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    • 专利摘要:
    tenofovir alafenamide hemifumarate composition, its methods of preparation and use. The present invention relates to a form of 9-[(r)-2-[[(s)-[[(s)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]-methoxy]propyl] hemifumarate] adenine (tenofovir alafenamide) and to antiviral therapy using tenofovir alafenamide hemifumarate (eg, anti-hiv and anti-hbv therapies).
    公开号:BR112014003420B1
    申请号:R112014003420-6
    申请日:2012-08-15
    公开日:2021-07-20
    发明作者:Dazhan Liu；Bing Shi；Fang Wang；Richard Hung Chiu Yu
    申请人:Gilead Sciences, Inc；
    IPC主号:
    专利说明:

    Cross Reference to Related Orders
    This Application claims the priority benefit of United States Provisional Patent Application No. 61/524,224, filed August 16, 2011, the contents of which are hereby incorporated in its entirety. BACKGROUND OF THE INVENTION Description of Related Art
    United States Patents Nos. 7,390,791 and 7,803,788 (the contents of each of which are incorporated by reference herein in their entirety) describe certain phosphonate nucleotide analogue prodrugs that are useful in therapy. Such a prodrug is 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine. This compound is also known by the Abstract Chemical name L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl] phenoxyphosphinyl]-, 1-methylethyl ester. United States Patents Nos. 7,390,791 and 7,803,788 also describe a monofumarate form of this compound and its method of preparation (see, for example, Example 4). SUMMARY OF THE INVENTION
    A form of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine hemifumarate is described. The name for 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine is tenofovir alafenamide. The tenofovir alafenamide hemifumarate form is also referred to herein as tenofovir alafenamide hemifumarate. In one embodiment of the invention tenofovir alafenamide hemifumarate is provided.
    In another modality, tenofovir alafenamide hemifumarate is provided, where the ratio of fumaric acid to tenofovir alafenamide is 0.5 ± 0.1, or 0.5 ± 0.05, or 0.5 ± 0.01 , or about 0.5. In one modality, tenofovir alafenamide hemifumarate is provided in a solid form.
    In one embodiment, tenofovir alafenamide hemifumarate is provided which has an X-ray powder diffraction (XRPD) pattern having 2theta values of 6.9 ± 0.2° and 8.6 ± 0.2°. In one modality, tenofovir alafenamide hemifumarate is provided where the XRPD pattern comprises 2theta values of 6.9 ± 0.2°, 8.6 ± 0.2°, 11.0 ± 0.2°, 15.9 ± 0.2°, and 20.2 ± 0.2°.
    In one modality, tenofovir alafenamide hemifumarate is provided, which is a differential scanning calorimetry (DSC) initiating endotherm of 131 ± 2 °C, or 131 ± 1 °C.
    In one embodiment, a pharmaceutical composition comprising tenofovir alafenamide hemifumarate and a pharmaceutically acceptable excipient is provided. In one embodiment, the pharmaceutical combination, also comprising an additional therapeutic agent, is provided. In another embodiment, the additional therapeutic agent is selected from the group consisting of human immunodeficiency virus (HIV) protease inhibiting compounds, HIV non-nucleoside reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors.
    In one embodiment, a method of treating a human immunodeficiency virus (HIV) infection is provided which comprises administering to an individual in need thereof a therapeutically effective amount of tenofovir alafenamide hemifumarate. In one embodiment, a method of treating an HIV infection is provided which comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising tenofovir alafenamide hemifumarate. In another embodiment, the method comprises administering to the subject one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors. -versa, HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, and CCR5 inhibitors.
    In one embodiment, a method of treating a hepatitis B virus (HBV) infection is provided which comprises administering to a subject in need thereof a therapeutically effective amount of tenofovir alafenamide hemifumarate. In one embodiment, a method of treating an HBV infection is provided which comprises administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition comprising tenofovir alafenamide hemifumarate.
    In one embodiment, a method for preparing a pharmaceutical composition is provided which comprises combining tenofovir alafenamide hemifumarate and a pharmaceutically acceptable excipient to provide the pharmaceutical composition.
