JP2001509786A - A combination comprising VX478, zidovudine, and / or 1592U89 for use in treating HIV - Google Patents

Abstract

(57) [Summary] The present invention relates to 3S- [3R ^* (1R ^* , 2S ^* )]-[3 [[(4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2-hydroxy- 1-phenyl-methyl) propyl] carbamic acid, tetrahydro-3-furanyl ester (141W94), 3'-azido-3'-deoxythymidine (zidovudine), and (1S, 4R) -cis-4- [2-amino -6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol (1592U89) having anti-HIV activity. The invention also relates to pharmaceutical compositions comprising this combination and their use in the treatment of HIV infection, such as infection by HIV mutants that are resistant to nucleoside and / or non-nucleoside inhibitors.

Description

DETAILED DESCRIPTION OF THE INVENTION           VX478, zidovudine for use in treating HIV;           And / or a combination comprising 1592U89   The present invention relates to 3S- [3R^*(1R^*, 2S^*)]-[3 [[(4-aminophenyl Ru) sulfonyl] (2-methylpropyl) -amino] -2-hydroxy-1-phenyl Enyl-methyl) propyl] carbamic acid, tetrahydro-3-furanylester ((3S) -tetrahydro-3-furanyl = N-((1S, 2R) -3- (4 -Amino-N-isobutylbenzenesulfonamido) -1-benzyl-2-hydrido Roxy-propyl) carbamate, 4-amino-N-((2 syn, 3S) -2- Hydroxy-4-phenyl-3-((S) -tetrahydrofuran-3-yloxy (Cyclocarbonylamino) -butyl) -N-isobutyl-benzenesulfonamide, 141W94, VX-478), 3'-azido-3'-deoxythymidine (zide Budin), and (1S, 4R) -cis-4- [2-amino-6- (cyclopro Pyramino) -9H-purin-9-yl] -2-cyclopentene-1-methano (1592U89) having anti-HIV activity Related. The present invention relates to pharmaceutical compositions comprising this combination, and nucleosides and And / or infection by HIV mutants resistant to non-nucleoside inhibitors And their use in the treatment of HIV infections.   Zidovudine is associated with AIDS, AIDS-related complications (ARC), and AIDS dementia Treatment of HIV infection, such as associated clinical symptoms such as disease (ADC) and / or Prevention and treatment of patients with asymptomatic HIV infection or positive for anti-HIV antibodies It is well positioned as an important and useful chemotherapeutic agent for treatment. Zidov When treated with gin, asymptomatic patients infected with HIV have a longer disease-free period, Symptomatic patients lose fat.   The widespread clinical use of zidovudine in the treatment of such infections and conditions In some cases, after prolonged treatment, the virus may respond to zidovudine. Develops some degree of resistance and may therefore lose sensitivity to the drug Have been observed.   Therapeutic agent 1592U89 (EP 0434450) describes HIV. Activity, low cytotoxicity, and AIDS and HIV such as ADC Promising anti-HI showing excellent brain penetration important for the treatment of central nervous system symptoms associated with V is a candidate for a chemotherapeutic agent.   4-amino-N-((2 syn, 3S) -2-hydroxy-4-phenyl-3- ((S) -tetrahydrofuran-3-yloxycarbonylamino) -butyl) -N-isobutyl-benzenesulfonamide (141W94) is available from HIV Aspa. It is a sulfonamide having rutile protease inhibitory activity. 141W94 is Particularly suitable for inhibiting HIV-1 and HIV-2 viruses. Virus A virus-encoded protease that is essential for the replication of Necessary for processing of protein precursor. Interfering with the processing of protein precursors can lead to infection The formation of sex virions is inhibited. Therefore, using inhibitors of viral protease Thus, chronic and acute viral infections can be prevented or treated.   To date, the treatment of HIV infection has largely consisted of zidovudine, didanosine (Ddl), zalcitabine (ddC), and sudavudine (d4T). Dependent on monotherapy with creoside reverse transcriptase inhibitors. However, this These drugs are ultimately less effective due to the emergence and toxicity of HIV-resistant mutants. Disappears. Therefore, new treatments are needed.   The combination of zidovudine and ddC or ddl has been shown in patients infected with HIV. Have shown promising results (New Eng. J. Med., 1992, 329 (9), 581-587; Conference Program Abstracts on 1993 and AIDS, 1993 9R, Abstract US-B2 5-1). However, drugs with the same site of action are antagonistic or additive. It should be noted that these results are unexpected, as they are often the case.   Surprisingly, 141W94, zidovudine and 1592U89 combined Was found to provide a synergistic anti-HIV effect. This pair of drugs By using synergism, a synergistic antiviral effect, a more complete viral Suppression, longer term suppression, limiting the emergence of drug-resistant HIV mutants And that better control of drug-related toxicity can be achieved. It is a feature.   According to one aspect of the present invention, 141W94 or a physiologically functional derivative thereof, zid Budin or a physiologically functional derivative thereof, and 1592U89 or its physiology Combinations comprising a functional derivative are provided.   Zidovudine can exist in keto or enol tautomeric forms, It will be appreciated that the use of such tautomeric forms is within the scope of the invention. 