WO2001000635A2 - Derivatives of (3s) tetrahydro-3-furanyl (1s,2r)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate - Google Patents

Derivatives of (3s) tetrahydro-3-furanyl (1s,2r)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate Download PDF

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WO2001000635A2
WO2001000635A2 PCT/EP2000/005785 EP0005785W WO0100635A2 WO 2001000635 A2 WO2001000635 A2 WO 2001000635A2 EP 0005785 W EP0005785 W EP 0005785W WO 0100635 A2 WO0100635 A2 WO 0100635A2
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compound
formula
amino
sulfonyl
aminophenyl
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PCT/EP2000/005785
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WO2001000635A3 (en
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Andrew David Searle
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Glaxo Group Limited
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Priority to AU58181/00A priority Critical patent/AU5818100A/en
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Publication of WO2001000635A3 publication Critical patent/WO2001000635A3/en

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    • 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
    • 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

Definitions

  • the present invention relates to antiviral compounds that are derivatives of (3S) tetrahydro-3-furanyl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1 - benzyl-2-(phosphonooxy)propylcarbamate, pharmaceutical compositions comprising them, their use in the treatment of retroviral infections, and processes for their preparation.
  • Virus-encoded proteases which are essential for viral replication, are required for the processing of viral protein precursors. Interference with the processing of protein precursors inhibits the formation of infectious virions. Accordingly, inhibitors of viral proteases may be used to prevent or treat chronic and acute viral infections.
  • (3S) tetrahydro-3-furanyl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1 - benzyl-2-(phosphonooxy) propylcarbamate has increased solubility in the pH range of the gastro-intestinal tract compared to the HIV protease inhibitor [3S- [3R * (1 R*,2S * )]]-[3-[[(4-aminophenyl)sulfonyl](2-methyl-propyl)amino]-2-hydroxy- 1-phenylmethyl)propyl]-tetrahydro-3-furanyl ester (amprenavir, 141W94).
  • a stable crystalline form of (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino] -1 -benzyl-2-(phosphonooxy)propylcarbamate suitable for formulation has been isolated, and is calcium (3S) tetrahydro-3-furanyl (1 S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1 -benzyl-2- (phosphonooxy)propylcarbamate.
  • the present invention includes derivatives of (3S) tetrahydro-3-furanyl (1S.2R)- 3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl- carbamate which are capable of delivering (3S) tetrahydro-3-furanyl (1S,2R)-3- [[(4-aminophenyl) sulfonyl](isobutyl)amino]-1 -benzyl-2-(phosphonooxy)propyl- carbamate.
  • These compounds may have desirable pharmacokinetic properties as well as other advantageous pharmaceutical properties.
  • X is selected from one of: a) [OP(0)(OH) 2 ]; b)
  • a preferred compound of formula (V) may be represented as formula (IIIA), (3S)-tetrahydrofuran-3-yl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-
  • a further preferred compound of formula (V) may be represented by formula (IIIB), (3S)-tetrahydrofuran-3-yl (1 S,2R,6R)-8-[(4-aminophenyl)sulfonyl]-2- ⁇ [[(4- aminophenyl) sulfonyl](isobutyl)-amino]methyl ⁇ -1 -benzyl-4-hydroxy-10-methyl-4- oxido-6-[(1 S)-2-phenyl-1 -( ⁇ [(3S)-tetrahydrofuran-3-yloxy] carbonyl ⁇ amino)ethyl]- 3,5-dioxa-8-aza-4-phospha-undec-1-ylcarbamate :
  • a further preferred compound of formula (V) may be represented by formula (IIIC), (3S)-tetrahydrofuran-3-yl (1S,2R,8R)-10-[(4-aminophenyl)sulfonyl]-2- ⁇ [[(4- aminophenyl)sulfonyl](isobutyl)-amino]methyl ⁇ -1-benzyl-4,6-dihydroxy-12- methyl-4,6-dioxido-8-[(1S)-2-phenyl-1-( ⁇ [(3S)-tetrahydrofuran-3-yloxy]carbonyl ⁇ amino)ethyl]-3,5,7-trioxa-10-aza-4,6-diphosphatridec-1 -ylcarbamate :
  • pharmaceutically acceptable derivative means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • Preferred pharmaceutically acceptable derivatives according to the invention are any pharmaceutically acceptable salt, ester or salt of an ester.
  • the compounds of the present invention may be used in the form of salts derived from inorganic or organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-e-sulfonic and benzenesulfonic acids.
  • Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium and alkyl) + salts.
  • the compounds of the present invention may be used in the form of esters, for example carboxylic acid esters in which the non-carbonyl moiety of the ester grouping is selected from straight or branched chain alkyl, e.g. n-propyl, t-butyl, n-butyl, alkoxyalkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl), aryioxyalkyl (e.g. phenoxymethyl), aryl (e.g.
  • phenyl optionally substituted by halogen, or or amino
  • sulphonate esters such as alkyl- or aralkylsulphonyl (e.g. methanesulphonyl); amino acid esters (e.g. L-valyl or L-isoleucyl); and mono-, di- or tri-phosphate esters.
  • Phosphate esters may be further esterified.
  • Any alkyl moiety preferably contains 1 to 18 carbon atoms, particularly 1 to 4 carbon atoms.
  • Any aryl moiety preferably comprises a phenyl group.
  • Compounds of the present invention may be isolated by methods known in the art, such as preparative column chromatography or preparative high performance liquid chromatography (HPLC), preferably high performance liquid chromatography (HPLC), from preparations of a compound of formula (III), (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1- benzyl-2-(phosphonooxy)propylcarbamate or from preparations of a compound of formula (I)
  • a compound of formula (I) may be prepared by dissolving a compound of formula (III)
  • a suitable solvent for example isopropanol, methanol or industrial methylated spirit
  • a source of calcium ions for example calcium acetate, calcium chloride or calcium hydroxide.
  • the compound of formula (I) may be prepared by the reduction of a compound of formula (IV), typically of the sodium salt formed in aqueous solution by addition of sodium bicarbonate, sodium carbonate or sodium hydroxide
  • the compound of formula (I) may be prepared by reaction of a compound of formula (II)
  • a phosphorylating agent for example phosphorus oxychloride, phosphorus pentachloride, or dibenzylchlorophosphate
  • a base for example pyridine, triethylamine or diisopropylethylamine
  • a solvent for example methylisobutylketone or dichloromethane
  • reduction typically of the sodium salt formed in aqueous solution by addition of sodium bicarbonate, sodium carbonate or sodium hydroxide
  • a reducing agent for example formic acid or hydrogen with palladium/ or platinum/carbon catalyst
  • a suitable solvent for example water, ethyl acetate, isopropanol, acetone, methanol, industrial methylated spirit or a mixture of two or more of the above solvents
  • water and a source of calcium ions for example calcium acetate, calcium chloride or calcium hydroxide, optionally in the presence of an additional solvent
  • each step may be followed by a standard isolation and purification procedure such as those detailed in the examples hereinafter.