    In one embodiment, a method for preparing tenofovir alafenamide hemifumarate comprising subjecting a solution comprising a suitable solvent; fumaric acid; tenofovir alafenamide; and, optionally, one or more seeds of tenofovir alafenamide hemifumarate to conditions that provide for the crystallization of fumaric acid and tenofovir alafenamide. In one embodiment, the solvent comprises acetonitrile. In one modality, the solution is subjected to a temperature in the range of about 0°C to about 75°C. In one modality, tenofovir alafenamide hemifumarate is provided for use in medical therapy.
    In one embodiment, the use of tenofovir alafenamide hemifumarate for the prophylactic or therapeutic treatment of an HIV infection is provided. In one embodiment, the use of tenofovir alafenamide hemifumarate to treat an HIV infection is provided. In another modality, the use of tenofovir alafenamide hemifumarate is provided for the preparation or manufacture of a drug for the treatment of an HIV infection. In another additional modality tenofovir alafenamide hemifumarat is provided for use in the treatment of an HIV infection.
    In one embodiment, the use of tenofovir alafenamide hemifumarate for the prophylactic or therapeutic treatment of an HBV infection is provided. In one embodiment, the use of tenofovir alafenamide hemifumarate to treat an HBV infection is provided. In another modality, the use of tenofovir alafenamide hemifumarate is provided for the preparation or manufacture of a drug for the treatment of an HBV infection. In an additional modality, tenofovir alafenamide hemifumarate is provided for use in the treatment of an HBV infection.
    In some embodiments of the invention, methods of treatment and the like comprise administering multiple daily doses. In other embodiments, methods of treatment and the like comprise administration of a single daily dose.
    In one embodiment of the invention a composition consisting essentially of tenofovir alafenamide hemifumarate is provided. BRIEF DESCRIPTIONS OF THE DRAWINGS
    Figure 1 shows the X-ray powder diffraction (XRPD) pattern of tenofovir alafenamide hemifumarate. Figure 2 shows a plot of the DSC analysis of tenofovir alafenamide hemifumarate. Figure 3 shows a plot of the analysis data (TGA) for tenofovir alafenamide hemifumarate. Figure 4 shows a graph of the dynamic vapor absorption (DVS) analysis of tenofovir alafenamide hemifumarate. DETAILED DESCRIPTION OF THE INVENTION
    The specific values listed in this description for radicals, substituents, and ranges are for illustration only; they do not exclude other defined values or other values in the defined ranges for the radicals and substituents.
    In one embodiment, a form of tenofovir alafenamide hemifumarate (ie, tenofovir alafenamide hemifumarate) is provided. This form may have a ratio (i.e., a stoichiometric or molar ratio) of fumaric acid to tenofovir alafenamide of 0.5 ± 0.1, 0.5 ± 0.05, 0.5 ± 0.01, or about of 0.5, or the like.
    In one embodiment, tenofovir alafenamide hemifumarate consists of fumaric acid and tenofovir alafenamide at a ratio of 0.5 ± 0.1.
    In one embodiment, tenofovir alafenamide hemifumarate consists essentially of fumaric acid and tenofovir alafenamide at a ratio of 0.5 ± 0.1.
    In one embodiment, tenofovir alafenamide hemifumarate has an XRPD pattern comprising 2theta values of 6.9 ± 0.2°, 8.6 ± 0.2°, 10.0 ± 0.2°, 11.0 ± 0 .2°, 12.2 ± 0.2°, 15.9 ± 0.2°, 16.3 ± 0.2°, 20.2 ± 0.2°, and 20.8 ± 0.2°.
    In one embodiment, tenofovir alafenamide hemifumarate has an XRPD pattern that comprises at least four 2theta values selected from 6.9 ± 0.2°, 8.6 ± 0.2°, 10.0 ± 0.2°, 11 .0 ± 0.2°, 12.2 ± 0.2°, 15.9 ± 0.2°, 16.3 ± 0.2°, 20.2 ± 0.2°, and 20.8 ± 0.2 °.
    In one embodiment, tenofovir alafenamide hemifumarate has a DSC onset endotherm of 131 ± 2 °C, or 131 ± 1 °C.
