WO1998056781A1 - Form v of amprenavir (vx-478) as antiviral compound - Google Patents

Form v of amprenavir (vx-478) as antiviral compound Download PDF

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Publication number
WO1998056781A1
WO1998056781A1 PCT/EP1998/003504 EP9803504W WO9856781A1 WO 1998056781 A1 WO1998056781 A1 WO 1998056781A1 EP 9803504 W EP9803504 W EP 9803504W WO 9856781 A1 WO9856781 A1 WO 9856781A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
hydroxy
phenylmethyl
tetrahydro
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Application number
PCT/EP1998/003504
Other languages
French (fr)
Inventor
Philip George Lake
Original Assignee
Glaxo Group Limited
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Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU84378/98A priority Critical patent/AU8437898A/en
Publication of WO1998056781A1 publication Critical patent/WO1998056781A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B63/00—Purification; Separation; Stabilisation; Use of additives

Definitions

  • the present invention relates to the antiviral compound [3S-[3R * (l R * ,2S*)]]-[3-[[(4- aminophenyOsulfonyl] (2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]- tetrahydro-3-furanyl ester, (also known as 4-amino-N-((2syn, 3S)-2-hydroxy-4- phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-but ⁇ l)-N-isobutyl- benzenesulfonamide; VX-478; 14lW94; amprenavir; a compound of formula (I)), pharmaceutical formulations thereof and their use in therapy.
  • 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- [3R * (1 R * ,2S * )]]-[3-[[(4-aminophenyl)sulfonyl] (2-methylpropyl)amino]-2-hydroxy-1 - (phenylmethyl)propyl]-tetrahydro-3-furanyl ester has HIV aspartyl protease inhibitory activity and is particularly well suited for inhibiting HIV-1 and HIV-2 viruses.
  • Form V a novel crystalline form
  • Form V is particularly stable and essentially non-hygroscopic. Batches of this crystalline form may be made to a high crystal form purity, i.e. where the proportion of other amorphous and crystalline forms of the compound of formula (I) is limited.
  • Form V may be readily formulated into pharmaceutical compositions such as tablets, capsules, and liquid systems. Form V may be characterized by its X-ray powder diffraction pattern.
  • the invention relates to crystalline Form V both in pure form, in mixtures of other crystalline forms of the compound of formula (I), and in admixture with other forms of the compound of formula (I) such as solvated crystalline forms.
  • forms of the compound of formula (I) such as solvated crystalline forms.
  • a reference to the compound of formula (I) means amorphous compound of formula (I).
  • Form V of the compound of formula (I) may be characterized by the X-ray powder diffraction pattern represented in Figures 1 and 2. Intense diffraction peaks characteristic of Form V may occur at the following approximate 2theta angles (using copper K ⁇ X-radiation): 10.48, 16.81 , 21.19, 19.77, 20.93, 9.68, 17.98, 19.38 and 12.77. Further details are presented in Table 3. Form V may be characterized by an X-ray powder diffraction pattern that contains at least five of the peaks listed in Table 3.
  • Form V may be characterized by d-spacing peaks at 13.53, 9.13, 8.44, 6.92, 6.08, 5.70, 5.27, 4.93, 4.58, 4.49, 4.42, 4.24, 4.19, 4.08, 3.91, 3.80, 3.74, 3.48, and 3.1 1 angstroms (rounded to the nearest 0.01 angstrom).
  • a suitable peak diagnostic for Form V in the presence of other crystal forms of the compound of formula (I) is the 13.53 d-spacing peak or a 2theta angle of about 6.53.
  • Form V may be characterized by an X-ray powder diffraction pattern that contains a d-spacing peak at about 13.53.
  • Form V may be characterized by an X-ray powder diffraction pattern that contains a peak at a 2theta angle of about 6.53.
  • Table 1 provides a list of 2theta angle peaks for a theoretical X-ray powder diffraction pattern calculated using atomic coordinates and unit cell parameters from single crystal X-ray diffraction analysis.
  • Form V may be characterized by an X-ray powder diffraction pattern which contains at least five of the peaks listed in Table 1.
  • a theoretical X-ray powder diffraction pattern using atomic coordinates from single crystal diffraction analysis and unit cell parameters from indexing of an experimental powder pattern is represented in Table 2 and Figure 3.
  • Form V may be characterized by an X-ray powder diffraction pattern that contains at least five of the peaks listed in Table 2.
  • Form V has a melting onset of about 130 °C.
  • Form V is particularly advantageous in that it is thermodynamicaliy stable. Slurried mixtures of other forms of the compound of formula I have been observed to convert completely to Form V within hours to days.
  • the present invention provides a process for the production of the compound of formula (I) in Form V which comprises treating the compound of formula (I) with a solubilising solvent serving to facilitate the conversion of an amount of a compound of formula (I) into said Form V and thereafter isolating said crystalline form or forms.
