a human or non- human mammal, such as a bovine, equine, canine, ovine, or feline.
  • therapeutic delivery device any device that provides for the release of a therapeutic agent.
  • exemplary therapeutic delivery devices include osmotic pumps, indwelling catheters, delayed-release and sustained-release biomaterials.
  • the terms “treat,” treating,” “treatment,” “therapeutic” and the like refer to reducing or ameliorating a disorder and/or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.
  • variant is meant an agent having structural homology to a reference agent/compound but varying from the reference in its biological activity. For example, variants can comprise optimized amino acid and nucleic acid sequences that are selected using the methods described herein as having one or more desirable characteristics.
  • One embodiment includes compounds having the Formula I shown below
  • R 1 , R" and R" 1 are each independently selected from the group consisting of hydrogen, ydroxyalkyl, halogen, independently 1, 2, 3, 4, or 5;
  • X is -Ar Or -CH 2 -Ar, wherein Ar is aryl or heteroaryl, either of which may be further substituted by one or more Ri 6 , wherein Ri 6 is independently selected from the group consisting o C 6 )hydroxyalkyl, halogen and - are each independently hydrogen or - .
  • substituents R', R", and R"' include H C(CH ) Cl B CH - - .
  • n is greater than 1, the substituents may be the same or different, and may be located at any position on the ring.
  • the terms "alkyl”, “alkoxy”, “hydroxyalkyl”, “alkoxyalkyl”, and “alkoxycarbonyl”, used alone or as part of a larger moiety include both straight and branched chains containing one to four carbon atoms, as well as cyclic structures such as cyclopropyl and cyclobutyl.
  • alkyl groups include methyl (Me), ethyl (Et), propyl (Pr) (including n-propyl ( n Pr or n-Pr), isopropyl ( 1 Pr or i-Pr) and cyclopropyl ( c Pr or C-Pr)), butyl (Bu) (including n-butyl ("Bu or n-Bu), isobutyl ( 1 Bu or i-Bu), tert-butyl ( 1 Bu or t-Bu) and cyclobutyl ( c Bu or C-Bu)) and so forth.
  • alkoxy refers to an -O-alkyl radical.
  • haloalkyl means alkyl, substituted with one or more halogen atoms, such as trifiuoromethyl.
  • halogen or “halo” means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety, refers to mono-, bi-, or tricyclic aromatic hydrocarbon ring systems having five to fourteen members, such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl.
  • aryl also refers to rings that are optionally substituted by R) 6 , defined previously.
  • aryl may be used interchangeably with the term “aryl ring”.
  • Aryl also includes fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Examples include 1- naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scope of the term "aryl”, as it is used herein, is a group in which an aromatic ring is fused to one or more non- aromatic rings, such as in an indanyl, phenanthridinyl or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.
  • heteroaryl used alone or as part of a larger moiety, refers to heteroaromatic ring groups having five to fourteen members, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S.
  • heteroaryl rings examples include 2-furanyl, 3-furanyl, N-imidazolyl, 2- imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyr ⁇ olyl, 2-pyrrolyl, 3- pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2- ⁇ yridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2- triazolyl, S-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benz
  • heteroaryl is a group in which a heteroaromatic ring is fused to one or more aromatic or nonaromatic rings where the radical or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyridof3,4-d]pyrimidinyl.
  • heteroaryl also refers to rings that are optionally substituted by Ri 6 , defined above.
  • the term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.
  • heteroaryoaralkyl refers to an alkyl group substituted by a heteroaryl.
  • FORMULA II wherein are each independently selected from the group consisting of hydrogen, )hydroxyalkyl, halogen and - n is independently 1, 2, 3, 4, or 5. Further embodiments include compounds according to Formula II, where (R')n and (R'") n are the same, as shown by Formula III below.
  • R' and R" are each independently selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, (C
  • n is independently 1, 2, 3, 4, or 5.
