MXPA01000617A - Calcium (3s) tetrahydro-3- furanyl(1s,2r)-3-[[(4-aminophenyl) sulfonyl](isobutyl) amino]-1-benzyl-2- (phosphonooxy) propylcarbamate - Google Patents

Abstract

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

Description

(3S) TETRAHYDRO-3-FURANIL (IS, 2R) -3- [[(4- AMINOPHENYL) SULFONYL] (ISOBUTIL) AMINO3-1-BENC L-2 - (PHOSPHONOOXI) CALCIUM PROPYLCARBAMATE BACKGROUND OF THE INVENTION The present invention describes an antiviral compound (3S) tet rahydro-3-furani 1 (1 S, 2 R) -3 - [[(4-aminophenyl) sulfonyl] (isobutyl) amino] -l-benzyl-2- (fos f onooxy) calcium propylcarbamate, pharmaceutical compositions containing it, its use in the treatment of retroviral infections, and processes for its preparation.

Proteases encoded by viruses, which are essential for viral replication, are required for the processing of viral protein precursors. Interference with the protein precursor process inhibits the formation of infectious virions. Accordingly, inhibitors of viral proteases can be used to prevent or treat chronic or acute viral infections.

Ref. No. (126613) A new antiviral compound, (3S) tetrahydro-3-furanyl (lS, 2R) -3 - [[(4-aminophenyl) sulfonyl] (isobutyl) amino] -l-benzyl-2 (fos fonoox i) propi 1 carbamate described in PCT / US98 / 04595, has inhibitory activity of HIV aspartyl protease and is particularly good followed by inhibition of HIV-1 and HIV-2 viruses. In addition, the (3 S) tet rahydro-3-furani 1 (1 S, 2R) -3- [[(4-aminophenyl) sulfonyl] (isobutyl) amino] -1-benzyl-2 - (fos fonooxy) propi 1 carbamate has increased solubility in the pH range of the gastrointestinal tract compared to the ester inhibitor of [3S [3R * (IR *, 2S *)]] - [3- [[(4-aminophenyl) sulfonyl] (2- methyl-propyl) amino] -2-hydroxy-1-phenylmethyl) propyl] -tetrahydro-3-furanyl of HIV protease (amprenavir, 141W94). Amprenavir, which has poor solubility and is thus available as a solution in gel capsules and has a high weight of pill. This new inhibitor of HIV protease with its increased solubility thus has the potential to reduce the perceived weight of the pill and can be formulated as a tablet.

Nonetheless, attempts to find a stable crystalline form of the (3S) tet rahydro-3-uranyl (SS, 2R) -3- [[(4-aminophenyl) sulfonyl] (isobutyl) amino] -l-benzyl-2- (fos fonooxi) -propi Icarbamate suitable for formulations that are problematic. A range of phosphoric acid salts is established (for example, di-sodium, di-potassium, magnesium, zinc, ethylenediamine, piperazine). Of these, the piperazine salt is a crystalline solid, but has the practical disadvantage of probable toxicity in the anticipated dose. Surprisingly, we find that the salt of (3 S) - tet rahi dr o- 3-fur ani 1 (1 S, 2R) -3 - [[(4-aminophenyl) sulfonyl] (isobutyl) amino] -l-benzyl- 2-fos fonooxi) propyl carbamate calcium, has a stable crystalline form. Additional detailed tests reveal that this salt has advantageous properties that make it suitable for tablet formulations. Thus, the compound of the present invention provides an opportunity to reduce the weight of the pill associated with some HIV protease inhibitor.

The structure of (3S) tet rahydro-3-f urani 1 (1S, 2R) -3 - [[(4-aminophenyl) sulfonyl] (isobutyl) amino] -l-benzyl-2-fonooxy) propylcarbamate or calcium, a compound of formula (I) is shown below: We have now found that the compound of formula (I) can be prepared in crystalline form, which exhibits particularly good pharmaceutical properties.

DETAILED DESCRIPTION OF THE INVENTION According to a first aspect of the invention, the compound of formula in crystalline form is provided, hereinafter referred to as Form (I) • The invention concerns Form (I) of the compound of formula (I) in crystalline form. Typically, Form (I) contains approximately 4 to 5 moles of water. However, in any batch containing Form (I) of the compound of formula (I) there may be other solvated crystalline forms of the compound of formula (I).