  • a further aspect of the invention is a process for the production of the compound of formula (I) in a crystalline form, said process comprising the steps of:
  • step b) optionally treating the compound of formula (I) with a solubilising solvent serving to convert an amount of the optionally dried compound of formula (I) from step b) into said crystalline form;
  • the compound of formula (I) may be prepared by any method known in the art, but preferably by the methods described in WO 94/05639 and U.S. Patent No. 5,585,397, incorporated herein by reference hereto.
  • the synthesis of the compound of formula (I) generally leads to the formation of the compound in solution in the reaction mixture from which it may be separated and purified as a solid product.
  • a number of factors influence the crystalline form of the solid product and in accordance with the present invention the conditions of separation and/or subsequent processing may be adjusted to produce the compound of formula (I) as Form V.
  • purified (for example by double recrystallization) Form I of the compound of formula (I) may be used as starting material or as seeding material for the formation of Form V.
  • the present invention also provides Form V of the compound of formula (I) for use in medical therapy, for example in the treatment of a viral disease in an animal, for example, a human.
  • the compound is 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.
  • retroviruses such as HIV infections, for example, Acquired Immune Deficiency Syndrome (AIDS) and AIDS-related complex (ARC)
  • AIDS Acquired Immune Deficiency Syndrome
  • ARC AIDS-related complex
  • Form V of the compound of formula (I) 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 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 Form V of the compound of formula (I).
  • the present invention also provides the use of Form V of the compound of formula (I) in the preparation of a medicament for the treatment of a viral infection.
  • Form V of the compound of formula (I), 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.
  • a suitable effective dose will be in the range of 5 to 100 mg per kilogram body weight of recipient per day, advantageously in the range of 8 to 70 mg per kilogram body weight per day, preferably in the range of 8 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 25, 50, 150, 200, or 250 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 therefor 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 by 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 any 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 mierometer- or nanometer-size particles of active ingredient, which formulation may contain other pharmaceutical agents and may optionally be converted to solid form.
  • a soft gelatin capsule formulation may be made by , for example, heating four (4) kilograms (kg) of Vitamin E TPGS (obtained from Eastman Chemical Co.) at 50°C until liquefied.
  • Vitamin E TPGS obtained from Eastman Chemical Co.
  • To the liquified Vitamin E TPGS 2.005 kg of polyethylene glycol 400 (PEG400) (low aldehyde, ⁇ 10 ppm, obtained from Union Carbide or Dow Chemical Co.) heated to 50° C may be added and mixed until a homogeneous solution is formed.
  • the resultant solution may be heated to 65° C.
  • 1.5 kg of the compound of formula (I) Form V may be dissolved in the liquefied solution of Vitamin E TPGS and PEG 400.
  • 0.395 kg of propylene glycol at room temperature may be added and mixed until a homogenous solution is formed.
  • the solution may be cooled to 28-35° C.
  • the solution may then de-gassed.
  • the mixture is advantageously encapsulated at 28-35° C at a fill weight equivalent to 150 mg of volatiles-free compound, into Size 12 oblong, white opaque soft gelatin capsules using a capsule filling machine.
  • the capsule shells may be dried to a constant fill moisture of 3-6% water and a shell hardness of 7-10 newtons, and placed in a suitable container.
  • 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 compound of formula (I) was dissolved in a solution consisting of polyethylene glycol 400 (PEG-400), Vitamin E TPGS, and propylene glycol in a ratio of 2:1 :0.2, giving a concentration of 19% by weight of the compound of formula (I).
  • PEG-400 polyethylene glycol 400
  • Vitamin E TPGS Vitamin E TPGS
  • propylene glycol in a ratio of 2:1 :0.2
  • a solution of 1 :1 water and PEG-400 giving a final concentration of the compound of formula (I) of 5-7.5% by weight.
  • fine needles of crystalline compound of formula (I) began to precipitate. These were isolated and identified as the Form 1 polymorph of the compound of formula (I).
  • Isopropanol/water A solution of the compound of formula (I) (41.0 kg) in isopropanol (406 L) was concentrated to about 1g/2.5 ml. The solution was cooled to 15-20° C and seeded with crystals of the Form 1 polymorph of the compound of formula (I). The mixture was stirred overnight to allow complete crystallization. Water (151 L) was added slowly while cooling the batch to 5-10° C. The suspension was held at 5-10° C for about one hour. The mixture was then filtered and the solids washed with 76 L of water, followed by 57 L of methyl terf-butyl ether. The product was dried in a vacuum oven at 50-60 °C for approximately 18 hours, yielding about 34.8 kg of the Form 1 polymorph of the compound of formula (I).
  • the compound of formula (I) (0.970 kg) was slurried in 3.88 L, (4.0 vol) of industrial methanol in a 10 L jacketed laboratory reactor. Heating was started with the jacket set at 50 °C. The suspension dissolved when the internal temperature reached 35 °C. The clear solution was heated at 40 °C for 30 minutes to ensure dissolution. Demineralised water (1.94 L, 2 vol) was added over 15 to 20 minutes. The jacket was then set to 20 °C. When the internal temperature reached ⁇ 25 °C, the solution was seeded with the compound of formula (I) Form I (10 g, 1 % w/w). The mixture was stirred at 20 °C to 23°C for I to 10 hours.
