Antiviral therapy

Abstract

To provide therapeutic agents suitable for use in combination and feasible pharmaceutical compositions for treating HIV infection.SOLUTION: The present invention relates to combinations of compounds comprising HIV integrase inhibitors and other therapeutic agents. Such combinations are useful in the inhibition of HIV replication, in the prevention and / or treatment of infection with HIV, and in the treatment of AIDS and / or ARC.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to combinations of compounds comprising an HIV integrase inhibitor and another therapeutic agent. [Background technology]

[0002] The human immunodeficiency virus ("HIV") is a virus that causes acquired immunodeficiency syndrome ("AIDS"), a condition that results in the destruction of the immune system, particularly CD4 + HIV is the causative agent of AIDS (a disease characterized by the destruction of T cells with resultant susceptibility to opportunistic infections) and its precursor, AIDS-related complex ("ARC"), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever, and weight loss. HIV is a retrovirus; its conversion of RNA to DNA is achieved by the action of the enzyme reverse transcriptase. Compounds that inhibit the function of reverse transcriptase inhibit the replication of HIV in infected cells. Such compounds are useful in the prevention or treatment of HIV infection in humans.

[0003] HIV requires a coreceptor in addition to CD4 to enter target cells. Chemokine receptors function together with CD4 as coreceptors for HIV. The chemokine receptors CXCR4 and CCR5 have been identified as the major coreceptors for HIV-1. CCR5 acts as the major coreceptor for macrophage-tropic HIV to fuse with and enter host cells. These chemokine receptors are thought to play an important role in the establishment and spread of HIV infection. Therefore, CCR5 antagonists are considered to be useful as effective therapeutic agents for HIV.

[0004] As in several other retroviruses, HIV encodes the production of proteases that perform post-translational cleavage of precursor polypeptides in a process necessary for the formation of infectious virions. These gene products include pol (encoding the virion's RNA-dependent DNA polymerase (reverse transcriptase)), endonuclease, HIV protease, and gag (encoding the virion's core protein).

[0005] One focus of antiviral drug design is to create compounds that inhibit the formation of infectious virions by interfering with the processing of viral polyprotein precursors. Processing of these precursor proteins requires the action of virally encoded proteases, which are essential for replication. The antiviral potential of inhibiting HIV protease has been demonstrated using peptidyl inhibitors.

[0006] A required step for HIV replication in human T cells is the insertion of proviral DNA into the host cell genome by the virus-encoded integrase. Integration is thought to be mediated by integrase in a process that involves the assembly of viral DNA sequences with a stable nucleoprotein complex, cleavage of two nucleotides from the 3' end of the linear proviral DNA, and covalent ligation of the 3' OH recessed end of the proviral DNA at the staggered cut generated at the host target site. Repair synthesis of the resulting gap can be carried out by cellular enzymes. Inhibitors of HIV integrase may be effective in treating AIDS and inhibiting viral replication.

[0007] Administration of combinations of therapeutic compounds in the treatment of HIV infection and related conditions can result in enhanced antiviral activity, reduced toxicity, delayed progression to resistance, and increased efficacy. Combinations administered as a single dosage unit can reduce pill burden and simplify dosing schedules, thereby increasing patient compliance. However, not all compounds are suitable for administration in combination. Factors that affect the success of a combination include the chemical instability of the compounds, the size of the dosage unit, the potential for antagonism or merely additive effects of the combined compounds, and problems in obtaining a suitable formulation.