  • the compound of formula (I) thus obtained may optionally be further purified by recrystallisation from an appropriate solvent, for example industrial methylated spirit, acetone, methanol or isopropanol and mixtures thereof with water, preferably a mixture of industrial methylated spirit and water.
  • a further optional purification step may be carried out by heating a slurry of the product in water to a temperature 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, most preferably 4 hours, followed by cooling to ambient temperature and harvesting the solid.
  • the compound of formula (II) may be prepared by any method known in the art, but preferably by the methods described in WO94/05639, incorporated herein by reference hereto.
  • the compound of formula (III) may be prepared by reaction of a compound of formula (II) with a phosphorylating agent, for example phosphorus oxychloride, phosphorus pentachloride or dibenzylchlorophosphate, in the presence of a base, for example pyridine, triethylamine or diisopropylethylamine, and optionally in the presence of a solvent, for example methylisobutylketone or dichloromethane; followed by reduction, typically of the sodium salt formed in aqueous solution by addition of sodium bicarbonate, sodium carbonate or sodium hydroxide, with a reducing agent, for example formic acid or hydrogen with a palladium/ or platinum/carbon catalyst; in the presence of a suitable solvent, for example water, ethyl acetate, isopropanol, methanol, acetone, industrial methylated spirit or a mixture of two or more of the above solvents.
  • a phosphorylating agent for example phosphorus oxy
  • the compound of formula (IV) may be prepared by the reaction of a compound of formula (II) with a phosphorylating agent, for example phosphorus oxychloride or phosphorus pentachloride, in the presence of a base, for example pyridine, triethylamine or diisopropylethylamine and optionally in the presence of a solvent, for example methylisobutylketone or dichloromethane.
  • a phosphorylating agent for example phosphorus oxychloride or phosphorus pentachloride
  • the phosphorylating agent is phosphorus oxychloride.
  • the base is pyridine.
  • the solvent is methyl isobutylketone.
  • the reducing agent is hydrogen with a palladium on carbon catalyst with a 5-10% loading of palladium.
  • the solvent is a mixture, of industrial methylated spirit and water
  • a UV chromatogram of a sample of the compound of formula (III) is presented in Figure 1. This was carried out using a 250x4.6mm Waters Symmetry 5 ⁇ m C18 column at 50°C at a flow rate of 1.5mL/min using UV260nm detection. Mobile phase A was 0.05M ammonium acetate adjusted to pH4 with acetic acid; Mobile phase B was 95:5 acetonitrile:tetrahydrofuran. The mobile phase gradient was changed over time according to the following Table 1
  • the compounds IIIA, IIIB and IIIC have utility as analytical markers. For example, they may be used as reference compounds for structure identification of impurity peaks found during analysis of a sample taken from a manufacturing batch of calcium (3S) tetrahydro-3-furanyl (1S, 2R)-3-[[(4-aminophenyl)- sulfonyl](isobutyl)amino]-1 -benzyl-2-(phosphonooxy)propyl-carbamate. They may also be used to verify whether test procedures for measuring levels of impurities in such samples are accurate or whether a correction factor needs to be applied.
  • the present invention also provides the compounds of formula IIIA, IIIB, and IIIC for use in medical therapy, for example in the treatment of a viral disease in an animal, for example, a human.
  • the compounds are especially useful for the treatment of diseases caused by retroviruses, such as HIV infections, for example, Acquired Immune Deficiency Syndrome (AIDS) and AIDS-related complex (ARC) as well as diseases caused by hepatitis B and hepatitis C.
  • HIV infections for example, Acquired Immune Deficiency Syndrome (AIDS) and AIDS-related complex (ARC)
  • ARC AIDS-related complex
  • the compounds of formula IIIA, IIIB, and IIIC can be administered to other animals for treatment of viral diseases, for example to other mammals.
  • the present invention also provides a method for the treatment of a viral infection, particularly a retrovirus infection such as an HIV infection, in an animal, for example, a mammal such as a human, which comprises administering to the animal an effective antiviral amount of the compounds of formula IIIA, IIIB, and IIIC.
  • the present invention also provides the use of the compounds of formula IIIA, IIIB, and IIIC in the preparation of a medicament for the treatment of a viral infection, particularly a retrovirus infection such as an HIV infection.
  • the compounds of formula IIIA, IIIB, and IIIC may be administered by any route appropriate to the condition to be treated, but the preferred route of administration is oral. It will be appreciated however, that the preferred route may vary with, for example, the condition of the recipient.
  • a suitable effective dose will be in the range of 0.1 to 150 mg per kilogram body weight of recipient per day, advantageously in the range of 0.5 to 70 mg per kilogram body weight per day, preferably in the range of 0.5 to 50 mg per kilogram body weight per day (unless otherwise indicated, all weights of the active ingredient are calculated with respect to the free base of the compound of formula (I)).
  • the desired dose is preferably presented as one, two, three or four or 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, 150, 200, 250, 300, 400, 450, 500, 570, 600, 750 or 1000 mg of active ingredient per unit dose form.
  • the active ingredient While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation.
  • the formulation comprises the active ingredient as above defined, together with one or more pharmaceutically acceptable excipients thereof and optionally other therapeutic ingredients.
  • the excipient(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral administration and may conveniently be presented in unit dosage form prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing in to association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, sachets of granules or tablets (such as a swallowable, dispersible or chewable tablet) each containing a predetermined amount of the active ingredient; 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.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • the active ingredient may also be presented in a formulation comprising micrometer- or nanometer-size particles of active ingredient, which formulation may contain other pharmaceutical agents and may optionally be converted to solid form.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose (as herein above recited) or an appropriate fraction thereof, of the active ingredient.
  • formulation of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents or taste masking agents.
  • the compounds of formula IIIA, IIIB, and IIIC may be combined with one or more other HIV anti-viral agents, for example Reverse Transcriptase Inhibitors (RTIs), Non Nucleoside Reverse Transcriptase Inhibitor (NNRTIs), and other HIV protease inhibitors.
  • RTIs Reverse Transcriptase Inhibitors
  • NRTIs Non Nucleoside Reverse Transcriptase Inhibitor
  • other HIV protease inhibitors for example Reverse Transcriptase Inhibitors (RTIs), Non Nucleoside Reverse Transcriptase Inhibitor (NNRTIs), and other HIV protease inhibitors.