The Solid State of Form (I) of the compound of formula (I) can be characterized by its powder X-ray diffraction pattern, shown in Figure 1. The diffraction traces are obtained by using a Phillips PW1800 diffractometer (series DY701) and radiation X Cu K a. The X-ray intensities are measured at 0.02 ° increments for intervals of 4 seconds using a scintillation counter, between the values of 2 and 45 ° 2 ?. The intense diffraction peaks characteristic of Form (I) can occur following the proximity of angles 2? (when using X copper radiation K a): 5.735, 9.945, 11.500, 13.780, 14.930, 15.225, 17.980, 19.745, 21.575, 22.170, 24.505, and 27.020. The additional details are presented in Table 1.

Those skilled in the art will appreciate that the compounds of formula (I) may be in the form of a solvate, for example a hydrate.

According to the additional aspects, the present invention provides a process for the production of the compound of formula (I) in a crystalline form, said process comprising the reaction of a compound of formula (II) (II) with a phosphorylating agent, for example phosphorus oxychloride, phosphorus pentachloride, or dibenzylchlorophosphate or, in the presence of a base, for example pyridine, triethylamine or diisopropylethylamine, and optionally in the presence of a solvent, example methyl isobutyl ketone or dichloromethane; followed by a reduction, typically of the sodium salt formed in aqueous solution by the addition of sodium bicarbonate, sodium carbonate or sodium hydroxide, with a reducing agent, for example formic acid or hydrogen with a palladium / plaque catalyst. / carbon in the presence of a suitable solvent, for example water, ethyl acetate, isopropanol, acetone, methanol, a methylated industrial 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 list mentioned above.

In a further aspect, the present invention also provides a process for the production of the compound of formula (I), which comprises dissolving a compound of formula (III) in a suitable solvent, for example isopropanol, methanol or an industrial methylated spirit, and adding to the solution water and a source of calcium ions, for example calcium acetate, calcium chloride or calcium hydroxide.

In a further aspect, the present invention also provides a process for the production of the compound of formula (I), which comprises the reduction of a compound of formula (IV), typically of the sodium salt formed in aqueous solution by the addition of sodium bicarbonate, sodium carbonate or sodium hydroxide in the presence of a suitable 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, acetone, methanol, a 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 list mentioned above.

Those skilled in the art will appreciate that each step can be followed by a standard isolation and purification procedure such as those detailed in the examples hereunder.

The compound of formula (I) thus obtained can optionally be additionally purified by recrystallization from a suitable solvent, for example an industrial methylated spirit, acetone, methanol or isopropanol and mixtures thereof with water, preferably a mixture of industrial methylated spirit and water.

An optional additional purification step can be carried out by heating a slurry of the product in water at a temperature in the range 70-99 ° C, preferably 85-97 ° C, more preferably 90-95 ° C, for approximately 2.5 -6 hours, preferably 3-5 hours, more preferably 4 hours, followed by cooling to room temperature and collection of the solid.

The compound of formula (II) can be prepared by any method known in the art, but preferably by the methods described in WO94 / 05639, incorporated herein by reference.

The compound of formula (III) can be prepared by the reaction of a compound of formula (II) with a phosphorous agent, for example phosphorus oxychloride, phosphorus pentachloride or fat dibenzyl 1, in the presence of a base, for example pyridine, triethylamine or diisopropylethylamine, and optionally in the presence of a solvent, for example methyl isobutyl ketone or dichloromethane; followed by the reduction, typically of the sodium salt formed in aqueous solution by the addition of sodium bicarbonate, sodium carbonate or sodium hydroxide, with a reducing agent, for example, formic acid or hydrogen with a palladium / platinum catalyst /carbon; in the presence of a suitable solvent, for example water, ethyl acetate, isopropanol, methanol, acetone, industrial methylated spirit a solution of two more of the above solvents The compound of formula (IV) can 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 methyl isobutyl ketone or dichloromethane.

Preferably the phosphorylating agent is phosphorus oxychloride. Preferably the base is pyridine. Preferably the solvent is methyl isobutyl ketone.

Preferably the reducing agent is hydrogen with a palladium on a carbon catalyst with 5-10% palladium loading. Preferably the solvent is a mixture of industrial methylated spirit and water.

The present invention also provides 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 hepat itis C.