1592U89 is usually provided substantially free of the corresponding enantiomer. Ie, the corresponding enantiomer is only about 5% (w / w), Or less than about 2% (weight / weight), especially less than 1% (weight / weight) .   As used herein, the term "physiologically functional derivative" refers to 141W94, zid. Budin, or any physiologically acceptable salt, ether, d Stels, salts of this ester, or any solvates thereof and their physiology When administered to a biologically functional derivative or recipient, such a compound or its compound Can provide (direct or indirect) antiviral active metabolites or residues And any other compound.   Preferred esters according to the invention are the following group: (1) carboxylic esters. The non-carbonyl residue of the carboxylic acid portion of the ester group is linear or branched Chain alkyl (eg, methyl, n-propyl, tert-butyl, or n-butyl) , Cycloalkyl, alkoxyalkyl (eg, methoxymethyl), aral Kill (eg, benzyl), aryloxyalkyl (eg, phenoxymethyi) ), Aryl (eg, optionally halogen, C_{1 ~Four}Alkyl or C_{1 ~Four} Phenyl substituted by alkoxy, etc.), or amino (2) alkyl- or aralkylsulfonyl (for example, methanesulfo (3) amino acid esters (for example, L-variate); Or L-isoleucyl); and (4) independently selected from phosphonates Is done. In such esters, any alkyl included, unless otherwise specified The residue is advantageously 1 to 18 carbon atoms, in particular 1 to 6 carbon atoms, more preferably Or 1 to 4 carbon atoms. Any cycloalkyl contained in such esters Alkyl residues advantageously contain 3 to 6 carbon atoms. Present in such esters The optional aryl residue advantageously comprises a phenyl group. Any of the above compounds Any expression for any includes its physiologically acceptable salt expression.   Particularly preferred esters are the mono-, di- and tri-phosphates of zidovudine. Or any other compound that, when administered to a human subject, Providing (directly or indirectly)-, di- and tri-phosphate esters; You can do it.   A preferred derivative of 1592U89 is the tri-phosphate ester of (-) carbovir. Tell.   141W94, a physiologically acceptable salt of zidovudine or 1592 U89, And examples of their physiologically acceptable derivatives include alkali metals (eg, Sodium), alkaline earths (eg magnesium), ammonium and And NX_Four ⁺(However, X is C_{1 ~Four}Derived from a suitable base such as Salt. Physiologically acceptable salts of hydrogen or amino groups Acetic acid, lactic acid, tartaric acid, malic acid, isethionic acid, lactobionic acid, and Organic carboxylic acids such as succinic acid, methanesulfonic acid, ethanesulfonic acid, ben Organic sulfonic acids such as zensulfonic acid, p-toluenesulfonic acid, and hydrochloric acid , Sulfuric acid, phosphoric acid, and salts of inorganic acids such as sulfamic acid. Hid Physiologically acceptable salts of the compounds of the roxy group include Na⁺, NH_Four ⁺,and NX_Four ⁺(However, X is C_{1 ~Four}In combination with a suitable cation such as And anions of the above compounds.   For therapeutic use, salts of 141W94, zidovudine and 1592U89 are: Are physiologically acceptable, that is, they are physiologically acceptable acids or Or a salt derived from a base. However, it is not physiologically acceptable Acid or base salts can also be present in the preparation or purification of physiologically acceptable compounds, for example. Can be used. Is it derived from a physiologically acceptable acid or base? All salts, whether or not, are within the scope of the present invention.   Preferred salts of 1592U89 are succinate and hemisulphate.   141W94 or a physiologically functional derivative thereof, zidovudine or a physiological derivative thereof Comprising a functional derivative, and 1592 U89 or a physiological functional derivative thereof. Combinations may be referred to hereinafter as combinations according to the present invention.   The invention relates to nucleoside inhibitors, in particular zidovudine, lamivudine, dd1, dd c or d4T, or a combination thereof, and nevirapine (B1-RG-5 87), non-nuclear compounds such as loviride (α-APA) and delabridine (BHAP). HIV infections, such as infections of HIV mutants that are resistant to creoside inhibitors Also provided is a combination according to the invention for use in the treatment of Further, the association according to the invention In addition, AIDS and AIDS-related complications (ARC), progressive systemic phosphorus Paposis (PGL), Kaposi's sarcoma, Idiopathic thrombocytopenic purpura, AIDS-related god Transformational symptoms, such as AIDS dementia complications, multiple sclerosis or tropical paraperesi And anti-HIV antibody positive and HIV positive symptoms, such as in asymptomatic patients It is particularly useful for treating related conditions such as these conditions.   According to another embodiment, the present invention relates to a mammal, such as an infected animal, for example a human. A method of treating HIV infection in a product, comprising 141W94, zidovudine and And 1592U89, or a therapeutically effective amount of a physiologically functional derivative thereof. There is provided a method comprising treating the animal.   