WO2000018383A2 - 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
WO2000018383A2
WO2000018383A2 PCT/EP1999/007132 EP9907132W WO0018383A2 WO 2000018383 A2 WO2000018383 A2 WO 2000018383A2 EP 9907132 W EP9907132 W EP 9907132W WO 0018383 A2 WO0018383 A2 WO 0018383A2
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WO
WIPO (PCT)
Prior art keywords
quinoxaline
dihydro
oxo
fluoro
ethyl
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PCT/EP1999/007132
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English (en)
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WO2000018383A3 (fr
Inventor
Hugh Brownlie Mcdade
Margaret Lynn Smiley
Martha Heider St. Clair
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Glaxo Group Limited
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Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU61967/99A priority Critical patent/AU6196799A/en
Publication of WO2000018383A2 publication Critical patent/WO2000018383A2/fr
Publication of WO2000018383A3 publication Critical patent/WO2000018383A3/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

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 a second therapeutic agent selected from 3'-azido-3'-deoxythymidine (zidovudine, AZTTM) and (2R,cis)-4-amino-1-(2-hydroxymethyl-1 ,3-oxathiolan-5- yl)-(1 H)-pyrimidin-2-one (lamivudine, 3TCTM).
  • 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.
  • Zidovudine and lamivudine are now well established as important and useful chemotherapeutic agents for the treatment and/or prophylaxis of HIV-infections including related clinical conditions such as AIDS, AIDS-related complex (ARC), AIDS dementia complex (ADC) and also for the treatment of patients who have an asymptomatic HIV infection or who are anti-HIV antibody-positive.
  • Treatment with zidovudine or lamivudine prolongs the disease-free interval in asymptomatic patients infected with HIV and delays death in symptomatic patients.
  • Combinations of, inter alia, zidovudine or lamivudine with quinoxaline non- nucleoside reverse transcriptase inhibitors of a genus including (S)-2-ethyl-7- fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester are disclosed in European patent application no. 0657166. There is no specific disclosure of combinations comprising (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H- quinoxaline-1-carboxylic acid isopropyl ester.
  • 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 a reverse transcriptase inhibitor selected from lamivudine and its physiologically functional derivatives and zidovudine and its physiologically functional derivatives.
  • a further feature of the present invention is a triple 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, lamivudine or a physiologically functional derivative thereof and zidovudine or a physiologically functional derivative thereof.
  • the ratios of the components of such combinations will conveniently be the same as the ratios of the relevant compounds in the double combinations of the invention.
  • 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 lamivudine or zidovudine; 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), ammonium and NX + (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.
  • an appropriate base such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX + (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.
  • 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 lamivudine and/or zidovudine, or physiologically functional derivatives 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 at least one of lamivudine or a physiologically functional derivative thereof and zidovudine or a physiologically functional derivative thereof.
  • 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.
  • Lamivudine and zidovudine are available commercially in a unitary dosage form under the trade mark COMBIVIRTM.
  • Administration to a patient of COMBIVIRTM and a pharmaceutical formulation comprising (S)-2-ethyl-7-fluoro-3-oxo-3,4- dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester represents a convenient embodiment of the present invention.
  • (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester will be presented as a formulation suitable for oral administration, preferably a tablet comprising, for example, 10 - 1200mg of (S)- 2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester, such as about 20mg of (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H- quinoxaline-1 -carboxylic acid isopropyl ester.
  • 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 at least one of lamivudine and zidovudine 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 lamivudine or zidovudine 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 lamivudine and/or zidovudine 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 0J 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 zidovudine will be in the range of 2 to 100 mg per kilogram body weight of the recipient per day, preferably in the range of 3 to 50 mg per kilogram body weight per day and most preferably in the range 4 to 12 mg per kilogram body weight per day.
  • a suitable daily dose will be in the range of from about 1 to about 100 mg per kilogram body weight of the recipient per day, preferably in the range of 2 to 40 mg per kilogram body weight per day, most preferably in the range of 3 to 10 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 formula 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 lamivudine and/or zidovudine 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 20mg to 200mg, and lamivudine and/or zidovudine in amounts of from 50mg to 2g each, for example, 100 mg to 600mg.
  • a particularly convenient unitary dosage formulation may contain (S)-2-ethyl-7- fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester in an amount of from 10-100mg, such as 20-50mg, lamivudine in an amount of 100- 200mg, such as 150mg, and zidovudine in an amount of 100-500mg, such as 300mg.
  • compositions are often prescribed to the patient in "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. It will be understood that the administration of the combination of the invention by means of a single patient pack, or patient packs of each formulation, containing within a package insert instructing the patient to the correct use of the invention is a desirable additional feature of this invention.
  • 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 and lamivudine or zidovudine and an information insert containing directions on the use of the combination of the invention.
  • a particularly convenient patient pack for use in accordance with the present invention comprises (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1 - carboxylic acid isopropyl ester in a formulation suitable for oral administration, for example a tablet, and COMBIVIRTM.
  • 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 (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • a binder e.g. povidone, gelatin, hydroxypropylmethyl cellulose
  • lubricant e.g. povidone, gelatin, hydroxypropylmethyl cellulose
  • inert diluent e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose
  • disintegrant e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose
  • 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. Formulations may be prepared suitable for continuous infusion by methods known in the art.
  • 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. Particularly preferred are tablets for oral administration.
  • 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.
  • combinations of the invention may be combined with one or more other 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.
  • Zidovudine can be prepared, for example, as described in U.S. Patent 4724232, incorporated herein by reference. Zidovudine can also be obtained from Aldrich Chemical Co., Milwaukee, Wl 53233, USA.
  • Active ingredient denotes (S)-2- ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1 -carboxylic acid isopropyl ester, lamivudine, zidovudine or multiples thereof or a physiologically functional derivative of any of the aforementioned compounds.
  • Example 1 Tablet Formulation
  • the formulation is prepared by wet granulation of the ingredients with a solution of povidone followed by the addition of magnesium stearate and compression.
  • 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.
  • 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.
  • 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 the glycofurol.
  • the benzyl alcohol is then added and dissolved, and water added to 3 ml.
  • the mixture is then filtered through a sterile micropore filter and sealed in sterile 3 ml amber glass vials (type l ).
  • Purified Water q.s. to 5.00 ml
  • 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.
  • 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 lamivudine (3TC) or zidovudine (AZT). Five days later, the cytopathic effect was quantitated using a standard propidium iodide assay.
  • Mutant HIV-1 strains emerging from the combination experiments were tested for their sensitivities against test compounds and analysed for the presence of resistance-conferring mutations in their pol genes.