  • One hundred mg - 200 mg of the compound of formula (I) acetone solvate was placed into 2 mL glass vials (e.g. Hewlett Packard HPLC vials P/N 5181 -3375 with closures P/N 5181 -1210) and sealed.
  • the vials were stored at 50 - 60 °C for one month, at which time the compound of formula (I) acetone solvate transformed to the compound of formula (I) Form V.
  • a solution of 50% v/v ethanol/water was prepared.
  • One gram of the compound of formula (I) was added to 10 ml of the 50% ethanol/water solution and stirred for 4 hours in a closed vessel, using a magnetic stirrer and stir bar.
  • An additional 300 mg of the compound of formula (I) was added to the solution and stirred in the closed vessel for 2 - 4 days.
  • the solid excess was isolated, dried and tested by Differential Scanning Calorimetry (DSC) analysis or X-ray powder diffraction.
  • Form V has a melting onset around 130°C.
  • the crystal structure of a single crystal of the compound of formula (I) Form V was determined using single crystal X-ray diffraction.
  • Single crystal X-ray diffraction data were collected on a Siemens P3 diffractometer with monochromatized Cu-K ⁇ X- Radiation.
  • a calculated X-ray powder diffraction pattern was determined. The 9 most intense peaks are listed in Table 1.
  • the 2theta values derived from single crystal data shown in Table 1 differ from the observed experimental powder diffraction values due to the lack of refinement in the unit cell parameters.
  • the experimental powder pattern was indexed to obtain a more accurate set of unit cell parameters.
  • the unit cell parameters from powder indexing and atomic (fractional) coordinates from single crystal X-ray diffraction a more accurate calculated powder diffraction pattern was obtained.
  • the relative intensity of the peaks in the calculated pattern is effected not only by the input single crystal data but also by the peak profile (shape and broadening) used in the calculation of the simulated powder pattern.
  • Table 3 provides the line list of the 19 most intense peaks from an experimental powder diffraction pattern of 141 W94 Form V.
  • the data was obtained on a Scintag XDS2000 diffractometer with fixed incident and receiving slits using a front packed sample preparation.
  • the 141W94 Form V sample was spiked with 1 -tetradecanol and NIST SRM 675 mica as internal standards. Contribution from K alpha II diffraction was mathematically removed prior to determination of peak position using a three point box car smoothing technique.
  • the relative intensity values were determined from a sample of 141 W94 Form V not spiked with internal standards.
  • the diffraction peaks listed in Table 3 would be 13.53, 9.13, 8.44, 6.92, 6.08, 5.70, 5.27, 4.93, 4.58, 4.49, 4.42, 4.24, 4.19, 4.08, 3.91 , 3.80, 3.74, 3.48, and 3.1 1.
  • the error in d-spacing determination is highest for the highest d-spacing and decreases with decreasing d-spacing.
  • the 13.53 d-spacing peak the observed difference between the observed and calculate patterns is 0.03 angstroms.
  • a more conservative estimate of error would be 0.05 angstroms at higher d-spacings (e.g. 13.53 angstroms) to 0.02 angstroms at lower d-spacings (e.g. 3.80 angstroms).
  • the experimental (both raw data and observed data stripped of K ⁇ II diffraction) and the calculated powder pattern traces (d iff ractog rams) for Form V are shown in Figures 1 , 2 and 3 respectively.
  • the calculated powder pattern trace for Form I is shown in figure 4. It should be appreciated that the observed relative peak intensities in experimental powder diffraction patterns may vary due to sample particle size, shape, crystallinity effects, variations in powder diffraction sample preparation and instrumental scan conditions.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to Form V [3S-[3R*(1R*,2S*) ]]-[3-[[(4-aminophenyl)sulfonyl] (2-methylpropyl) amino]-2-hydroxy-1-(phenylmethyl)propyl] -tetrahydro-3-furanyl ester and processes for producing Form V.

Description

FORM V OF AMPRENAVIR (VX-478) AS ANΗVIRAL COMPOUND
BACKGROUND OF THE INVENTION
The present invention relates to the antiviral compound [3S-[3R*(l R*,2S*)]]-[3-[[(4- aminophenyOsulfonyl] (2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]- tetrahydro-3-furanyl ester, (also known as 4-amino-N-((2syn, 3S)-2-hydroxy-4- phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butγl)-N-isobutyl- benzenesulfonamide; VX-478; 14lW94; amprenavir; a compound of formula (I)), pharmaceutical formulations thereof and their use in therapy.
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- [3R*(1 R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl] (2-methylpropyl)amino]-2-hydroxy-1 - (phenylmethyl)propyl]-tetrahydro-3-furanyl ester has HIV aspartyl protease inhibitory activity and is particularly well suited for inhibiting HIV-1 and HIV-2 viruses.