  • RTIs examples include zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), abacavir, lamivudine (3TC) and FTC.
  • NNRTIs examples include HEPT, TIBO derivatives, atevirdine, L- ofloxacin, L-697,639, L-697-661 , nevirapine (BI-RG-587), loviride ( ⁇ -APA), delavuridine (BHAP), phosphonoformic acid, benzodiazepinones, dipyridodiazepinones, 2-pyridones, bis(heteroaryl)piperazines, 6-substituted pyrimidines, imidazopyridazines, 1 ,4-dihydro-2H-3,1-benzoxazin-2-ones, such as (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1 ,4-dihydro-2H-3, 1 - benzoxazin-2-one (L-743,726 or DMP-266), and quinoxalines, such as isopropyl (2S)-7-fluoro-3,
  • HIV protease inhibitors examples include those disclosed in WO 94/05639, WO 95/24385, WO 94/13629, WO 92/16501 , WO 95/16688,
  • the compounds of formula IIIA, IIIB, and IIIC and combinations thereof with RTIs, NNRTIs and/or HIV protease inhibitors are especially useful for 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 such as AIDS dementia complex, multiple sclerosis or tropical paraperesis, and also anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
  • ARC AIDS related complex
  • PDL progressive generalized lymphadenopathy
  • Kaposi's sarcoma Kaposi's sarcoma
  • thrombocytopenic purpura AIDS-related neurological conditions
  • AIDS dementia complex dementia complex
  • multiple sclerosis or tropical paraperesis and also anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
  • Water content by Karl Fisher analysis is 11.1 % w/w.
  • the methyl-isobutylketone solution was concentrated to ca 600mL in vacuo and then water (1500mL) and sodium bicarbonate (94.g) were added. After stirring for 20 minutes, the phases were separated, and the aqueous solution was washed with ethyl acetate (3 x 200mL). The aqueous solution was treated with 10% palladium on carbon catalyst (30g), left under vacuum for 5 minutes, treated with industrial methylated spirit (1200mL) then stirred under hydrogen at below 30°C for 2.5h. The catalyst was filtered off, washing with industrial methylated spirit (600mL).
  • the filtrate was warmed to 40-50°C and a solution of calcium acetate monohydrate (99.5g) in water (300mL) was added over 20 minutes, then the resulting suspension was stirred at 40-50°C for 30 minutes, then cooled to ambient temperature over 30 minutes.
  • the product was filtered and washed with 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).
  • the methyl-isobutylketone solution was concentrated to ca 70L in vacuo and then water (150L) and 32% sodium hydroxide (14.3kg) were added. After stirring for 15 minutes, the phases were separated, and the aqueous solution was washed with methyl-isobutylketone (3 x 34L). The aqueous solution was treated with 5% palladium on carbon catalyst (1.7kg), treated with industrial methylated spirit (136L) then stirred under hydrogen at below 30°C for 8h. The catalyst was filtered off, washing with industrial methylated spirit (170L).
  • 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 was stirred at 40-50°C for 30 minutes, then cooled to ambient temperature 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 water (340L) for 4h at 90-95°C then cooled to 20-25°C.
  • the solid was filtered and 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).
  • the components are weighed from bulk containers and then sieved using a Russell-SIV equipped with 14 mesh (1.4mm opening) or an equivalent sieve and mesh, and deposited into a stainless-steel blending container.
  • a compound of formula IIIA, IIIB or IIIC, microcrystalline cellulose NF, croscarmellose sodium, povidone USP and colloidal silicon dioxide NF are blended for 20 minutes using a suitable blender, such as a Matcon-Buls bin-type blender, a V-blender or equivalent.
  • the magnesium stearate is then added to the mixture and blending is continued for approximately 2 minutes.
  • the blend is then compressed using a suitable rotary tablet press, typically a Courtoy R-190, R-200 or equivalent.
  • In-process controls for tablet weight and hardness are applied at appropriate intervals throughout the compression run and adjustments to the tablet press are made as necessary.

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Abstract

The invention relates to derivatives of (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate, to processes for their preparation, and to their use as analytical markers and in the treatment of diseases caused by retroviruses.

Description

DERIVATIVES OF (3S) TETRAHYDRO-3-FURANYL (1S,2R)-3-[[(4-
AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-
(PHOSPHONOOXY)PROPYLCARBAMATE
BACKGROUND OF THE INVENTION
The present invention relates to antiviral compounds that are derivatives of (3S) tetrahydro-3-furanyl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1 - benzyl-2-(phosphonooxy)propylcarbamate, pharmaceutical compositions comprising them, their use in the treatment of retroviral infections, and processes for their preparation.
Virus-encoded proteases, which are essential for viral replication, are required for the processing of viral protein precursors. Interference with the processing of protein precursors inhibits the formation of infectious virions. Accordingly, inhibitors of viral proteases may be used to prevent or treat chronic and acute viral infections.
A new antiviral compound, (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate, described in PCT/US98/04595, has HIV aspartyl protease inhibitory activity and is particularly well suited for inhibiting HIV-1 and HIV-2 viruses. Moreover, (3S) tetrahydro-3-furanyl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1 - benzyl-2-(phosphonooxy) propylcarbamate has increased solubility in the pH range of the gastro-intestinal tract compared to the HIV protease inhibitor [3S- [3R*(1 R*,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 gel capsules, has a high pill burden. (3S) Tetrahydro-3-furanyl (1S,2R)-3-[[(4- aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl- carbamate is a new HIV protease inhibitor with increased solubility thus has the potential to reduce the perceived pill burden and may be formulated as a tablet. A stable crystalline form of (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino] -1 -benzyl-2-(phosphonooxy)propylcarbamate suitable for formulation has been isolated, and is calcium (3S) tetrahydro-3-furanyl (1 S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1 -benzyl-2- (phosphonooxy)propylcarbamate.
The present invention includes derivatives of (3S) tetrahydro-3-furanyl (1S.2R)- 3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl- carbamate which are capable of delivering (3S) tetrahydro-3-furanyl (1S,2R)-3- [[(4-aminophenyl) sulfonyl](isobutyl)amino]-1 -benzyl-2-(phosphonooxy)propyl- carbamate. These compounds may have desirable pharmacokinetic properties as well as other advantageous pharmaceutical properties.
DETAILED DESCRIPTION OF THE INVENTION
According to a first aspect of the invention there is provided a compound of formula (V)
Figure imgf000004_0001
wherein X is selected from one of: a) [OP(0)(OH)2]; b)
Figure imgf000005_0001
or, c)
Figure imgf000005_0002
and pharmaceutically acceptable derivatives thereof.