In addition to its use in human medical therapy, the compound of formula (I) can be administered to other animals for the 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 compound of formula (I) The present invention also provides the use of the compound of formula (I) in the preparation of a medicament for the treatment of a viral infection, particularly a retrovirus infection such as an HIV infection.

The compound of formula (I), also referred to herein as the active ingredient, can 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 this preferred route may vary with, for example, the condition of the container.

For each of the above-indicated utilities, indications of the required amounts of the active ingredient (as defined above) will depend on a number of factors including the severity of the condition to be treated and the identity of the recipient and will ultimately be of discretion. of the attending physician or veterinarian. In general, however, for each of these utilities and indications, an adequate effective dose will be in the range of 0.1 to 150 mg per kilogram of container body weight per day, advantageously in the range of 0.5 to 70 mg per kilogram of weight per day, preferably in the range of 0.5 to 50 mg per kilogram of body weight per day (unless otherwise indicated), all active ingredient weights will be 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 sub-doses administered at appropriate intervals throughout the day. These sub-doses can be administered in the form of unit doses, for example, containing approximately 25 to 2000 mg, preferably approximately 50, 100, 150, 200, 250, 300, 450, 500, 570, 750 or 1000 mg of ingredient. active per unit dose form.

- While it is possible for the active ingredient to be administered alone, it is preferable that it be presented as a pharmaceutical formulation. The formulation comprises the active ingredient as defined above, together with one or more pharmaceutically acceptable excipients thereof and optionally other therapeutic ingredients. The excipient (s) to be more "acceptable" in the sense of being compatible with other ingredients of the formulation and not harmful to the container thereof.

The formulations include those suitable for oral administration and can be conveniently presented in the form of unit doses prepared by any of the methods known in the pharmacy specialty. Such methods include the presentation step in association with the active ingredient with the carrier that constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately presenting the active ingredient in association with liquid carriers or finely divided solid carriers or both, and then, if necessary, forming the product.

Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, sachets, granule sachets 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 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 can also be presented as a bolus, electuary or paste.

A tablet can be made by compression or molding with one or more accessory ingredients. Compressed tablets may be prepared by compression in a machine suitable for the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface activator or dispersing agent. The molding of tablets can be done by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets can optionally be coated or labeled some can be formulated to provide slow or controlled release of the active ingredient inside.

The active ingredient may also be presented in a formulation comprising particles of micrometric or nanometric size 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 daily unit sub-doses (as discussed above) 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 the invention may include other agents conventional in the art which take into consideration the type of formulation in question, for example those suitable for oral administration, may include flavoring agents or masking agents of the invention. flavor.

It will be further understood that the compound of formula (I) can be combined with one or more other HIV antiviral agents, for example Reverse Transcriptase Inhibitors (RTIs). Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs), and other HIV protease inhibitors.

Examples of suitable RTIs include zidovudine, didanosine (ddl), zalcitabine (ddC), stavudine (d4T), abacavir, lamivuidine (3TC) and FTC.

Examples of NNRTIs include HEPT, TIBO derivatives, ateviridin, L-ofloxacin, L-697, 639, L-697-661, nevirapine (BI-RG-587), loviride (a-APA), delavuridine (BHAP), fos fonofórmi co, benzodia zepinonas, dipi r idodia zepinonas, 2- pyridones, bi s (he t er oa ri 1) piper azas, pyrimidines 6-subs tu tiidas, imidazopiridazinas, 1, 4-dihidro-2H- 3, 1 - ben zoxa z-ina-2-anes, such as (-) 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-l-4-dihydro-2H-3, l-benzoxazin-2-one (L-743, 726 or DMP-266), and quinoxal inas, such as isopropyl (2S) -7-fluoro-3,4-dihydro-2-yl-3-oxo-1- (2H) -quinoxalinecarboxylate (HBY 1293) or HBY 097.