The structure of [3S-[3R*(1 R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl] (2- methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro-3-furanyl ester, a compound of formula (I), is shown below:
Figure imgf000003_0001
We have now found that the compound of formula (I) can be prepared in a novel crystalline form, Form V, exhibiting particularly good pharmaceutical properties. Form V is particularly stable and essentially non-hygroscopic. Batches of this crystalline form may be made to a high crystal form purity, i.e. where the proportion of other amorphous and crystalline forms of the compound of formula (I) is limited. Furthermore Form V may be readily formulated into pharmaceutical compositions such as tablets, capsules, and liquid systems. Form V may be characterized by its X-ray powder diffraction pattern.
DETAILED DESCRIPTION OF THE INVENTION
According to a first aspect of the invention there is provided a novel crystalline form of the compound of formula (I), Form V.
The invention relates to crystalline Form V both in pure form, in mixtures of other crystalline forms of the compound of formula (I), and in admixture with other forms of the compound of formula (I) such as solvated crystalline forms. For example in any batch containing Form V of the compound of formula (I), there may also be other solvated or non-solvated crystalline forms of the compound of formula (I). Unless otherwise specified, a reference to the compound of formula (I) means amorphous compound of formula (I).
In a first aspect of the present invention, there is provided Form V of the compound of formula (I). Form V may be characterized by the X-ray powder diffraction pattern represented in Figures 1 and 2. Intense diffraction peaks characteristic of Form V may occur at the following approximate 2theta angles (using copper K α X-radiation): 10.48, 16.81 , 21.19, 19.77, 20.93, 9.68, 17.98, 19.38 and 12.77. Further details are presented in Table 3. Form V may be characterized by an X-ray powder diffraction pattern that contains at least five of the peaks listed in Table 3. Form V may be characterized by d-spacing peaks at 13.53, 9.13, 8.44, 6.92, 6.08, 5.70, 5.27, 4.93, 4.58, 4.49, 4.42, 4.24, 4.19, 4.08, 3.91, 3.80, 3.74, 3.48, and 3.1 1 angstroms (rounded to the nearest 0.01 angstrom). A suitable peak diagnostic for Form V in the presence of other crystal forms of the compound of formula (I) is the 13.53 d-spacing peak or a 2theta angle of about 6.53. Form V may be characterized by an X-ray powder diffraction pattern that contains a d-spacing peak at about 13.53. Form V may be characterized by an X-ray powder diffraction pattern that contains a peak at a 2theta angle of about 6.53.
Table 1 provides a list of 2theta angle peaks for a theoretical X-ray powder diffraction pattern calculated using atomic coordinates and unit cell parameters from single crystal X-ray diffraction analysis. Form V may be characterized by an X-ray powder diffraction pattern which contains at least five of the peaks listed in Table 1.
A theoretical X-ray powder diffraction pattern using atomic coordinates from single crystal diffraction analysis and unit cell parameters from indexing of an experimental powder pattern is represented in Table 2 and Figure 3. Form V may be characterized by an X-ray powder diffraction pattern that contains at least five of the peaks listed in Table 2.
Form V has a melting onset of about 130 °C. Form V is particularly advantageous in that it is thermodynamicaliy stable. Slurried mixtures of other forms of the compound of formula I have been observed to convert completely to Form V within hours to days.
According to a further aspect, the present invention provides a process for the production of the compound of formula (I) in Form V which comprises treating the compound of formula (I) with a solubilising solvent serving to facilitate the conversion of an amount of a compound of formula (I) into said Form V and thereafter isolating said crystalline form or forms. Accordingly, a further aspect of the invention is a process for the production of the compound of formula (I) in a crystalline form, said process comprising the steps of:
a) forming the compound of formula (I) in solution in free base form;
b) isolating the compound of formula (I) from the solution and optionally removing unbound (damp, non-solvated) solvent leaving the compound of formula (I) in substantially dry form;
c) optionally treating the compound of formula (I) with a solubilising solvent serving to convert an amount of the optionally dried compound of formula (I) from step b) into said crystalline form; and
d) isolating said crystalline form.
The compound of formula (I) may be prepared by any method known in the art, but preferably by the methods described in WO 94/05639 and U.S. Patent No. 5,585,397, incorporated herein by reference hereto.
The synthesis of the compound of formula (I) generally leads to the formation of the compound in solution in the reaction mixture from which it may be separated and purified as a solid product. A number of factors influence the crystalline form of the solid product and in accordance with the present invention the conditions of separation and/or subsequent processing may be adjusted to produce the compound of formula (I) as Form V. Advantageously, purified (for example by double recrystallization) Form I of the compound of formula (I) may be used as starting material or as seeding material for the formation of Form V.
The present invention also provides Form V of the compound of formula (I) for use in medical therapy, for example in the treatment of a viral disease in an animal, for example, a human. The compound is 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, Form V of the compound of formula (I) 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 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 Form V of the compound of formula (I).
