Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-04-20
2003-02-04
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C549S218000
Reexamination Certificate
active
06514953
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the antiviral compound calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate, pharmaceutical compositions comprising it, its use in the treatment of retroviral infections, and processes for its 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 (1S,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*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methyl-propyl)amino]-2-hydroxy-1-phenylmethyl)propyl]-tetrahydro-3-furanyl ester (amprenavir, 141W94). Amprenavir, which has poor solubility and is thus available as a solution in gel capsules and has a high pill burden. This new HIV protease inhibitor with its increased solubility thus has the potential to reduce the perceived pill burden and may be formulated as a tablet.
However, attempts to find 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 proved problematic. A range of salts of the phosphoric acid were made (for example, di-sodium, di-potassium, magnesium, zinc, ethylene diamine, piperazine). Of these, the piperazine salt was a crystalline solid, but had the practical disadvantage of likely toxicity at the anticipated dose. Surprisingly, we have found that the calcium salt, calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-phosphonooxy)propylcarbamate, has a stable crystalline form. Detailed further examination revealed that this salt has advantageous properties making it suitable for formulation into tablets. Thus the compound of the present invention provides an opportunity to reduce the pill burden associated with some HIV protease inhibitors.
The structure of calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate, a compound of formula (I), is shown below:
We have now found that the compound of formula (I) can be prepared in crystalline form, exhibiting particularly good pharmaceutical properties.
DETAILED DESCRIPTION OF THE INVENTION
According to a first aspect of the invention there is provided the compound of formula (I) in crystalline form, hereinafter referred to as Form (I).
The invention relates to Form (I) of the compound of formula (I) in crystalline form. Typically, Form (I) contains about 4 to 5 moles of water. However, in any batch containing Form (I) of the compound of formula (I) there may also be other solvated crystalline forms of the compound of formula (I).
Solid State Form (I) of the compound of formula (I) can be characterised by it's X-ray powder diffraction pattern, shown in FIG.
1
. Diffraction traces were obtained using a Phillips PW1800 diffractometer (serial DY701) and Cu K &agr; radiation. X-ray intensities were measured at 0.02° increments for 4 second intervals using a scintillation counter, between values of 2 and 45° 2&thgr;. Intense diffraction peaks characteristic of Form (I) may occur at the following approximate 2theta angles (using copper K &agr; X-radiation): 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. Further details are presented in Table 1.
It will be appreciated by those skilled in the art that the compound of formula (I) may be in the form of a solvate, for example a hydrate.
According to a further aspect, 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)
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.
In a further aspect, the present invention also provides a process for the production of the compound of formula (I), comprising dissolving a compound of formula (III)
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.
In a further aspect, the present invention also provides a process for the production of the compound of formula (I), comprising 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
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.
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 pentacloride or dibenzylchlorophosphate, in the presence of a base, for example pyridine, triethylamine or diisopropylethylamine, and optiona
Armitage Ian Gordon
Searle Andrew David
Singh Hardev
Prus Karen L.
Robinson Binta
Rotman Alan L.
SmithKline Beecham Corporation
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