MXPA98010386A - Combinations that include vx478, zidovudina and / or 1592u89 for use in the treatment of - Google Patents

Abstract

The present invention relates to the therapeutic combinations of 3S- [3R * (1R *, 2S *)] - [3 - [[4-aminophenyl) sulfonyl] 2-methylpropyl) -amino] -2-hydroxy-1-phenylmethyl ) carbamic propyl, tetrahydro-3-furanylester (141W94), 3-azido-3-deoxythymidine (zidovudine) and (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9- il] -2-cyclopenten-1-methanol (1592U89), which have anti-HIV activity. The present invention also relates to pharmaceutical compositions containing such combinations and their use in the treatment of HIV infections including infections with HIV mutants that have resistance to nucleoside inhibitors and / or non-nucleoside inhibitors.

Description

QÜE COMBINATIONS INCLUDE VX478, ZIDOVUDINA AND / OR 1592U89 FOR USE IN THE TREATMENT OF VTtf Field of the Invention The present invention relates to therapeutic combinations of 3S- [3R * (IR *, 2S *)] - [3- [[(4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2-idroxy-1 acid phenyl-methyl) propyl] carbamic, ((3S) -Tetrahydro-3-furyl-N- ((1S, 2R) -3- (4-amino-N-isobutyl-benzenesulfonamido) -l-benzyl-2-hydroxy -propyl) tetrahydro-3-furanyl ester carbamate, 4-amino-N- ((2sin, 3S) -2-hydroxy-4-phenyl-3- ((s) -tetrahydrofuran-3-yloxy-carbonylamino) -butyl) -N-isobutyl-benzenesulfonamide, 141W94, t. "X-478), 3 '-azido-3'-deoxythymidine (zidovudine), and (ls, 4R) -cis-4- [2-amino-6 - (cyclopropyla ino) -9H-purin-9-yl] -2-cyclopenten-1-methanol (1592U89), which have anti-HIV activity The present invention also relates to pharmaceutical compositions containing such combinations and their use in the treatment of HIV infections including infections with HIV mutants that have resistance to nucleoside inhibitors and / or non-nucleoside inhibitors REF. : 29047 Background of the invention Zidovudine is now well established as an important and useful chemotherapeutic agent for the treatment and / or prophylaxis of HIV infections including related clinical conditions such as AIDS, AIDS-related complex (CRS), AIDS dementia complex (CDS) and also for the treatment of patients who have an asymptomatic HIV infection or who have anti-HIV antibody positive. Treatment with zidovudine prolongs the free interval of the disease in asymptomatic patients infected with HIV and delays the death in symptomatic patients. Following the widespread clinical use of zidovudine in the treatment of such infections and conditions, it has been observed that in certain cases after prolonged treatment, the virus may develop a certain level of resistance to zidovudine and therefore a loss of sensitivity to zidovudine. drug. The therapeutic agent 1592U89 (Specification European EP0434450) is a promising anti-HIV chemotherapeutic candidate (International Conference on Antiviral Research, April 23, 1995) which shows potent anti-HIV activity, low toxicity and excellent penetration in the brain, which is important for the treatment of AIDS and central nervous system conditions linked to HIV, such as CDS.

Description of the Invention 4-amino-N- ((2 sin, 3S) -2-hydroxy-4-phenyl-3- ((S) -tetrahydrofuran-3-yloxycarbonylamino) -butyl) -N-isobutyl-benzenesulfonamide ( 141W94) is a sulfonamide with inhibitory activity of HIV aspartyl protease. 141W94 is particularly well suited to inhibit HIV-1 and HIV-2 viruses. Proteases encoded by the virus, which are essential for viral duplication, are required for the processing of viral protein precursors. Interference with the processing of protein precursors inhibit the formation of infectious virions. Accordingly, inhibitors of viral proteases can be used to prevent or treat chronic and acute viral infections. To date, the treatment of HIV infection has depended to a large extent on monotherapy with nucleoside reverse transcriptase inhibitors such as zidovudine, didanosine (ddl), zalcitabine (ddc) and stavudine (d4T). However, these drugs eventually become less effective due either to the emergence of HIV-resistant mutants or due to toxicity. In this way, new therapies are necessary. The combination of zidovudine with either ddC or ddl has shown promising results in patients infected with HIV (New Eng. J. Med. 1992, 329 (9) 581-587, Summary of the 1993 9R Program of the International AIDS Conference, Summary US-B25-1). However, it should be noted that these results are surprising because drugs with the same site of action are frequently antagonists or additives (Rev Infect., 4, 255-260). Unexpectedly, it has now been found that by combining 141W94, zidovudine and 1592U89 a synergistic anti-HIV effect is obtained. A feature of this invention is that the use of this drug combination will provide synergistic antiviral effects, more complete viral suppression, viral suppression over a longer period, limit the emergence of drug resistant HIV mutants and allow better management of the drugs. toxicities related to the drug.

