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WO2000018384A2 - Combinaisons antivirales renfermant un ester isopropylique d'acide (s)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2h-quinoxaline-1-carboxylique - Google Patents

Combinaisons antivirales renfermant un ester isopropylique d'acide (s)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2h-quinoxaline-1-carboxylique Download PDF

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Publication number
WO2000018384A2
WO2000018384A2 PCT/EP1999/007134 EP9907134W WO0018384A2 WO 2000018384 A2 WO2000018384 A2 WO 2000018384A2 EP 9907134 W EP9907134 W EP 9907134W WO 0018384 A2 WO0018384 A2 WO 0018384A2
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WIPO (PCT)
Prior art keywords
ethyl
quinoxaline
dihydro
oxo
fluoro
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PCT/EP1999/007134
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English (en)
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WO2000018384A3 (fr
Inventor
Hugh Brownlie Mcdade
Margaret Lynn Smiley
Martha Heider St. Clair
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Glaxo Group Limited
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Publication date
Priority claimed from GBGB9820999.2A external-priority patent/GB9820999D0/en
Priority claimed from GBGB9827109.1A external-priority patent/GB9827109D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU63295/99A priority Critical patent/AU6329599A/en
Publication of WO2000018384A2 publication Critical patent/WO2000018384A2/fr
Publication of WO2000018384A3 publication Critical patent/WO2000018384A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide

