OA11706A - Calcium (3S) tetrahydro-3-furaranyl (1S,2R)-3-[[(4-aminophenyl)sulfony](isobutyl) amino]-1-benzyl-2-(phosphonooxy)propylcarbamate. - Google Patents

Calcium (3S) tetrahydro-3-furaranyl (1S,2R)-3-[[(4-aminophenyl)sulfony](isobutyl) amino]-1-benzyl-2-(phosphonooxy)propylcarbamate. Download PDF

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OA11706A
OA11706A OA1200100016A OA1200100016A OA11706A OA 11706 A OA11706 A OA 11706A OA 1200100016 A OA1200100016 A OA 1200100016A OA 1200100016 A OA1200100016 A OA 1200100016A OA 11706 A OA11706 A OA 11706A
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Ian Gordon Armitage
Andrew David Searle
Hardev Singh
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Glaxo Group Ltd
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    • C—CHEMISTRY; METALLURGY
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants

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Description

117 0 6 1 CALCIUM (3S) TETRAHYDRO-3-FURANYL (1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-(PHOS-
PHONOOXY)PROPYLCARBAMÀTE
5 BACKGROUND OF THE INVENTION
The présent invention relates to the antivirai compound calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phos-phonooxy)propylcarbamate, pharmaceutical compositions comprising it, its use 10 in the treatment of retroviral infections, and processes for its préparation.
Virus-encoded proteases, which are essential for viral réplication, are required for the processing of viral protein precursors. Interférence with the processing of * protein precursors inhibits the formation of infectious virions. Accordingly, 15 inhibitors of viral proteases may be used to prevent or treat chronic and acuteviral infections. A new antiviral compound, (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyI](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate, described 20 in PCT/US98/04595, has HIV aspartyl protease inhibitory activity and isparticularly well suited for inhibiting HIV-1 and HIV-2 viruses. Moreover, (3S)tetra hydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate has increased solubility in the pHrange of the gastro-intestinal tract compared to the HIV protease inhibitor [3S- 25 [3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methyl-propyl)amino]-2-hydroxy- 1-phenylmethyl)propyl]-tetrahydro-3-furanyl ester (amprenavir, 141W94).Amprenavir, which has poor solubility and is thus available as a solution in gelcapsules and has a high pill burden. This new HIV protease inhibitor with. itsincreased solubility thus has the potential to reduce the perceived pill burden 30 and may be formulated as a tablet.
However, attempts to find a stable crystalline form of (3S) tetrahydro-3-furanyl(1 S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino] -1 -benzyl-2-
(phosphonooxy)propylcarbamate suitable for formulation proved problematic. A 35 range of salts of the phosphoric acid were made (for example, di-sodium, di- 2 11706 potassium, magnésium, zinc, ethylene diamine, piperazine). Of these, thepiperazine sait was a crystalline solid, but had the practical disadvantage oflikely toxicity at the anticipated dose. Surprisingly, we hâve found that thecalcium sait, calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl) 5 sulfonyl](isobutyl)amino]-1-benzyl-2-phosphonooxy)propylcarbamate, has astable crystalline form. Detailed further examination revealed that this sait hasadvantageous properties making it suitable for formulation into tablets. Thus thecompound of the présent invention provides an opportunity to reduce the pillburden associated with some HIV protease inhibitors. 0
The structure of calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate, a compound of formula (I), is shown below:
We hâve now found that the compound of formula (I) can be prepared. incrystalline form, exhibiting particularly good pharmaceutical properties.
20 DETAILED DESCRIPTION OF THE INVENTION
According to a first aspect of the invention there is provided the compound offormula (I) in crystalline form, hereinafter referred to as Form (I). 25 The invention relates to Form (I) of the compound of formula (I) in crystallineform. Typically, Form (I) contains about 4 to 5 moles of water. However, in any 117 06 3 batch containing Form (I) of the compound of formula (I) there may also be othersolvated crystalline forms of the compound of formula (I).
Solid State Form (I) of the compound of formula (I) can be characterised by it's 5 X-ray powder diffraction pattern, shown in Figure 1. Diffraction traces wereobtained using a Phillips PW1800 diffractometer (serial DY701) and Cu K aradiation. X-ray intensifies were measured at 0.02° incréments for 4 secondintervals using a scintillation counter, between values of 2 and 45° 2Θ. Intensediffraction peaks characteristic of Form (I) may occur at the following 10 approximate 2theta angles (using copper K a X-radiation): 5.735, 9.945, 11.500, 13.780, 14.930, 15.225, 17.980, 19.745, 21.575, 22.170, 24.505, and27.020. Further details are presented in Table 1.