  • Ar is aryl or heteroaryl, either of which may be further substituted by one or more wherein is independently selected from the group consisting of ( ] 6 )alkyl, ( )alkoxy, ( i 6)haloalkyl, C 6 )hydroxyalkyl, halogen, and - N and are each independently hydrogen or ( J lkyl; and CN or -
  • X is -Ar or -CH 2 -Ar, wherein Ar is aryl or heteroaryl, either of which may be further substituted by one or more wherein is independently selected from the group consisting o C 6 )hydroxyalkyl, halogen, , and - 9 are each independently hydrogen or (Ci-C6)alkyl; and
  • Ri 5 is -CN or -
  • a further embodiment includes compounds according to Formula V where Y is -
  • CH-CH- and X is -Ar.
  • Ri-R 9 arc each independently selected from the group consisting of hydrogen, (C r C 6 )alkyl, (C,-C 6 )alkoxy, (C
  • R9 are all hydrogen, and at least one of R 1 and R 5 is not H.
  • One specific embodiment includes compounds RS-2-5 and RS-2-19, shown below.
  • One specific embodiment according to Formula VIII includes the compound RS- 4-2Pl, shown below.
  • R I0 -R M are each independently selected from the group consisting of hydrogen, (C]-C 6 )alkyl, (C
  • R IO -R M are each independently selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, (C
  • X is -Ar.
  • R ⁇ o-Ri4 are each independently selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, (d-C 6 )alkoxy, (Ci-C 6 )haloalkyl, (d-C 6 )hydroxyalkyl, halogen, -NR 17 Ri 8 , -COH, -CO 2 Ri 9 , -CONR 17 Ri 8 , -OH, -CN, -CF 3 , and -NO 2 ;
  • R 15 is -CN or -CO 2 R 19 ;
  • X is -Ar or -CH 2 -Ar, wherein Ar is aryl or heteroaryl, cither of which may be further substituted by one or more Ri 6 , wherein R
  • Further embodiments include compounds of Formulas IX, X and XI, where at least one of R 13 and R ⁇ is not hydrogen.
  • Further embodiments include compounds of Formulas IX, X and XI, where at least one of Rio. Rn, and Ri 2 is not hydrogen.
  • Further embodiments include compounds of Formulas IX, X and XI 1 where Ar is phenyl, pyridyl, thiophenyl, thiazolyl, indolyl, pyrrolyl, furanyl, or bezothiazolyl. [0069] Further embodiments include compounds of Formulas IX, X and XI, where Ar is one of the structures shown below:
  • R ⁇ is independently selected from the group consisting of (C ⁇ -C6)alkyl, (Ci- C 6 )alkoxy, (Ci-C 6 )haloalkyl, (C
  • the compounds of the present invention may have an IC 50 against Heptatitis C Virus NS3/4A Protease of equal to or less than 50 ⁇ M. In certain embodiments the compounds may have an ICsoof 25 ⁇ M or less, 10 ⁇ M or less, or 5 ⁇ M or less.
  • the compounds may be synthesized, for example, according to the synthetic schemes shown in Fig. 5 and further exemplified in Fig. 6, 7, and 8.
  • Further embodiments include derivatives of the compounds, such as pharmaceutically acceptable salts, ether derivatives, ester derivatives, acid derivatives, and aqueous solubility altering derivatives of the active compound.
  • Derivatives include all individual enantiomers, diastereomers, racemates, and other isomers of the compounds.
  • Derivatives also include all polymorphs and solvates, such as hydrates and those formed with organic solvents, of these compounds. Such isomers, polymorphs, and solvates may be prepared by methods known in the art, such as by regiospecific and/or enantioselective synthesis and resolution.
  • Suitable salts of the compound include, but are not limited to, acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid; salts made with saccharin; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; and salts formed with
  • Additional suitable salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium cdetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt,
  • a further embodiment includes pharmaceutical compositions comprising the HCV
  • compositions may include one or more than one inhibitor, and may further contain other suitable substances and excipients, including but not limited to physiologically acceptable buffering agents, stabilizers (e.g. antioxidants), flavoring agents, agents to effect the solubilization of the compound, and the like.