Accordingly, in one aspect of the invention there is provided a combination comprising 141 94 or a physiologically functional derivative thereof, zidovudine or a physiologically functional derivative thereof, and 1592U89 or a physiologically functional derivative thereof. It should be appreciated that zidovudine may exist in tautomeric keto or enol form and the use of such a tautomeric form is within the scope of this invention. The 1592U89 will normally be provided substantially free of the corresponding enantiomer, ie not more than about 5% w / w of the corresponding enantiomer, preferably not more than about 2% w / w, in particular less than 1% in weight / weight will be present. As used herein, the term "physiologically functional derivative" includes any salt, ether, ester, salt of such ester of 141W94, zidovudine or physiologically acceptable 1592U89; or solvates of any of them and their physiologically functional derivatives; or any other compounds which upon their administration to the recipient, are capable of providing (directly or indirectly) such a compound or an antivirally active metabolite or residue thereof.

Preferred esters according to the invention are independently selected from the following group: (1) carboxylic acid esters in which the non-carbonyl portion of the carboxylic acid moiety of the ester group is selected from a straight or branched chain alkyl (eg example, methyl, n-propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl), aryl (e.g., phenyl) optionally substituted by, for example, halogen, C? _4 alkyl, or C? _4 alkoxy), or amino acid; (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (eg, L-valyl or L-isoleucyl; and (4) phosphonate esters .. In such esters, unless otherwise specified, any present alkyl moiety advantageously contains from 1 to 18 carbon atoms, particularly of the β carbon atoms, more particularly of 1 to 4 carbon atoms Any cycloalkyl portion present in such esters advantageously contains 3 to 6 carbon atoms Any aryl portion 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 The particularly preferred esters are the esters of mono-, di-, and triphosphate of zidovudine or any other compound which upon being administered to a human subject is capable of providing (directly or indirectly), such a mono-, di-, or triphosphate ester. 1592U89 is the (-) carbovir triphosphate ester. Examples of physiologically acceptable salts of 141-94, zidovudine or 1592U89 and their physiologically acceptable derivatives include salts derived from an appropriate base, such as an alkali metal (eg, sodium), an alkaline earth (eg, magnesium), ammonium and NX + (wherein X is C? - alkyl). Physiologically acceptable salts of a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic, and succinic acids, organic sulfonic acids, such as methanesulfonic, ethanesulfonic acids , benzenesulfonic and p-toluenesulfonic and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids. The physiologically acceptable salts * of a compound of a hydroxy group include the anion of such a compound in combination with a suitable cation such as Na +, NH + and NX4 + (wherein X is a C1-4 alkyl group). For its therapeutic use, the salts of 141 94, zidovudine and 1592U89 should be physiologically acceptable, ie they should be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases that 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. Preferred salts of 1592U89 are the succinate salt and the hemisulfate salt. Combinations of 141W94 or a physiologically functional derivative thereof, and 1592U89 or a physiologically functional derivative thereof may be referred to hereinbelow 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 that includes infections with HIV mutants that have resistance to nucleoside inhibitors, particularly zidovudine, lamivudine, ddl; ddC, or d4T or combinations thereof and non-nucleoside inhibitors such as nevirapine (BI-RG-587), loviride (a-APA) and delavuridine (BHAP). In addition, the combinations according to the invention are especially useful for the treatment of AIDS and related clinical conditions such as the AIDS-related complex (CRS), progressive generalized lymphadenopathy (PGL), Kaposi's sarcoma, thrombocytopenic purpura, neurological conditions related to AIDS such as the AIDS dementia complex, multiple sclerosis or tropical paraperesis, and also anti-HIV positive antibody and HIV positive conditions, including such conditions in asymptomatic patients. According to another aspect, 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 such an animal with a therapeutically effective amount of a combination. of 141W94, zidovudine and 1592U89 or a physiologically functional derivative thereof.