The present invention also provides the use of Form V of the compound of formula (I) in the preparation of a medicament for the treatment of a viral infection.
Form V of the compound of formula (I), 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 5 to 100 mg per kilogram body weight of recipient per day, advantageously in the range of 8 to 70 mg per kilogram body weight per day, preferably in the range of 8 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 25, 50, 150, 200, or 250 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 therefor 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 by 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 any 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 mierometer- or nanometer-size particles of active ingredient, which formulation may contain other pharmaceutical agents and may optionally be converted to solid form.
A soft gelatin capsule formulation may be made by , for example, heating four (4) kilograms (kg) of Vitamin E TPGS (obtained from Eastman Chemical Co.) at 50°C until liquefied. To the liquified Vitamin E TPGS, 2.005 kg of polyethylene glycol 400 (PEG400) (low aldehyde, <10 ppm, obtained from Union Carbide or Dow Chemical Co.) heated to 50° C may be added and mixed until a homogeneous solution is formed. The resultant solution may be heated to 65° C. 1.5 kg of the compound of formula (I) Form V may be dissolved in the liquefied solution of Vitamin E TPGS and PEG 400. 0.395 kg of propylene glycol at room temperature may be added and mixed until a homogenous solution is formed. The solution may be cooled to 28-35° C. The solution may then de-gassed. The mixture is advantageously encapsulated at 28-35° C at a fill weight equivalent to 150 mg of volatiles-free compound, into Size 12 oblong, white opaque soft gelatin capsules using a capsule filling machine. The capsule shells may be dried to a constant fill moisture of 3-6% water and a shell hardness of 7-10 newtons, and placed in a suitable container.
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.
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 [3S-[3R*(l R*,2S*)]3-[3-[[(4-aminophenyl)sulfonyl] (2- methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro-3-furanyl ester Form I
The compound of formula (I) was dissolved in a solution consisting of polyethylene glycol 400 (PEG-400), Vitamin E TPGS, and propylene glycol in a ratio of 2:1 :0.2, giving a concentration of 19% by weight of the compound of formula (I). To this solution was added a solution of 1 :1 water and PEG-400, giving a final concentration of the compound of formula (I) of 5-7.5% by weight. Upon standing for 4-24 hours at ambient temperature, fine needles of crystalline compound of formula (I) began to precipitate. These were isolated and identified as the Form 1 polymorph of the compound of formula (I).
Example 2
Preparation of [3S-[3R*(1 R*,2S*)1]-[3-[[(4-aminop enyl)sulfonyl] (2- methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]-tetrahydro-3-furanyl ester Form I by Seeding
Isopropanol/water: A solution of the compound of formula (I) (41.0 kg) in isopropanol (406 L) was concentrated to about 1g/2.5 ml. The solution was cooled to 15-20° C and seeded with crystals of the Form 1 polymorph of the compound of formula (I). The mixture was stirred overnight to allow complete crystallization. Water (151 L) was added slowly while cooling the batch to 5-10° C. The suspension was held at 5-10° C for about one hour. The mixture was then filtered and the solids washed with 76 L of water, followed by 57 L of methyl terf-butyl ether. The product was dried in a vacuum oven at 50-60 °C for approximately 18 hours, yielding about 34.8 kg of the Form 1 polymorph of the compound of formula (I).
Example 3 Preparation of [3S-[3R*(l R\2S*)]]-[3-[[(4-aminophenyl)sulfonyl] (2- methylpropyl)amino3-2-hydroxy-1 -(phenylmethyl)propyl]-tetrahydro-3-furanyl ester Form V
The compound of formula (I) (0.970 kg) was slurried in 3.88 L, (4.0 vol) of industrial methanol in a 10 L jacketed laboratory reactor. Heating was started with the jacket set at 50 °C. The suspension dissolved when the internal temperature reached 35 °C. The clear solution was heated at 40 °C for 30 minutes to ensure dissolution. Demineralised water (1.94 L, 2 vol) was added over 15 to 20 minutes. The jacket was then set to 20 °C. When the internal temperature reached <25 °C, the solution was seeded with the compound of formula (I) Form I (10 g, 1 % w/w). The mixture was stirred at 20 °C to 23°C for I to 10 hours. Water (2.91 L, 3 vol) was then added over 2 hours at ambient temperature. The suspension was then aged at 10 °C to 12 °C for 1 hour and the resulting Form V was harvested by filtration in vacuo (fast filtration). Form V was dried in vacuo at 50 °C for 24 hours. Characterization: X-ray powder diffraction pattern of Figure 1.
Example 4
Preparation of [3S-[3R*(l R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl] (2- methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]-tetrahydro-3-furanyl ester Acetone Solvate
Approximately 10 g of the compound of formula (I) (Form I) was added to approximately 8 mL of acetone and stirred for several minutes at room temperature. The compound of formula (I) acetone solvate took minutes to hours to precipitate. The mixture, in a closed container, was allowed to stand at room temperature for 2-7 days to allow for crystal ripening. The compound of formula (I) acetone solvate crystals were isolated by vacuum filtering. After air drying for a few hours, the acetone solvate was stored in a sealed glass vial. The acetone solvate was reasonably stable at room temperature for several days to weeks.