It will be appreciated by those skilled in the art that the compound of formula (I) 15 may be in the form of a solvaté, for example a hydrate.
According to a further aspect, the présent invention provides a process for theproduction of the compound of formula (I) in a crystalline form, said processcomprising the reaction of a compound of formula (II) 20
with a phosphorylating agent, for example phosphorus oxychloride, phosphoruspentachloride, or dibenzylchlorophosphate, in the presence of a base, for 25 example pyridine, triethylamine or diisopropylethylamine, and optionally in thepresence of a solvent, for example methyüsobutylketone or dichloromethane;followed by réduction, typically of the sodium sait formed in aqueous solution by 117 06 4 addition of sodium bicarbonate, sodium carbonate or sodium hydroxide, with areducing agent, for example formic acid or hydrqgen with palladium/ orplatinum/carbon catalyst, in the presence of a suitable solvent, for examplewater, ethyl acetate, isopropanol, acetone, methanol, industrial methylated spirit 5 or a mixture of two or more of the above solvents; followed by the addition ofwater and a source of calcium ions, for example calcium acetate, calciumchloride or calcium hydroxide, optionally in the presence of an additional solventselected from the above-mentioned list. 10 In a further aspect, the présent invention also provides a process for theproduction of the compound of formula (I), comprising dissolving a compound offormula (III)
in a suitable solvent, for example isopropanol, methanol or industrial methylated 15 spirit, and adding to the solution water and a source of calcium ions, for examplecalcium acetate, calcium chloride or calcium hydroxide.
In a further aspect, the présent invention also provides a process for theproduction of the compound of formula (I), comprising the réduction of a 20 compound of formula (IV), typically of the sodium sait formed in aqueoussolution by addition of sodium bicarbonate, sodium carbonate or sodiumhydroxide 5 11706
in the presence of a suitable reducing agent, for example formic acid orhydrogen with palladium/ or platinum/carbon catalyst, in the presence of a 5 suitable solvent, for example water, ethyl acetate, isopropanol, acetone,methanol industrial methylated spirit or a mixture of two or more of the abovesolvents; followed by the addition of water and a source of calcium ions, forexample calcium acetate, calcium chloride or calcium hydroxide, optionally in thepresence of an additional solvent selected from the above-mentioned list. 10
It will be appreciated by those skilled in the art that each step may be followedby a standard isolation and purification procedure such as those detailed in theexamples hereinafter. 15 The compound of formula (I) thus obtained may optionally be further purified byrecrystallisation from an appropriate solvent, for example industrial methylatedspirit, acetone, methanol or isopropanol and mixtures thëreof with water,preferably a mixture of industrial methylated spirit and water. 20 A further optional purification step may be carried out by heating a slurry of theproduct in water to a température in the range 70-99°C, preferably 85-97°C,most preferably 90-95°C, for about 2.5-6 hours, preferably 3-5 hours, mostpreferably 4 hours, followed by cooling to ambient température and harvestingthe solid. 25 117 06 6
The compound of formula (II) may be prepared by any method known ih the art,but preferably by the methods described in WO94/05639, incorporated herein byreference hereto. 5 The compound of formula (III) may be prepared by reaction of a compound offormula (II) with a phosphorylating agent, for example phosphorus oxychloride,phosphorus pentacloride or dibenzylchlorophosphate, in the presence of a base,for example pyridine, triethylamine or diisopropylethylamine, and optionally inthe presence of a solvent, for example methylisobutylketone or 10 dichloromethane; followed by réduction, typically of the sodium sait formed inaqueous solution by addition of sodium bicarbonate, sodium carbonate orsodium hydroxide, with a reducing agent, for example formic acid or hydrogenwith a palladium/ or platinum/carbon catalyst; in the presence of a suitablesolvent, for exadiple water, ethyl acetate, isopropanol, methanol, acetone, 15 industrial methylated spirit or a mixture of two or more of the above solvents.
The compound of formula (IV) may be prepared by the reaction of a compoundof formula (II) with a phosphorylating agent, for example phosphorus oxychlorideor phosphorus pentachloride, in the presence of a base, for example pyridine, 20 triethylamine or diisopropylethylamine and optionally in the presence of asolvent, for example methylisobutylketone or dichloromethane.