Definitions

  • the present invention relates to therapeutic combinations comprising (S)-2- ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester and 4-amino-N-((2 syn, 3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3- yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide (amprenavir, 141W), or a physiologically functional derivative thereof.
  • the present invention is also concerned with pharmaceutical compositions containing said combinations and their use in the treatment of HIV infections including infections with HIV mutants bearing resistance to nucleoside and/or non-nucleoside inhibitors of the replication of HIV.
  • Amprenavir also known as (3S)-tetrahydro-3-furyl N-((1 S,2R)-3-(4-amino-N- isobutylbenzenesulfamido)-1-benzyl-2-hydroxypropyl carbamate or carbamic acid 3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1- (phenylmethyl)propyl]-, tetrahydro-3-furanyl ester, [3S-[3R*(1 R * ,2S*)]]-, is a sulfonamide with HIV aspartyl protease inhibitory activity.
  • VV94 is particularly well suited for inhibiting HIV-1 and HIV-2 viruses.
  • Virus-encoded proteases which are essential for viral replication, are required for the processing of viral protein precursors. Interference with the processing of protein precursors inhibits the formation of infectious virions. Accordingly, inhibitors of viral proteases may be used to prevent or treat chronic and acute viral infections.
  • amprenavir In common with other protease inhibitors, amprenavir has somewhat low oral bioavaiiability and aqueous solubility. Amprenavir is currently formulated as a liquid dosage form in a soft gelatin capsule.
  • a combination of (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester and amprenavir or the compound of formula (I) therefore represents a particularly effective treatment for HIV. It is a feature of this invention that the use of such a drug combination will provide one or more of the following effects : synergistic antiviral effects, more complete viral suppression, viral suppression over a longer period, limit the emergence of drug resistant HIV mutants, and/or allow better management of drug-related toxicities.
  • a combination comprising (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester, or a physiologically functional derivative thereof, and amprenavir or a physiologically functional derivative thereof.
  • a combination comprising (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester, or a physiologically functional derivative thereof, and the compound of formula (I) or a physiologically functional derivative thereof.
  • 3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester, or a physiologically functional derivative thereof and calcium (3S) tetrahydro-3-furanyl (1 S,2R)-3- [[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2- (phosphonooxy)propylcarbamate.
  • physiologically functional derivative includes any physiologically acceptable solvate, salt, ether, ester, salt of such ester, or solvates of any such salt, ether or ester, of (S)-2-ethyl-7-fluoro-3-oxo-3,4- dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester or amprenavir; or any other compound which upon administration to the recipient, is capable of providing (directly or indirectly) such a compound or an antivirally active metabolite or residue thereof.
  • Preferred esters in accordance with the invention are independently selected from the following group: (1 ) carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n- butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C alkyl, or C alkoxy), or amino; (2) sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methanesulphonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); and (4) phosphonate esters.
  • any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms.
  • Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms.
  • Any aryl moiety present in such esters advantageously comprises a phenyl group. Any reference to any of the above compounds also includes a reference to a physiologically acceptable salt thereof.
  • physiologically acceptable salts include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium, calcium), ammonium and NX 4 (wherein X is C alkyl). Salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
  • a preferred salt of the compound of formula (I) is the calcium salt.
  • Combinations of (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1 - carboxylic acid isopropyl ester, or a physiologically functional derivative thereof, and amprenavir or the compound of formula (I) or a physiologically functional derivative thereof, may hereinafter be referred to as combinations according to the invention.
  • the present invention further provides combinations according to the invention for use in the treatment of an HIV infection including infections with HIV mutants bearing resistance to nucleoside inhibitors, particularly zidovudine, lamivudine, abacavir, ddl, ddC, DOTC or d4T or combinations thereof and HIV protease inhibitors.
  • nucleoside inhibitors particularly zidovudine, lamivudine, abacavir, ddl, ddC, DOTC or d4T or combinations thereof and HIV protease inhibitors.
  • the present invention provides a method for the treatment of an HIV infection in an infected animal, for example, a mammal including a human, which comprises treating said animal with a therapeutically effective amount of a combination of (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid isopropyl ester, or a physiologically functional derivative thereof, and amprenavir or a physiologically functional derivative thereof, preferably the compound of formula (I) or a physiologically functional derivative, more preferably calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4- aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)- propylcarbamate.
  • Reference herein to treatment extends to prophylaxis as well as the treatment of established infections or symptoms.
  • the compounds of the combination may be administered simultaneously, either in the same or different pharmaceutical formulations or sequentially. If there is sequential administration, the delay in administering the second and any subsequent active ingredient should not be such as to lose the benefit of a synergistic therapeutic effect of the combination of the active ingredients. It will also be understood that the compounds of the combination or the physiologically functional derivatives of any thereof, whether presented simultaneously or sequentially, may be administered individually or in multiples or in any combination thereof.
  • the present invention also provides the use of (S)-2-ethyl-7-fluoro-3-oxo-3,4- dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester in the manufacture of a medicament for administration simultaneously or sequentially with amprenavir or a physiologically functional derivative thereof for the treatment and/or prophylaxis of HIV infections and associated clinical conditions hereinbefore described.