[0008] There is a continuing need to identify therapeutic agents and viable pharmaceutical compositions suitable for use in combination to treat HIV infection. Certain HIV integrase inhibitors are attractive as components in combination therapies due to their high potency and pharmacokinetic profile. Summary of the Invention [Means for solving the problem]

[0009] The present invention relates to combinations of compounds comprising an HIV integrase inhibitor and another therapeutic agent. Such combinations are useful in inhibiting HIV replication, preventing and / or treating infection by HIV, and treating AIDS and / or ARC. The present invention also features pharmaceutical compositions comprising an HIV integrase inhibitor. [Brief explanation of the drawings]

[0010] [Figure 1] Inhibition of HIV-1IIIB by the compound of formula (I) GSK1349572A in combination with abacavir (ABC). [Figure 2] Inhibition of HIV-1IIIB by the compound of formula (I) GSK1349572A in combination with efavirenz (EFV). [Figure 3] Inhibition of HIV-1IIIB by the compound of formula (I) GSK1349572A in combination with lopinavir (LPV). DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention provides a compound of formula (I), (II) or (III): [ka] [ka] [ka]

[0012] or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from the group consisting of a nucleotide reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor, a CCR5 antagonist, a CXCR4 antagonist, a fusion inhibitor, a maturation inhibitor, and an integrase inhibitor.

[0013] The present invention relates to methods for treating HIV infection, AIDS, and AIDS-related symptoms by administering to a subject a compound of Formula (I), (II), or (III) and one or more therapeutic agents selected from the group consisting of a nucleotide reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor, a CCR5 antagonist, a CXCR4 antagonist, a fusion inhibitor, a maturation inhibitor, and an integrase inhibitor.

[0014] The compound of formula (I) is also known as GSK1349572. The chemical name of the compound of formula (I) is (4R,12aS)-N-[2,4-fluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide.

[0015] The chemical name of the compound of formula (II) is (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-6-hydroxy-3-methyl-5,7-dioxo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide.

[0016] The chemical name of the compound of formula (III) is (4aS,13aR)-N-[2,4-difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-8-carboxamide.

[0017] The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of the invention, which does not impair its pharmacological activity and which is non-toxic when administered in dosages sufficient to deliver a therapeutic amount of an antiviral agent.

[0018] As used herein, the term "treatment" refers to the alleviation of symptoms of a particular disorder in a patient or the improvement of an ascertainable measurement associated with a particular disorder, and may also include the suppression of recurrence of symptoms in asymptomatic patients, such as patients with subclinical viral infections. Treatment may also include prophylaxis, which refers to the prevention of a disease or condition in a patient, or the prevention of the onset of symptoms of such a disease or condition. As used herein, the term "patient" refers to a mammal, including a human.

[0019] As used herein, the term "subject" refers to a patient, animal, or biological sample.

[0020] Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid (salicyclic acid), succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Other acids, such as oxalic acid, although not inherently pharmaceutically acceptable, may be used in the preparation of salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium) salts, alkaline earth metal (e.g., magnesium) salts, ammonium salts, NW4 salts, and the like. + Salt (where W is C 1-4 alkyl) and other amine salts. A useful salt is the sodium salt.

[0021] Salts of the compounds of the present invention can be prepared by methods known to those skilled in the art, for example, by treating the compound of the present invention with an appropriate base or acid in an appropriate solvent to obtain the corresponding salt.

[0022] The present invention relates to a method for treating or preventing a viral infection, e.g., HIV infection, in a human, comprising administering to the human a therapeutically effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof in combination with one or more therapeutic agents selected from the group consisting of a nucleotide reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor, a CCR5 antagonist, a CXCR4 antagonist, a fusion inhibitor, a maturation inhibitor, and an integrase inhibitor. The combination may be administered simultaneously or sequentially.

[0023] The compounds of formula (I), (II) and (III) are particularly suitable for the treatment or prevention of HIV infection and associated conditions. References herein to treatment may extend to prevention as well as treatment of established infection, symptoms and associated clinical conditions (e.g., AIDS-related complex (ARC), Kaposi's sarcoma and AIDS dementia).

[0024] Combination therapy involves the administration of a compound of the present invention or a pharmaceutically acceptable salt thereof and another pharmaceutically active substance. The active ingredient and the pharmaceutically active substance may be administered simultaneously (i.e., together) in the same or different pharmaceutical compositions, or sequentially in any order. The amounts of the active ingredient and the pharmaceutically active substance, as well as the relative timing of administration, are selected to achieve a desired combined therapeutic effect.