    In one embodiment, a tenofovir alafenamide hemifumarate composition comprises less than about 5% by weight of tenofovir alafenamide monofumarate.
    In one embodiment, a tenofovir alafenamide hemifumarate composition comprises less than about 1% by weight of tenofovir alafenamide monofumarate.
    In one embodiment, a tenofovir alafenamide hemifumarate composition comprises less than about 0.5% by weight of tenofovir alafenamide monofumarate.
    In one embodiment, a tenofovir alafenamide hemifumarate composition does not comprise any detectable tenofovir alafenamide monofumarate.
    Tenofovir alafenamide (ie, the compound 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine) can be prepared as described in United States Patent 7,390,791. Selective Crystallization
    In one embodiment, tenofovir alafenamide hemifumarate can be prepared using selective crystallization. An example of a scheme for this method of preparation is as follows.

    The method can be carried out by subjecting a solution comprising: a) a suitable solvent; b) fumaric acid; c) tenofovir alafenamide; and, optionally, d) one or more seeds comprising tenofovir alafenamide hemi-fumarate, at conditions which provide for the crystallization of fumaric acid and tenofovir alafenamide. The starting solution may contain the single diastereomer of tenofovir alafenamide or a mixture of tenofovir alafenamide and one or more of its other diastereomers (eg, GS-7339, as described in U.S. Patent No. 7,390,791).
    Selective crystallization can be carried out in any suitable solvent. For example, it can be carried out in a protic solvent or an aprotic organic solvent, or a mixture thereof. In one embodiment, the solvent comprises a protic solvent (eg, water or isopropyl alcohol). In one embodiment, the solvent comprises an aprotic organic solvent (eg, acetone, acetonitrile (ACN), toluene, ethyl acetate, ethyl acetate, heptane, tetrahydrofuran (THF), 2-methyl THF, methyl ethyl ketone, or methyl isobutyl ketone, or a mixture thereof). In one embodiment, the solvent comprises ACN or a mixture of ACN and up to about 50% methylene chloride (by volume). Selective crystallization can also be carried out at any suitable temperature, for example a temperature in the range of about 0°C to about 70°C. In a specific modality, the resolution is carried out at a temperature of about 0 °C.
    A major advantage of the hemifumarate form of tenofovir alafenamide over the monofumarate form is its exceptional ability to purge GS-7339 (ie, 9-[(R)-2-[[(R)-[[(S)- 1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine; described in, for example, United States Patent No. 7,390,791), which is the major diastereomeric impurity in the active pharmaceutical ingredient. Thus, the hemifumarate form of tenofovir alafenamide can be more easily separated from impurities than the monofumarate form. Other key advantages of tenofovir alafenamide hemifumarate over the monofumarate form include improved thermodynamic and chemical stability (including long-term storage stability), superior process reproducibility, superior product content uniformity, and a higher melting point. high.
    Tenofovir alafenamide hemifumarate is useful in the treatment and/or prophylaxis of one or more viral infections in humans or animals, including infections caused by DNA viruses. RNA viruses, herpesviruses (eg CMV, HSV 1, HSV 2, VZV), retroviruses, hepadnaviruses (eg HBV), papillomaviruses, hantaviruses, adenoviruses and HIV. United States Patent No. 6,043,230 (incorporated by reference herein in its entirety) and other publications describe the antiviral specificity of nucleotide analogues, such as tenofovir disoproxil. Like tenofovir disoproxil, tenofovir alafenamide is another form of tenofovir prodrug, and can be used in the treatment and/or prophylaxis of the same conditions.
    Tenofovir alafenamide hemifumarate can be administered by any routine appropriate to the condition being treated. Suitable routines include oral, rectal, nasal, topical (including ocular, buccal, and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). Generally, tenofovir alafenamide hemifumarate is given orally, but it can be given by any of the routines noted here.
    Accordingly, pharmaceutical compositions include those suitable for topical or systemic administration, including oral, rectal, nasal, buccal, sublingual, vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural) administration. The formulations are in unit dosage form and are prepared by any of the methods well known in the art of pharmacy.