Preferably the phosphorylating agent is phosphorus oxychloride. Preferably thebase is pyridine. Preferably the solvent is methyl isobutylketone. 25
Preferably the reducing agent is hydrogen with a palladium on carbon catalystwith a 5-10% loading of palladium. Preferably the solvent is a mixture ofindustrial methylated spirit and water 30 The présent invention also provides the compound of formula (I) for use inmedical therapy, for example in the treatment of a viral disease in an animal, forexample, a human. The compound is especially useful for the treatment ofdiseases caused by retroviruses, such as HIV infections, for example, AcquiredImmune Deficiency Syndrome (AIDS) and AIDS-related complex (ARC) as well 35 as diseases caused by hepatitis B and hepatitis C. 117 06 7
In addition to its use in human medical therapy, the compound of formula (I)can be administered to other animais for treatment of viral diseases, for exampleto other mammals. 5
The présent invention also provides a method for the treatment of a viralinfection, particularly a retrovirus infection such as an HIV infection, in an animal,for example, a mammal such as a human, which comprises administering to theanimal an effective antiviral amount of the compound of formula (I). 10
The présent invention also provides the use of the compound of formula (I) inthe préparation of a médicament for the treatment of a viral infection, particularly a retrovirus infection such as an HIV infection. ♦ 15 The compound of formula (I), also referred to herein as the active ingrédient,may be administered by any route appropriate to the condition to be treated, butthe preferred route of administration is oral. It will be appreciated however, thatthe preferred route may vary with, for example, the condition of the récipient. 20 For each of the above-indicated utilities and indications the amounts required ofthe active ingrédient (as above defïned) will dépend upon a number of factorsincluding the severity of the condition to be treated and the identity of therécipient and will ultimately be at the discrétion of the attendant physician orveterinarian. In general however, for each of these utilities and indications, a 25 suitable effective dose will be in the range of 0.1 to 150 mg per kilogram bodyweight of récipient per day, advantageously in the range of 0.5 to 70 mg perkilogram body weight per day, preferably in the range of 0.5 to 50 mg perkilogram body weight per day (unless otherwise indicated, ail weights of theactive ingrédient are calculated with respect to the free base of the compound of 30 formula (I)). The desired dose is preferably presented as one, two, three or fouror more subdoses administered at appropriate intervals throughout the day.These sub-doses may be administered in unit dosage forms, for example,containing about 25 to 2000 mg, preferably about 50, 100, 150, 200, 250, 300,450, 500, 570, 750 or 1000 mg of active ingrédient per unit dose form. 35 8
While it is possible for the active ingrédient to be administered alûne, it ispréférable to présent it as a pharmaceutical formulation. The formulationcomprises the active ingrédient as above defined, together with one or morepharmaceutically acceptable excipients thereof and optionally other therapeutic 5 ingrédients. The excipient(s) must be “acceptable” in the sense of beingcompatible with the other ingrédients of the formulation and not deleterious tothe récipient thereof.
The formulations include those suitable for oral administration and may 10 conveniently be presented in unit dosage form prepared by any of the methodswell known in the art of pharmacy. Such methods include the step of bringinginto association the active ingrédient with the carrier which constitutes one ormore accessory ingrédients. In general, the formulations are prepared byuniformly and intimately bringing in to association the active ingrédient with liquid 15 carriers or finely divided solid carriers or both, and then, if necessary, shapingthe product.
Formulations of the présent invention suitable for oral administration may bepresented as discrète units such as capsules, cachets, sachets of granules or 20 tablets (such as a swallowable, dispersible or chewable tablet) each containing apredetermined amount of the active ingrédient; as a powder or granules; as asolution or a suspension in an aqueous liquid or a non-aqueous liquid; or as anoil-in-water liquid émulsion or a water-in-oil liquid émulsion. The activeingrédient may also be presented as a bolus, electuary or paste. 25 A tablet may be made by compression or moulding optionally with one or moreaccessory ingrédients. Compressed tablets may be prepared by compressing ina suitable machine the active ingrédient in a free-flowing form such as a powderor granules, optionally mixed with a binder, lubricant, inert diluent, preservative, 30 surface active or dispersing agent. Moulded tablets may be made by mouldingin a suitable machine a mixture of the powdered compound moistened with aninert liquid diluent. The tablets may optionally be coated or scored any may beformulated so as to provide slow or controlled release of the active ingrédienttherein. 35 11706 9
The active ingrédient may also be presented in a formulation cômprisingmicrometer- or nanometer-size particles of active ingrédient, which formulationmay contain other pharmaceutical agents and may optionally be converted tosolid form. 5
Preferred unit dosage formulations are those containing a daily dose or unit dailysub-dose (as herein above recited) or an appropriate fraction thereof, of theactive ingrédient. 10 It should be understood that in addition to the ingrédients particularly mentionedabove the formulation of this invention may include other agents conventional inthe art having regard to the type of formulation in question, for example thosesuitable for oral administration may include flavoring agents or taste maskingagents. 15
It will be further understood that the compound of formula (I) may be combinedwith one or more other HIV anti-viral agents, for example Reverse TranscriptaseInhibitors (RTIs), Non Nucleoside Reverse Transcriptase Inhibitor (NNRTIs), andother HIV protease inhibitors. 20
Examples of suitable RTIs include zidovudine, didanosine (ddl), zalcitabine(ddC), stavudine (d4T), abacavir, lamivuidine (3TC) and FTC.