[0025] Examples of such therapeutic agents include, but are not limited to, agents effective in treating viral infections or related conditions, such as nucleotide reverse transcriptase inhibitors, acyclic nucleoside phosphonates, e.g., (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC), [[[2-(6-amino-9H-purin-9-yl)ethoxy]methyl]phosphinylidene]bis(oxymethylene)-2,2-dimethylpropanoic acid (bis-POM), and the like. PMEA, adefovir dipivoxil), adefovir, [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid (tenofovir), tenofovir disoproxil fumarate, and (R)-[[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid bis-(isopropoxycarbonyloxymethyl)ester (bis-POC-PMPA); nucleoside reverse transcriptase inhibitors, such as 3'-azido-3'-deoxythymidine (AZT, zidovudine), 2',3'-dideoxycytidine (ddC, zalcitabine), 2',3'-dideoxyadeoxy Inosine, 2',3'-dideoxyinosine (ddI, didanosine), 2',3'-didehydrothymidine (d4T, stavudine), (-)-cis-1-(2-hydroxymethyl)-1,3-oxathiolan-5-yl)-cytosine (lamivudine), cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC, emtricitabine), (-)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (abacavir), fozivudine tidoxin tidoxil, alovudine, amdoxovir, elvucitabine, apricitabine, and festinavir (OBP-601);Protease inhibitors, such as indinavir, ritonavir, nelfinavir, amprenavir, saquinavir, fosamprenavir, lopinavir, atazanavir, tipranavir, darunavir, brecanavir, parinavir, lasinavir, TMC-310911, DG-17, PPL-100, and SP1-2 56; Non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine, delavirdine, efavirenz, GSK2248761 (IDX-12899), lersivirine (UK-453,061), rilpivirine (TMC-278), etravirine, loviride, immunocal, oltipraz, capravirin capravirine and RDEA-806; integrase inhibitors, such as raltegravir, elvitegravir and JTK-656; CCR5 and / or CXCR4 antagonists, such as maraviroc, vicriviroc (Sch-D), TBR-652 (TAK-779), TAK-449, PRO-140, GSK7067 69 and SCH-532706; fusion inhibitors such as enfuvirtide (T-20), T-1249, PRO-542, ibalizumab (TNX-355), BMS-378806 (BMS-806), BMS-488043, KD-247, 5-Helix inhibitors and HIV attachment inhibitors; and maturation inhibitors such as bevirimat (PA-344 and PA-457).

[0026] The present invention provides compounds of formula (I): [ka]

[0027] or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivirine, lopinavir, fosamprenavir, and atazanavir.

[0028] The invention also features a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from abacavir, efavirenz, or lopinavir. The invention also features a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and abacavir.

[0029] The invention features a method for treating HIV infection, the method comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivirine, lopinavir, fosamprenavir, and atazanavir.

[0030] The invention features a method for treating HIV infection, the method comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with one or more therapeutic agents selected from the group consisting of abacavir, efavirenz, and lopinavir. The invention features a method for treating HIV infection, the method comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof and abacavir.

[0031] The present invention features a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, efavirenz, tenofovir, GSK2248761, lersivirine, lopinavir, fosamprenavir, and atazanavir, together with a pharmaceutically acceptable carrier therefor.

[0032] The present invention features a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from the group consisting of abacavir, efavirenz, and lopinavir, together with a pharmaceutically acceptable carrier therefor. The present invention features a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and abacavir, together with a pharmaceutically acceptable carrier therefor.

[0033] The present invention relates to a compound of formula (II): [ka]

[0034] or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivirine, lopinavir, fosamprenavir and atazanavir.

[0035] The invention also features a combination comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from abacavir, efavirenz, and lopinavir. The invention also features a combination comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and abacavir.