  • physiologically acceptable buffering agents e.g. antioxidants
  • stabilizers e.g. antioxidants
  • flavoring agents agents to effect the solubilization of the compound, and the like.
  • the composition may be in any suitable form such as a solution, a suspension, an emulsion, an infusion device, or a delivery device for implantation or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use.
  • the composition may include suitable parenterally acceptable carriers and/or excipients.
  • the compositions may comprise an effective amount of an inhibitor in a physiologically-acceptable carrier.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for a particular route of administration. Suitable carriers and their formulation are described, for example, in Remington's Pharmaceutical Sciences by E. W. Martin.
  • the inhibitor may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition.
  • the composition may be provided in a dosage form that is suitable for parenteral (e.g., subcutaneously, intravenously, intramuscularly, or intraperitoneally) or oral administration route.
  • parenteral e.g., subcutaneously, intravenously, intramuscularly, or intraperitoneally
  • the pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
  • the compositions may be in a form suitable for administration by sterile injection.
  • a parenterally acceptable liquid vehicle water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution and dextrose solution.
  • the aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl or n-propyl p-hydroxybenzoate).
  • the carrier will usually comprise sterile water, though other ingredients, for example, ingredients that aid solubility or for preservation, may be included. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed.
  • Formulations suitable for parenteral administration usually comprise a sterile aqueous preparation of the inhibitor, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution).
  • Such formulations may include suspending agents and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • the formulations may be presented in unit-dose or multi-dose form.
  • Parenteral administration may comprise any suitable form of systemic delivery or localized delivery.
  • Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal (e.g., intraperitoneal), etc., and may be effected by infusion pumps (external or implantable) or any other suitable means appropriate to the desired administration modality.
  • the compositions may be in a form suitable for oral administration.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like.
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient as a powder or granules.
  • a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught.
  • Formulations for oral use include tablets containing active ingredient(s) in a mixture with pharmaceutically acceptable excipients. Such formulations are known to the skilled artisan.
  • Excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiad
  • a syrup may be made by adding the inhibitor to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s).
  • accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.
  • the composition may be in a form of nasal or other mucosal spray formulations (e.g. inhalable forms).
  • formulations comprise purified aqueous solutions of the active compounds with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes. Alternatively, they can be in the form of finely divided solid powders suspended in a gas carrier. Such formulations may be delivered by any suitable means or method, e.g., by nebulizer, atomizer, metered dose inhaler, or the like. (0088] In some embodiments, the composition may be in a form suitable for rectal administration. These formulations may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.
  • a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.
  • the composition may be in a form suitable for transdermal administration.
  • These formulations may be prepared by incorporating the active compound in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.
  • a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose
  • compositions of the invention may further include one or more accessory ingredient(s) selected from encapsulants, diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.
  • accessory ingredient(s) selected from encapsulants, diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.
  • compositions may be formulated for immediate release, sustained release, delayed-onset release or any other release profile known to one skilled in the art.
  • the pharmaceutical composition may be formulated to release the active compound substantially immediately upon administration or at any predetermined time or time period after administration.
  • controlled release formulations include (i) formulations that create a substantially constant concentration of the drug within the body over an extended period of time; (ii) formulations that after a predetermined lag time create a substantially constant concentration of the drug within the body over an extended period of time; (iii) formulations that sustain action during a predetermined time period by maintaining a relatively constant, effective level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active substance (sawtooth kinetic pattern); (iv) formulations that localize action by, e.g., spatial placement of a controlled release composition adjacent to or in the central nervous system or cerebrospinal fluid; (v) formulations that allow for convenient dosing, such that doses are administered, for example, once every one or two weeks; and (vi) formulations that target the site of
  • controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings.
  • the inhibitor is formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the inhibitor in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, molecular complexes, nanoparticles, patches, and liposomes.