Examples of suitable NNRTIs include HEPT, TIBO dérivatives, atevirdine, L- 25 ofloxacin, L-697,639, L-697-661, nevirapine (BI-RG-587), loviride ( oc-APA),delavuridine (BHAP), phosphonoformic acid, benzodiazepinones,dipyridodiazepinones, 2-pyridones, bis(heteroary!)piperazines, 6-substitutedpyrimidines, imidazopyridazines, 1,4-dihydro-2H-3,1-benzoxazin-2-ones, suchas (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1- 30 benzoxazin-2-one (L-743,726 or DMP-266), and quinoxalines, such as isopropyl(2S)-7-fluoro-3,4-dihydro-2-ethyl-3-oxo-1 - (2H)-quinoxalinecarboxylate (HBY1293) or HBY 097.
Examples of suitable HIV protease inhibitors include those disclosed in WO 35 94/05639, WO 95/24385, WO 94/13629, WO 92/16501., WO 95/16688, 117 06 10 WO/US94/13085, WO/US94/12562, US 93/59038, EP 541168, WO 94/14436.WO 95/09843, WO 95/32185, WO 94/15906, WO 94/15608, WO 94/04492, WO92/08701, WO 95/32185, and U.S. Patent No. 5,256,783, in particular (S)-N-((.alpha.S)-((1 R)-2-((3S, 4aS,8aS)-3-(tert-Butylcarbamoyl)octahydro-2-(1 H)- 5 isoquinolyl)-1-hydroxyethyl)phenethyl)-2-quinaldaminosuccinamide monomethanesulfonate (saquinavir), N-(2(R)-Hydroxy-1 (S)indanyl)-2(R)-(phenylmethyl)-4(S)-hydroxy-5-[1-[4-(3-pyridylmethyl)-2(S)-(N-tert- butylcarbamoyl)piperazinyl]]pentaneamide (indinavir), 10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)- 10 2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester (ritonavir), ( N-(1,1- dimethyl)decahydro-2-[2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]- 3-isoquinolinecarboxamide monomethanesulfonate(nelfinavir), and related compounds. 15 The compound of formula (I) and combinations thereof with RTIs, NNRTIsand/or HIV protease inhibitors are especially useful for the treatment of AIDSand related clinical conditions such as AIDS related complex (ARC), progressivegeneralized lymphadenopathy (PGL), Kaposi’s sarcoma, thrombocytopéniepurpura, AIDS-related neurological conditions such as AIDS dementia complex, 20 multiple sclerosis or tropical paraperesis, and also anti-HIV antibody-positiveand HlV-positive conditions, including such conditions in asymptomatic patients. «
The following examples are intended for illustration only and are not intended tolimit the scope of the invention in any way. 25
Example 1
Préparation of Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-amino-phenyl)-sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl-carbamate (I) from (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)- 30 sulfonyl](isobutyl)amino]-1 -benzyl-2-(phosphonooxy)propylcarbamate (III) (3S) tetrahydro-3-furanyl (1S,2R)-3-([(4-aminophenyl)sulfonyl](isobutyi)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate (10g) was dissolved in industrialmethylated spirit (60ml) and heated to 50°C. A solution of calcium acetate 35 (2.43g) in water (60ml) was added slowly, causing a white crystalline precipitate 11706 11 to form. The mixture was allowed to cool slowly to 20°C. The solid wàs filteredoff, washed with industrial methylated spirit/water (1:1, 2 x 25ml) and water(25ml), then dried in vacuo at 20°C to give the tîtle compound as whitemicrocrystalline needles (7.52g). 5 NMR (Solvent 0.1 N DCI in D2O) 0.8-0.9ppm (m 6H), 1.2-1.3ppm (m, 0.5H), 1.85-2.2ppm (m, 2.5H), 2.6-2.75ppm (m, 1H, J = 13.0Hz), 2.9-3.2ppm (m, 3H),3.34 (m 1H) 3.42ppm (d, 1H, J = 10.8Hz), 3.55-3.9ppm (m, 4H), 4.2-4.3ppm (m,1H, J = 10.3Hz), 4.55ppm (m 1H), 4.8-5.Oppm (m, 1H masked by HOD signal), 10 7.3-7.4ppm (m, 5H), 7.6-7.7ppm (m, 2H, J = 8.3Hz), 8.0-8.1ppm (d, 2H, J = 8.8Hz). Ethanol content by NMR 2.7% w/w.