[0036] The invention features a method for treating HIV infection, the method comprising administering to a subject a compound of formula (II) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivirine, lopinavir, fosamprenavir, and atazanavir.

[0037] The invention features a method for treating HIV infection, the method comprising administering to a subject a compound of formula (II) or a pharmaceutically acceptable salt thereof, together with one or more therapeutic agents selected from the group consisting of abacavir, efavirenz, and lopinavir. The invention features a method for treating HIV infection, the method comprising administering to a subject a compound of formula (II) or a pharmaceutically acceptable salt thereof and abacavir.

[0038] The present invention features a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivirine, lopinavir, fosamprenavir, and atazanavir, together with a pharmaceutically acceptable carrier therefor.

[0039] The present invention features a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from the group consisting of abacavir, efavirenz, and lopinavir, together with a pharmaceutically acceptable carrier therefor. The present invention features a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and abacavir, together with a pharmaceutically acceptable carrier therefor.

[0040] The present invention relates to a compound of formula (III): [ka]

[0041] or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivirine, lopinavir, fosamprenavir and atazanavir.

[0042] The invention also features a combination comprising a compound of formula (III) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from abacavir, efavirenz, and lopinavir. The invention also features a combination comprising a compound of formula (III) or a pharmaceutically acceptable salt thereof and abacavir.

[0043] The invention features a method for treating HIV infection, the method comprising administering to a subject a compound of formula (III) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivirine, lopinavir, fosamprenavir, and atazanavir.

[0044] The invention features a method for treating HIV infection, the method comprising administering to a subject a combination of a compound of formula (III) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from the group consisting of abacavir, efavirenz, and lopinavir. The invention features a method for treating HIV infection, the method comprising administering to a subject a compound of formula (III) or a pharmaceutically acceptable salt thereof and abacavir.

[0045] The present invention features a pharmaceutical composition comprising a compound of formula (III) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivirine, lopinavir, fosamprenavir, and atazanavir, together with a pharmaceutically acceptable carrier therefor.

[0046] The present invention features a pharmaceutical composition comprising a compound of formula (III) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents selected from the group consisting of abacavir, efavirenz, and lopinavir, together with a pharmaceutically acceptable carrier therefor. The present invention features a pharmaceutical composition comprising a compound of formula (III) or a pharmaceutically acceptable salt thereof and abacavir, together with a pharmaceutically acceptable carrier therefor.

[0047] The present invention features the combinations, methods of treatment and pharmaceutical compositions as described above, wherein the pharmaceutically acceptable salt of a compound of Formula (I), (II) or (III) is a sodium salt.

[0048] The invention features combinations, methods of treatment, and pharmaceutical compositions as described above, wherein one or more therapeutic agents is a pharmaceutically acceptable salt of said therapeutic agent, e.g., abacavir hemisulfate, fosamprenavir calcium, atazanavir sulfate, tenofovir disoproxil sulfate, vicrivirocumarate, or bevirimat dimeglumine.

[0049] The invention features a method of treatment as described above, wherein the subject is a human.

[0050] The present invention features combinations, methods of treatment and pharmaceutical compositions as described above, wherein the combination is administered sequentially.

[0051] The present invention features combinations, methods of treatment and pharmaceutical compositions as described above, wherein the combinations are administered simultaneously or concomitantly.

[0052] Compounds of formula (I), (II) and (III) may be produced by the methods disclosed in WO 2006 / 116764, U.S. Patent Application No. 61 / 193,634 (WO 2010 / 068253) or U.S. Patent Application No. 61 / 193,636 (WO 2010 / 068262), which are incorporated herein by reference.

[0053] Abacavir can be produced by the methods disclosed in U.S. Patent Nos. 5,034,394; 5,089,500; 6,294,540; 5,641,889; 5,840,990; 5,919,941; 5,808,147; 6,392,085; 6,448,403; 5,917,041; 6,087,501; 5,917,042; 6,555,687; 6,552,193; 6,870,053; 6,294,540; 6,340,587; or 6,646,125.