    For therapeutic administration, tenofovir alafenamide hemifumarate can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such pharmaceutical compositions and preparations will typically contain at least 0.1% tenofovir alafenamide hemifumarate. The percentage of this active compound in the compositions and preparations can, of course, be varied and can conveniently be from about 2% to about 60% or more of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful pharmaceutical compositions is preferably such that an effective dosage level will be obtained upon administration of a single unit dosage (e.g., tablet). Other dosage formulations can provide therapeutically effective amounts of tenofovir alafenamide hemifumarate upon repeated administration of subclinically effective amounts thereof. Preferred unit dosage formulations include those containing a daily dose (eg, a single daily dose), as well as those containing a subclinical daily unit dose, or an appropriate fraction thereof (eg, multiple daily doses), of tenofovir hemifumarate alafenamide.
    Pharmaceutical compositions suitable for oral administration may be presented as discrete units, such as capsules, seals, or tablets, each containing a predetermined amount of tenofovir alafenamide hemifumarate; as a powder or granules; as a solution or a 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. Tenofovir alafenamide hemifumarate may also be presented as a cake, electuary, or paste.
    Tenofovir alafenamide hemifumarate is preferably administered as part of a pharmaceutical composition or formulation. Such pharmaceutical composition or formulation comprises tenofovir alafenamide hemifumarate together with one or more pharmaceutically acceptable carriers/excipients, and optionally other therapeutic ingredients. The excipient(s)/vehicle(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Excipients include, but are not limited to substances that can function as a vehicle or medium for tenofovir alafenamide hemifumarate (eg, a vehicle diluent). They can be enclosed in soft or hard shell gelatin capsules, can be compressed into tablets, or can be incorporated directly with the patient's dietary food.
    Accordingly, tablets, troches, pills, capsules, and the like may also contain, without limitation, the following: a binder(s), such as hydroxypropyl cellulose, povidone, or hydroxypropyl methylcellulose; a filler(s), such as microcrystalline cellulose, pregelatinized starch, starch, mannitol, or lactose monohydrate; a disintegrating agent(s), such as croscarmellose sodium, cross-linked povidone, or sodium starch glycollate; a lubricant(s), such as magnesium stearate, stearic acid, or other metallic stearates; a sweetening agent(s), such as sucrose, fructose, lactose, or aspartame; and/or a flavoring agent(s) such as peppermint, oil of wintergreen, or a cherry flavoring. When the unit dosage form is a capsule, it may contain, in addition to materials of the above types, a liquid carrier such as a vegetable oil or polyethylene glycol. Various other materials can be present as coatings or otherwise modifying the physical form of the unit dosage form. For example, tablets, pills, or capsules can be coated with gelatin, polymers, wax, shellac, or sugar and the like. Of course, any material used in preparing any dosage unit form will typically be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, tenofovir alafenamide hemifumarate can be incorporated into extended-release devices and preparations.
    For infections of the eye or other external tissues, for example, mouth and skin, the pharmaceutical compositions are preferably applied as a topical ointment or cream containing tenofovir alafenamide hemifumarate in an amount of, for example, 0.01 to 10% by weight/ weight (including active ingredient in a range between 0.1% and 5% in 0.1% w/w increments such as 0.6% w/w, 0.7% w/w, etc.) , preferably 0.2 to 3% w/w and more preferably 0.5 to 2% w/w. When formulated in an ointment, the active ingredient can be used with a paraffinic base or water-miscible ointment. Alternatively, the active ingredient can be formulated in an oil-in-water cream base.
    Pharmaceutical compositions suitable for topical administration in the mouth include lozenges comprising tenofovir alafenamide hemifumarate in a flavored base, for example sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid vehicle.
    Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
    Pharmaceutical formulations suitable for parenteral administration are sterile and include aqueous and non-aqueous injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which make the solution isotonic with the intended recipient's blood; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Formulations may be presented in single-dose or multi-dose containers, eg sealed ampoules and vials with elastomeric buffers, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of sterile liquid vehicle (by eg water for injections) immediately before use. Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
    In addition to the ingredients particularly mentioned above, the pharmaceutical compositions/formulations may include other ingredients conventional in the art, taking into account the type of formulation in question.