Melting Point 282-284°C (dec) ♦ 15 Example 2
Préparation of Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)-sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl-carbamate (!) from (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-nitrophenyl)-sulfonyl](isobutyl)amino]-1-benzyI-2-(phosphonooxy)propylcarbamate (IV) 20 A solution of (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-nitrophenyl)sulfonyl]-(isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate (17.34g) inindustrial methylated spirit (68ml) and water (17ml) was treated with 10%palladium on carbon catalyst (3.4g). The mixture was stirred under hydrogen at 25 ambient température for 3h. The catalyst was filtered off, washing with industrialmethylated spirit (34ml). The filtrate was warmed to 50°C and a solution ofcalcium acetate (4.45g) in water (85ml) was added slowly, causing a whitecrystalline precipitate to form. The mixture was allowed to cool slowly to 20°C.The solid was filtered off, washed with industrial methylated spirit/water (1:2, 2 x 30 25ml), then dried in vacuo at 20°C to give the title compound as white microcrystalline needles (14.04g). NMR (Solvent 0.1 N DCI in D2O) 0.65-0.75ppm (m 6H), 1.1-1.2ppm (m, 0.5H),1.7-2.05ppm (m, 2.5H), 2.45-2.55ppm (m, 1H, J = 13.0Hz), 2.8-3.05ppm (m, 35 3H), 3.15 (m, 1H) 3.3ppm (d. 1H, J = 10.8Hz), 3.4-3.8ppm (m, 4H), 4.05- 11706 12 4.15ppm (m, 1H, J = 10.3Hz), 4.35ppm (m 1H), 4.6-4.8ppm (m, 1H màsked byHOD signal), 7.3-7.4ppm (m, 5H), 7.6ppm (m, 2H, J = 8.3Hz), 7.9ppm (d, 2H, J= 8.3Hz). Signais shifted upfield due to lost lock. Ethanol content by NMR 3.4%w/w. 5
Water content by Karl Fisher analysis is 11.1 % w/w.
Example 3
Préparation of Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4- 10 aminophenyl)-sulfonyIJ(isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl-carbamate (I) from (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-nitrophenyl)-sulfonyl](isobutyl)amino]-1-benzyl-2-(hydroxy)propylcarbamate (II)
Phosphorus oxychloride (69ml) was added to a suspension of (3S) tetrahydro-3- 15 furanyi (1 S,2R)-3-[[(4-nitrophenyl)sulfonyl](isobutyl)amino]-1 -benzyl-2- (hydroxy)propylcarbamate (300g) in pyridine (450ml) and methyl-isobutylketone(1500ml). After stirring at 25-30°C for 2.5h, phosphorus oxychloride (7ml) wasadded. After a further 1h, the resulting suspension was added to 6Mhydrochloric acid (500ml). The mixture was then heated at 50-55°C for 2h, then 20 cooled. The phases were separated and the aqueous phase was extracted withmethyl-isobutylketone (600ml). The combined organic solutions were washedwith water (2 x 600ml).
The methyl-isobutylketone solution was concentrated to ca 600ml in vacuo and 25 then water (1500ml) and sodium bicarbonate (94.g) were added. After stirringfor 20 minutes, the phases were separated, and the aqueous solution waswashed with ethyl acetate (3 x 200ml). The aqueous solution was treated with10% palladium on carbon catalyst (30g), left under vacuum for 5 minutes,treated with industrial methylated spirit (1200ml) then stirred under hydrogen at 30 below 30°C for 2.5h. The catalyst was filtered off, washing with industrialmethylated spirit (600ml).