[0054] Lamivudine can be produced by the methods disclosed in U.S. Patent Nos. 5,047,407; 7,119,202; 5,905,082; 5,696,254; 5,663,320; 5,693,787; 6,051,709; or 6,329,522.

[0055] Tenofovir can be produced according to U.S. Patent Nos. 5,922,695; 5,935,946; 5,977,089; 6,043,230, and 6,069,249.

[0056] Efavirenz can be produced by the methods disclosed in U.S. Patent Nos. 5,519,021; 5,663,169; 5,811,423; 6,555,133; 6,639,071; or 6,939,964.

[0057] GSK2248761 may be produced by the method disclosed in US Pat. No. 7,534,809.

[0058] Lersivirine can be produced by the method disclosed in US Pat. No. 7,109,228.

[0059] Lopinavir can be produced by the method disclosed in US Pat. No. 5,914,332.

[0060] Fosamprenavir can be produced by the methods disclosed in US Pat. Nos. 6,436,989; 6,514,953; or 6,281,367.

[0061] Atazanavir can be produced by the methods disclosed in US Pat. Nos. 5,849,911 or 6,087,383.

[0062] The combination therapeutic agents may be produced according to published methods or by any method known to those skilled in the art.

[0063] In one aspect of the present invention, a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, may be formulated into a composition with one or more therapeutic agents. The composition may be a pharmaceutical composition, comprising a compound of Formula (I), (II), or (III), one or more therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant, or excipient. In one embodiment, the composition comprises a combination of the present invention in an amount effective to treat or prevent a viral infection, e.g., HIV infection, in a biological sample or in a patient. In another embodiment, the pharmaceutical composition comprising a combination of the present invention and an amount effective to inhibit viral replication or an amount effective to treat or prevent a viral infection or viral disease or disorder, e.g., HIV infection, and a pharmaceutically acceptable carrier, adjuvant, or excipient may be formulated for administration to a patient, e.g., oral administration.

[0064] The present invention features combinations according to the present invention for use in medical therapy, e.g., for the treatment or prevention of viral infections, e.g., HIV infection and related conditions. The compounds according to the present invention are particularly useful in the treatment of AIDS and related clinical conditions, such as AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi's sarcoma, thrombocytopenic purpura, AIDS-related neurological conditions (e.g., AIDS dementia complex, multiple sclerosis or tropical paraparesis), anti-HIV antibody positivity and HIV-positive states, including such conditions in asymptomatic patients.

[0065] According to another aspect, the present invention provides a method for treating or preventing the symptoms or effects of a viral infection in an infected patient, e.g. a mammal, including a human, which method comprises administering to said patient a pharmaceutically effective amount of a combination according to the invention. According to one aspect of the invention, the viral infection is a retroviral infection, in particular an HIV infection.

[0066] The present invention further comprises the use of a combination according to the invention in the manufacture of a medicament for simultaneous (concurrent) or sequential administration to a subject for the treatment of a viral infection, in particular an HIV infection.

[0067] The present invention further provides a method for treating a clinical condition in a patient, e.g., a mammal, including a human, including any of the symptoms discussed herein above, the method comprising treating the patient with a pharmaceutically effective amount of a compound according to the present invention. The present invention also includes a method for treating or preventing any of the aforementioned diseases or conditions.

[0068] The compounds of the present invention can be administered with substances known to inhibit or reduce the metabolism of the compounds, such as ritonavir. Thus, the present invention features a method for treating or preventing diseases such as those described above by administering the compounds of the present invention in combination with a metabolic inhibitor. Such combinations can be administered simultaneously or sequentially.