A preferred compound of formula (V) may be represented as formula (IIIA), (3S)-tetrahydrofuran-3-yl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-
1-benzyl-2-{[hydroxy(phosphonooxy) phosphoryl]oxy}propylcarbamate :
Figure imgf000005_0003
and pharmaceutically acceptable derivatives thereof. A further preferred compound of formula (V) may be represented by formula (IIIB), (3S)-tetrahydrofuran-3-yl (1 S,2R,6R)-8-[(4-aminophenyl)sulfonyl]-2-{[[(4- aminophenyl) sulfonyl](isobutyl)-amino]methyl}-1 -benzyl-4-hydroxy-10-methyl-4- oxido-6-[(1 S)-2-phenyl-1 -({[(3S)-tetrahydrofuran-3-yloxy] carbonyl}amino)ethyl]- 3,5-dioxa-8-aza-4-phospha-undec-1-ylcarbamate :
Figure imgf000006_0001
and pharmaceutically acceptable derivatives thereof.
A further preferred compound of formula (V) may be represented by formula (IIIC), (3S)-tetrahydrofuran-3-yl (1S,2R,8R)-10-[(4-aminophenyl)sulfonyl]-2-{[[(4- aminophenyl)sulfonyl](isobutyl)-amino]methyl}-1-benzyl-4,6-dihydroxy-12- methyl-4,6-dioxido-8-[(1S)-2-phenyl-1-({[(3S)-tetrahydrofuran-3-yloxy]carbonyl} amino)ethyl]-3,5,7-trioxa-10-aza-4,6-diphosphatridec-1 -ylcarbamate :
Figure imgf000007_0001
and pharmaceutically acceptable derivatives thereof.
The term, "pharmaceutically acceptable derivative", means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an inhibitorily active metabolite or residue thereof. Preferred pharmaceutically acceptable derivatives according to the invention are any pharmaceutically acceptable salt, ester or salt of an ester.
Compounds of formula IIIA, IIIB, and IIIC and their pharmaceutically acceptable derivatives are referred to herein as compounds of the present invention.
The compounds of the present invention may be used in the form of salts derived from inorganic or organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-e-sulfonic and benzenesulfonic acids.
Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium and alkyl) + salts. The compounds of the present invention may be used in the form of esters, for example carboxylic acid esters in which the non-carbonyl moiety of the ester grouping is selected from straight or branched chain alkyl, e.g. n-propyl, t-butyl, n-butyl, alkoxyalkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl), aryioxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl optionally substituted by halogen,
Figure imgf000008_0001
or
Figure imgf000008_0002
or amino); sulphonate esters such as alkyl- or aralkylsulphonyl (e.g. methanesulphonyl); amino acid esters (e.g. L-valyl or L-isoleucyl); and mono-, di- or tri-phosphate esters. Phosphate esters may be further esterified. Any alkyl moiety preferably contains 1 to 18 carbon atoms, particularly 1 to 4 carbon atoms. Any aryl moiety preferably comprises a phenyl group.
Compounds of the present invention may be isolated by methods known in the art, such as preparative column chromatography or preparative high performance liquid chromatography (HPLC), preferably high performance liquid chromatography (HPLC), from preparations of a compound of formula (III), (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1- benzyl-2-(phosphonooxy)propylcarbamate or from preparations of a compound of formula (I)
Figure imgf000008_0003
A compound of formula (I) may be prepared by dissolving a compound of formula (III)
Figure imgf000009_0001
in a suitable solvent, for example isopropanol, methanol or industrial methylated spirit, and adding to the solution water and a source of calcium ions, for example calcium acetate, calcium chloride or calcium hydroxide.
The compound of formula (I) may be prepared by the reduction of a compound of formula (IV), typically of the sodium salt formed in aqueous solution by addition of sodium bicarbonate, sodium carbonate or sodium hydroxide
Figure imgf000009_0002
in the presence of a suitable reducing agent, for example formic acid or hydrogen with palladium/ or platinum/carbon catalyst, in the presence of a suitable solvent, for example water, ethyl acetate, isopropanol, acetone, methanol, industrial methylated spirit or a mixture of two or more of the above solvents; followed by the addition of water and a source of calcium ions, for example calcium acetate, calcium chloride or calcium hydroxide, optionally in the presence of an additional solvent selected from the above-mentioned list. The compound of formula (I) may be prepared by reaction of a compound of formula (II)
Figure imgf000010_0001
with a phosphorylating agent, for example phosphorus oxychloride, phosphorus pentachloride, or dibenzylchlorophosphate, in the presence of a base, for example pyridine, triethylamine or diisopropylethylamine, and optionally in the presence of a solvent, for example methylisobutylketone or dichloromethane; followed by reduction, typically of the sodium salt formed in aqueous solution by addition of sodium bicarbonate, sodium carbonate or sodium hydroxide, with a reducing agent, for example formic acid or hydrogen with palladium/ or platinum/carbon catalyst, in the presence of a suitable solvent, for example water, ethyl acetate, isopropanol, acetone, methanol, industrial methylated spirit or a mixture of two or more of the above solvents; followed by the addition of water and a source of calcium ions, for example calcium acetate, calcium chloride or calcium hydroxide, optionally in the presence of an additional solvent selected from the above-mentioned list.
It will be appreciated by those skilled in the art that each step may be followed by a standard isolation and purification procedure such as those detailed in the examples hereinafter.
The compound of formula (I) thus obtained may optionally be further purified by recrystallisation from an appropriate solvent, for example industrial methylated spirit, acetone, methanol or isopropanol and mixtures thereof with water, preferably a mixture of industrial methylated spirit and water. A further optional purification step may be carried out by heating a slurry of the product in water to a temperature 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, most preferably 4 hours, followed by cooling to ambient temperature and harvesting the solid.
The compound of formula (II) may be prepared by any method known in the art, but preferably by the methods described in WO94/05639, incorporated herein by reference hereto.
The compound of formula (III) may be prepared by reaction of a compound of formula (II) with a phosphorylating agent, for example phosphorus oxychloride, phosphorus pentachloride or dibenzylchlorophosphate, in the presence of a base, for example pyridine, triethylamine or diisopropylethylamine, and optionally in the presence of a solvent, for example methylisobutylketone or dichloromethane; followed by reduction, typically of the sodium salt formed in aqueous solution by addition of sodium bicarbonate, sodium carbonate or sodium hydroxide, with a reducing agent, for example formic acid or hydrogen with a palladium/ or platinum/carbon catalyst; in the presence of a suitable solvent, for example water, ethyl acetate, isopropanol, methanol, acetone, 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 compound of formula (II) with a phosphorylating agent, for example phosphorus oxychloride or phosphorus pentachloride, in the presence of a base, for example pyridine, triethylamine or diisopropylethylamine and optionally in the presence of a solvent, for example methylisobutylketone or dichloromethane.