  • synergistic effects of the combination of (S)-2-ethyl-7-fluoro-3-oxo-3,4- dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester and amprenavir may be seen over a ratio, for example, of 1 : 200 to 200: 1 , such as 1 :20 to 20:1 to 20 (by weight), preferably 1 :10 to 10:1 (by weight).
  • each compound may be employed in the combination in an amount at which it exhibits antiviral activity when used alone.
  • the amount of a combination of (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid isopropyl ester and amprenavir or a physiologically functional de ⁇ vative thereof required to be effective as an anti-HIV agent may, of course, vary and is ultimately at the discretion of the medical practitioner.
  • the factors to be considered include the route of administration and nature of the formulation, the animal's body weight, age and general condition and the nature and severity of the disease to be treated.
  • a suitable dose of (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid isopropyl ester for administration to a human for treatment of an HIV infection may be in the range of 0.1 to 20 mg per kilogram body weight of the recipient per day, preferably in the range of 0.2 to 5 mg per kilogram body weight per day and most preferably in the range 0.2 to 3.5 mg per kilogram body weight per day.
  • a suitable dose of amprenavir or the compound of formula (I) or its calcium salt for administration to a human may be in the range of 0.1 to 150 mg per kilogram body weight per day, advantageously in the range of 0.5 to 80 mg per kilogram body weight per day, preferably in the range of 0.5 to 50 mg per kilogram body weight per day.
  • the desired dose may preferably be presented as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing from 1 to 1200 mg, preferably from 5 to 1000 mg, most preferably from 10 to 700 mg of active ingredient per unit dosage form. Alternatively, if the condition of the recipient so requires, the dose may be administered as a continuous infusion.
  • the components of the combination which may be referred to as active ingredients may be administered for therapy to an animal e.g. a mammal including a human in a conventional manner.
  • compositions according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the individual components of the combination are administered separately they are generally each presented as a pharmaceutical formulation.
  • the references hereinafter to formulations refer unless otherwise stated to formulations containing either the combination or a component thereof.
  • a combination of (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1- carboxylic acid isopropyl ester and amprenavir or a physiologically functional derivative of any thereof may conveniently be presented as a pharmaceutical formulation in a unitary dosage form.
  • a convenient unitary dosage formulation contains (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester in an amount of from 10mg to 1200mg, for example, 10mg to 300mg, such as 20mg to 50mg and amprenavir or a physiologically functional derivative thereof in an amount of from 10mg to 2000mg, for example, 20mg to 1000mg, preferably 20mg.
  • Patient packs containing the whole course of treatment in a single package, usually a blister pack.
  • Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in traditional prescriptions.
  • the inclusion of a package insert has been shown to improve patient compliance with the physician's instructions and, therefore, lead generally to more successful treatment.
  • a multiple, for example, double or triple, pack comprising at least (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro- 2H-quinoxaline-1 -carboxylic acid isopropyl ester or a physiologically functional derivative thereof and the compound of formula (I) or a physiologically functional derivative thereof and an information insert containing directions on the use of the combination of the invention.
  • Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant
  • a binder e.g. povidone, gelatin, hydroxypropylmethyl cellulose
  • Moulded tablets may be made by moulding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • the tablets may optionally be coated or scored any may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Topical administration may also be by means of a transdermal iontophoretic device.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories.
  • Suitable carriers include cocoa butter and other materials commonly used in the art.
  • the suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which 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 sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or daily subdose of the active ingredients, as hereinbefore recited, or an appropriate fraction thereof.
  • compositions suitable for oral administration are preferred. It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral. administration may include such further agents as sweeteners, thickeners and flavoring agents.
  • HIV anti-viral agents for example other Reverse Transcriptase Inhibitors (RTIs), other Non Nucleoside Reverse Transcriptase Inhibitor (NNRTIs), HIV protease inhibitors and fusion inhibitors.
  • RTIs Reverse Transcriptase Inhibitors
  • NRTIs Non Nucleoside Reverse Transcriptase Inhibitor
  • HIV protease inhibitors HIV protease inhibitors and fusion inhibitors.
  • the compounds of the combination of the present invention may be obtained in a conventional manner.
  • (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester may be prepared by the method described in European Specification EP0509398 and EP078093 which are incorporated herein by reference.
  • Amprenavir may be prepared by the method described in PCT Application WO 94/05639 which is incorporated herein by reference.
  • the compound of formula (I) may readily be prepared from the compound of formula (II) by conventional methods, for example, as shown below.
  • the compound of formula (II) may be prepared by the method described in PCT Application WO 94/05639.
  • the calcium salt of the compound of formula (I) may be prepared by reacting a compound of formula (II) with a phosphorylating agent, for example, phosphorus oxychloride, phosphorus pentachloride, or dibenzylchlorophosphate, in the presence of a base, for example, pyridine, triethylamine or diisopropylethylamine, and optionally in the presence of a solvent, for example, methylisobutylketone or dichloromethane; followed by reduction, typically of the sodium salt formed in aqueous solution by addition of sodium bicarbonate, sodium carbonate or sodium hydroxide, with a reducing agent, for example, formic acid or hydrogen with palladium/ or platinum/carbon catalyst, in the presence of a suitable solvent, for example, water, ethyl acetate, isopropanol, acetone, methanol, industrial methylated spirit or a mixture of two or more of the above solvents; followed by the addition of water and