The filtrate was warmed to 40-50°C and a solution of calcium acetatemonohydrate (99.5g) in water (300ml) was added over 20 minutes, then the 35 resulting suspension was stirred at 40-50°C for 30 minutes, then cooled to 11706 13 ambient température over 30 minutes. The product was filtered and washedwith industrial methylated spirit/water (1:1, 2 x 600ml), then dried in vacuo at 35-40°C to give the title compound as white microcrystalline needles (293.28g). 5 NMR (Solvent 0.1N DCI in D2O) 0.8-0.9ppm (m 6H), 1.2-1.3ppm (m, 0.5H), 1.85-2.2ppm (m, 2.5H), 2.6-2.75ppm (m, 1H, J = 13.0Hz), 2.9-3.2ppm (m, 3H),3.34 (m 1H) 3.42ppm (d, 1H, J = 10.8Hz), 3.55-3.9ppm (m, 4H), 4.2-4.3ppm (m,1H, J = 10.3Hz), 4.55ppm (m 1H), 4.8-5.0ppm (m, 1H masked by HOD signal), 7.3-7.4ppm (m, 5H), 7.6-7.7ppm (m, 2H, J = 8.3Hz), 8.0-8.1ppm (d, 2H, J = 10 8.8Hz). Ethanol content by NMR 1.7% w/w.
Example 4
Recrystallisation of Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-amino-phenyl)sulfonyl(isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyI- 15 carbamate (I)
Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl]-(isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate (5g; prepared in asimilar manner to that described in any of examples 1,2 or 3) was suspended in 20 industrial methylated spirit (75ml) and heated to 70°C. The mixture was clarifiedthrough a bed of filter-aid, washing through with industrial methylated spirit(25ml). The filtrate was reheated to 70°C, then water (15ml) was added. Theresulting suspension was slowly cooled to 20°C, then the product was filteredoff, washed with industrial methylated spirit/water (1:1, 2 x 10ml), then dried in 25 vacuo at 20°C to give the title compound as white microcrystalline needles(4.58g). NMR (Solvent 0.1N DCI in D2O) 0.8-0.9ppm (m 6H), 1.2-1.3ppm (m, 0.5H), 1.85-2.2ppm (m, 2.5H), 2.6-2.75ppm (m, 1H, J = 13.0Hz), 2.9-3.2ppm (m, 3H), 30 3.34 (m 1H) 3.42ppm (d, 1H, J = 10.8Hz), 3.55-3.9ppm (m, 4H), 4.2-4.3ppm (m, 1H, J = 10.3Hz), 4.51ppm (m 1H), 4.8-5.0ppm (m, 1H masked by HOD signal), 7.3-7.4ppm (m, 5H), 7.6-7.7ppm (m, 2H, J = 8.3Hz), 8.0-8.1ppm (d, 2H, J =8.8Hz). Ethanol content by NMR 3.1% w/w. 35 Melting Point 282-284°C (dec) 117 06 14
Example 5
Préparation of Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)-sulfonyl](isobutyl)amino]-1 -benzyl-2-(phosphonooxy)propy|- 5 carbamate (I) from (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-nitrophenyl)-su!fonyl](isobutyl)amino]-1-benzyI-2-(hydroxy)propyIcarbamate (II)
Phosphorus oxychloride (24.1kg) was added to a suspension of (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-nitrophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2- 10 (hydroxy)propylcarbamate (37kg) in pyridine (48.5kg) and methyl-isobutylketone(170L). After stirring at 25-30°C for 2.5h, the resulting suspension was added to2N hydrochloric acid (120L). The mixture was then heated at 65-70°C for 3h,then cooled. The phases were separated and the aqueous phase was extractedwith methyl-isobufylketone (70L). The combined organic solutions were washed 15 with water (2 x 70L).