Preferably the phosphorylating agent is phosphorus oxychloride. Preferably the base is pyridine. Preferably the solvent is methyl isobutylketone.
Preferably the reducing agent is hydrogen with a palladium on carbon catalyst with a 5-10% loading of palladium. Preferably the solvent is a mixture, of industrial methylated spirit and water A UV chromatogram of a sample of the compound of formula (III) is presented in Figure 1. This was carried out using a 250x4.6mm Waters Symmetry 5μm C18 column at 50°C at a flow rate of 1.5mL/min using UV260nm detection. Mobile phase A was 0.05M ammonium acetate adjusted to pH4 with acetic acid; Mobile phase B was 95:5 acetonitrile:tetrahydrofuran. The mobile phase gradient was changed over time according to the following Table 1
Table 1
Time (mins) %A %B
0 70 30
10 40 60
20 20 80
21 70 30
lonisation was positive ion electrospray, capillary voltage was 3.8kV, cone voltage was 30V and source temperature was 80°C. Compounds of formula (IIIA), (IIIB) and (IIIC) were identified at retention times of 3.23, 10.62, and 8.19 mins respectively and ions observed at m/z 666, m/z 1090, and m/z 1153, 1170 respectively.
The compounds IIIA, IIIB and IIIC have utility as analytical markers. For example, they may be used as reference compounds for structure identification of impurity peaks found during analysis of a sample taken from a manufacturing batch of calcium (3S) tetrahydro-3-furanyl (1S, 2R)-3-[[(4-aminophenyl)- sulfonyl](isobutyl)amino]-1 -benzyl-2-(phosphonooxy)propyl-carbamate. They may also be used to verify whether test procedures for measuring levels of impurities in such samples are accurate or whether a correction factor needs to be applied.
The present invention also provides the compounds of formula IIIA, IIIB, and IIIC for use in medical therapy, for example in the treatment of a viral disease in an animal, for example, a human. The compounds are especially useful for the treatment of diseases caused by retroviruses, such as HIV infections, for example, Acquired Immune Deficiency Syndrome (AIDS) and AIDS-related complex (ARC) as well as diseases caused by hepatitis B and hepatitis C.
In addition to its use in human medical therapy, the compounds of formula IIIA, IIIB, and IIIC can be administered to other animals for treatment of viral diseases, for example to other mammals.
The present invention also provides a method for the treatment of a viral infection, particularly a retrovirus infection such as an HIV infection, in an animal, for example, a mammal such as a human, which comprises administering to the animal an effective antiviral amount of the compounds of formula IIIA, IIIB, and IIIC.
The present invention also provides the use of the compounds of formula IIIA, IIIB, and IIIC in the preparation of a medicament for the treatment of a viral infection, particularly a retrovirus infection such as an HIV infection.
The compounds of formula IIIA, IIIB, and IIIC, also referred to herein as the active ingredient, may be administered by any route appropriate to the condition to be treated, but the preferred route of administration is oral. It will be appreciated however, that the preferred route may vary with, for example, the condition of the recipient.
For each of the above-indicated utilities and indications the amounts required of the active ingredient (as above defined) will depend upon a number of factors including the severity of the condition to be treated and the identity of the recipient and will ultimately be at the discretion of the attendant physician or veterinarian. In general however, for each of these utilities and indications, a suitable effective dose will be in the range of 0.1 to 150 mg per kilogram body weight of recipient per day, advantageously in the range of 0.5 to 70 mg per kilogram body weight per day, preferably in the range of 0.5 to 50 mg per kilogram body weight per day (unless otherwise indicated, all weights of the active ingredient are calculated with respect to the free base of the compound of formula (I)). The desired dose is preferably presented as one, two, three or four or 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, 150, 200, 250, 300, 400, 450, 500, 570, 600, 750 or 1000 mg of active ingredient per unit dose form.
While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation. The formulation comprises the active ingredient as above defined, together with one or more pharmaceutically acceptable excipients thereof and optionally other therapeutic ingredients. The excipient(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral administration and may conveniently be presented in unit dosage form prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing in to association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, sachets of granules or tablets (such as a swallowable, dispersible or chewable tablet) each containing a predetermined amount of the active ingredient; 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. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
The active ingredient may also be presented in a formulation comprising micrometer- or nanometer-size particles of active ingredient, which formulation may contain other pharmaceutical agents and may optionally be converted to solid form.
Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose (as herein above recited) or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above the formulation of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents or taste masking agents.
It will be further understood that the compounds of formula IIIA, IIIB, and IIIC may be combined with one or more other HIV anti-viral agents, for example Reverse Transcriptase Inhibitors (RTIs), Non Nucleoside Reverse Transcriptase Inhibitor (NNRTIs), and other HIV protease inhibitors.
Examples of suitable RTIs include zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), abacavir, lamivudine (3TC) and FTC.
Examples of suitable NNRTIs include HEPT, TIBO derivatives, atevirdine, L- ofloxacin, L-697,639, L-697-661 , nevirapine (BI-RG-587), loviride ( α-APA), delavuridine (BHAP), phosphonoformic acid, benzodiazepinones, dipyridodiazepinones, 2-pyridones, bis(heteroaryl)piperazines, 6-substituted pyrimidines, imidazopyridazines, 1 ,4-dihydro-2H-3,1-benzoxazin-2-ones, such as (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1 ,4-dihydro-2H-3, 1 - 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 (HBY 1293) or HBY 097.
Examples of suitable HIV protease inhibitors include those disclosed in WO 94/05639, WO 95/24385, WO 94/13629, WO 92/16501 , WO 95/16688,
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, WO 92/08701 , WO 95/32185, and U.S. Patent No. 5,256,783, in particular (S)-N- ((.alpha.S)-((1 R)-2-((3S, 4αS,8αS)-3-(tert-Butylcarbamoyl)octahydro-2-(1 H)- 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(phenyimethyl)- 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.
The compounds of formula IIIA, IIIB, and IIIC and combinations thereof with RTIs, NNRTIs and/or HIV protease inhibitors are especially useful for 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 such as AIDS dementia complex, multiple sclerosis or tropical paraperesis, and also anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way. Example 1
Preparation of Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-amino- phenyl)-sulfonyl](isobutyl)amino]-1-benzyI-2-(phosphonooxy)propyl- carbamate (I) from (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)- sulfonyl](isobutyl)amino]-1 -benzyl-2-(phosphonooxy)propy lcarbamate (III)
(3S) tetrahydro-3-furanyl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1 - benzyl-2-(phosphonooxy)propylcarbamate (10g) was dissolved in industrial methylated spirit (60mL) and heated to 50°C. A solution of calcium acetate (2.43g) in water (60mL) was added slowly, causing a white crystalline 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 :1 , 2 x 25mL) and water (25mL), then dried in vacuo at 20°C to give the title compound as white microcrystalline needles (7.52g).