Examples of suitable HIV protease inhibitors include those set forth in WO 94/05639, WO 95/24385, WO 94/13629, WO 92/16501, WO 95/16688, WO / US94 / 13085, WO / US 9/12562, 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 US Pat. No. 5,256,783, in particular S) -N- alpha. S) - ((IR) -2- ((3S 4aS, 8aS) -3- (tert -but ilcarbamoyl) octahydro-2- (ÍH) -isoquinolyl) -1-hydroxyethyl) phenethyl) -2 -quina ldami nos uccinami da monomet ansul fonato (saquinavir), N- (2 (R) -hydroxy-1- (S) indanyl) -2 (R) -phenylmethyl) - (S) -hydroxy-5- [1- [4- (3-pyridylmethyl) - 2- (S) - (N-tert -buti lcarbamoll) piperazinyl]] pentanoamide (indinavir), ester 5 - 1 ia zol i lme ti 1 i co of 10-hydroxy-2-methyl-1 - 5 - (1 -met i le ti 1) - 1 - [2 - (1-methylethyl) -4-thiazolyl] -3,6-dioxo-8, -l-bis (phenylmethyl) -2,4,7,16-tetraazatridecan- oico, (ritonavir), monomet ansulphonate (N- (1, 1-dimethyl) decahydro-2- [2-hydroxy-3- [(3-hydroxy-2-methylbenzoyl) amino] -4- (phenylthio) butyl] -3 i soquinol i ncarboxamide (nel fina vir), and related compounds.

The compound of formula (I) 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 the AIDS-related complex (ARC), 1 progressive generalized adenopathy. (PGL), Kaposi's sarcoma, purple rhomboid t opium, neurological conditions related to AIDS such as AIDS dementia complex, multiple sclerosis or tropical paraperesis, and also positive anti-HIV antibody and HIV positive conditions, including such conditions in patients as in t omá ti cos.

The following examples are an attempt to illustrate only and not to limit the scope of the invention in any way.

E n gle 1 Preparation of (3 S) tet rahydr or- 3-fur ani 1 (1 S, 2R) -3 [[(4-amino-f-enyl) -sul fonill (isobuti 1) amino] -1-benz 1 -2 - (fos fonooxy) propilcarbamate or calcium (I) from (3S) tetr ahydro-3-furanyl (IS, 2R) -3 - [[(4-aminophenyl) -sulfonyl] (isobutyl) amino] -1-benz 1 -2 - (fos fonooxi) propi lcarbamat or (III).

Dissolve (3 S) tetr ah idr o- 3-f ur ani 1 (1 S, 2R) -3- [[(4-aminophenyl) -sulfonyl] (isobutyl) amino] -1-benzyl 1 -2 - ( fos fonooxi) propi lcarbamat or (10 g) in an industrial methylated spirit (60 ml) and heated to 50 ° C. Slowly add a solution of calcium acetate (2.43 g) in water (60 ml) to form a white crystalline precipitate. The mixture is allowed to cool slowly to 20 ° C. The solid is removed from the filter, washed with industrial methylated spirit / water (1: 1, 2 X 25 ml) and water (25 ml), then dried in vacuo at 20 ° C to give the title compound as microcrystalline needles. white (7.52 g).

NMR (Solvent DCl 0.1 N in D20) 0.8-0.9 ppm (m 6H), 1.2-1.3 ppm (m, 0.5H), 1.85-2.2 ppm (m, 2.5H), 2.6-2.75 ppm (m, HI, J) = 13.0 Hz), 2.9-3.2 ppm (m, 3H), 3.34 (mIH) 3.42 ppm (d, ÍH, J = 10.8 Hz), 3.55-3.9 ppm (m, 4H), 4.2- 4.3 ppm (m, HH, J = 10.3 Hz), 4.55 ppm (HH), 4.8-0.5 ppm) (m, HH masked by the HOD signal), 7.3-7.4 ppm (m, 5H), 7.6-7.7 ppm (m, 2H, J = 8.3 Hz), 8.0- 8.1 ppm (d, 2H, J = 8.8 Hz). Ethanol content by NMR 2.7% by weight. Fusion Point 282-284 ° C (dec) E n gle 2 Preparation of (3 S) tet rahydr o- 3 - f ur an i 1 (1 S, 2R) - 3 [[(4-aminophenyl) -sulfonyl]] (isobutyl) amino] -1-benzyl 1 -2- (Phosphonoxy) propylcarbamate or calcium (I) from (3S) t et rahydr o- 3-f ur ani 1 (1 S, 2 R) - 3 - [[(4-nitrophenyl) sulfonyl ] (isobutyl) amino] -1-benzyl- '2- (phosphonooxy) propylcarbamate (IV) Treat a solution of (3 S) tetr ahydr o -3-furanyl (lS, 2R) -3- 4-n-t-oryl) -sul f oni 1] - (isobutyl) amino] -l-benzyl-2- (fos fonooxy) propylcarbamate (17.34 g) in industrial methylated spirit (68 ml) and water (17 ml) with 10% palladium on a carbon catalyst (3.4 g). The mixture is stirred under hydrogen at room temperature for 3 hours. The catalyst is removed from the filtrate, washed with industrial methylated spirit (34 ml). The filtrate is heated to 50 ° C and a solution of calcium acetate (4.45 g) in water (85 ml) is added slowly, forming a white crystalline precipitate. The mixture is cooled slowly to 20 ° C. The solid is removed from the filtrate, washed with methylated spirit indus t r a 1 / water (1: 2, 2 X 25 ml), then dried under vacuum at 20 ° C to give the title compound as microcrystalline white needles (14.04 g).