The reference here to treatment extends to prophylaxis as well as to the treatment of established infections or symptoms. It should be appreciated that the compounds of the combination can be administered simultaneously, either in the same or different pharmaceutical formulations or sequentially. If sequential administration exists, the delay in the administration of the second and third active ingredients should not be such that the benefit of a synergistic therapeutic effect of the combination of the active ingredients is lost. It should also be understood that 141W94, zidovudine and 1592U89, or the physiologically functional derivatives of any of them, if present simultaneously or sequentially, may be administered individually or in multiples or in any combination thereof. 141W94, zidovudine and 1592U89 are preferably administered simultaneously or sequentially in separate pharmaceutical formulations, most preferably simultaneously. The present invention also provides the use of 141 94 in the manufacture of a medicament for simultaneous or sequential administration with zidovudine and 1592U89, respectively, for the treatment and / or prophylaxis of HIV infections and the associated clinical conditions described herein. previously. It should be appreciated that 141W94, zidovudine or 1592U89 or any combination thereof may be used in the manufacture of the above medicament. The synergistic effects of the combination of 141W94, zidovudine and 1592U89 or a physiologically functional derivative of any of them are observed on a ratio, for example, from 1 to 20: 20: 1 to 10 (by weight), so preferable from 1 to 10: 1 to 10: 1 to 5: (by weight), particularly from 1 to 3: 1 to 3: 1 to 2 (by weight). Conventional relations of 141W94: zidovudine: 1592U89 include 1.5: 1: 1,, 2: 1: 1, 3: 1: 1 and 4: 1: 1. Conveniently each compound can be used in combination in an amount to which it exhibits antiviral activity when used alone. The amount of a combination of 141 94, zidovudine and 1592U89 required to be effective as an anti-HIV agent can, of course, vary and is ultimately at the discretion of the attending physician. Factors to be considered include the route of administration and nature of the formulation, animal body weight, age and general condition and the nature and severity of the disease to be treated. In general, an appropriate dose of 141 94 for administration to a human can be in the range of 5 to lOOmg per kilogram of body weight per day, advantageously in the range of 8 to 70 mg per kilogram of body weight per day. , preferably in the range of 8 to 50 mg per kilogram of body weight per day and more preferably in the range of 10 to 30 mg per kilogram of body weight per day. An adequate dose of zidovudine may be in the range of 3 to 120 mg per kilogram of body weight of the receptor per day, preferably in the range of 6 to 90 mg per kilogram of body weight per day and more preferably in the range of 10. at 30mg per kilogram I achieve body weight per day. In general, a suitable dose of 1592U89 for the administration of a human for the treatment of an HIV infection may be in the range of 0. 1 to 100mg per kilogram of body weight of the recipient per day, so preferable in the range of 0.5 to 50 mg per kilogram achieved body weight per day and more preferably in the range of 7 to 30 mg per kilogram achieved body weight per day. Unless otherwise indicated, all weights of the active ingredients were calculated in terms of drug per se. In the case of a physiologically functional derivative of 141 94, zidovudine, 1592U89, or a solvate of any of the same, the figures could be increased proportionally. The desired dose may preferably be presented as a, two, three, four, five, six or more sub-doses administered at appropriate intervals during the day. These sub-doses may be administered in unit dosage forms, for example, containing from 1 to 1500 mg, preferably from 5 to 1000 mg, more 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 that can be preferred as active ingredients can be administered for therapy to an animal for example a mammal, including a human in a conventional manner. Although it is possible for the active ingredients of the combination to be administered as the crude chemical it is preferred to present them as a pharmaceutical formulation. The pharmaceutical formulations according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and other optional therapeutic agents. The carriers must be acceptable in the sense of being compatible with the other ingredients of the formula and not be harmful to the recipient thereof. When the individual components of the combination are administered separately, each is generally presented as a pharmaceutical formulation. Subsequent references to the formulations refer unless stated otherwise to formulations containing either the combination or a component thereof. A combination of 141W94, zidovudine, and 1592U89, or a physiologically functional derivative of any of them may conveniently be presented as a pharmaceutical formulation in a unit dosage form. A convenient, unit dosage formulation contains the active ingredients in amounts of 50 mg. at 3 g each, for example, from 100 mg to 2 g. It is also possible to combine any of two of the active ingredients in a unit dosage form for simultaneous or sequential administration with a third active ingredient, for example, a typical unit dose may contain 50 mg to 3 g of each of 141W94 and zidovudine, preferably 100 * mg to 2 g each of 141W94 and zidovudine or 50 mg to 3 g each of 141W94 and 1592U89, preferably 100 mg to 2 g each of 141W94 and 1592U89 . As a further feature of the present invention it is presented as a unit dosage form comprising at least two active ingredients selected from 141-94, zidovudine, and 1592U89 or physiologically functional derivatives of any of them and a pharmaceutically acceptable carrier thereof. It should be appreciated that administration of two active compounds selected from 141W94, zidovudine, and 1592U89 is an essential part of the invention, preferably as a prelude to the remaining third active ingredient that has been administered. The combinations of 141W94 and zidovudine, and 141W94 and 1592U89 are preferred. It has also been found that when the compounds described above are combined a synergistic effect is also found. A further feature