  • the composition may comprise a "vectorized" form, such as by encapsulation of the inhibitor in a liposome or other encapsulate medium, or by fixation of the inhibitor, e.g., by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.
  • a suitable biomolecule such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.
  • the composition can be incorporated into microspheres, microcapsules, nanoparticles, liposomes, or the like for controlled release.
  • the composition may include suspending, solubilizing, stabilizing, pH-adjusting agents, tonicity adjusting agents, and/or dispersing, agents.
  • the inhibitor may be incorporated in biocompatible carriers, implants, or infusion devices.
  • Materials for use in the preparation of microspheres and/or microcapsules are, e.g., biodegradable/bioerodible polymers such as polygalactia poly-(isobutyl cyanoacrylate), poly(2-hydroxyethyl-L-glutamine) and, poly(lactic acid).
  • Biocompatible carriers that may be used when formulating a controlled release parenteral formulation are carbohydrates (e.g., dextrans), proteins (e.g., albumin), lipoproteins, or antibodies.
  • Materials for use in implants can be non-biodegradable (e.g., polydimethyl siloxane) or biodegradable (e.g., poly(caprolactone), poly(lactic acid), poly(glycolic acid) or poly(ortho esters) or combinations thereof).
  • biodegradable e.g., poly(caprolactone), poly(lactic acid), poly(glycolic acid) or poly(ortho esters) or combinations thereof.
  • compositions of all embodiments can comprise various pharmaceutically acceptable salts, ether derivatives, ester derivatives, acid derivatives, and aqueous solubility altering derivatives of the inhibitor.
  • Certain embodiments can comprise all individual enantiomers, diastereomers, racemates, and other isomer of compounds of the invention.
  • the invention also includes all polymorphs and solvates, such as hydrates and those formed with organic solvents, of this compound.
  • Such isomers, polymorphs, and solvates may be prepared by methods known in the art, such as by regiospecific and/or enantioselective synthesis and resolution, based on the disclosure provided herein.
  • Suitable salts of the compound include, but are not limited to, acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid; salts made with saccharin; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; and salts formed with
  • Additional suitable salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylatc, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate,.napsylate, nitrate, N-methylglucamine ammonium salt
  • a further embodiment includes methods for altering the physiology of a subject infected with HCV.
  • the method comprises administering a composition comprising a compound of Formula I to a subject that is infected with HCV.
  • a preparation comprising the inhibitor formulated for oral administration is orally given to a patient infected with HCV.
  • the preparation is administered such that the free concentration of inhibitor in serum is higher than the Ki (inhibition constant) of the inhibitor.
  • the free concentration of inhibitor in serum is 10 times the Ki. In another embodiment, the concentration of inhibitor in serum is sufficient to inhibit 90% or more of the protease molecules.
  • RS-2-5 is characterized by a Ki of 0.25 ⁇ M, and as such, a concentration of 3 ⁇ M inhibits 90% of the viral protease molecules.
  • the inhibitor is administered in combination with an antiviral agent that targets a different essential viral protein.
  • an antiviral agent that targets a different essential viral protein.
  • in combination means that they are administered concurrently or sequentially or a combination thereof.
  • Combination therapy targets inhibits or alters two or more aspects relevant to HCV lifecycle.
  • a composition according to the above embodiments that inhibits the NS3/4A protease, and a composition that targets NS5B polymerase are used in combination.
  • the NS5B polymerase is another viral protein essential for the viral life cycle.
  • HCV NS5B polymerase inhibitors are disclosed in the scientific literature.
  • the NS3/4A inhibitor, RS-2-19 is given in combination with a polymerase inhibitor.
  • the simultaneous inhibition of essential protein(s) accelerates viral killing and results in a drop in viral count of several orders of magnitude within one week.
  • the NS3/4A inhibitor according to the present invention may be administered in combination with other therapeutic agents.
  • the NS3/4A inhibitor, RS-2-19 may be administered in combination with pegylated interferon (peglFN- ⁇ ).