As used herein, the term treatment refers not only to treating an infectious disease or condition that has developed, It is extended to prevention.   The compounds of the combination may be administered simultaneously or sequentially in the same or different pharmaceutical formulations. It will be appreciated that it can be administered. In the case of sequential administration, the second The administration of the third and the third active ingredient will result in a synergistic therapeutic effect of the combination of these active ingredients. You should not be late enough to lose. In addition, 141W94, zidovudine, and And 1592U89, or any physiologically functional derivative thereof, were administered simultaneously. Administered sequentially or sequentially, individually or in multiples, or any of them. Can be administered in combination. 141W94, zidovudine and 1592 U89 is preferably a simultaneous or sequential separate pharmaceutical formulation, most preferably the same. Sometimes administered.   The present invention relates to the treatment and / or treatment of HIV infection and related clinical conditions as described above. Or simultaneously or sequentially with zidovudine and 1592U89 for prevention Also provided is the use of 141W94 in the manufacture of a medicament for subsequent administration. 141 W94, zidovudine or 1592U89, or any combination thereof, It will be understood that they can also be used for the manufacture of the medicament described.   141W94, zidovudine or 1592U89, or any of their physiology The synergistic effect of the combination of biologically functional derivatives is, for example, 1-20: 1-20: 1-10 (Weight), preferably 1-10: 1 to 10: 1 to 5 (weight), particularly 1 to 3: 1 3: 1 to 2 (weight). 141W94: zidovudine: 15 For a convenient human of 92U89, 1.5: 1: 1, 2: 1: 1, 3: 1: 1, And 4: 1: 1.   Advantageously, each compound, when used alone, is an antiviral Can be used in combination in an amount that exhibits activity.   141W94, zidovudine and 15 required to be effective as anti-HIV drugs Of course, the amount of the 92U89 combination can vary, and ultimately Is at the doctor's discretion. Possible factors include route of administration and treatment. Nature of the object, weight, age and general symptoms of the animal, and the nature of the disease being treated And severity.   Generally, a suitable dose of 141W94 for human administration is 5-100 m g / kg body weight / day, advantageously in the range of 8 to 70 mg / kg body weight / day. And preferably in the range of 8-50 mg / kg body weight / day.   Suitable dosages of zidovudine range from 3 to 120 mg / kg recipient body weight / day. Yes, preferably in the range of 6-90 mg / kg body weight / day, most preferably It can range from 0 to 30 mg / kg body weight / day.   Generally, 1592 U89 suitable for administration to humans for the treatment of HIV injection The dosage ranges from 0.1 to 100 mg / kg recipient body weight / day, preferably 0.5-50 mg / kg body weight / day, most preferably 7-30 mg / kg body weight / day. kg body weight per day.   Unless otherwise noted, all active ingredient weights are calculated relative to the drug itself . 141W94, zidovudine, 1592U89, or any solvate thereof In the case of the physiologically functional derivative of, the numbers increase proportionately. The desired dosage is One, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day Giving It can be preferably provided as an amount. These sub-doses are, for example, units 1 to 1500 mg, preferably 5 to 1000 m, of active ingredient per dosage form g, most preferably from 10 to 700 mg in unit dosage form. . Alternatively, administer the dose as a continuous infusion if required by the recipient's symptoms can do.   The combination of ingredients, which can be referred to as the active ingredient, is a mammal, e.g. The animal can be administered for therapeutic purposes in the usual manner.   It is possible for the active ingredient to be administered as the raw compound in combination, Preferably they are provided as commodities. Pharmaceutical formulations according to the invention According to one or more pharmaceutically acceptable carriers or excipients, and And optionally together with other therapeutic agents. The carrier (s) are prescribed In the sense that it is compatible with the other ingredients and is not harmful to its recipients Must be acceptable. Administer the individual components of the combination individually Sometimes, they are generally each provided as a pharmaceutical formulation. After that, prescription The expression product refers to a combination or formulation containing its components, unless otherwise specified. You.   141W94, zidovudine and 1592U89, or any of their physiology The combination of biologically functional derivatives is conveniently provided as a pharmaceutical formulation in a single dosage form can do. Advantageous unit dosage formulations are 50 mg to 3 g each, e.g. It contains active ingredients in amounts of, for example, 100 mg to 2 g.   