[0069] Typically, appropriate doses for each of the above conditions may range from 0.01 to 250 mg per kilogram of recipient (e.g., human) body weight per day, including 0.1 to 100 mg / kilogram body weight / day, 1 to 30 mg / kilogram body weight / day, and 0.5 to 20 mg / kilogram body weight / day. Unless otherwise specified, the total weight of the active ingredients is calculated as the parent compound of Formula (I), (II), or (III) and other therapeutic agents. In the case of salts thereof, the weights will be increased proportionately. The desired dose may be provided in one, two, three, four, five, six, or more subdoses administered at appropriate intervals throughout the day. In some cases, the desired dose may be administered on different days. These subdoses may be administered as unit dosage forms, for example, containing 1 to 2000 mg, 5 to 500 mg, 10 to 400 mg, or 20 to 300 mg of each active ingredient per unit dosage form.

[0070] The combination may be administered to achieve peak plasma concentrations of each active ingredient.

[0071] Although it is possible for the active ingredient to be administered alone, it is preferable to provide the active ingredient as a pharmaceutical composition.The composition of the present invention comprises the active ingredient as defined above, together with one or more acceptable carriers thereof and one or more additional therapeutic agents.Each carrier must be acceptable in the sense that it is compatible with the other components of the composition and is not harmful to the patient.

[0072] Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal, and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and intravitreal) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. Such methods represent a further feature of the present invention and comprise bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0073] The present invention further includes a pharmaceutical composition as defined herein above, wherein a compound of the invention or a pharmaceutically acceptable derivative thereof and another therapeutic agent are provided separately from each other as part of a kit.

[0074] Compositions suitable for transdermal administration may be provided as discrete patches adapted to remain in intimate contact with the recipient's epidermis for a prolonged period of time. Such patches suitably contain 1) the active compound in an optionally buffered aqueous solution, or 2) the active compound dissolved and / or dispersed in an adhesive, or 3) the active compound dispersed in a polymer. Suitable concentrations of the active compound are about 1% to 25%, preferably about 3% to 15%. In one particular possibility, the active compound may be delivered from the patch by electrotransport or iontophoresis, as broadly described in Pharmaceutical Research 3(6), 318 (1986).

[0075] Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units (e.g., capsules, caplets, cachets, or tablets, each containing a predetermined amount of the active ingredient); as a powder or granules; as a solution or suspension in an aqueous liquid or a 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.

[0076] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (e.g., powder or granules) mixed with binders (e.g., povidone, gelatin, hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose), surfactants, or dispersants in a suitable machine. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets can be optionally coated or scored, and can be formulated to provide delayed or controlled release of the active ingredient therein, using, for example, various proportions of hydroxypropyl methylcellulose to obtain the desired release profile. Tablets can also be provided with an enteric coating, if desired, to allow release in parts of the digestive tract other than the stomach.

[0077] Pharmaceutical compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base (e.g., gelatin and glycerin, or sucrose and acacia); and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0078] Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays. Pharmaceutical compositions may contain, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0079] Pharmaceutical compositions for rectal administration may be presented as suppositories containing suitable carriers, such as cocoa butter or salicylates or other materials commonly used in the art. The suppositories may be conveniently formed by admixture of the active combination with the softened or melted carriers, followed by chilling and shaping in molds.

[0080] Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the pharmaceutical composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents; as well as liposomes or other microparticulate systems designed to target the compound to blood components or one or more organs. The pharmaceutical compositions may be presented in single-dose or multi-dose sealed containers, such as ampoules and vials, and may be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier (e.g., water for injection) immediately before use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type described above.

[0081] Unit dosage pharmaceutical compositions include those compositions containing a daily dose or daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

[0082] The pharmaceutical compositions of the invention may be presented as patient packs containing one or more courses of treatment in a single package, for example a blister pack, It will be appreciated that administration of the combination of the invention using a single patient pack or patient packs for each composition is an additional feature of the invention.