    In another embodiment, veterinary compositions are provided which comprise tenofovir alafenamide hemifumarate together with a veterinary vehicle therefor. Veterinary vehicles are materials useful for the purpose of administering the composition to cats, dogs, horses, rabbits, and other animals, and can be solid, liquid or gaseous materials that are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These pharmaceutical compositions can be administered orally, parenterally, or by any other desired routine.
    Tenofovir alafenamide hemifumarate can be used to provide controlled release pharmaceutical formulations containing an absorbent material or matrix and an active ingredient of the invention, where the release of the active ingredient can be controlled and regulated to allow less frequent dosing or improve the pharmacokinetic profile or toxicity of the compound. Controlled release formulations adapted for oral administration, in which discrete units comprising the compounds of the invention, can be prepared according to conventional methods.
    Useful dosages of tenofovir alafenamide hemifumarate can be determined by comparing in vitro activities, and in vivo activities in animal models. Methods for extrapolating effective amounts/dosages in mice and other animals to therapeutically effective amounts/dosages in humans are known in the art.
    The amount of tenofovir alafenamide hemifumarate required for use in treatment will vary with a number of factors including, but not limited to, the routine of administration, the nature of the condition being treated, and the age and condition of the patient; finally, the amount administered will be at the discretion of the attending physician or clinician. The therapeutically effective amount/dose of tenofovir alafenamide hemifumarate depends at least on the nature of the condition being treated, any toxicity or drug interaction issues, if the compound is being used prophylactically (eg, some sometimes requiring lower doses) or against an active disease or condition, the delivery method, and the pharmaceutical formulation, and will be determined by the physician using dose escalation studies.
    In one embodiment, the oral dose of tenofovir alafenamide hemifumarate may range from about 0.0001 to about 100 mg/kg of body weight per day, for example, from about 0.01 to about 10 mg/ kg of body weight per day, from about 0.01 to about 5 mg/kg of body weight per day, from about 0.5 to about 50 mg/kg of body weight per day, from about 1 to about 30 mg/kg of body weight per day, from about 1.5 to about 10 mg/kg of body weight per day, or from about 0.05 to about 0.5 mg/kg of body weight per day . As a non-limiting example, the candidate daily dose for a human adult of about 70 kg of body weight will range from about 0.1 mg to about 1000 mg, or from about 1 mg to about 1000 mg, or from about 5mg to about 500mg, or about 1mg to about 150mg, or about 5mg to about 150mg, or about 5mg to about 100mg, and can adopt the single-dose or multiple-dose form.
    The pharmaceutical compositions described herein may also include one or more therapeutic agents, in addition to tenofovir alafenamide hemifumarate. In a specific embodiment of the invention, the additional therapeutic agent may be selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors, ini - reverse transcriptase HIV nucleotide inhibitors, HIV integrase inhibitors, and CCR5 inhibitors.
    Therapeutic methods include administering tenofovir alafenamide hemifumarate to an individual/patient in need thereof as a therapeutic or preventive treatment. Thus, tenofovir alafenamide hemifumarate can be administered to an individual/patient having a medical disorder or to an individual who may acquire the disorder. One of skill in the art will appreciate that such treatment is provided in order to ameliorate, prevent, delay, cure, and/or reduce the severity of a symptom or set of symptoms of a disorder (including a recurrent disorder). Treatment may also be provided to prolong an individual's survival, for example, beyond the expected survival time in the absence of such treatment. Medical disorders that can be treated with tenofovir alafenamide hemifumarate include those described herein, including without limitation, HIV infection and HBV infection. The following examples are non-limiting, illustrative examples. Example 1
    Tenofovir alafenamide monofumarate (5.0 g) and 9-[(R)-2-[[(R)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl] solids adenine (GS-7339) monofumarate solids (0.75 g) were charged into 35 g of MTBE at 22°C and the mixture was stirred for 1 hour. A suspension was formed and was dried on a rotary evaporator. 58 g of acetonitrile (ACN) was charged to the solids and the mixture was heated to reflux to dissolve the solids. The resulting solution was allowed to cool naturally while stirring. A suspension formed, and the suspension was also cooled by an ice-water bath. Solids were isolated by filtration and washed with 5 g of ACN. The solids were dried in a microwave oven at 40 °C overnight. 5.52 g of off-white solids were obtained. The solids were analyzed by XRPD and found to contain tenofovir alafenamide monofumarate, GS-7339 monofumarate, and tenofovir alafenamide hemifumarate.