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, 1 H, J = 13.0Hz), 2.9-3.2ppm (m, 3H), 3.34 (m 1 H) 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 = 8.8Hz). Ethanol content by NMR 2.7% w/w.
Melting Point 282-284°C (dec)
(3S)-tetrahydrofuran-3-yl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1 - benzyl-2-{[hydroxy(phosphonooxy) phosphoryl]oxy}propylcarbamate (IIIA),
(3S)-tetrahydrofuran-3-yl (1S,2R,6R)-8-[(4-aminophenyl)sulfonyl]-2-{[[(4- aminophenyl) sulfonyl](isobutyl)amino]methyl}-1 -benzyl-4-hydroxy-10-methyl-4- oxido-6-[(1 S)-2-phenyl-1 -({[(3S)-tetrahydrofuran-3-yloxy] carbonyl}amino)ethyl]- 3,5-dioxa-8-aza-4-phospha-undec-1-ylcarbamate (IIIB), and (3S)- tetrahydrofuran-3-yl (1 S,2R,8R)-10-[(4-aminophenyl)sulfonyl]-2-{[[(4- aminophenyl)sulfonyl](isobutyl)amino]methyl}-1-benzyl-4,6-dihydroxy-12-methyl- 4,6-dioxido-8-[(1S)-2-phenyl-1-({[(3S)-tetrahydrofuran-3-yloxy]carbonyl} amino)ethyl]-3,5,7-trioxa-10-aza-4,6-diphosphatridec-1-ylcarbamate (IIIC) may be isolated from this preparation in trace amounts by methods known in the art. Example 2
Preparation of Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4- aminophenyl)-sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyI- carbamate (I) from (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-nitrophenyl)- sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate (IV)
A solution of (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-nitrophenyl)sulfonyl]- (isobutyl)amino]-1 -benzyl-2-(phosphonooxy)propylcarbamate (17.34g) in industrial methylated spirit (68mL) and water (17mL) was treated with 10% palladium on carbon catalyst (3.4g). The mixture was stirred under hydrogen at ambient temperature for 3h. The catalyst was filtered off, washing with industrial methylated spirit (34mL). The filtrate was warmed to 50°C and a solution of calcium acetate (4.45g) in water (85mL) was added slowly, causing a white crystalline 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 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, 1 H, J = 13.0Hz), 2.8-3.05ppm (m, 3H), 3.15 (m, 1 H) 3.3ppm (d, 1 H, J = 10.8Hz), 3.4-3.8ppm (m, 4H), 4.05- 4.15ppm (m, 1 H, J = 10.3Hz), 4.35ppm (m 1 H), 4.6-4.8ppm (m, 1 H masked by HOD signal), 7.3-7.4ppm (m, 5H), 7.6ppm (m, 2H, J = 8.3Hz), 7.9ppm (d, 2H, J = 8.3Hz). Signals shifted upfield due to lost lock. Ethanol content by NMR 3.4% w/w.
Water content by Karl Fisher analysis is 11.1 % w/w.
(3S)-tetrahydrofuran-3-yl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1 - benzyl-2-{[hydroxy(phosphonooxy) phosphoryl]oxy}propylcarbamate (IIIA),
(3S)-tetrahydrofuran-3-yl (1S,2R,6R)-8-[(4-aminophenyl)sulfonyl]-2-{[[(4- aminophenyl) sulfonyl](isobutyl)amino]methyl}-1-benzyl-4-hydroxy-10-methyl-4- oxido-6-[(1S)-2-phenyl-1-({[(3S)-tetrahydrofuran-3-yloxy] carbonyl}amino)ethyl]- 3,5-dioxa-8-aza-4-phospha-undec-1-ylcarbamate (NIB), and (3S)- tetrahydrofuran-3-yl (1 S,2R,8R)-10-[(4-aminophenyl)sulfonyl]-2-{[[(4- aminophenyl)sulfonyl](isobutyl)amino]methyl}-1-benzyl-4,6-dihydroxy-12-methyl- 4,6-dioxido-8-[(1S)-2-phenyl-1-({[(3S)-tetrahydrofuran-3-yloxy]carbonyl} amino)ethyl]-3,5,7-trioxa-10-aza-4,6-diphosphatridec-1-ylcarbamate (IIIC) may be isolated from this preparation in trace amounts by methods known in the art.
Example 3
Preparation of Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4- aminophenyl)-sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl- carbamate (I) from (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-nitrophenyl)- sulfonyl](isobutyl)amino]-1 -benzy l-2-(hydroxy)propylcarbamate (II)
Phosphorus oxychloride (69mL) was added to a suspension of (3S) tetrahydro- 3-furanyl (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) was added. After a further 1 h, the resulting suspension was added to 6M hydrochloric acid (500mL). The mixture was then heated at 50-55°C for 2h, then cooled. The phases were separated and the aqueous phase was extracted with methyl-isobutylketone (600mL). The combined organic solutions were washed with water (2 x 600mL).
The methyl-isobutylketone solution was concentrated to ca 600mL in vacuo and then water (1500mL) and sodium bicarbonate (94.g) were added. After stirring for 20 minutes, the phases were separated, and the aqueous solution was washed with ethyl acetate (3 x 200mL). The aqueous solution was treated with 10% palladium on carbon catalyst (30g), left under vacuum for 5 minutes, treated with industrial methylated spirit (1200mL) then stirred under hydrogen at below 30°C for 2.5h. The catalyst was filtered off, washing with industrial methylated spirit (600mL).
The filtrate was warmed to 40-50°C and a solution of calcium acetate monohydrate (99.5g) in water (300mL) was added over 20 minutes, then the resulting suspension was stirred at 40-50°C for 30 minutes, then cooled to ambient temperature over 30 minutes. The product was filtered and washed with 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).
NMR (Solvent 0.1 N DCI in D20) 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, 1 H, J = 13.0Hz), 2.9-3.2ppm (m, 3H), 3.34 (m 1 H) 3.42ppm (d, 1 H, J = 10.8Hz), 3.55-3.9ppm (m, 4H), 4.2-4.3ppm (m, 1 H, J = 10.3Hz), 4.55ppm (m 1 H), 4.8-5.0ppm (m, 1 H 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 1.7% w/w.