The methyl-isobutylketone solution was concentrated to ca 70L in vacuo andthen water (150L) and 32% sodium hydroxide (14.3kg) were added. Afterstirring for 15 minutes, the phases were separated, and the aqueous solution 20 was washed with methyl-isobutylketone (3 x 34L). The aqueous solution wastreated with 5% palladium on carbon catalyst (1.7kg), treated with industrialmethylated spirit (136L) then stirred under hydrogen at below 30°C for 8h. Thecatalyst was filtered off, washing with industrial methylated spirit (170L). 25 The filtrate was warmed to 40-50°C and a solution of calcium acetate hydrate(9.5kg) in water (136L) was added over 2h, then the resulting suspension wasstirred at 40-50°C for 30 minutes, then cooled to ambient température over 2h.The product was filtered and washed with industrial methylated spirit/water (1:1,2 x 68L), then water (2 x 68L). The product was then stirred and heated with 30 water (340L) for 4h at 90-95°C then cooled to 20-25°C. The solid was filteredand washed with industrial methylated spirits (3 x 34L) then dried in vacuo at 35-40°C to give the title compound as white microcrystalline needles (25.8kg). NMR (Solvent 0.1 N DCI in D2O) 0.8-0.9ppm (m 6H), 1.2-1,3ppm (m, 0.5H), 35 1.85-2.2ppm (m, 2.5H), 2.6-2.7ppm (m, 1H, J = 13.0Hz), 2.9-3.2ppm (m, 3H), 15 3.3-3.4ppm (m 1H) 3.42ppm (d, 1H, J = 10.8Hz), 3.55-3.9ppm (m, 4H), 4.2-4.3ppm (m, 1H, J = 10.3Hz), 4.5ppm (m 1H), 4.8-5.0ppm (m, 1H masked byHOD signal), 7.3-7.4ppm (m, 5H), 7.6-7.7ppm (m, 2H, J = 8.3Hz), 8.0-8.1ppm(d, 2H, J = 8.8Hz). Ethanol content by NMR 1.0% w/w. 5
Water content by Karl Fisher analysis is 10.9% w/w.
Example 6Tablet Formulation 10
Ingrédient Actual mg/tablet Compound of formula (I) 576.1* Microcrystalline Cellulose, NF 102.2 CroscarmeNose Sodium 38.0 Povidone, USP 34.2 Colloïdal Silicon Dioxide, NF 1.9 Magnésium Stéarate, NF 7.6 Total 760 *weight of calcium sait, équivalent to 465 mg free acid based on a 1.239 factor
Préparation Method
First, the components are weighed from bulk containers and then sieved using a15 Russell-SIV equipped with 14 mesh (1.4mm opening) or an équivalent sieve and mesh, and deposited into a stainless-steel blending container.
The compound of formula (I), microcrystalline cellulose NF, croscarmellosesodium, povidone USP and colloïdal Silicon dioxide NF are blended for 20minutes using a suitable blender, such as a Matcon-Buls bin-type blender, a V- 20 blender or équivalent. The magnésium stéarate is then added to the mixtureand blending is continued for approximately 2 minutes.
The blend is then compressed using a suitable rotary tablet press, typically aCourtoy R-190, R-200 or équivalent. In-process Controls for tablet weight andhardness are applied at appropriate intervals throughout the compression run 25 and adjustments to the tablet press are made as necessary. 117 0 6 16
Relative Oral Bioavailability of the compound of formula (I) compared toamprenavir in Beagle dogs.
The relative oral bioavailability of the compound of formula (I) was measured in5 Beagle dogs, as compared to the bioavailability of amprenavir (141W94) in thesame animais. This existing model had previously been used for testing the oralbioavailability of amprenavir and other compounds. The results were obtained from dosing in three animais. 10 Oral dosing of the compound of formula (I) directly to the dogs resulted in arelative bioavailability of 23.8+23.8% as compared to amprenavir.
Oral dosing of the compound of formula (I) to dogs given an oral gavage of 0.1 NHCl before administration of the drug, resulted in a relative bioavailability of 15 58.4+11.5% as compared to amprenavir.
These results suggested that the compound of formula (I) was less bioavailablethan amprenavir itself. However, the pH in the stomach of dogs is typicallymuch higherthan in man.
Aqueous Solubility
The aqueous solubility of amprenavir is 0.095mg/ml at pH 6.3, and the solubilityin 0.1 N Hcl (~pH 1) is 0.29mg/ml.