    Example 2: Preparation of Tenofovir Alafenamide Hemifumarate by Selective Crystallization 9-[(R)-2-[[[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine as an suspension in ACN (9.7 kg suspension, 13.8 wt%, a diastereomeric mixture of 1.0 kg (2.10 mol, 1 mol equivalent) of 9-[(R)-2-[[(S) )-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]methoxy]propyl]adenine and 0.35 kg of 9-[(R)-2-[[(R)-[[(S )-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine was charged to a reactor and further rinsed with dichloromethane (5 kg) The mixture was concentrated in vacuo at about 3 L at jacket temperature below 40°C. The concentrate was then co-evaporated with ACN (6 kg) under vacuum at about 3 L with jacket temperature below 40°C. The concentrate was diluted with ACN (8.5 kg) and heated to 40°C. 46 °C The hot mixture was filtered in a second reactor and the filtrate was cooled to 19 to 25 °C.
    To the above solution, fumaric acid (0.13 kg, 1.12 mol, 0.542 mol equivalent) was charged followed by ACN (1 kg), and the mixture was 67 at 73°C. The hot mixture was transferred into a reactor through a polishing filter, and then adjusted to 54 to 60 °C. Seed crystals (5 g) of the tenofovir alafenamide hemifumarate form were loaded (for example, the mixture can be seeded with the tenofovir alafenamide hemifumarate formed in Example 1 or a subsequent production), and the resulting mixture was stirred to 54 to 60 °C for about 30 minutes. The mixture was cooled for a minimum of 4 hours at 0 to 6°C, then stirred at 0 to 6°C for a minimum of 1 hour. The resulting suspension was filtered and rinsed with ACN (2 kg) and cooled (0 to 6 °C). The product was dried under vacuum below 45 °C until the limits of loss on drying (LOD) and volatile organic impurities (OVI) were known (LOD < 1.0%, dichloromethane content < 0.19%, acetonitrile content < 0.19%) to provide the final compound of tenofovir alafenamide hemifumarate form as a white to off-white powder (typical yield about 0.95 kg). 1H NMR (400 MHz, d6 DMSO): δ 1.06 (d, J = 5.6 Hz, 3H), 1.12-1.16 (m, 9H), 3.77 (dd, J = 10, 4, 11.6 Hz, 1H), 3.84-3.90 (m, 2H), 3.94 (m, 1H), 4.14 (dd, J = 6.8, 14.8 Hz, 1H ), 4.27 (m, 1H), 4.85 (heptet, J = 6.0 Hz, 1H), 5.65 (t, J = 11.2 Hz, 1H), 6.63 (s, 1H ), 7.05 (d, J = 7.6 Hz, 2H), 7.13 (t, J = 7.2 Hz, 1H), 7.24 (s, 2H), 7.29 (t, J = 7.6 Hz, 2H), 8.13 (t, J = 13.6 Hz, 2H), 31P NMR (162 MHz, d6 DMSO): δ 23.3.
    Example 3: Preparation of Tenofovir alafenamide Hemifumarate
    To a jacket reactor equipped with an overhead stirrer, 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]methoxy]propyl] was charged adenine (10 g), fumaric acid (1.22 g), and ACN (100 mL). The mixture was heated to 70 to 75°C to dissolve solids. Any undissolved particulates were removed by filtration through a cartridge filter. The filtered solution was cooled to 60 to 65°C, and seeded with 1% (by weight) tenofovir alafenamide hemifumarate. The suspension was aged for 30 minutes and cooled to 0 to 5°C for 2 hours. The temperature was maintained for 1 to 18 hours, and the resulting suspension was filtered and washed with 2 ml of cold ACN (0 to 5°C). The solids were dried under vacuum at 50°C to provide the tenofovir alafenamide hemifumarate form, which was characterized as described below.