NMR (Solvent DCl 0. ÍN in D20) 0.65-0.75 ppm (m 6H), 1.1-1.2 ppm (m, 0.5H), 1.7- 2.05 ppm (m, 2.5H), 2.45-2.55 ppm (m, ÍH, J = 13.0 Hz), 2.8- 3.05 ppm (m, 3H), 3.15 (m, HH) 3.3ppm (d, HH, J = 10.8Hz), 3.4-3.8ppm (m, 4H), 4.05-4.15ppm ( m, HH, J = 10.3 Hz), 4.35 ppm (m H H), 4.6-4.8 ppm (m, H H masked by the HOD signal), 7.3-7.4 ppm (m, 5H), 7.6 ppm (m, 2H, J = 8.3 Hz), 7.9 ppm (d, 2H, J = 8.3 Hz). Signals on arrows above the field due to loss of union. The ethanol content by NMR 3.4% by weight. Water content by Karl Fisher analysis is 11.1% by weight.

E j emple 3 Preparation of (3 S) tetr ah i dr o- 3 - f ur ani 1 (1 S, 2 R) -3 [[(4-aminophenyl) -sul foni 1] (isobutyl) amino] - Calcium 1-benzyl-2- (fofonooxy) propylcarbamate (I) from (3S) tetrahydro-3-f-uranyl (SS, 2R) -3- [[(4-nitrophenyl) -sulf oni 1]] isobutyl) amino] -l-benzyl-2- (hydroxy) propylcarbamate or (II) Phosphorus oxychloride (69 ml) is added to a suspension of (3S) t et rahydro-3-furani 1 (1 S, 2 R ) - 3 - [[(-nitrophenyl) sulphonyl] (isobutyl) aminol-1-benzyl-2 - (hydroxy) propylate rbamate (300 g) in pyridine (450 ml) and me ti 1 i sobul t ice (1500 ml). After stirring at 25-30 ° C for 2.5 hours phosphorus oxychloride (7 ml) is added. After an additional hour, the resulting suspension is added to 6M hydrochloric acid (500 ml). The mixture is then heated to 50-55 ° C for 2 hours, then cooled. The phases are separated and the aqueous phase is extracted with methylene chloride (600 ml). The combined organic solutions are washed with water (2 X 600 ml).

The methyl isobutyl ketone solution is concentrated to about 600 ml in vacuo and then water (1500 ml) and sodium bicarbonate (94 g) are added. The filtrate is heated to 40-50 ° C and a solution of calcium acetate monohydrate (99.5 g) in water (300 ml) is added over 20 minutes, then the resulting suspension is stirred at 40-50 ° C for 30 minutes, then it is cooled to room temperature over 30 minutes. After stirring for 20 minutes, the phases are separated, and the aqueous solution is washed with ethyl acetate (3 X 200 ml). The aqueous solution is treated with 10% palladium on a carbon catalyst (30 g), under vacuum for five minutes, treated with industrial methylated spirit (1200 ml) then stirred under hydrogen at less than 30 ° C for 2.5 hours . The catalyst is removed from the filtrate, washed in an industrial methylated spirit (600 m).

The filtrate is washed at 40-50 ° C and a solution of calcium acetate monohydrate (99.5 g) in water (300 ml) is added about 20 minutes, then the resulting suspension is stirred at 40-50 ° C for 30 minutes. , then cooled to room temperature about 30 minutes. The product is filtered and washed with a methylated spirit, trihydride / water (1: 1, 2 X 600 ml.), Then dried under vacuum at 35-40 ° C to give the title compound as white microcrystalline needles (293.28). g).