Example 5
Preparation of [3S-[3R*(1 R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl] (2- methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]-tetrahydro-3-furanyl ester Form V from Acetone Solvate
One hundred mg - 200 mg of the compound of formula (I) acetone solvate was placed into 2 mL glass vials (e.g. Hewlett Packard HPLC vials P/N 5181 -3375 with closures P/N 5181 -1210) and sealed. The vials were stored at 50 - 60 °C for one month, at which time the compound of formula (I) acetone solvate transformed to the compound of formula (I) Form V.
Example 6
Slurry test for [3S-[3R*(l *,2S*)]]-[3-[[(4-aminophenyl)sulfonyl] (2- methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]-tetrahydro-3-furanyl ester Form V
A solution of 50% v/v ethanol/water was prepared. One gram of the compound of formula (I) was added to 10 ml of the 50% ethanol/water solution and stirred for 4 hours in a closed vessel, using a magnetic stirrer and stir bar. An additional 300 mg of the compound of formula (I) was added to the solution and stirred in the closed vessel for 2 - 4 days. The solid excess was isolated, dried and tested by Differential Scanning Calorimetry (DSC) analysis or X-ray powder diffraction. Form V has a melting onset around 130°C. Example 7
X-ray Powder Diffraction Pattern for βS-fcR'π R'^S'JJHS-t^aminophenyQsulfonyl]
(2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]-tetrahydro-3-furanyl ester Form V Using Single Crystal X-Ray Diffraction Data
The crystal structure of a single crystal of the compound of formula (I) Form V was determined using single crystal X-ray diffraction. Single crystal X-ray diffraction data were collected on a Siemens P3 diffractometer with monochromatized Cu-Kα X- Radiation. The unit cell parameters determined from 12 reflections were monoclinic crystal system, P2(1 ), with a = 9.289, b = 10.529, c = 13.754 (a, b, c units in angstroms), and β = 102.09°. Using the atomic coordinates and unit cell parameters, a calculated X-ray powder diffraction pattern was determined. The 9 most intense peaks are listed in Table 1.
Table 1
X-Ray Powder Diffraction Pattern for [3S-[3R*(l R*,2S )]]-[3-[[(4- aminopheny sulfonyl] (2-methyipropyl)amino]-2-hydroxy-1 - (phenylmethyl)propyl]-tetrahydro-3-furanyl ester Form V using Single Crystal X- ray Diffraction Data
List of the 9 Hiqhest Peaks
peak h k I 2theta Relative intensity
A -1 1 2 16.896 100.000
B 1 1 2 19.856 94.133
C -1 0 1 10.536 85.307
D 2 1 0 21.263 83.700
E 0 2 1 18.071 70.646
F 1 2 0 19.467 48.176
G -2 1 1 21.047 42.372
H 1 0 0 9.753 41.564
I 1 1 0 12.857 30.529 Example 7
X-ray Powder Diffraction Pattern (Calculated) for [3S-[3R (l R*,2S*)]]-[3-[[(4- aminophenyQsulfonyl] (2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]- tetrahydro-3-furanyl ester Form V Using Atomic Coordinates from Single Crystal Diffraction Analysis and Unit Cell Parameters from Indexing of an Experimental Powder Pattern
The 2theta values derived from single crystal data shown in Table 1 differ from the observed experimental powder diffraction values due to the lack of refinement in the unit cell parameters. Using 2theta values determined from experimental X-ray powder diffraction, the experimental powder pattern was indexed to obtain a more accurate set of unit cell parameters. Using the unit cell parameters from powder indexing and atomic (fractional) coordinates from single crystal X-ray diffraction, a more accurate calculated powder diffraction pattern was obtained.
Table 2 provides the line list of 19 intense peaks from the calculated pattern, based on the following unit cell parameters: a = 9.3305, b = 10.5818, c = 13.8040 (a, b, c units in angstroms), and β = 102.13°. The relative intensity of the peaks in the calculated pattern is effected not only by the input single crystal data but also by the peak profile (shape and broadening) used in the calculation of the simulated powder pattern.