    Characterization of Tenofovir Alafenamide Hemifumarate from Example 3
    Tenofovir alafenamide hemifumarate of Example 3 consists of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine and half of one equivalent of fumaric acid. Tenofovir alafenamide hemifumarate is anhydrous, non-hygroscopic, and has a DSC-onset endotherm of about 131 °C. X-ray powder diffraction
    The XRPD pattern of tenofovir alafenamide hemifumarate was obtained at the following experimental parameter: 45 KV, 45 mA, Kα1=1.5406 A, scan range 2. - 40th grade size 0.0 084th count time: 8 .25 s. The XRPD pattern for tenofovir alafenamide hemifumarate is shown in Figure 1. Characteristic peaks include: 6.9 ± 0.2°, 8.6 ± 0.2°, 10.0 ± 0.2°, 11 .0 ± 0.2°, 12.2 ± 0.2°, 15.9 ± 0.2°, 16.3 ± 0.2°, 20.2 ± 0.2°, and 20.8 ± 0.2°. Single Crystal X-Ray Diffraction
    The crystal size was 0.32 x 0.30 x 0.20 mm3. The sample was held at 123 K and data were collected using a radiation source with a wavelength of 0.71073 A in the theta range of 1.59 to 25.39°. Conditions of, and data collected from single crystal X-ray diffraction are shown in table 1.
    DSC Analysis
    DSC analysis was conducted using 2.517 mg tenofovir alafenamide hemifuma-rat. It was heated at 10 °C/minute over the range of 40 to 200 °C. The onset endotherm was found to be around 131°C (Figure 2). TGA data
    TGA data were obtained using 4.161 mg of tenofovir alafenamide-rat hemifuma. It was heated to 10 °C/minutes over the range of 25 to 200 °C. The sample lost 0.3% in weight before melting (Figure 3). It was determined to be an anhydrous form. DVS Analysis
    DVS analysis was conducted using 4.951 mg tenofovir alafenamide hemifuma-rat. Material kept at 25 °C in nitrogen at humidity ranging from 10% to 90% relative humidity; each step was balanced for 120 minutes. The absorption isotherm is shown in figure 4. The material was found to be non-hygroscopic, and to absorb 0.65% water at a relative humidity of 90%. Diastereomeric Impurity Purging
    In the earlier synthesis of tenofovir alafenamide, one of the major impurities is typically the diastereomer 9-[(R)-2-[[(R)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl ]adenine. The tenofovir alafenamide hemifumarate form of Example 3 has an exceptional ability to purge this diastereomeric impurity compared to the ability of the monofumarate form (described in U.S. Patent No. 7,390,791). The data in Table 2 (below) demonstrate that tenofovir alafenamide hemifumarate (Batch 2) purged the diastereomeric impurity to less than one-tenth of the starting concentration, while the tenofovir alafenamide monofumarate form (Batch 1) purged only slightly the diastereomeric impurity.
    Chemical stability
    The chemical stability of the hemifumarate form of tenofovir alafenamide was compared to the monofumarate form. As shown in Table 3 (below), under identical conditions, the tenofovir alafenamide hemifumarate form was chemically more stable and exhibited better long-term storage stability, with significantly less degradation (% total degradation of products) than the form of monofumarate. Conditions evaluated include temperature, relative humidity, (RH), and the open or closed state of the container lid.
    TA is tenofovir alafenamide Thermodynamic stability
    Stable form analysis of tenofovir alafenamide hemifumarate showed it to be thermodynamically stable in most solvents such as ACN, toluene, ethyl acetate, methyl tert-butyl ether (MTBE), acetone, THF, and 2- methyl THF. A similar form-stable analysis of the monofumarate form showed that this form is not thermodynamically stable in the solvents listed above. When suspended in these solvents, tenofovir alafenamide monofumarate form fully converts to the hemifumarate form in THF and 2-methyl THF, and partially converts to the hemifumarate form in ACN, ethyl acetate, MTBE, and acetone as well as at room temperatures. Thermal stability
    As shown by the DSC data, the tenofovir alafenamide hemifumarate form has a melting point that is about 10°C higher than the monofumarate form, indicating that the hemifumarate form has improved thermal stability compared to the form of monofumarate.