of the present invention features a combination comprising two compounds selected from 141-94, zidovudine, and 1592U89 provided that the two compounds are not zidovudine and 1592U89. Preferred are combinations comprising 141W94 and 1592U89. The ratios of the components of such double combinations will conveniently be the same as the ratios of the relevant compounds in the triple combinations of the invention. Pharmaceutical formulations are often prescribed to the patient in "patient packs" that contain the entire course of treatment in a single package, usually a packet of ampoules. Patient packages have the advantage over traditional prescriptions, where a pharmacist divides the patient's supply of a drug from a bulk supply, in which the patient always has access to the package insert contained in the patient package, normally omitted in the traditional prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician's instructions and, therefore, generally leads to more successful treatment. It should be understood that the administration of the combination of the invention by means of a single patient package, or patient packs of each formulation, containing within a package insert instructions for the patient to make correct use of the invention is a characteristic additional desirable of this invention. According to a further aspect of the invention there is provided a double or triple package comprising at least one active ingredient of 141W94, zidovudine, or 1592U89 of the combination of the invention and an information insert containing the instructions on the use of the combination of the invention. According to a further aspect of the invention there is provided a patient package comprising in association for separate administration 141W94 or a physiologically functional derivative thereof together with at least one of zidovudine or a physiologically functional derivative thereof and 1592U89 or a physiologically functional derivative thereof. The formulations include those for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations can be conveniently presented in unit dosage forms and can be prepared by any methods well known in the pharmacy art. Such methods represent a further feature of the present invention and include the step of bringing the active ingredients into association with the carrier, which constitutes one or more accessory ingredients. In general, 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 to form 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 of which contain a predetermined amount of the active ingredients; as a powder or granules; as a solution or suspension in aqueous or non-aqueous liquid; or as a liquid emulsion oil in body water or a liquid emulsion water in oil. The active ingredient can also be presented as a bolus, electuary or paste. A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable form the active ingredients in a free flowing form such as a powder, or granules optionally mixed with a binder (for example povidone, gelatin, hydropropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycol, crosslinked povidone, cross-linked sodium carboxymethyl cellulose) surfactants or dispersants. The molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the active ingredients using, for example, hydroxypropylmethyl cellulose in various proportions to provide the desired release profile. The tablets may optionally be provided with an enteric coating, to provide release in parts of the intestine in place of the stomach. Formulations suitable for topical administration in the mouth include dragees comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; the tablets comprise the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouth rinses comprise the active ingredient in a suitable liquid carrier. Formulations for rectal administration should be presented as suppositories with a suitable base comprising, for example, cocoa ittanteca or a salicylate. Topical administration can 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 carriers such as those known in the art to be appropriate. Suitable therapeutic formulations for rectal administration wherein the carrier is a solid are more preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by mixing the active combination with the softened or molten carrier followed by cooling and forming into molds. Formulations suitable for parenteral administration include sterile aqueous and non-aqueous isotonic 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 microparticle systems that are designed to direct the compound to the blood components or one or more organs. The formulations can be presented in unit doses or sealed containers with multiple doses, for example, ampoules and flasks, and can be stored in a freeze-dried condition (lyophilized) requiring only the addition of the sterile liquid carrier, eg water for injection, immediately before of its use. Extemporaneous injection and suspension solutions can be prepared from sterile powders, granules and tablets of the type described above. Preferred unit dosage formulations are those containing a daily dose or daily sub-dose of the active ingredients, as cited hereinabove, or an appropriate fraction thereof. 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 the type of formulation in question, for example, those suitable for oral administration may include agents such as sweeteners, thickeners and flavoring agents. The compounds of the combination of the present invention can be obtained in conventional manner. Zidovudine can be prepared, for example, as described in U.S. Patent No. 4,724,232, incorporated herein by reference. Zidovudine can also be obtained from Aldrich Chemical Co., Milwaukee, WI 5 ~ 233, USA. • 141W94 can be prepared by the method described in PCT Application WO 94/05639 which is incorporated herein by reference. The 1592U89 can be prepared by the method described in the European Specification EP0434450 or in the PCT application PCT / GB / 4500225 which are incorporated herein by reference. The following examples are intended to be illustrative only and are not intended to limit the scope of the invention in any way. The "active ingredient" denotes 141W94, zidovudine, 1592U89 or multiples thereof or a physiologically functional derivative of any of the compounds mentioned above.