[0083] It should be understood that the pharmaceutical compositions of the present invention may contain, in addition to the ingredients particularly mentioned above, other substances conventional in the art, having regard to the type of pharmaceutical composition in question; for example, pharmaceutical compositions suitable for oral administration may contain additional substances such as sweeteners, thickeners and flavorings. [Example]

[0084] Example 1: Biological activity Assay method Antiviral HIV activity was measured using a tetrazolium-based colorimetric method in MT-4, a cell line transformed with human T-cell leukemia virus type 1 (HTLV-1). Aliquots of test compounds were vertically diluted in deep-well master assay plates containing medium (RPMI 1640, 10% vol. / vol. fetal bovine serum (FBS), and 10 μg / mL gentamicin) to concentrations approximately 40-fold higher than the final assay concentration. Serial dilutions were made at 1:2 or 1:3.16 ratios. HIV inhibitors were diluted horizontally in the master assay plate to concentrations approximately 40-fold higher than the final assay concentration. Small aliquots of both vertically and horizontally diluted compounds were mixed in daughter plates using an automated 96-well pipetting system (RapidPlate-96, Zymark Corp.). Dilutions were arranged in a checkerboard style so that all concentrations of test compound were tested in the presence and absence of all concentrations of HIV inhibitor. Anti-HIV activity tests were performed on each combination of triplicate assays or more. Exponentially growing MT-4 cells were harvested and centrifuged at 1,000 rpm for 10 minutes in a Jouan centrifuge (Model CR412). The cell pellet was collected at 1.25 x 10 6 Resuspend in fresh medium (RPMI 1640, 20% vol. / vol. FBS, 20% vol. / vol. IL-2, and 10 μg / mL gentamicin) to a density of 1 × 10 cells / mL. 4Cell aliquots were infected by adding diluted HIV-1 (strain IIIB) to achieve a multiplicity of infection (MOI) of 73 pfU per cell. A mock-infected control was obtained by diluting a similar cell aliquot with medium. Cell infection proceeded for 1 hour at 37°C in a tissue culture incubator with a humidified 5% CO2 atmosphere. After 1 hour of incubation, the virus / cell suspension was added to each well of the plate containing the pre-diluted compounds. The plate was then placed in a tissue culture incubator with a humidified 5% CO2 atmosphere for 5 days. At the end of the incubation period, 40 μL of CellTiter 96 MTS reagent (Promega no. G3581) was added to each well of the incubation plate. The plate was incubated at 37°C for 2–3 hours to allow color development. The OD was measured at 492 nM using a microplate absorbance reader (Tecan no. 20-300).

[0085] Virus used Wild-type laboratory strain HIV-1 IIIB, viral titer = 6.896E4 TCID 50 / mL.

[0086] Data analysis Although some assay formats may theoretically miss antagonism due to the cytotoxicity of the combination, the approach described herein should not miss antagonism. The readout in the MT-4 cell assay utilizes the tetrazolium-based dye MTS, where the change in optical density (OD) of the reagent is used to estimate the total number of cells remaining after treatment. The final MT-4 cell number may be reduced due to two effects. First, if HIV kills more than 75% of MT-4 cells within 5 days after infection, HIV-induced cytotoxicity may occur. Second, if a compound directly kills MT-4 cells or prevents cell growth (quiescence) in either infected or uninfected cells over a 5-day period, compound-induced cytotoxicity may occur. In either of these situations, the OD is lower compared to infected cells protected by the anti-HIV-1 compound or compared to untreated and uninfected control cells. Because both cytotoxicity and antagonism of anti-HIV activity can reduce OD, we should not miss antagonism due to the cytotoxicity of the combination, but may underestimate synergistic combinations.

[0087] The cytotoxicity of the combinations was assessed by comparing wells containing uninfected MT-4 cells in the assay plates containing the highest concentration of the test compound or control compound with wells containing HIV-1-infected MT-4 cells at the corresponding highest concentration of the combination. Each of these values ​​was represented by one well per assay plate, and therefore at least three wells per combination assay. While this does not constitute a formal combination cytotoxicity analysis, the ratio of the compounds in the combination to the compounds alone provides a measure of the cytotoxicity of the compound combination at the concentrations examined.