NMR (Solvent DCl 0.1 N in D20) 0.8-0.9 ppm (m 6H), 1.2-1.3 ppm (m, 0.5H), 1.85-2.2 ppm (m, 2.5H), 2.6- 2.75 ppm (m, HI, J) = 13.0 Hz), 2.9-3.2 ppm (m, 3H), 3.34 (mIH) 3.42 ppm (d, ÍH, J = 10.8 Hz), 3.55-3.9 ppm (m, 4H), 4.2-4.3 ppm (m, ÍH, J = 10.3 Hz), 4.55 ppm (mH), 4.8- 5.0 ppm (m, HH masked by HOD signal), 7.3-7.4 ppm (m, 5H), 7.6-7.7 ppm (m, 2H, J = 8.3 Hz), 8.0-8.1 ppm (d, 2H, J = 8.8 Hz). Ethanol content by NMR 1.7% by weight.

E xplo 4 Recrystallization of 3S tetrahydro-3-furanyl (lS, 2 R) - 3 - [[(4-amino-phenyl) sulfonyl (isobutyl) amino] -l-benzyl-2- (phosphonooxy) propylcarbamate calcium (I) Suspend (3 S) tet rahydr o- 3-f ur ani 1 - (1 S, 2 R) -3 - [[(4-aminophenyl) sulfonyl (isobutyl) amino] -1-benzyl-2 - (f) f onoox i) propi 1 ca rma to calcium (I) (5 g, prepared in a manner similar to that described in any of examples 1, 2 or 3) in industrial methylated spirit (75 ml) and heated to 70 ° C.

The mixture is clarified through a filter aid bed, washed through with industrial methylated spirit (25 ml). The filtrate is reheated to 70 ° C, then water (15 ml) is added. The resulting suspension is cooled slowly to 20 ° C, then the product is removed from the filtrate, washed with methylated spirit, 1% water (1: 1, 2 X 10 ml), then dried under vacuum at 20 ° C. to give the title compound as white microcrystalline needles (4.58 g).

NMR (Solvent DCl 0.1 N in D20) 0.8-0.9 ppm (m 6H), 1.2-1.3 ppm (m, 0.5H), 1.85-2.2 ppm (m, 2.5H), 2.6- 2.75 ppm (m, HI, J) = 13.0 Hz), 2.9-3.2 ppm (m, 3H), 3.34 (mIH) 3.42 ppm (d, ÍH, J = 10.8 Hz), 3.55-3.9 ppm (m, 4H), 4.2-4.3ppm (m, ÍH, J = 10.3 Hz), 4.51 ppm (m H H), 4.8-5.0 ppm (m, H H masked by the HOD signal), 7.3-7.4 ppm (m, 5H), 7.6-7.7 ppm (m, 2H, J = 8.3 Hz), 8.0-8.1 ppm (d, 2H, J = 8.8 Hz). Ethanol content by NMR 3.1% by weight. Melting point 282-284 ° C (dec) - E j plic 5 Preparation of (3 S) tet rahydro-3-f urani 1 (IS, 2R) -3 [[(4-aminophenyl) -sul-fonyl] (isobutyl) amino] -1-benzyl 1 -2- (fos fonooxy) calcium propylcarbamate (I) from (3S) tet rahydr o -3-furanyl (lS, 2R) -3 - [[(4-nitrophenyl) -sulfonyl] (isobutyl) amino] -1-benzyl -2- (hydroxy) propylcarbamate (II) Phosphorus oxychloride (24.1 Kg) is added to a suspension of (3S) t and rahydro-3-furani 1 (1 S, 2R) - [[(4-nitrophenyl) -sulfonyl] (isobutyl) amino] -l-benzyl -2- (hydroxy) propylcarbamate or (37 Kg) in pyridine (48.5) Kg) and me t i 1 - i sobut i lcet ona (170 L). After stirring at 25-30 ° C for 2.5 hours, the resulting suspension is added to 2N hydrochloric acid (120 L).

The mixture is then heated to 65-70 ° C for 3 hours, then cooled. The phases are separated and the aqueous phase is extracted with methyl isobutyl ketone. (70 L). The combined organic solutions are washed with water (2 X 70 L).