Example 1: Tablet Formulation The following formulations A, B and C were prepared by wet granulation of the ingredients with a povidone solution, followed by the addition of magnesium stearate and compression.

Formulation A mg / tablet Active Ingredient 250 Lactose B. P. 210 Povidone B. P. 15 Sodium Starch Glycolate 20 Magnesium Stearate 5 500 Formulation B mg / tablet Active Ingredient 250 Lactose B.P. 150 Avicel PH 101 60 Povidone B. P. 15 Sodium Starch Glycolate 20 Magnesium Stearate 500 Formulation C mg / tablet Active Ingredient 250 Lactose B. P. 200 Starch 50 Povidone 5 Magnesium Stearate 4 359 The following formulations, D and E, were prepared by direct compression of the mixed ingredients. The lactose in formulation E is of the direct compression type (Dairy Crest- "Zeparox").

Formulation D mg / tablet Active Ingredient 250 Pregelatinized Starch NF15 150 : 00 Formulation E mg / tablet Active Ingredient 250 Lactose B. P. 150 Avicel 100 500 Formulation F (Controlled Release Formulation) The formulation was prepared by wet granulation of the ingredients with a povidone solution followed by the addition of magnesium stearate and compression. mg / tablet Active Ingredient 500 Hydroxypropylmethylcellulose 112 (Methocel K4M) Premium) Lactose B. P. 53 Povidone B. P. 28 Magnesium Stearate 700 The release of the drug takes place over a period of about 6-8 hours and is completed after 12 hours.

Example 2: Capsule Formulations Formulation A A capsule formulation is prepared by mixing the ingredients of Formulation D in Example 1 above and filling a two part hard gelatin capsule. Formulation B (infra) was prepared in a similar manner.

Formulation B mg / capsule Active Ingredient 250 Lactose B. P. 143 Sodium Starch Glicolate 25 Magnesium Stearate 420 Formulation C mg / capsule Active Ingredient 250 Macrogel 4000 B. P. 350 600 The capsules of Formulation C were prepared by melting Macrogel 4000 B.P., dispersing the active ingredient in the melt in a two part hard gelatin capsule.

Formulation D mg / capsule Active Ingredient 250 Lecithin 100 Arachis Oil 100 450 The capsules of Formulation D were prepared by dispersing the active ingredient in lectin * and arachis oil and filling the dispersion into soft, elastic gelatin capsules.