(3S)-tetrahydrofuran-3-yl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1 - benzyl-2-{[hydroxy(phosphonooxy) phosphoryl]oxy}propylcarbamate (IIIA), (3S)-tetrahydrofuran-3-yl (1S,2R,6R)-8-[(4-aminophenyl)sulfonyl]-2-{[[(4- aminophenyl) sulfonyl](isobutyl)amino]methyl}-1 -benzyl-4-hydroxy-10-methyl-4- oxido-6-[(1S)-2-phenyl-1-({[(3S)-tetrahydrofuran-3-yloxy] carbonyl}amino)ethyl]- 3,5-dioxa-8-aza-4-phospha-undec-1-ylcarbamate (IIIB), and (3S)- tetrahydrofuran-3-yl (1 S,2R,8R)-10-[(4-aminophenyl)sulfonyl]-2-{[[(4- aminophenyl)-sulfonyl](isobutyl)amino]methyl}-1-benzyl-4,6-dihydroxy-12- methyl-4,6-dioxido-8-[(1S)-2-phenyl-1-({[(3S)-tetrahydrofuran-3-yloxy]carbonyl} amino)ethyl]-3,5,7-trioxa-10-aza-4,6-diphosphatridec-1-ylcarbamate (IIIC) may be isolated from this preparation in trace amounts by methods known in the art.
Example 4
Recrystallisation of Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-amino- phenyl)sulfonyl(isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl- carbamate (I)
Calcium (3S) tetrahydro-3-furanyl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl]- (isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate (5g; prepared in a similar manner to that described in any of examples 1 ,2 or 3) was suspended in industrial methylated spirit (75mL) and heated to 70°C. The mixture was clarified through a bed of filter-aid, washing through with industrial methylated spirit (25mL). The filtrate was reheated to 70°C, then water (15mL) was added. The resulting suspension was slowly cooled to 20°C, then the product was filtered off, washed with industrial methylated spirit/water (1 :1 , 2 x 10mL), then dried in vacuo at 20°C to give the title compound as white microcrystalline needles (4.58g).
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 1 H) 3.42ppm (d, 1 H, J = 10.8Hz), 3.55-3.9ppm (m, 4H), 4.2-4.3ppm (m, 1 H, J = 10.3Hz), 4.51ppm (m 1 H), 4.8-5.0ppm (m, 1 H 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.
Melting Point 282-284°C (dec)
(3S)-tetrahydrofuran-3-yl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1- benzyl-2-{[hydroxy(phosphonooxy) phosphoryl]oxy}propylcarbamate (IIIA), (3S)-tetrahydrofuran-3-yl (1 S,2R,6R)-8-[(4-aminophenyl)sulfonyl]-2-{[[(4- aminophenyl) sulfonyl](isobutyl)amino]methyl}-1 -benzyl-4-hydroxy-10-methyl-4- oxido-6-[(1S)-2-phenyl-1-({[(3S)-tetrahydrofuran-3-yloxy] carbonyl}amino)ethyl]- 3,5-dioxa-8-aza-4-phospha-undec-1-ylcarbamate (NIB), and (3S)- tetrahydrofuran-3-yl (1 S,2R,8R)-10-[(4-aminophenyl)sulfonyl]-2-{[[(4- aminophenyl)sulfonyl](isobutyl)amino]methyl}-1 -benzyl-4,6-dihydroxy-12-methyl- 4,6-dioxido-8-[(1S)-2-phenyl-1-({[(3S)-tetrahydrofuran-3-yloxy]carbonyl} amino)ethyl]-3,5,7-trioxa-10-aza-4,6-diphosphatridec-1-ylcarbamate (IIIC) may be isolated from this preparation in trace amounts by methods known in the art.
Example 5
Preparation of Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4- aminophenyl)-sulfonyl](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 (24.1 kg) was added to a suspension of (3S) tetrahydro- 3-furanyl (1 S,2R)-3-[[(4-nitrophenyl)sulfonyl](isobutyl)amino]-1 -benzyl-2-
(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 to 2N 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 extracted with methyl-isobutylketone (70L). The combined organic solutions were washed with water (2 x 70L).
The methyl-isobutylketone solution was concentrated to ca 70L in vacuo and then water (150L) and 32% sodium hydroxide (14.3kg) were added. After stirring for 15 minutes, the phases were separated, and the aqueous solution was washed with methyl-isobutylketone (3 x 34L). The aqueous solution was treated with 5% palladium on carbon catalyst (1.7kg), treated with industrial methylated spirit (136L) then stirred under hydrogen at below 30°C for 8h. The catalyst was filtered off, washing with industrial methylated spirit (170L).
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 was stirred at 40-50°C for 30 minutes, then cooled to ambient temperature 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 water (340L) for 4h at 90-95°C then cooled to 20-25°C. The solid was filtered and 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 D20) 0.8-0.9ppm (m 6H), 1.2-1.3ppm (m, 0.5H), 1.85-2.2ppm (m, 2.5H), 2.6-2.7ppm (m, 1 H, J = 13.0Hz), 2.9-3.2ppm (m, 3H), 3.3-3.4ppm (m 1 H) 3.42ppm (d, 1 H, J = 10.8Hz), 3.55-3.9ppm (m, 4H), 4.2- 4.3ppm (m, 1 H, J = 10.3Hz), 4.5ppm (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 1.0% w/w.
Water content by Karl Fisher analysis is 10.9% w/w.
(3S)-tetrahydrofuran-3-yl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1 - benzyl-2-{[hydroxy(phosphonooxy) phosphoryl]oxy}propylcarbamate (IIIA),
(3S)-tetrahydrofuran-3-yl (1S,2R,6R)-8-[(4-aminophenyl)sulfonyl]-2-{[[(4- aminophenyl) sulfonyl](isobutyl)amino]methyl}-1-benzyl-4-hydroxy-10-methyl-4- oxido-6-[(1 S)-2-phenyl-1 -({[(3S)-tetrahydrofuran-3-yloxy] carbonyl}amino)ethyl]- 3,5-dioxa-8-aza-4-phospha-undec-1-ylcarbamate (1MB), and (3S)- tetrahydrofuran-3-yl (1 S,2R,8R)-10-[(4-aminophenyl)sulfonyl]-2-{[[(4- aminophenyl)sulfonyl](isobutyl)amino]methyl}-1-benzyl-4,6-dihydroxy-12-methyl- 4,6-dioxido-8-[(1S)-2-phenyl-1-({[(3S)-tetrahydrofuran-3-yloxy]carbonyl} amino)ethyl]-3,5,7-trioxa-10-aza-4,6-diphosphatridec-1-ylcarbamate (IIIC) may be isolated from this preparation in trace amounts by methods known in the art.