Any two active ingredients in unit dosage form for simultaneous or sequential administration can be combined with a third It is also possible to combine with the active ingredients, for example a typical unit dosage is 14 Each of 1W94 and zidovudine is 50 mg to 3 g, preferably 141W94. And zidovudine from 100 mg to 2 g, respectively, or 141W94 and 15 92U89 in 50 to 3 g each, preferably 141W94 and 1592U8 9 in amounts of 100 mg to 2 g each.   Another feature of the invention is that 141W94, zidovudine and 1592 At least two selected from U89 or any physiologically functional derivative thereof Unit dosage form comprising a class of active ingredients and their pharmaceutically acceptable carriers State is provided.   Two activities selected from 141W94, zidovudine and 1592U89 Administration of the compound is preferably as a step prior to administration of the remaining third active ingredient. It is an essential part of the invention. Combination of 141W94 and zidovudine, and 1 41W94 and 1592U89 are preferred.   Furthermore, it was found that a synergistic effect was observed when the above compounds were combined. did.   Another feature of the invention is that 141W94, zidovudine and 1592 A combination comprising two compounds selected from U89, wherein the two Compounds are provided wherein the compound is not zidovudine and 1592U89. 141W Combinations comprising 94 and 1592 U89 are preferred. Two such The proportions of the components of the combination of compounds are advantageously in the three combinations of the present invention. Of the related compounds.   Pharmaceutical formulations include all steps of treatment in a single package, usually a blister pack Often prescribed to patients in "patient packs". Patient pack Compared to traditional prescriptions, pharmacists subdivide drug supply from bulk supply to patient The patient must always be able to use the package It has the advantage that an insert can be obtained. The physician can mix the packaging inserts Patients will be more likely to follow the instructions of Indicated.   A single patient contained within a packaging insert that directs the patient for correct use of the invention Administration of the combination of the invention in packs or patient packs of the respective formulation It will be appreciated that this is another desirable feature of the present invention.   According to another aspect of the present invention, at least one activity of the combination of the present invention. Active ingredient 141W94, zidovudine or 1592U89, and the combination of the present invention. A two-component or three-component composition comprising an information insert containing the use of A minute pack is provided.   According to another aspect of the present invention, 141W94 or its associated with individual administration. A physiologically functional derivative of zidovudine or a physiologically functional derivative thereof; 592U89 or at least one of its physiologically functional derivatives. A patient pack is provided.   Formulations include oral, rectal, nasal, topical (dermal, buccal and sublingual), vaginal Suitable for intra-or parenteral (subcutaneous, intramuscular, intravenous and transdermal) administration Can be The formulations may conveniently be presented in unit dosage form and It can be prepared by any method known in the art. Such a method Another feature of the present invention is that the active ingredient constitutes one or more types of modifying ingredients. Includes combining with the carrier. In general, formulations include the active ingredient in a liquid form. Uniform and tight assembly with body carrier or finely divided solid carrier or both It is prepared by combining and then, if necessary, shaping the product.   Formulations of the present invention suitable for oral administration include capsules, caplets, Tablets or tablets, each containing a predetermined amount of active ingredient and As a powder or granules, as an aqueous or non-aqueous liquid solution or suspension Or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion can do. Active ingredient provided as a bolus, electuary or paste You can also.   Tablets may be compressed or molded, optionally with one or more modifying ingredients. Can be manufactured. Compressed tablets may be prepared in suitable equipment, optionally with a binder ( For example, povidone, gelatin, hydroxypropyl methylcellulose), lubricant , Inert diluents, preservatives, disintegrants (eg sodium starch glycolate, cross-linking) Povidone, cross-linked sodium carboxymethylcellulose), surfactants Compresses the active ingredient in free-flowing form, such as a powder or granules, mixed with a dispersant. Can be prepared. Molded tablets may be prepared in an appropriate Manufactured by molding a mixture of powdered compounds moistened with a liquid diluent . Tablets can optionally be coated or shallowly scored, In addition, hydroxypropyl methylcellulose can be used to obtain a desired release curve. Formulated for sustained or controlled release of the active ingredient in various ratios You can also. Tablets may be provided with an enteric coating, Can be released in parts of the digestive tract.   