The solution is concentrated to about 70 L in vacuo and water (150 L) and 32% sodium hydroxide (14.3 K) are added. After stirring for 15 minutes, the phases are separated, and the aqueous solution is washed with methyl isobutyl ketone (3 X 34 L). The aqueous solution is treated with 5% palladium on a carbon catalyst (1.7 Kg), treated with industrial methylated spirit (136 L) then stirred under hydrogen at a temperature below 30 ° C for 8 hours. The catalyst is removed from the filtrate, washed with industrial methylated spirit (170 L).

The filtrate is heated to 40-50 ° C and a solution of calcium acetate hydrate (9.5 Kg) in water (136 L) is added around 2 hours, then the resulting suspension is stirred at 40-50 ° C for 30 minutes , then cooled to room temperature up to 2 hours. The product is filtered and washed with methylated spirit i ndu s t r i a 1 / water (1: 1, 2 X 68 L), then water (2 X 68 L). The product is then stirred and heated with water (340 L) for 4 hours at 90-95 ° C then cooled to 20-25 ° C. The solid is filtered and washed with industrial methylated spirit (3 X 34 L) then dried under vacuum at 35-40 ° C to give the title compound as microcrystalline white needles (25.8 Kg) NMR (Solvent DCl 0.1 N in D20) 0.8-0.9 ppm (m 6H), 1.2-1.3 ppm (, 0.5H), 1.85-2.2 ppm (m, 2.5H), 2.6-2.7 ppm (m, ÍH, J = 13.0 Hz), 2.9-3.2 ppm (m, 3H), 3.3-3.4 ppm (mIH) 3.42 ppm (d, ÍH, J = 10.8 Hz), 3.55-3.9 ppm (m, 4H), 4.2-4.3 ppm ( m, HH, J = 10.3 Hz), 4.5 ppm (m H H), 4.8- 5.0 ppm (m, H H masked by the HOD signal), 7.3-7.4 ppm (m 5H), 7.6-7.7 ppm (m, 2H, J = 8.3 Hz), 8.0-8.1 ppm (d, 2H, J = 8.8 Hz). The content of ethanol per NMR 1.0% by weight.

The water content by Karl Fisher analysis is 10.9% by weight.

E j us 6 Tablet Formulation * weight of calcium salt, equivalent to 465 mg of free acid based on a factor of 1,239 Preparation method First, the components are weighed from the bulk containers and then screened using a Russell-SIV equipped with 14 mesh (1.4 mm opening) or a sieve and equivalent mesh, and deposited in a stainless steel mixing vessel.

The compound of formula (I), microcrystalline cellulose NF, croscar amellose sodium, povidone USP, and colloidal silicon dioxide NF are mixed for 20 minutes using an appropriate mixer, such as a Malcolm-Buls piggy-type mixer, a mixer V or the equivalent. The magnesium stearate is then added and mixing is continued for about 2 minutes.

The mixture is then compressed using a suitable rotary tablet compressor, typically a Courtoy R-190, R-200 or equivalent. In-process controls for tablet weight and hardness are applied at appropriate intervals through the compression run and adjustments are made to tablet pressure as necessary.

Relative oral bioavailability of the compound of formula (I) in comparison to amprenavir in Beagle dogs.

The relative oral bioavailability of the compound of formula (I) is measured in Beagle dogs, compared to the bioavailability of amprenavir (141W94) in the same animals. The existing model had to be used previously to examine the oral bioavailability of amprenavir and other compounds. Dosage results are obtained in three animals.

Oral dosing of the compound of formula (I) directly to dogs results in a relative bioavailability of 23.8 ± 23.8% compared to amprenavir.

Oral dosage of the compound of formula (I) to dogs that give a 0.1N HCl priming prior to administration of the drug, results in a relative bioavailability of 58.4 ± 11. 5% compared to amprenavir.

These results suggest that the compound of formula (I) has less bioavailability than amprenavir itself. However, the pH in the stomach of dogs is typically higher than in man.

Aqueous Solubility The aqueous solubility of amprenavir is 0.095 mg / ml at pH 6.3, and the solubility in 0.1 N HCl (~ pH 1) is 0.29 mg / ml.

The aqueous solubility profile of the compound of formula (I) is These data illustrate that the surprising increase and pH depend on the aqueous solubility of the compound of formula (I) compared to amprenavir. The solubility is remarkably good between about 3 and 4.