  • peglFN- ⁇ pegylated interferon
  • the compounds or compositions which are administered may be administered in any of many forms which are well-known to those of skill in the art. For example, they may be administered in any of a variety of art-accepted forms such as tablets, capsules, various injectable formulations, liquids for oral administration and the like, as suitable for the desired means of administration.
  • the preparation which is administered may include one or more than one inhibitory compound, and may further contain other suitable substances and excipients, including but not limited to physiological acceptable buffering agents, stabilizers (e.g. antioxidants), flavoring agents, agents to effect the solubilization of the compound, and the like.
  • Administration of the compounds may be effected by any of a variety of routes that are well-known to those of skill in the art, including but not limited to oral, parenteral, intravenously, via inhalation, and the like. Further, the compounds may be administered in conjunction with other appropriate treatment modalities, for example, with nutritional supplements, agents to reduce symptoms and treatment with other agents.
  • the compositions may be administered orally. Administration to human patients or other animals is generally carried out using a physiologically effective amount of a compound of the invention in a physiologically- acceptable carrier. Suitable carriers and their formulation are described, for example, in Remington's Pharmaceutical Sciences by E. W. Martin.
  • compositions may be administered systemically, for example, formulated in a pharmaceutically-acceptable buffer such as physiological saline.
  • routes of administration include, for example, subcutaneous, intravenous, intraperitoneally, intramuscular, or intradermal injections that provide continuous, sustained levels of the drug in the patient.
  • Administration to human patients or other animals is generally carried out using a physiologically effective amount of a compound of the invention in a physiologically- acceptable carrier. Suitable carriers and their formulation are described, for example, in Remington's Pharmaceutical Sciences by E. W. Martin.
  • compositions according to the invention may be provided in a form suitable for administration by sterile injection.
  • the compositions(s) are dissolved or suspended in a parenterally acceptable liquid vehicle.
  • acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution and dextrose solution.
  • the aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl or n-propyl p-hydroxybenzoate).
  • compositions may be provided in unit dosage forms (e.g., in single-dose ampules), or in vials containing several doses and in which a suitable preservative may be added.
  • a composition of the invention may be in any suitable form such as a solution, a suspension, an emulsion, an infusion device, or a delivery device for implantation or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use.
  • the composition may include suitable parenterally acceptable carriers and/or excipients.
  • the amount of the compound/agent to be administered varies depending upon the manner of administration, the age and body weight of the subject/patient, and with the subject's symptoms and condition.
  • compositions including biologically active fragments, variants, or analogs thereof can be administered by any suitable route including, but not limited to: oral, intracranial, intracerebral, intraventricular, intraperitoneal, intrathecal, intraspinal,, topical, rectal, transdermal, subcutaneous, intramuscular, intravenous, intranasal, sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, intraarticular, intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterille administration, and other dosage forms for systemic delivery of active ingredients.
  • the precise quantity of such a compound to be administered will vary from case to case, and is best determined by a skilled practitioner such as a physician.
  • the amount may vary based on several characteristics of the patient, e.g. age, gender, weight, overall physical condition, extent of disease, and the like.
  • the individual characteristics of the compound itself e.g. Ki, selectivity, ICso, solubility, bioavailability, and the like
  • Ki selectivity
  • ICso solubility
  • bioavailability bioavailability
  • the required amount will be such that the concentration of compound in the blood stream of the patient is about equal to or larger than the IC 50 or K, of the compound.
  • compositions may be administered parenterally by injection, infusion or implantation in dosage forms, formulations, or via suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and/or adjuvants.
  • the compositions are added to a retained physiological fluid, such as cerebrospinal fluid, blood, or synovial fluid.
  • the compositions of the invention can be amenable to direct injection, application or infusion at a site of disease or injury.
  • a composition of the invention is provided within an implant, such as an osmotic pump, or in a graft comprising appropriately transformed cells. Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • biocompatible polymers including hydrogels
  • biodegradable and non-degradable polymers can be used to form an implant for the sustained release of a bioactive factor at a particular target site.