    All publications, patents, and patent documents are incorporated by reference herein, as if individually incorporated by reference. The invention has been described with reference to various specific and preferred techniques and embodiments. However, it should be understood that many variations and modifications can be made while still remaining within the spirit and scope of the invention.
    权利要求:
    Claims (18)
    [0001]
    1. Compound, characterized in that it is tenofovir alafenamide hemifumarate.
    [0002]
    2. Compound according to claim 1, characterized in that the ratio of fumaric acid to tenofovir alafenamide is 0.5 ± 0.1.
    [0003]
    3. Compound according to claim 2, characterized in that the ratio of fumaric acid to tenofovir alafenamide is 0.5 ± 0.05.
    [0004]
    4. Compound according to claim 2, characterized in that the ratio of fumaric acid to tenofovir alafenamide is 0.5 ± 0.01.
    [0005]
    5. A compound according to claim 1, characterized in that it is tenofovir alafenamide hemifumarate having an X-ray powder diffraction pattern comprising 2theta values of 6.9 ± 0.2° and 8.6 ± 0.2 ° when measured using radiation of wavelength 1.5406 A.
    [0006]
    6. Hemifumarate compound according to claim 5, characterized in that the X-ray powder diffraction pattern comprises 2theta values of 6.9 ± 0.2°, 8.6 ± 0.2°, 11.0 ± 0.2°, 15.9 ± 0.2° and 20.2 ± 0.2° when measured using radiation of wavelength 1.5406 A.
    [0007]
    7. Hemifumarate compound according to claim 1, characterized in that it is a differential scanning calorimetry (DSC) start endotherm of 131 ± 2°C.
    [0008]
    8. Hemifumarate compound according to claim 7, characterized in that it is a DSC onset endotherm of 131 ± 1°C.
    [0009]
    9. Pharmaceutical composition, characterized in that it comprises hemifumarate, as defined in any one of claims 1 to 8, and a pharmaceutically acceptable excipient.
    [0010]
    10. Pharmaceutical composition according to claim 9, characterized in that it further comprises an additional therapeutic agent.
    [0011]
    11. Pharmaceutical composition according to claim 10, characterized in that the additional therapeutic agent is selected from the group consisting of human immunodeficiency virus (HIV) protease inhibiting compounds, HIV non-nucleoside reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors and CCR5 inhibitors.
    [0012]
    12. Method for the preparation of a pharmaceutical composition, characterized in that it comprises combining the hemifumarate, as defined in any one of claims 1 to 8, and a pharmaceutically acceptable excipient to provide the pharmaceutical composition.
    [0013]
    13. Method for the preparation of tenofovir alafenamide hemifumarate, characterized in that it consists in submitting a solution comprising: a) a suitable solvent; b) fumaric acid; c) tenofovir alafenamide; and d) one or more seeds of tenofovir alafenamide hemifumarate, under conditions which provide for the crystallization of fumaric acid and tenofovir alafenamide.
    [0014]
    14. Method according to claim 13, characterized in that the solvent comprises acetonitrile.
    [0015]
    15. Method according to claim 13, characterized in that the solution is subjected to a temperature in the range of about 0°C to about 75°C.
    [0016]
    16. Use of hemifumarate, as defined in any one of claims 1 to 8, or a composition, as defined in any one of claims 9 to 11, characterized in that it is for the preparation of a drug for medical therapy.
    [0017]
    17. Use of hemifumarate as defined in any one of claims 1 to 8, or a composition as defined in any one of claims 9 to 11, characterized in that it is for the preparation of a drug for the prophylactic or therapeutic treatment of a HIV infection in an individual in need of it.
    [0018]
    18. Use of hemifumarate as defined in any one of claims 1 to 8, or a composition as defined in any one of claims 9 to 11, characterized in that it is for the preparation of a drug for the prophylactic or therapeutic treatment of a HBV infection in an individual in need of it.
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-06-02| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2020-06-16| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-06-01| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-07-20| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 15/08/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201161524224P| true| 2011-08-16|2011-08-16|
    US61/524,224|2011-08-16|
    PCT/US2012/050920|WO2013025788A1|2011-08-16|2012-08-15|Tenofovir alafenamide hemifumarate|
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