  • the phosphorylating agent is phosphorus oxychloride.
  • the base is pyridine.
  • the solvent is methyl isobutylketone.
  • the reducing agent is hydrogen with a palladium on carbon catalyst with a 5-10% loading of palladium.
  • the solvent is a mixture of industrial methylated spirit and water
  • the calcium salt may be prepared by dissolving the compound of formula (I) in a suitable solvent, for example, isopropanol, methanol or industrial methylated spirit, and adding to the solution water and a source of calcium ions, for example, calcium acetate, calcium chloride or calcium hydroxide.
  • a suitable solvent for example, isopropanol, methanol or industrial methylated spirit
  • the calcium salt may be prepared by reduction of a compound of formula (III), typically of the sodium salt formed in aqueous solution by addition of sodium bicarbonate, sodium carbonate or sodium hydroxide in the presence of a suitable reducing agent, for example formic acid or hydrogen with palladium/ or platinum/carbon catalyst, in the presence of a suitable solvent, for example water, ethyl acetate, isopropanol, acetone, methanol industrial methylated spirit or a mixture of two or more of the above solvents; followed by the addition of water and a source of calcium ions, for example calcium acetate, calcium chloride or calcium hydroxide, optionally in the presence of an additional solvent selected from the above-mentioned list.
  • a suitable reducing agent for example formic acid or hydrogen with palladium/ or platinum/carbon catalyst
  • a suitable solvent for example water, ethyl acetate, isopropanol, acetone, methanol industrial methylated spirit or a mixture of two or more of the above
  • the calcium salt thus obtained may optionally be further purified by recrystallisation from an appropriate solvent, for example industrial methylated spirit, acetone, methanol or isopropanol and mixtures thereof with water, preferably a mixture of industrial methylated spirit and water.
  • a further optional purification step may be carried out by heating a slurry of the product in water to a temperature in the range 70-99°C, preferably 85-97°C, most preferably 90- 95°C, for about 2.5-6 hours, preferably 3-5 hours, most preferably 4 hours, followed by cooling to ambient temperature and harvesting the solid.
  • an appropriate solvent for example industrial methylated spirit, acetone, methanol or isopropanol and mixtures thereof with water, preferably a mixture of industrial methylated spirit and water.
  • a further optional purification step may be carried out by heating a slurry of the product in water to a temperature in the range 70-99°C, preferably 85-97°C, most preferably 90- 95°C, for about 2.5
  • Active ingredient denotes (S)-2- ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester, the compound of formula (I), or multiples thereof or a physiologically functional derivative of any of the aforementioned compounds.
  • Example 1 Tablet Formulation
  • the following formulations are prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.
  • the formulation is prepared by wet granulation of the ingredients with a solution of povidone followed by the addition of magnesium stearate and compression.
  • Drug release takes place over a period of about 6-8 hours and is complete after 12 hours.
  • Capsules are prepared by melting the Macrogel 4000 B.P., dispersing the active ingredient in the melt and filling the melt into a two-part hard gelatin capsule. Active Ingredient 150.0
  • Vitamin E TPGS obtained from Eastman Chemical Co.
  • TPGS obtained from Eastman Chemical Co.
  • PEG400 polyethylene glycol 400
  • the resultant solution was heated to 65°C.
  • 1.5 kg of active ingredient was dissolved in the liquefied solution of Vitamin E TPGS and PEG 400.
  • 0.395 kg of propylene glycol at room temperature was added and mixed until a homogenous solution was formed. The solution was cooled to 28-35°C.
  • the solution was then de-gassed.
  • the mixture was preferably encapsulated at 28-35°C at a fill weight equivalent to 150 mg of volatiles-free compound, into Size 12 oblong, white opaque soft gelatin capsules using a capsule filling machine.
  • the capsule shells were dried to a constant fill moisture of 3-6% water and a shell hardness of 7-10 newtons, and placed in a suitable container.
  • the following controlled release capsule formulation is prepared by extruding ingredients a,b, and c using an extruder, followed by spheronization of the extrudate and drying. The dried pellets are then coated with release-controlling membrane (d) and filled into a two-piece, hard gelatin capsule.
  • the following controlled release capsule formulation is prepared by extruding ingredients a,b, and c using an extruder, followed by spheronization of the extrudate and drying. The dried pellets are then coated with release-controlling membrane (d) and filled into a two-piece, hard gelatin capsule. mg/capsule
  • Active Ingredient 200 Hydro chloric Acid Solution 0.1 M or
  • the active ingredient is dissolved in most of the water (35° - 40° C) and the pH adjusted to between 4.0 and 7.0 with the hydrochloric acid or the sodium hydroxide as appropriate.
  • the batch is then made up to volume with water and filtered through a sterile micropore filter into a sterile 10 ml amber glass vial (type 1 ) and sealed with sterile closures and overseals.
  • the active ingredient is dissolved in a mixture of the glycerol and most of the purified water.
  • An aqueous solution of the sodium benzoate is then added to the solution, followed by addition of the sorbitol solution and finally the flavor.
  • the volume is made up with purified water and mixed well.
  • Example 6 Suppository mg/capsule suppository
  • Witepsol H15 is melted in a steam-jacketed pan at 45°C maximum.
  • the active ingredient is sifted through a 200 ⁇ m sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until a smooth dispersion is achieved. Maintaining the mixture at 45° C, the remaining Witepsol H15 is added to the suspension and stirred to ensure a homogenous mix.
  • the entire suspension is passed through a 250 ⁇ m stainless steel screen and, with continuous stirring, is allowed to cool to 45° C. At a temperature of 38° C to 40° C, 2.02 g of the mixture is filled into suitable, 2 ml plastic moulds. The suppositories are allowed to cool to room temperature.
  • Example 7 Pessaries mg/pessary
  • MT4 cells were infected with HIV-1 3B and, after a 1 hour incubation, were exposed to combinations of (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid isopropyl ester (COMPOUND A) and amprenavir (141W). Five days later, the cytopathic effect was quantitated using a standard propidium iodide assay.