  • the administration of a compound may be by any suitable means that results in a concentration of the compound that, combined with other components, is effective in preventing, diagnosing, prognosing, ameliorating, reducing, or stabilizing a deficit or disorder.
  • the amount of administered agent of the invention will be empirically determined in accordance with information and protocols known in the art. Often the relevant amount will be such that the concentration of compound in the blood stream of the patient is about equal to or larger than the IC50 or Kj of the compound. Typically agents are administered in the range of about 10 to 1000 ⁇ g/kg of the recipient. Other additives may be included, such as stabilizers, bactericides, and anti-fungals. These additives are present in conventional amounts.
  • kits for the treatment, diagnosis, prophylaxis or prognosis of disease or injury.
  • the kit includes a composition according to the above embodiments containing an effective amount of a compound according to the above embodiments in unit dosage form.
  • the kit comprises an outer container or package.
  • the kit can comprise a sterile container which contains the composition according to the above embodiments, such sterile containers can be boxes, ampules, bottles, vials, tubes, bags, pouches, blister-packs, or other suitable container forms known in the art.
  • Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding medicaments.
  • a composition according to the above embodiments is provided together with instructions for administering it to a subject.
  • Instructions may include information about the use and effects of the composition.
  • the instructions will include at least one of the following: description of composition of the invention, dosage schedule and administration protocols, precautions, warnings, indications, counter- indications, overdosage information, adverse reactions, animal pharmacology, clinical studies, and/or references.
  • the instructions may be printed directly on a container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, insert, or folder supplied in or with the container.
  • the instructions may be a separate item in the kit, or be imprinted, embossed, molded or otherwise affixed to another item in the kit; instructions may be printed on an outer container and also included as an insert item in the kit.
  • Ethencsulfonamide (RS-2-5): Compound 1 (140 mg, 0.6 mmol, 2 eq.) and 3- chlorobenzenamine (38.7 mg, 0.3 mmol, 1 eq.) were poured into a 50 mL round bottom flask and dissolved with 6 mL of acetonitrile. After all components were dissolved, TEA (0.1 mL, 0.66 mmol, 2.2 eq.) was added and the reaction mixture was stirred at RT for 12 h. Water was added and the solid formed was filtered and washed twice with AN. After drying the product, RS-2-5 (99.4 mg, 0.19 mmol) was obtained in 63% yield.
  • Fig. 7 As set forth in Fig. 7, the synthesis of compounds of Formula X starts with the reaction of substituted sulfonyl chlorides (for example, prepared according to step 1 of
  • Example 1 Example 1 and anilines.
  • the reaction is carried out in the presence of a lM-solution of sodium carbonate at the pH range of 6.5-7.0 for about 2h.
  • the aniline has
  • an amide intermediate is initially formed by treating compound 2 with NaH and, then this reactive intermediate is allowed to react with electrophile X-CH2-Br to form the final product.
  • exemplary compounds according to Formula XI is shown by example in Fig. 8.
  • the synthesis of compounds of Formula XI begins with the reaction of an aniline derivative with an ⁇ -cyano aldehyde (3) (prepared for example according to the methods described by Xiao et al. (Bioorganic & Medicinal Chemistry, vol. 15, no'. 12, pp. 4212-4219, 2007) or Du et al. (Organic Letters , vol. 8, no. 26, pp. 5919-5922, 2006) to form an enamine (4).
  • the enamine (4) is treated with NaH and then allowed to react with a sulfonyl chloride.
  • the sulfonyl chloride may be prepared for example according to step 1 of Example 1.
  • the synthesis of other embodied compounds follows the same process with different aldehydes, anilines, or sulfonyl chlorides.
  • Example 4 Inhibition of HCV NS3/4A Protease, determination of IC ⁇ [00139]
  • the HCV protease inhibition assay was performed using a commercially available fluorogenic 5-FAM/QXLTM520 FRET substrate pair (Ac-DE-Dap(QXL520)-EE- Abu- ⁇ -[COO]-AS-C(5-FAMsp)-NH2) purchased from ANASPEC, San Jose, CA.