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Abstract

La présente invention concerne des combinaisons thérapeutiques renfermant un ester isopropylique d'acide (S)-2-éthyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1-carboxylique et un deuxième agent thérapeutique choisi parmi 3'-azido-3'-désoxythymidine (zidovudine) et (2R,cis)-4-amino-1-(2-hydroxyméthyl-1,3-oxythiolan-5-yl)-(1H)-pyrimidin-2-one (lamivudine). 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/EP1999/007132 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 WO2000018383A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU61967/99A AU6196799A (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 (2)

Application Number Priority Date Filing Date Title
GB9821000.8 1998-09-28
GBGB9821000.8A GB9821000D0 (en) 1998-09-28 1998-09-28 Antiviral combinations

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WO2000018383A2 true WO2000018383A2 (fr) 2000-04-06
WO2000018383A3 WO2000018383A3 (fr) 2000-07-06

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PCT/EP1999/007132 WO2000018383A2 (fr) 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

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AU (1) AU6196799A (fr)
GB (1) GB9821000D0 (fr)
WO (1) WO2000018383A2 (fr)

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Publication number Priority date Publication date Assignee Title
WO2005048978A2 (fr) * 2003-10-01 2005-06-02 Lupin Limited Composition pharmaceutique a liberation controlee et procede de preparation de cette composition
US8481554B2 (en) 2009-05-27 2013-07-09 Hetero Research Foundation Solid oral dosage forms of lamivudine

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EP0657166A1 (fr) * 1993-12-09 1995-06-14 Hoechst Aktiengesellschaft Composition contenant un quinixaline et un nucléoside
DE19703131A1 (de) * 1997-01-29 1998-07-30 Bayer Ag Verwendung von Chinoxalin in Dreier-Kombination mit Protease-Inhibitoren und Reverse Transkriptaseinhibitoren als Arzneimittel zur Behandlung von AIDS und/oder HIV-Infektionen

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EP0657166A1 (fr) * 1993-12-09 1995-06-14 Hoechst Aktiengesellschaft Composition contenant un quinixaline et un nucléoside
DE19703131A1 (de) * 1997-01-29 1998-07-30 Bayer Ag Verwendung von Chinoxalin in Dreier-Kombination mit Protease-Inhibitoren und Reverse Transkriptaseinhibitoren als Arzneimittel zur Behandlung von AIDS und/oder HIV-Infektionen

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BALZARINI ET AL.: "The thiocarboxanilides UC-10 and UC-781 have an additive inhibitory effect against human immunodeficiency virus type 1 reverse transcriptase and replication in cell culture when combined with other antiretroviral drugs." ANTIVIRAL CHEMISTRY AND CHEMOTHERAPY, vol. 8, 1997, pages 197-204, XP000885652 *
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005048978A2 (fr) * 2003-10-01 2005-06-02 Lupin Limited Composition pharmaceutique a liberation controlee et procede de preparation de cette composition
WO2005048978A3 (fr) * 2003-10-01 2006-02-23 Lupin Ltd Composition pharmaceutique a liberation controlee et procede de preparation de cette composition
EA008944B1 (ru) * 2003-10-01 2007-10-26 Люпин Лимитед Фармацевтическая композиция управляемого высвобождения и способ ее получения
AP1826A (en) * 2003-10-01 2008-02-08 Lupin Ltd A controlled release pharmaceutical composition and a process for preparing the same
US8481554B2 (en) 2009-05-27 2013-07-09 Hetero Research Foundation Solid oral dosage forms of lamivudine

Also Published As

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AU6196799A (en) 2000-04-17
WO2000018383A3 (fr) 2000-07-06
GB9821000D0 (en) 1998-11-18

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