The aqueous solubility profile of the compound of formula (I) is 30 pH 6.27 0.531 mg/ml pH 5.02 3.20 mg/ml pH4.11 9.41 mg/ml pH 3.27 61.1 mg/ml pH 1.47 3.20 mg/ml
These data illustrate the surprisingly increased and pH dépendent aqueoussolubility of the compound of formula (I) as compared to amprenavir. Thesolubility is notably good between about pH 3 and 4. 35 11706 17
Table 1 Angles 20 and their relative intensifies compared to the strongest peak for the X-ray powder diffraction pattern of the compound of formula (1) Angle 20 rel. int. Angle 2Θ rel. int. 5 5.7350 100 35.2950 3 9.9450 38 35.8050 2 11.1150 7 36.4600 3 11.5000 10 36.8300 2 13.7800 18 37.8400 2 10 14.9300 10 38.6550 2 15.2250 16 39.5350 2 17.9800 35 39.6150 2 19.7450 14 40.5850 3 19.9600 5 41.3550 2 15 20.8050 , 8 41.8100 2 21.5750 12 42.2350 2 22.1700 15 42.6900 3 22.3550 7 43.2000 2 22.9100 6 43.9200 1 20 23.1350 5 44.4000 2 24.5050 14 25.0350 2 25.2550 2 25.8600 7 25 26.5050 2 27.0200 10 27.7850 3 28.2150 4 28.3650 6 30 28.8250 2 28.9450 2 29.4150 4 30.1950 2 30.5750 O «J 35 31.1200 2 31.7950 2 32.2450 4 32.7750 3 32.8900 3 40 33.8150 2 34.9050 2 *

Claims (10)

117 06 18 CLAIMS
1. Calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl) sulfonyl]-(isobuty!)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate. 5
2. A pharmaceutical composition comprising a compound as claimed in claim1 together with at least one pharmaceutically acceptable diluent or carriertherefor. 10 3. A compound as claimed in claim 1 for use in medical therapy.
4. Use of a compound as claimed in claim 1 in the préparation of amédicament for Jhe treatment of a retrovirus infection. 15
5. A pharmaceutical composition according to claim 2 in the form of a20 powder. 6· A pharmaceutical composition according to claim 2 in the form of asuspension. 75 7 A pharmaceutical composition according to claim 2 in the form of a tablet. S A process for the préparation of a compound of formula (I)
(i) 11706 19 comprising i) reacting a compound of formula (II)
5 with a phosphorylating agent; ii) reducing »the résultant compound with a reducing agent in a suitablesolvent; and iii) adding to the résultant compound a source of calcium ions in the presenceof a suitable solvent. 0 <4 A process for the préparation of a compound of formula (I)
15 comprising dissolving a compound of formula (III) 117 06 20
(ΠΙ) in a suitable solvent, and adding to the solution water and a source of calciumions.
10. A process* for the préparation of a compound of formula (I)
comprising the réduction of a compound of formula (IV)
in the presence of a suitable reducing agent in a suitable solvent, followed byadding water and a source of calcium ions. 11706 21
11. A process for the préparation of a compound of formula (I) as claimed inclaim 8, wherein the phosphorylating agent is phosphorus oxychloride.
12.. A process for the préparation of a compound of formula (I) as claimed in5 claim ΰ or 11, wherein the phosphorylating agent is added in the presence of a base.
13. A process for the préparation of a compound of formula (I) as claimed inclaim8, 11 or /2, wherein the product of step i) is converted to its sodium sait 10 prior to step ii). A process for the préparation of a compound of formula (I) as claimed inclaim 8 or 10, wherein the reducing agent is hydrogen with a palladium oncarbon catalyst. 15 1S. A process for the préparation of a compound of formula (I) as claimed in any of daims g, cy and Ίσ, wherein the calcium ion source is calcium acetate. *
16- A process for the préparation of a compound of formula (I) as claimed in20 any of daims#, and 10, additionally comprising recrystallising the compound from an appropriate solvent. 1?. A process for the préparation of a compound of formula (I) as claimed inclaim I6\ wherein the solvent is a mixture of industrial methylated spirit and 25 water.
13. A process for the préparation of a compound of formula (I) as claimed inany of daims β, °| and 10, additionally comprising heating the product in waterto a température in the range 70 to 99°C for 2.5 to 6 hours, then cooling to 30 ambient température and harvesting to solid. 19 The compound of formula (I) as claimed in claim 1 being pure morphicForm (I) characterised by an X-ray powder diffraction trace substantially asshown in Figure 1.
OA1200100016A 1998-07-18 1999-07-15 Calcium (3S) tetrahydro-3-furaranyl (1S,2R)-3-[[(4-aminophenyl)sulfony](isobutyl) amino]-1-benzyl-2-(phosphonooxy)propylcarbamate. OA11706A (en)

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BG105253A (en) 2001-12-29
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AU766056B2 (en) 2003-10-09
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BRPI9912156B8 (pt) 2021-05-25
ID28070A (id) 2001-05-03
EP1098898A1 (fr) 2001-05-16
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PL345620A1 (en) 2002-01-02
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IL140824A (en) 2004-09-27
DE69904600D1 (de) 2003-01-30
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CN1324363A (zh) 2001-11-28
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CA2337857C (fr) 2011-01-25
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