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Abstract

La présent invention concerne des combinaisons thérapeutiques renfermant un ester isopropylique d'acide (S)-2-éthyl-7-fluoro-3-oxo-3,4dihydro-2H-quinoxaline-1-carboxylique et 4-amino-N-((2 syn, 3S)-2-hydroxy-4-phényl-3-((S)-tétrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzènesulfonamide (amprénavir) ou un dérivé physiologiquement fonctionnel de ce composé, notamment (3S) tétrahydro-3-furanyl(1S, 2R)-3-[[(4-aminophényl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate ou calcium (3S) tétrahydro-3-furanyl (1S, 2R)-3-[[(4-aminophényl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate. La présente invention concerne également des compositions pharmaceutiques renfermant lesdites combinaisons, ainsi que leur utilisation dans le traitement des infections par le VIH, notamment les infections par des mutants du VIH offrant une résistance aux inhibiteurs nucléosidiques et/ou non nucléosidiques de la réplication du VIH.
PCT/EP1999/007134 1998-09-28 1999-09-27 Combinaisons antivirales renfermant un ester isopropylique d'acide (s)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2h-quinoxaline-1-carboxylique WO2000018384A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU63295/99A AU6329599A (en) 1998-09-28 1999-09-27 Antiviral combinations comprising (s)-2-ethyl -7-fluoro -3-oxo-3, 4-dihydro -2h-quinoxaline -1-carboxylic acid isopropyl ester

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9820999.2 1998-09-28
GBGB9820999.2A GB9820999D0 (en) 1998-09-28 1998-09-28 Antiviral combinations
GB9827109.1 1998-12-09
GBGB9827109.1A GB9827109D0 (en) 1998-12-09 1998-12-09 Antiviral combinations

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WO2000018384A2 true WO2000018384A2 (fr) 2000-04-06
WO2000018384A3 WO2000018384A3 (fr) 2000-06-08

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1240903A2 (fr) * 1998-07-18 2002-09-18 Glaxo Group Limited Combinaison de (3S) tétrahydro-3-furanyl(1S,2R)-3-[[(4-aminophènyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate de calcium et de ritonavir
US9233943B2 (en) 2012-01-10 2016-01-12 Council Of Scientific & Industrial Research Process for synthesis of syn azido epdxide and its use as intermediate for the synthesis of amprenavir and saquinavir
EP1819323B1 (fr) 2004-12-03 2016-11-16 Merck Sharp & Dohme Corp. Composition pharmaceutique renfermant un agent d'anti-nucleation

Citations (3)

* Cited by examiner, † Cited by third party
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EP0728481A2 (fr) * 1995-02-27 1996-08-28 Bayer Ag Utilisation de quinoxaline et d'inhibiteurs de protéase dans un médicament contre le SIDA et/ou les infections HIV
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EP1240903A2 (fr) * 1998-07-18 2002-09-18 Glaxo Group Limited Combinaison de (3S) tétrahydro-3-furanyl(1S,2R)-3-[[(4-aminophènyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate de calcium et de ritonavir
EP1240903A3 (fr) * 1998-07-18 2003-02-12 Glaxo Group Limited Combinaison de (3S) tétrahydro-3-furanyl(1S,2R)-3-[[(4-aminophènyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate de calcium et de ritonavir
EP1819323B1 (fr) 2004-12-03 2016-11-16 Merck Sharp & Dohme Corp. Composition pharmaceutique renfermant un agent d'anti-nucleation
EP1819323B2 (fr) † 2004-12-03 2023-03-22 Merck Sharp & Dohme Corp. Composition pharmaceutique renfermant un agent d'anti-nucleation
US9233943B2 (en) 2012-01-10 2016-01-12 Council Of Scientific & Industrial Research Process for synthesis of syn azido epdxide and its use as intermediate for the synthesis of amprenavir and saquinavir

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