Table 2
X-ray Powder Diffraction Pattern (Calculated) using Atomic Coordinates from Single Crystal Diffraction Analysis and Unit Cell Parameters from Indexing of an
Experimental Powder Pattern
Calculated Pattern
2theta h k I Relative Intensity spacing
6.5439 13.49580 0 0 1 16
9.6877 9.12218 1 0 0 42
10.4936 8.42334 -1 0 1 74
12.7937 6.91363 1 0 1 12
14.5838 6.06882 -1 0 2 11
15.5618 5.68953 0 1 2 25
16.8271 5.26447 -1 1 2 100
17.9930 4.92588 0 2 1 76
19.3781 4.57679 1 2 0 66
19.7833 4.48396 1 1 2 94
20.0731 4.41987 -1 0 3 17
20.9412 4.23857 -2 1 1 49
21.1941 4.18856 2 1 0 86
21.7735 4.07840 -1 1 3 17
22.7051 3.91312 -2 1 2 14
23.4015 3.79822 2 1 1 22
23.8014 3.73531 1 0 3 13
25.5572 3.48252 -2 2 1 12
28.6823 3.10979 -3 0 1 15
Example 8 Observed X-ray Powder Diffraction Pattern for [3S-[3R*(l R*,2S*)J]-[3-[[(4- aminophenyQsulfonyl] (2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]- tetrahydro-3-furanyl ester Form V
Table 3 provides the line list of the 19 most intense peaks from an experimental powder diffraction pattern of 141 W94 Form V. The data was obtained on a Scintag XDS2000 diffractometer with fixed incident and receiving slits using a front packed sample preparation. To determine the error in 2theta determination, the 141W94 Form V sample was spiked with 1 -tetradecanol and NIST SRM 675 mica as internal standards. Contribution from K alpha II diffraction was mathematically removed prior to determination of peak position using a three point box car smoothing technique. The relative intensity values were determined from a sample of 141 W94 Form V not spiked with internal standards.
Comparison of the accepted values of 2theta with the observed 2theta values for the internal standards indicated that the error in the observed 2theta values was less than ± 0.02 degrees. The error in determining observed 2theta values is affected by errors in diffractometer alignment and sample preparation. The error in 2theta and d- spacing values presented in Table 3 is the difference between the observed and calculated (see Table 2) values. It should be appreciated that the observed relative intensities are dependent on the diffractometer geometry as well as the sample preparation technique. Additionally, closely spaced diffraction lines which are not fully resolved by the diffractometer may affect observed relative intensity values.
Table 3
Observed X-ray Powder Diffraction Pattern for [3S-[3R*(l R#,2S*)]]-[3-[[(4- aminopheny sulfonyl] (2-methylpropyl)amino]-2-hydroxy-1 -
(phenylmethyl)propyl]-tetrahydro-3-furanyl ester Form V
Experimental Δ2Θ Δd-spaciπg (spiked sample)
2theta d-spaαnq h k 1 Relative Intensity (Obs. -Cal) (Obs. -Cal)
6.5291 13.52686 0 0 1 8 -0.0148 0.03106
9.6750 9.13435 1 0 0 47 -0.0127 0.01217
10.4775 8.43646 -1 0 1 100 -0.0161 0.01312
12.7747 6.92408 1 0 1 25 -0.0190 0.01045
14.5647 6.07689 -1 0 2 15 -0.0191 0.00807
15.5425 5.69671 0 1 2 18 -0.0193 0.00718
16.8106 5.26972 -1 1 2 89 -0.0165 0.00525
17.9788 4.92988 0 2 1 37 -0.0142 0.00400
19.3719 4.57837 1 2 0 34 -0.0062 0.00158
19.7672 4.48770 1 1 2 86 -0.0161 0.00374
20.0631 4.42216 -1 0 3 13 -0.0100 0.00229
20.9334 4.24024 -2 1 1 63 -0.0078 0.00167
21.1922 4.18905 2 1 0 87 -0.0019 0.00049
21.7634 4.08036 -1 1 3 11 -0.0101 0.00196
22.6953 3.91489 -2 1 2 9 -0.0098 0.00177
23.3862 3.80076 2 1 1 14 -0.0153 0.00254
23.7922 3.73683 1 0 3 9 -0.0092 0.00152
25.5619 3.48199 -2 2 1 8 0.0047 -0.00053
28.6716 3.11101 -3 0 1 13 -0.0107 0.00122 Observed 2theta values and d-spacings are significant to the nearest 0.01 degree and 0.01 angstroms, repectively. The highest errors in d-spacing occur at the lowest 2theta angles. In addition to the experimental error in determining the 2theta and d- spacing values from a single 141W94 form V sample, the observed 2theta and d- spacing values of form V will also vary from sample to sample due to variations in crystallinity and crystal lattice strain. Ranges in 2theta values of up to ± 0.09 degrees 2theta have been observed.
Rounded to the nearest 0.01 angstrom, the diffraction peaks listed in Table 3 would be 13.53, 9.13, 8.44, 6.92, 6.08, 5.70, 5.27, 4.93, 4.58, 4.49, 4.42, 4.24, 4.19, 4.08, 3.91 , 3.80, 3.74, 3.48, and 3.1 1. The error in d-spacing determination is highest for the highest d-spacing and decreases with decreasing d-spacing. For the 13.53 d-spacing peak, the observed difference between the observed and calculate patterns is 0.03 angstroms. A more conservative estimate of error would be 0.05 angstroms at higher d-spacings (e.g. 13.53 angstroms) to 0.02 angstroms at lower d-spacings (e.g. 3.80 angstroms).