Formulations suitable for topical administration in the mouth include flavored bases, usually Loin and gum arabic or tragacanth containing active ingredients Such as Zenji, gelatin and glycerin, or sucrose and gum arabic Tablets containing the active ingredient in an inert base, such as a paste, and a suitable liquid Gargles comprising the active ingredient in carriers. Formulation for rectal administration Is a suppository having a suitable base comprising, for example, cocoa butter or salicylate. Can be provided.   Topical administration can also be performed by a transdermal iontophoresis device.   Formulations suitable for vaginal administration include pessaries, tampons, creams, gels and pastes , Foams, or active ingredients are known in the art to be suitable. Can be provided as a spray formulation containing such a carrier.   Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferred. Also preferably provided as unit dose suppositories. A suitable carrier is Kaka Fats and other materials commonly used in the art. suppository Mixes active combination with softened or molten carrier (s) After that, it can be conveniently produced by cooling and molding in a mold.   Formulations suitable for parenteral administration include antioxidants, buffers, bacteriostats, and Aqueous solutions that can contain solutes that render the product isotonic with the blood of the intended recipient And non-aqueous isotonic sterile injectable solutions, and water which can contain suspending agents and thickening agents. Sterile aqueous and non-aqueous suspensions and liposomes, or compounds Include other particulate systems designed to target more than one organ It is. These formulations may be presented in unit-dose or multi-dose sealed containers, such as amplifiers. Bottles and vials, and provide a sterile liquid container, such as water for injection, immediately before use. The carrier can be stored under lyophilized conditions by simply adding a carrier. You. Extemporaneous injection solutions and suspensions may be sterile powders, granules and tablets of the kind previously described. Can be prepared.   Preferred unit dosage formulations are the daily doses or daily doses of the active ingredients cited above. A substance containing a subdose (daily sudose), or an appropriate fraction thereof.   The formulation of the present invention comprises, in addition to the components specifically described above, Other agents common in the art with respect to type can be formulated, e.g., oral Suitable for administration include other agents such as sweeteners, thickeners, and flavoring agents. It should be understood that they can be combined.   The compounds of the combination according to the invention can be obtained in a customary manner. Zidovudine For example, by the method described in US Pat. No. 4,724,232. And the contents of the above patent specification are cited herein as a part of the disclosure. . Zidovudine is available from Aldrich Chemical Co., Milwaukee, Wyoming, USA It can also be obtained from.   141W94 is prepared according to the method described in PCT application WO 94/05639. The content of the above patent specification is hereby incorporated by reference as part of its disclosure. Quoted in the handbook.   1592U89 is described in EP 0 434 450 or PCT application It can be produced by the method described in PCT / GB / 4500225. The contents of the above patent specification are incorporated herein by reference as part of the disclosure thereof.   The following examples are for illustrative purposes only and are not intended to limit the scope of the invention. It does not do. "Active ingredient" is 141W94, zidovudine, 1592U8 9, or a complex thereof, or a physiologically functional derivative of any of the above compounds RepresentsExample 1 Tablet Formulation   Formulations A, B and C below were wet-granulated with a solution of povidone into ingredients followed by Prepared by adding and compressing magnesium stearate.Formulation A mg / tablet Active ingredient 250 Lactose, British Pharmacopoeia 210 Povidone, British Pharmacopoeia 15 Sodium starch glycolate 20 Magnesium stearate 5                                         500Formulation B mg / tablet Active ingredient 250 Lactose, British Pharmacopoeia 150 Avicel PH 101 60 Povidone, British Pharmacopoeia 15 Sodium starch glycolate 20 Magnesium stearate 5                                         500Formulation C mg / tablet Active ingredient 250 Lactose, British Pharmacopoeia 200 Starch 50 Popidone 5 Magnesium stearate 4                                         359   The following formulations D and E are prepared by direct compression of the mixed ingredients. Formulation E Lactose is of the direct compression type (Dairy Crest- "Zeparox").Formulation D mg / tablet Active ingredient 250 Pregelatinized starch NF15150                                       400Formulation E mg / tablet Active ingredient 250 Lactose, British Pharmacopoeia 150 Avicel100                                         500Formulation F (Controlled Release Formulation)   The formulation is wet-granulated with a solution of povidone, followed by magnesium stearate. Prepared by adding and compressing.                                         