  • the change in fluorescence intensity was monitored in a Cary Eclipse fluorescence spectrophotometer (Varian) with 490 and 520 nm for excitation and emission wavelengths respectively.
  • IC50 determination of compound RS-2-19 (Fig. 10) is shown in Fig. 9.
  • IC 50 values for exemplary compounds are shown in the following table.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des compositions et des utilisations de celles-ci qui inhibent le cycle de vie de VHC en inhibant l'action de la protéase NS3/4A de VHC. Un mode de réalisation comprend un composé appelé RS-2-19.
PCT/US2009/038253 2008-03-25 2009-03-25 Inhibiteurs à haute affinité de protéase ns3/4a du virus de l'hépatite c Ceased WO2009120783A1 (fr)

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WO2013056079A1 (fr) * 2011-10-13 2013-04-18 The Johns Hopkins University Inhibiteurs de bêta-lactamases à forte affinité
WO2013039985A3 (fr) * 2011-09-12 2013-06-27 The Johns Hopkins University Inhibiteurs de sérine protéase
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
EP2899207A1 (fr) 2014-01-28 2015-07-29 Amikana.Biologics Nouveau procédé pour tester l'inhibition de la protéase du HCV
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK
CN112174855A (zh) * 2020-11-16 2021-01-05 福州大学 一种磺酰氟类产物的制备方法
CN116444728A (zh) * 2023-04-20 2023-07-18 浙江南洋华诚科技有限公司 一种风电电容器高耐压高耐温薄膜及其制备方法

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US20050043364A1 (en) * 2003-08-11 2005-02-24 Kennedy Robert Michael Novel pyrrole-based HMG-CoA reductase inhibitors
WO2005097773A1 (fr) * 2004-04-07 2005-10-20 Applied Research Systems Ars Holding N.V. Derives de 1,1'-(1,2-ethynediyle)bis-benzene inhibiteurs de ptp 1-b

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Publication number Priority date Publication date Assignee Title
WO2000050391A1 (fr) * 1999-02-26 2000-08-31 Merck & Co., Inc. Nouveaux composes de sulfonamide et utilisations correspondantes
US20050043364A1 (en) * 2003-08-11 2005-02-24 Kennedy Robert Michael Novel pyrrole-based HMG-CoA reductase inhibitors
WO2005097773A1 (fr) * 2004-04-07 2005-10-20 Applied Research Systems Ars Holding N.V. Derives de 1,1'-(1,2-ethynediyle)bis-benzene inhibiteurs de ptp 1-b

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013039985A3 (fr) * 2011-09-12 2013-06-27 The Johns Hopkins University Inhibiteurs de sérine protéase
US20150080451A1 (en) * 2011-09-12 2015-03-19 The Johns Hopkins University Serine protease inhibitors
US9371307B2 (en) 2011-09-12 2016-06-21 The Johns Hopkins University Serine protease inhibitors
WO2013056079A1 (fr) * 2011-10-13 2013-04-18 The Johns Hopkins University Inhibiteurs de bêta-lactamases à forte affinité
US9730913B2 (en) 2011-10-13 2017-08-15 The Johns Hopkins University High affinity beta lactamase inhibitors
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK
EP2899207A1 (fr) 2014-01-28 2015-07-29 Amikana.Biologics Nouveau procédé pour tester l'inhibition de la protéase du HCV
CN112174855A (zh) * 2020-11-16 2021-01-05 福州大学 一种磺酰氟类产物的制备方法
CN112174855B (zh) * 2020-11-16 2021-09-24 福州大学 一种磺酰氟类产物的制备方法
CN116444728A (zh) * 2023-04-20 2023-07-18 浙江南洋华诚科技有限公司 一种风电电容器高耐压高耐温薄膜及其制备方法

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