If 141W94 Form V is a minor component in the presence of other crystal form(s), not all of the Form V diffraction peaks in Tables 1 -3 may be observed due to overlaps with peaks from other crystal forms and variations in sample crystallinity.
The experimental (both raw data and observed data stripped of K α II diffraction) and the calculated powder pattern traces (d iff ractog rams) for Form V are shown in Figures 1 , 2 and 3 respectively. The calculated powder pattern trace for Form I is shown in figure 4. It should be appreciated that the observed relative peak intensities in experimental powder diffraction patterns may vary due to sample particle size, shape, crystallinity effects, variations in powder diffraction sample preparation and instrumental scan conditions.

Claims

CLAIMS 1. Form V [3S-[3R (1 R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl] (2- methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]-tetrahydro-3-furanyl ester.
Form V of the compound of formula (I)
Figure imgf000018_0001
3. A crystalline form of [3S-[3R*(1 R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl] (2- methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]-tetrahydro-3-furanyl ester characterised in that its X-ray powder diffraction pattern contains a peak at at least five of the following angles 2 theta): 10.48, 16.81 , 21.19, 19.77, 20.93, 9.68, 17.98, 19.38 and 12.77.
4. A crystalline form of [3S-[3R*(l R*,2S#)]]-[3-[[(4-aminophenyl)sulfonyl] (2- methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propγl]-tetrahydro-3-furanyl ester characterised by the presence of a 13.53 angstroms d-spacing peak.
5. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 4 and at least one pharmaceutically acceptable carrier therefor.
6. A compound as claimed in any one of claims 1 to 4 for use in medical therapy.
7. Use of a compound as claimed in any one of 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 a human which comprises administering to the human host, an effective anti-retrovirus treatment amount of a compound as claimed in any one of claims 1 to 4.
9. A process for the production of a compound as claimed in any one of claims 1 to 4, said process comprising crystallization of Form V [3S-[3R*(l R*,2S*)]]-[3-[[(4- aminophenyl)sulfonyl] (2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]- tetrahydro-3-furanyl ester from aqueous solution.
10. A pharmaceutical composition according to claim 5 in the form of a powder.
1 1. A pharmaceutical composition according to claim 5 in the form of a suspension.
12. A pharmaceutical composition according to claim 5 in the form of a soft gelatin capsule.
13. A pharmaceutical composition according to claim 5 comprising nanometer-size particles of [3S-[3R*(1 R*.2S*)]]-[3-[[(4-aminophenyl)sulfonyl] (2-methylpropyl)amino]-
2-hydroxy-1 -(phenylmethyl)propyl]-tetrahydro-3-furanyl ester optionally converted to solid form.
14. The compound of formula (I) as claimed in any of claims 1 to 4 being pure polymorphic Form V characterised by an X-ray powder diffraction trace substantially as shown in Figure 1.
PCT/EP1998/003504 1997-06-13 1998-06-11 Form v of amprenavir (vx-478) as antiviral compound WO1998056781A1 (en)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
WO2001082919A2 (en) * 2000-05-04 2001-11-08 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Methods of and compounds for inhibiting calpains
USRE43596E1 (en) 1992-08-25 2012-08-21 G.D. Searle Llc α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US8518987B2 (en) 2002-05-16 2013-08-27 Janssen R&D Ireland Pseudopolymorphic forms of a HIV protease inhibitor

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US5585397A (en) * 1992-09-08 1996-12-17 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
JPH0971575A (en) * 1995-09-07 1997-03-18 Kissei Pharmaceut Co Ltd New crystalline sulfonamide compound

Patent Citations (2)

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US5585397A (en) * 1992-09-08 1996-12-17 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
JPH0971575A (en) * 1995-09-07 1997-03-18 Kissei Pharmaceut Co Ltd New crystalline sulfonamide compound

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DATABASE WPI Week 9722, Derwent World Patents Index; AN 97-238986, XP002081828 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE43596E1 (en) 1992-08-25 2012-08-21 G.D. Searle Llc α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
WO2001082919A2 (en) * 2000-05-04 2001-11-08 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Methods of and compounds for inhibiting calpains
WO2001082919A3 (en) * 2000-05-04 2002-05-10 Us Gov Health & Human Serv Methods of and compounds for inhibiting calpains
US6448245B1 (en) 2000-05-04 2002-09-10 The United States Of America As Represented By The Department Of Health And Human Services Methods of and compounds for inhibiting calpains
US8518987B2 (en) 2002-05-16 2013-08-27 Janssen R&D Ireland Pseudopolymorphic forms of a HIV protease inhibitor
US10000504B2 (en) 2002-05-16 2018-06-19 Janssen Sciences Ireland Uc Pseudopolymorphic forms of a HIV protease inhibitor
US10858369B2 (en) 2002-05-16 2020-12-08 Janssen Sciences Ireland Unlimited Company Pseudopolymorphic forms of a HIV protease inhibitor

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