[0088] The interaction of each pair of compound combinations was analyzed by the method described in Selleseth, D.W. et al. (2003) Antimicrobial Agents and Chemotherapy 47:1468-71. Synergism and antagonism are defined as the deviation from dose-wise additivity that occurs when two drugs interact as if they were the same drug. A value for the mean deviation from additivity ranging from -0.1 to -0.2 may indicate weak synergy, while a value approximately equal to -0.5 may indicate strong synergy of the interaction. Conversely, a positive value of 0.1 to 0.2 may indicate weak antagonism between the treatments.

[0089] result The compound of formula (I) was found to be additive with raltegravir, adefovir, and maraviroc, and was not affected by the presence of ribavirin. The compound of formula (I) was found to be synergistic with stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, and enfuvirtide.

[0090] The present invention also relates to the following aspects: Item 1 Compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, together with one or more therapeutic agents selected from the group consisting of abacavir, efavirenz and lopinavir. Section 2 The combination of paragraph 1, wherein the therapeutic agent is abacavir. Section 3 Item 3. The combination according to item 1 or 2, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a sodium salt. Section 4 Item 3. The combination according to item 2, further comprising lamivudine. Section 5 Compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof in combination with one or more therapeutic agents selected from the group consisting of abacavir, efavirenz, and lopinavir to a human for the treatment of HIV infection. Section 6 Item 6. The method according to Item 5, wherein the therapeutic agent is abacavir. Section 7 Item 7. The method according to item 5 or 6, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a sodium salt. Section 8 Item 7. The method according to item 6, further comprising lamivudine. Section 9 A pharmaceutical composition comprising the compound of formula (I) according to item 1 or 2 and one or more therapeutic agents selected from the group consisting of abacavir, efavirenz and lopinavir, together with a pharmaceutically acceptable carrier therefor. Item 10 Item 10. The pharmaceutical composition according to Item 9, wherein the therapeutic agent is abacavir. Section 11 Item 11. The pharmaceutical composition according to item 9 or 10, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a sodium salt. Section 12 Item 11. The pharmaceutical composition according to Item 10, further comprising lamivudine. Item 13 Item 5. The combination according to any one of Items 1 to 4, wherein the combination is administered simultaneously. Item 14 Item 5. The combination according to any one of Items 1 to 4, wherein the combination is administered sequentially. Item 15 Item 9. The method of treatment according to any one of Items 5 to 8, wherein the compound of formula (I) and the therapeutic agent are administered simultaneously. Section 16 Item 9. The method of treatment according to any one of Items 5 to 8, wherein the compound of formula (I) and the therapeutic agent are administered consecutively. Item 17 A patient pack comprising the compound of formula (I) according to item 1 and one or more therapeutic agents selected from the group consisting of abacavir, efavirenz and lopinavir.

Claims

1. A combination comprising (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-6-hydroxy-3-methyl-5,7-dioxo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide or a pharmaceutically acceptable salt thereof, and rilpivirine.

2. A pharmaceutical composition for treating HIV infection, comprising (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-6-hydroxy-3-methyl-5,7-dioxo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered together with rilpivirine.

3. The pharmaceutical composition of claim 2, which is administered simultaneously with rilpivirine.

4. The pharmaceutical composition of claim 2, which is administered sequentially with rilpivirine.

5. A kit for treating HIV infection, comprising (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-6-hydroxy-3-methyl-5,7-dioxo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide or a pharmaceutically acceptable salt thereof, and rilpivirine.

6. The kit according to claim 5, wherein (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-6-hydroxy-3-methyl-5,7-dioxo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide or a pharmaceutically acceptable salt thereof and rilpivirine are administered simultaneously.

7. The kit according to claim 5, wherein (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-6-hydroxy-3-methyl-5,7-dioxo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide or a pharmaceutically acceptable salt thereof and rilpivirine are administered consecutively.

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