Formulation E mg / capsule Active Ingredient 150.0 Vitamin E TPGS 400.0 Polyethylene Glycol 400 NF 200.5 Propylene Glycol USP 39.5 Four (4) kilograms (kg) of Vitamin E TPGS (obtained from Eastman Chemical Co.) were heated at 50 ° C until they were liquefied. Vitamin E TPGS liquefied, 2,005 kg of polyethylene glycol 400 (PEG400) (under the aldehyde, <10 ppm, obtained from Union Carbide of Dow Chemical Co.) heated to 50 ° C were added and mixed until a homogeneous solution. The resulting solution was heated to 65 ° C. 1.5 kg of active ingredient was dissolved in the liquefied solution of Vitamin E TPGS and PGE 400. 0.395 kg of propylene glycol was added at room temperature and mixed until a homogeneous solution was formed. The solution was cooled to 28-35 ° C. The solution was then degassed. The mixture was preferably encapsulated at 28-35 ° C to a filling equivalent weight of 150 mg of volatile-free compound in opaque, white, oblong, size 12 soft gelatin capsules using a capsule filling machine. The capsule caps were dried at a constant fill moisture of 3-6% water and a cap hardness of 7-10 newtons, and placed in a suitable container.

Formulation F (Controlled Release Capsule) The following controlled release capsule formulation was prepared by extruding ingredients a, b, and c using an extruder, followed by spherolization of the extrudate and drying. The dried pills were then coated with release control membrane (d) and filled into a two-piece hard gelatin capsule. mg / capsule (a) Active Ingredient 250 (b) Microcrystallized Cellulose 125 (c) Lactose B. P. 125 (d) Ethyl Cellulose 13 513 Example 3: Injectable Formulation Formulation A mg Active Ingredient 200 0.1 M Hydrochloric Acid Solution or 0.1 M Sodium Hydroxide Solution c.s. for pH 4.0 to 7.0 Sterile water c. s. for 10 ml The active ingredient was dissolved in most of the water (35 ° -40 ° C) and the pH was adjusted to between 4.0 and 7.0 with hydrochloric acid or sodium hydroxide as appropriate. The batch was then brought to the volume with the water and filtered through a sterile micropore filter in a sterile 10 ml amber glass bottle (type 1) and sealed with sterile seals and overlaps.

Formulation B Active Ingredient 125 mg Phosphate Absorber Sterile, Pyrogen Free, pH 7, c. S. for 25 ml Example 4: Intramuscular Injection Active Ingredient 200 mg Benzyl Alcohol O.lOmg Glycofurol 75 1.45 g Water for injection c. s. for 3.00ml The active ingredient was dissolved in the glycofurol. Then the benzyl alcohol was added and dissolved, and water was added to 3 ml. The mixture was then filtered through a sterile micropore filter and sealed in sterile 3 ml amber glass bottles (type 1).

Example 5: Syrup Active Ingredient 250 mg Sorbitol Solution 1.50 g Glycerol 2.00 g Sodium Benzoate 0.005 g Flavor, Peach 17.42.3169 0.0125 ml Purified Water c. s. for 5.00 ml The active ingredient was dissolved in a mixture of glycerol and most of the purified water. Then an aqueous solution of sodium benzoate was added to the solution, followed by the addition of the sorbital solution and finally the taste. The volume was completed with purified water and mixed well.

Example 6: Suppository mg / suppository in capsule form Active Ingredient 250 Fat Dura P. B. (Witepsol H15-Dynamit Nobel) 1770 2020 A quito of Witepsol H15 was melted in a container with a steam jacket at a maximum 45 ° C. The active ingredient was sieved through a 200μm mesh and the molten base was added with mixing, using a Silverson equipped with a cutting head, until a uniform dispersion was achieved. Maintaining the mixture at 45 ° C, the remainder of Witepsol H15 was added to the suspension and stirred to ensure a homogeneous mixture. The entire suspension was passed through a 250 μm stainless steel sieve and, with continued stirring, allowed to cool to 45 ° C. At a temperature of 38 ° C to 40 ° C, 2.02 g were filled into suitable 2 ml plastic molds. The suppositories were allowed to cool to room temperature. Example 7: Pessaries mg / pessary Active Ingredient 250 Dextrose Anhydrous 380 Potato Starch 363 Magnesium Stearate 7 1000 The above ingredients were mixed directly and the pessaries were prepared by direct compression of the resulting mixture.

Results of the Biological Test Maximum and Minimum Plasma Levels The maximum and minimum values in the micromolar concentrations used in this study come from the clinically determined maximum and minimum plasma levels. These values reflect the actual maximum and minimum levels achieved in patients when therapeutic doses of each drug are used as a single agent.