- Table 1 Angles 2? And their relative intensities compared to the peak force for the X-ray diffraction pattern of the powder of the compound of formula (I) Anaulo 2T laughed. int. Angle 2T laugh int. 5.7350 100 35.2950 3 14.9450 10 38.6550 2 15.2250 16 39.5350 2 17.9800 35 39.6150 2 19.7450 14 40.5850 3 19.9600 5 41.3550 2 20.8050 8 41.8100 2 21.5750 12 42.2350 2 22.1700 15 42.6900 3 22.3550 7 25.8600 7 26.5050 2 27..0001 10 27.7850 3 23.2350 4 28.3650 6 28.8250 2 28.9450 2 29.4150 4 30.1950 2 30.5750 3 31.1200 2 31.7950 2 32.2450 4 32.7750 3 - 32.8900 3 33.8150 2 34.9050 2 - It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (20)

1. CLAIMS 1. (3S) tetrahydro-3 ~ -furanyl (SS, 2R) -3 - [[(4-aminophenyl) sulfonyl] - (isobutyl) amino] -L-benzyl 1-2- (fos fonoxy) propylcarbamate calcium.
2. 2. A pharmaceutical composition characterized in that it comprises a compound as claimed in claim 1 together with at least one pharmaceutically acceptable diluent or vehicle thereof
3. 3. A compound as claimed in claim 1, characterized in that it is for use in medical therapy.
4. 4. The use of a compound as claimed in claim 1 characterized in that it is used in the preparation of a medicament for the treatment of a retrovirus infection.
5. 5. A method for the treatment of a retrovirus infection in a human characterized - - because it comprises administering to said human, an amount of a compound as claimed in claim 1 effective in antiretroviral treatment.
6. 6. A pharmaceutical composition according to claim 2 characterized in that it is in the form of a powder.
7. 7. A pharmaceutical composition according to claim 2 characterized in that it is in the form of a suspension.
8. 8. A pharmaceutical composition according to claim 2 characterized in that it is in the form of a tablet.
9. 9. A process for the preparation of a compound of formula (I) - - characterized in that it comprises i) the reaction of a compound of formula (II) with a phosphorylating agent; ii) reducing the resulting compound with a reducing agent in a suitable solvent; and iii) adding to the resulting compound a source of calcium ions in the presence of a suitable solvent.
10. 10. A process for the preparation of uri compound of formula (I) characterized in that it comprises dissolving a compound of formula (III) in a suitable solvent, and add water and a source of calcium ions to the solution.
11. 11. A process for the preparation of a compound of formula (I) - 4 - characterized in that it comprises the reduction of a compound of formula (IV) in the presence of a suitable reducing agent in a suitable solvent, followed by the addition of water and a source of calcium ions.
12. 12. A process for the preparation of a compound of formula (I) as claimed in claim 9, characterized in that the phosphorylating agent is phosphorus oxychloride. - -
13. 13. A process for the preparation of a compound of formula (I) as claimed in claim 9 or 12, characterized in that the phosphorylating agent is added in the presence of a base.
14. 14. A process for the preparation of a compound of formula (I) as claimed in claim 9, 12 or 13, characterized in that the product of step i) is converted to its sodium salt prior to step ii).
15. 15. A process for the preparation of a compound of formula (I) as claimed in claim 9 or 11, characterized in that the reducing agent is hydrogen with a palladium on carbon catalysis.
16. 16. A process for the preparation of a compound of formula (I) as claimed in any of claims 9, 10 and 11, characterized in that the source of calcium ions is calcium acetate. - -
17. 17. A process for the preparation of a compound of formula (I) as claimed in any of the rei indications 9, 10 and 11, characterized in that it additionally comprises recrystallization of the compound in an appropriate solvent.
18. 18. A process for the preparation of a compound of formula (I) as claimed in claim 17, characterized in that the solvent is a mixture of industrial methylated spirit and water.
19. 19. A process for the preparation of a compound of formula (I) as claimed in any of claims 9, 10 and 11, characterized in that it additionally comprises heating the product in water at a temperature in the range of 70 to 99 ° C per 2.5 at 6 hours, then it is cooled to room temperature and collected from the solid.
20. 20. The compound of formula (I) as claimed in claim 1 which is pure morphological Form (I) characterized by a powder diffraction trace in X-rays substantially as shown in Figure 1.