mg / tablet Active ingredient 500 Hydroxypropyl methylcellulose 112 (Methocel K4M Premium) Lactose, British Pharmacopoeia 53 Povidone, British Pharmacopoeia 28 Magnesium stearate 7                                         700   The drug is released over about 6-8 hours and is complete after 12 hours.Example 2: Capsule formulation Formulation A   Mix the capsule formulation with the ingredients of Formulation D of Example 1 above and mix Prepared by filling into hard gelatin capsules. Formulation B (described below) Is prepared in a similar manner.Formulation B mg / capsule Active ingredient 250 Lactose, British Pharmacopoeia 143 Sodium starch glycolate 25 Magnesium stearate 2                                         420Formulation C mg / capsule Active ingredient 250 Macrogel 4000, British Pharmacopoeia350                                         600   Formula C capsules melt Macrogel 4000, British Pharmacopoeia and dissolve the active ingredient Dispersed in the melt and filling the melt into a two-part hard gelatin capsule. And prepared byFormulation D mg / capsule Active ingredient 250 Lecithin 100 Peanut oil100                                         450   Capsules of formulation D are prepared by dispersing the active ingredient in lecithin and peanut oil Is prepared by filling 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   Add 4 kg of Vitamin E TPGS (obtained from Eastman Chemical Co.) at 50 ° C. Heated and liquefied. Add liquefied vitamin E TPGS to the polyet Tylene glycol 400 (PEG400) (low aldehyde, <10 ppm, Unio n from Carbide or Dow Chemical Co.) and mix to form a homogeneous solution. Was completed. The resulting solution was heated to 65C. 1.5 kg of active ingredient, vitamin E It was dissolved in a liquefied solution of TPGS and PEG400. Propylene glycol 0. 395 kg was added and mixed at room temperature to form a homogeneous solution. Solution 28-35 C. Next, the solution was degassed. The mixture is preferably 28-3 At 5 ° C., 150 mg of the volatile-free compound at a filling weight of 150 mg using a capsule filling machine Encapsulated in a rectangular white opaque soft gelatin capsule of size 12. Capsule shell with constant filling moisture 3-6% and shell hardness 7-10 Newt And dried in a suitable container.Formulation F (Controlled Release Capsule)   The following controlled release capsule formulation is prepared by extruding components a, b and c using an extruder. After extrusion by extrusion, the extruded product is prepared by spheroidization and drying. next The dried pellets are coated with a controlled release membrane (d) and consist of two parts Hard Quality gelatin capsules.                                         mg / capsule (a) Active ingredient 250 (b) microcrystalline cellulose 125 (c) Lactose, British Pharmacopoeia 125 (d) Ethyl cellulose13                                         513Example 3: Formulation for injection Formulation A mg Active ingredient 200 0.1 M hydrochloric acid solution or sodium hydroxide An appropriate amount of 0.1 M solution was added to adjust the pH to 4.0 to 7.0. Add sterile water and an appropriate amount to make the total amount 10 ml   Dissolve the active ingredient in most of water (35 ° -40 ° C) and add hydrochloric acid or sodium hydroxide The pH is adjusted to 4.0 to 7.0 by adding an appropriate amount of lithium. Then, this batch with water As a constant volume, filter through a sterile microporous filter and sterilize 10 ml of amber Place in a glass vial (type 1) and seal with a sterile lid and overseal.Formulation B Active ingredient 125mg Sterile, pyrogen-free, pH 7 phosphoric acid Add an appropriate amount of buffer to make a total volume of 25 ml.Example 4: Intramuscular injection Active ingredient 200mg Benzyl alcohol 0.10g Glycofurol 75 1.45g Add an appropriate amount of water for injection to make the total amount 3.00 ml.   The active ingredient is dissolved in glycofurol. Next, add benzyl alcohol Dissolve and add water to make up to 3 ml. The mixture is then sterilized with a microporous filter. And sealed in a sterile 3 ml amber glass vial (type 1).Example 5: Syrup Active ingredient 250mg Sorbitol solution 1.50g Glycerol 2.00g Sodium benzoate 0.005g Flavor, Peach 17.42.3169 0.0125ml Add an appropriate amount of purified water to make the total amount 5.00 ml.   