Example 6
Tablet Formulation
Figure imgf000023_0001
Preparation Method
First, the components are weighed from bulk containers and then sieved using a Russell-SIV equipped with 14 mesh (1.4mm opening) or an equivalent sieve and mesh, and deposited into a stainless-steel blending container.
A compound of formula IIIA, IIIB or IIIC, microcrystalline cellulose NF, croscarmellose sodium, povidone USP and colloidal silicon dioxide NF are blended for 20 minutes using a suitable blender, such as a Matcon-Buls bin-type blender, a V-blender or equivalent. The magnesium stearate is then added to the mixture and blending is continued for approximately 2 minutes. The blend is then compressed using a suitable rotary tablet press, typically a Courtoy R-190, R-200 or equivalent. In-process controls for tablet weight and hardness are applied at appropriate intervals throughout the compression run and adjustments to the tablet press are made as necessary.

Claims

1. A compound of Formula (V):
Figure imgf000024_0001
wherein X is selected from one of: b) [OP(O)(OH)2];
b)
Figure imgf000024_0002
or, c)
Figure imgf000024_0003
and pharmaceutically acceptable derivatives thereof.
2. The compound of formula (V) as claimed in claim 1 which is (3S)- tetrahydrofuran-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1- benzyl-2-{[hydroxy(phosphonooxy)phosphoryl]oxy}propylcarbamate.
3. The compound of formula (V) as claimed in claim 1 which is (3S)- tetrahydrofuran-3-yl (1S,2R,6R)-8-[(4-aminophenyl)sulfonyl]-2-{[[(4-aminophenyl) sulfonyl](isobutyl)amino]methyl}-1 -benzyl-4-hydroxy-10-methyl-4-oxido-6-[(1 S)- 2-phenyl-1-({[(3S)-tetrahydrofuran-3-yloxy]carbonyl}amino)ethyl]-3,5-dioxa-8- aza-4-phospha-undec-1-ylcarbamate.
4. The compound of formula (V) as claimed in claim 1 which is (3S)- tetrahydrofuran-3-yl (1 S,2R,8R)-10-[(4-aminophenyl)sulfonyl]-2-{[[(4- aminophenyl)sulfonyl](isobutyl)amino]methyl}-1-benzyl-4,6-dihydroxy-12-methyl- 4,6-dioxido-8-[(1S)-2-phenyl-1-({[(3S)-tetrahydrofuran-3-yloxy]carbonyl} amino)ethyl]-3,5,7-trioxa-10-aza-4,6-diphosphatridec-1-ylcarbamate.
5. A pharmaceutical composition comprising a compound as claimed in claims 1 to 4 together with at least one pharmaceutically acceptable diluent or carrier therefor.
6. A compound as claimed in claims 1 to 4 for use in medical therapy.
7. Use of a compound as claimed in claims 1 to 4 in the preparation of a medicament for the treatment of a retrovirus infection.
8. A method for the treatment of a retrovirus infection in a human which comprises administering to said human, an effective anti-retrovirus treatment amount of a compound as claimed in claims 1 to 4.
9. A pharmaceutical composition according to claim 5 in the form of a tablet.
10. A pharmaceutical composition according to claim 5 in the form of a suspension.
11. A method of identifying impurities found during analysis of a sample of calcium (3S) tetrahydro-3-furanyl (1S, 2R)-3-[[(4-aminophenyl)-sulfonyl]- (isobutyl)amino]-1 -benzyl-2-(phosphonooxy)propylcarbamate, wherein said method comprises use of a compound according to any of claims 1 to 4 as an analytical marker.
12. A process for the preparation of a compound of formula (V) as defined in any of claims 1 to 4 which process comprises:
a) the preparation of a compound of formula (III)
Figure imgf000026_0001
by reaction of a compound of formula (II),
with a phosphoralating agent, in the presence of a base, and optionally in the presence of a solvent; followed by reduction in the presence of a suitable solvent; and
b) subsequent isolation of a compound according to any of claims 1 to 4 from the reaction mixture thereof.
13. A process for the preparation of a compound of formula (V) as defined in any of claims 1 to 4 which process comprises:
a) the preparation of a compound of formula (I),
Figure imgf000027_0001
by reaction of a compound of formula (II) as defined in claim 12, with a phosphoralating agent, in the presence of a base, and optionally in the presence of a solvent, followed by reduction in the presence of a suitable solvent; followed by the addition of water and a source of calcium ions; and
b) subsequent isolation of a compound according to any of claims 1 to 4 from the reaction mixture thereof.
14. A process for the preparation of a compound of formula (V) as defined in any of claims 1 to 4 which process comprises: a) the preparation of a compound of formula (I) as defined in claim 13 by the addition of water and a source of calcium ions to a solution of a compound of formula (III),
Figure imgf000028_0001
; and
b) subsequent isolation of a compound according to any of claims 1 to 4 from the reaction mixture thereof.
15. A process for the preparation of a compound of formula (V) as defined in any of claims 1 to 4 which process comprises:
a) the preparation of a compound of formula (I) by the reduction of a compound of formula (IV),
Figure imgf000028_0002
in the presence of a suitable solvent; followed by the addition of water and a source of calcium ions, optionally in the presence of an additional solvent; and
b) subsequent isolation of a compound according to any of claims 1 to 4 from the reaction mixture thereof.
PCT/EP2000/005785 1999-06-24 2000-06-23 Derivatives of (3s) tetrahydro-3-furanyl (1s,2r)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate WO2001000635A2 (en)

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WO2005061450A2 (en) * 2003-12-11 2005-07-07 Abbott Laboratories Hiv protease inhibiting sulfonamides
EP2003120A1 (en) 2007-06-12 2008-12-17 Concert Pharmaceuticals Inc. Azapeptide derivatives as HIV protease inhibitors
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US8193227B2 (en) 2003-12-11 2012-06-05 Abbott Laboratories HIV protease inhibiting compounds
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1240903A2 (en) * 1998-07-18 2002-09-18 Glaxo Group Limited Combination of calcium (3S) tetrahydro-3-furanyl(1S,2R)-3- [[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate with ritonavir
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US20120220786A1 (en) * 2009-09-16 2012-08-30 Ranbaxy Laboratories Limited Process for the preparation of fosamprenavir calcium
US9085592B2 (en) 2009-09-16 2015-07-21 Ranbaxy Laboratories Limited Process for the preparation of fosamprenavir calcium
US20110165202A1 (en) * 2010-01-07 2011-07-07 Pliva Hrvatska D.O.O. Solid state forms of fosamprenavir calcium salt and processes for preparation thereof

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