Antiviral activity alone or in combination Anti-HIV assay. The MT4 cell line transformed from human T cell lymphatic virus type 1 was grown and infected with the HIV strain 3B or the MN strain (Advanced Biotechnologies Inc., Columbia, Maryland) at 10 times the amount needed to cause 50% growth reduction of MT4 cells (10 x TCID50, 2 x 104 plaque forming units / cell), unless otherwise indicated. Uninfected cells were also prepared. After 1 hour of incubation, the cells were pipetted onto a 96-well disk at 12 x 10 4 cells / well. The wells contained several concentrations of zidovudine, and maximum or minimum plasma levels of 141W94 and 1592U89. The infected T lymphoblastoid cells were incubated for 5 days to allow inhibition of growth mediated by HIV-1. The plates were then treated with 28μl of 5% Nonidet P-40 (Sigma) in phosphate buffered saline (PBS) and 60μl samples were transferred to the bottom filters., 96 well plates (Idexx Corp.). The plates were placed in an automated test instrument (Idexx Screen Machine) which added propidium iodide to each well, formed a series of washes, and determined the resulting fluorescence (E). The fluorescence has been shown to directly correlate with the number of cells, allowing the quantification of the cytopathic effect (CPE) mediated by HIV-1. It was determined that the uninfected cells had a CPE of 0% and it was determined that the untreated infected cells had a CPE of 100%. The percent inhibition of CPE induced by HIV-1 and IC95 (inhibitory concentration with 95%) were determined. Figure 1 shows graphically the results of the combination of 141W94 (O.lμM, zidovudine (O.OßμM), and 1592U89 (0.35μM) against 141W94, zidovudine, and 1592U89 alone.Double Combinations: 141W94 and 1592U89 Dose matrices were prepared of in vitro response in triplicate using MT2 cells infected with HIV-1 strain IIIB.To take into account the effects of protein binding, the tissue culture medium with 10% fetal bovine serum is supplemented with the proteins human serum acid glycoprotein ai (1 mg / ml) and albumin (40 mg / ml). The interaction surface of the 3-D drug for 1592U89 and 141W94 was constructed using the MacSynergy II program. Analyzed in relation to the null reference model of independence of Bliss, this combination was synergistic with synergy volumes exceeding 100 (99% confidence). The analysis of the data set with a totally parametric form of an equation for the quantification of the drug interaction developed by Greco et al. He also indicated synergy. The parameters, with 95% confidence intervals are shown below: EC 50, l lw m-. iv CE 50, 1592u Alpha Effect 1592ii Control Estimated 394 nM 2.20 626 nM 1.60 1.14 99.99% Cl of 365-422 2.05-2.36595-656 1.51-1.68 0.53-1.75 99.98-95% 100.0 The EC50 is half the concentration of the maximum response. "m" is the parameter of the slope. Alpha is the parameter of synergism. A positive alpha and 95% Cl not including 0.0 demonstrate a statistically significant synergism. Both methods agree that this combination is significantly synergistic.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (21)

1. A combination, characterized in that it comprises 3S- [3R * (1R * 2S *)] - [3- [[(4-aminophenyl) sulfonyl] (2-methyl-propyl) -amino] -2-hydroxy-l-phenyl -methyl) propyl] carbamic, tetrahydro-3-furanyl ester, zidovudine, and (ÍS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten -l-methanol.

2. A combination, characterized in that it comprises two compounds selected from 3S- [3R * (1R *, 2S *)] - [3- [[(4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2- hydroxy-1-phenyl-methyl) propyl] -carbamic acid, tetrahydro-3-furanyl ester, zidovudine, and (SS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9- il] -2-cyclopenten-l-methanol provided that the two compounds are not zidovudine and (1S, 4R) -cis-4- [2-amino-6- (cyclo propylamino) -9H-purin-9-yl] - 2-cyclopenten-l-methanol.

3. A combination, characterized in that it comprises two compounds selected from 3S- [3R * (IR *, 2S *)] - [3- [[(4-aminophenyl) sulfonyl] (2-methylpro-? Ii) -amino] -2-hydroxy-1-phenylmethyl) propyl] carbamic, tetrahydro-3-furanyl ester or a physiologically functional derivative thereof, zidovudine or a physiologically functional derivative thereof, and (ÍS, 4R) -cis-4 - [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol or a physiologically functional derivative thereof.