The active ingredient is dissolved in most mixtures of glycerol and purified water. Next, Benzo After adding an aqueous solution of sodium citrate to the solution, add the sorbitol solution and finally Add the bar. Make up to volume with purified water and mix well.Example 6: Suppository mg / capsule suppository Active ingredient 250 Hard fat, British Pharmacopoeia (Witepsol H15-Dynamit Nobel)1770                                         2020   One fifth of Witepsol H15 was fitted with a steam jacket with a maximum temperature of 45 ° C Melt in a pan. The active ingredient is sized with a 200μm sieve and equipped with a cutting head. Using the obtained Silverson, add to the molten base with mixing to obtain a smooth dispersion. Mixed While keeping the mixture at 45 ° C, add Witepsol H15 to the suspension and stir to homogenize. Make a mixture. The whole suspension was stirred for 250 μm with continuous stirring. Pass through a stainless steel screen and cool to 45 ° C. 38 ° C to 40 ° C temperature At the end, 2.02 g of the mixture is filled into a suitable 2 ml plastic mold. Suppository Allow to cool to room temperature.Example 7: Pessary mg / pessary Active ingredient 250 Dextrose anhydrous 380 Potato starch 363 Magnesium stearate 7                                         1000   The above ingredients are directly mixed to form a pessary, and the resulting mixture is prepared by direct compression. To make.Biological test results Highest and lowest plasma concentrations   The highest and lowest micromolar concentrations used in this study were Obtained from the highest and lowest crystal concentrations measured. These values are The actual maximum concentration that can be obtained in patients when using therapeutic doses of each drug and And the lowest concentration (trough level).Antiviral activity alone or in combination Anti-HIV assay   Cells transformed with human T-cell lymphotropic virus type 1 Grow line MT4 and reduce MT4 cell growth by 50% unless otherwise noted 10 times the amount required for (10 x TCID₅₀, 2 × 10^FourPlaque-forming unit / cell ) HIV-1 strain 3B or MN (Advanced Biotechnologies Inc., Colombia) A, Maryland). Mock infected cells were also prepared. One hour After incubation, cells were placed in a 96-well dish at 12 × 10^FourCells / well Collected. Wells contain various concentrations of zidovudine, 141W94 and 1592. It contained the highest and lowest crystal concentrations of U89. Infected T lymphoblastoid cells Incubation for 5 days to effect HIV-1 mediated growth inhibition Was. The plate was then plated with 5% Nonidet P-40 (Sigma) / phosphate buffered saline (PBS). ) Treat with 28 μl and transfer 60 μl of sample to 96 well plate with filter bottom (Idexx Corp.). Plate with propidium iodide in each well Into an automatic analyzer (Idexx Screen Machine) with the addition of Fluorescence (E) was measured. Fluorescence directly correlates with cell number, It has been shown that the mediated cytotoxic effect (CPE) can be quantified. Not yet Infected cells were determined to have 0% CPE and infected untreated cells were 100% Determined to have CPE. Inhibition rate of CPE induced by HIV-1 and IC₉₅(95% inhibitory concentration) was measured.   FIG. 1 shows 141W94 (0.1 μM), zidovudine (0.06 μM) and The combination of 1592U89 (0.35 μM) was combined with 141W94, zidovudine and 3 shows a graph of the result of comparison with 1592U89 alone.Two combinations: 141W94 and 1592U89   Three in vitro dose matrices were infected with the HIV-1111B strain. Prepared using MT-2 cells. To explain the effect of protein binding, Tissue culture containing 0% fetal calf serum contains human serum protein α.₁Acid sugar protein Quality (1 mg / ml) and albumin (40 mg / ml). 1592 The 3-D drug interaction surface for U89 and 141W94 was Constructed using cSynergy II. Bliss Independence Analysis shows that this combination is synergistic, with a synergistic capacity of over 100 (99% reliability). Quantification of drug interactions developed by Greco et al. Analysis of data with the full parametric form of the equation for It was shown that. Parameters with 95% confidence intervals are shown below.   EC₅₀Is the half-maximal reaction concentration. “M” is the slope parameter. α is , Synergistic parameters. Positive and 95% Cl not including 0.0 are statistical It shows a chemically significant synergy. In both cases, this combination is significantly synergistic There is some agreement.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31:63) A61K 31:63) (A61K 31/7072 (A61K 31/7072 31:52) 31:52 (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ) , BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK EE, ES, FI, GB, GE, GH, HU, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK , MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor David, Walter, Barry, North Carolina, USA, Chapel, Hill, South, Lakeshore, Drive, 1810

Claims (1)

[Claims] 1. 3S- [3R ^* (1R ^* , 2S ^* )]-[3 [[(4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2-hydroxy-1-phenylmethyl) propyl] carbamic acid, Tetrahydro-3-furanyl ester, zidovudine, and (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol Comprising, combinations. 2. 3S- [3R ^* (1R ^* , 2S ^* )]-[3 [[(4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2-hydroxy-1-phenylmethyl) propyl] carbamic acid, From tetrahydro-3-furanyl ester, zidovudine, and (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol A combination comprising two selected compounds, wherein the two compounds are zidovudine and (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino)- 9H-Purin-9-yl] -2-cyclopenten-1-methanol. 3. 3S- [3R ^* (1R ^* , 2S ^* )]-[3 [[(4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2-hydroxy-1-phenylmethyl) propyl] carbamic acid, Tetrahydro-3-furanyl ester or a physiologically functional derivative thereof, zidovudine or a physiologically functional derivative thereof, and (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purine- 9-yl] -2-cyclopentene-1-methanol or a physiologically functional derivative thereof. 4. 3S- [3R ^* (1R ^* , 2S ^* )]-[3 [[(4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2-hydroxy-1-phenylmethyl) propyl] carbamic acid, Tetrahydro-3-furanyl ester or a physiologically functional derivative thereof, zidovudine or a physiologically functional derivative thereof, and (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purine- 3. The combination according to claim 2, comprising 9-yl] -2-cyclopentene-1-methanol or a physiologically functional derivative thereof. 5. 3S- [3R * (1R ^* , 2S ^* )]-[3 [[(4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2-hydroxy-1-phenylmethyl) propyl] carbamic acid, Ratio of tetrahydro-3-furanyl ester: zidovudine: (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol Is 1 to 20: 1 to 20: 1 to 10 (weight). 6. The combination according to any one of claims 1 to 5, for use in medical treatment. 7. Pharmaceutical formulation comprising a combination according to any one of claims 1 to 5 together with one or more pharmaceutically acceptable carriers thereof. 8. 8. The formulation according to claim 7, in unit dosage form. 9. A method of treating HIV infection in an infected animal, comprising administering to said animal a therapeutically effective amount of the combination of any one of claims 1-4. 10. 10. The method of claim 9, wherein at least two of the components of the combination are co-administered. 11. 10. The method of claim 9, wherein at least two of the components of the combination are administered sequentially. 12. 10. The method of claim 9, wherein the combination is administered as a single combined formulation. 13. The method according to any one of claims 9 to 12, wherein the animal is a human. 14． Zidovudine and (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-for the treatment and / or prevention of HIV infection. In the manufacture of a medicament for simultaneous or sequential administration with cyclopentene-1-methanol, 3S- [3R ^* (1R ^* , 2S ^* )]-[3 [[(4-aminophenyl) sulfonyl] (2-methylpropyl ) -Amino] -2-hydroxy-1-phenylmethyl) propyl] carbamic acid, tetrahydro-3-furanyl ester. 15. For the purpose of treating and / or preventing HIV infection, 3S- [3R ^* (1R ^* , 2S ^* )]-[3 [[(4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2. -Hydroxy-1-phenylmethyl) propyl] carbamic acid, tetrahydro-3-furanyl ester or (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl Use of zidovudine in the manufacture of a medicament for simultaneous or sequential administration with 2-cyclopentene-1-methanol. 16. For the purpose of treating and / or preventing HIV infection, 3S- [3R ^* (1R ^* , 2S ^* )]-[3 [[(4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2. -Hydroxy-1-phenylmethyl) propyl] carbamic acid, tetrahydro-3-furanyl ester or zidovudine in the manufacture of (1S, 4R) -cis-4- [2-amino-6 in the manufacture of a medicament for simultaneous or sequential administration. Use of-(cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol. 17． Zidovudine, 3S- [3R ^* (1R ^* , 2S ^* )]-[3 [[(4-aminophenyl) sulfonyl] (2-methylpropyl) in the manufacture of a medicament for the treatment and / or prevention of HIV infection -Amino-2-hydroxy-1-phenylmethyl) propyl] carbamic acid, tetrahydro-3-furanyl ester and (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H- Purine-9-yl] -2-cyclopentene-1-methanol. 18. 19. Use according to any one of claims 14 to 18 for the treatment of an HIV infection resistant to nucleoside or non-nucleoside inhibitors. 19. Use according to any one of claims 14 to 18 for the treatment of AIDS. 20. Use according to any one of claims 14 to 18 in the treatment of AIDS-related symptoms or AIDS dementia complications. 21. 3S- [3R ^* (1R ^* , 2S ^* )]-[3 [[(4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2-hydroxy-1-phenylmethyl) propyl] carbamic acid, From tetrahydro-3-furanyl ester, zidovudine, and (1S, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol At least one active ingredient selected and at least 3S- [3R ^* (1R ^* , 2S ^* )]-[3 [[(4-aminophenyl) sulfonyl] (2-methylpropyl) -amino] -2- (Hydroxy-1-phenylmethyl) propyl] carbamic acid, tetrahydro-3-furanyl ester, and (1S, 4R) -cis-4- [2-amino-6- ( Black propylamino) -9H- purin-9-yl] - 2-cyclopentene-1-methanol in combination with comprising an information insert containing usage when used, the patient pack.