4. A combination, according to claim 2, characterized in that it comprises acid 3S- [3R * (1R *, 2S *)] - [3- [[(4-aminophenyl) sulfonyl] (2-methyl-propyl) -amino] -2-hydroxy-l-phenyl-methyl)? Ropil] carbamic, tetrahydro-3-furanyl ester, or a physiologically functional derivative thereof, zidovudine or a physiologically functional derivative thereof, and (ÍS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) - 9H-purin-9-yl] -2-cyclopenten-1-methanol or a physiologically functional derivative thereof.

5. A combination, according to claim 3, characterized in that wherein the ratio of 3S- [3R * (1R *, 2S *)] - [3- [[(4-aminophenyl) sulfonyl] (2-methylpropyl ) -amino] -2-hydroxy-l-phenyl-methyl) propyl] carbamic acid, tetrahydro-3-furanyl ester, zidovudine: (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H -purin-9-yl] -2-cyclopenten-1-methanol is in the ratio of 1 to 20: 1 to 20: 1 to 10 by weight.

6. A combination according to any of claims 1 to 5 for use in medical therapy.

7. A pharmaceutical formulation characterized in that it comprises a combination according to claims 1 or 5 in association with one or more pharmaceutically acceptable carriers thereof.

8. A formulation according to claim 7 in unit dosage form.

A method for the treatment of an HIV infection in an infected animal, characterized in that it comprises treating the animal with a therapeutically effective amount of a combination as defined in any of claims 1 to 4.

10. A method of according to claim 9, characterized in that at least two of the components of the combination are administered simultaneously.

11. A method according to claim 9, characterized in that in which at least two of the components of the combination are administered sequentially.

12. A method according to claim 9, characterized in that the combination is administered as a single combined formulation.

13. A method according to any of claims 9 to 12, characterized in that the animal is a human.

14. The use of 3S- [3R * (IR *, 2S *] -. {3, 3- [[4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2-hydroxyjr-1-phenyl-methyl) propyl acid ] carbamic, tetrahydro-3-furanyl ester in the manufacture of a medicament for administration either simultaneously or sequentially with zidovudine, and (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H- purin-9-yl] -2-cyclopenten-1-methanol, for the treatment and / or prophylaxis of an HIV infection.

15. The use of zidovudine in the manufacture of a drug to be administered simultaneously or sequentially with 3S- [3R * (IR *, 2S *)] - [3- [[(4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2-hydroxy-l-phenyl-methyl) propyl] carbamic acid, tetrahydro-3-furanyl ester or , 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol for the treatment of HIV infection.

16. The use (ÍS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol in the manufacture of a medicament for simultaneous administration or sequentially with 3S- [3R * (1R *, 2S *)] - [3- [[(4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2-hydroxy-1-phenylmethyl) propyl] carbamic acid , tetrahydro-3-furanyl ester or zidovudine for the treatment of an HIV infection.

17. The use of zidovudine, 3S- [3R * (IR *, 2S *)] - [3- [[(4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2-hydroxy-1-phenylmethyl) propyl] carbamic, tetrahydro-3-furanyl ester and (ÍS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclo-penten-l-methanol in the manufacture of a medicament for the treatment and / or prophylaxis of an HIV infection.

18. The use as claimed in any of claims 14 to 18 for the treatment of an HIV infection resistant to nucleoside or non-nucleoside inhibitors.

19. The use as claimed in any of claims 14 to 18 in the treatment of AIDS.

20. Use as claimed in any of claims 14 to 18 in the treatment of conditions related to AIDS or the AIDS dementia complex. 21.

21. A patient package characterized in that it comprises at least one active ingredient selected from 3S- [3R * (1R *, 2S *)] - [3- [[(4-aminophenyl) sulfonyl] (2-rneti1- propyl) -amino] -2-hydroxy-l-phenyl-methyl) propyl] carbamic, tetrahydro-3-furanyl ester, zidovudine, and (ÍS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclo-penten-1-methanol and an information insert containing instructions on the use of at least 3S- [3R * (1R *, 2S *)] - [3- [[(4-aminophenyl) sulfonyl] (2-methyl-propyl) -amino] -2-hydroxy-l-phenyl-methyl) propyl] carbamic acid, tetrahydro-3-furanyl ester, and (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol together in combination.