Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-02
2001-09-25
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S424000
Reexamination Certificate
active
06294572
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to derivatives of N-acetl neuraminic acid and their use in medicine. More particularly the invention is concerned with particular physical forms of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2enopyranosonic acid (the 4-guanidino analogue of DANA; also known as 5-(acetylamino)-2,6 andydro-3,4,5-trideoxy-4-guanidino-D-glycereo-D-galacto-non-2-enonic acid), pharmaceutical formulations thereof and their use in therapy.
2. Description of Related Art
PCT/AU91/00161 (publication no. WO91/16320) describes a number of derivatives of 5-acetamidino-2,3,5-trideoxy-D-glycero-D-galacto-non-2-enopyranosonic acid (2,3,-dideoxy-2,3-didehydro-N-acetyl-neuraminic acid; DANA) including the 4-guanidino analogue of DANA. The 4-guanidino analogue of DANA is prepared by the reaction of the corresponding O-acyl protected 4-amino analogue of DANA by reaction with S-methylisourea followed by deprotection, purification by chromatography and freeze-drying.
The structure of the 4-guanidino analogue of DANA is shown below:
We have now found that the compound of formula (1) can be obtained in crystalline form.
SUMMARY OF THE INVENTION
There is thus provided in a first aspect of the invention 5-acetamido-2,3,4,5-tetradeoxy-4guanidino-D-glycero-D-glacto-non-2enopyramosonic acid in crystalline form.
We have further found that the compound of formula (I) may be obtained by crystallisation under certain conditions in the form of a crystalline hydrate (hereinafter Hydrate I). Hydrate I exists in the form of crystals having a low aspect ratio, for example, tabular crystals, which are favoured for pharmaceutical formulation because of their physical properties, e.g. good flow characteristics. The water content of Hydrate I is related to relative humidity (RH). Water uptake of Hydrate I varies from zero at RH of 0% up to 10% at RH of 90-100%.
The compound of formula (I) may also be crystallised in the form of dihydrate (hereinafter Hydrate II). Hydrate II exists in the form of crystals having a high aspect ratio, for example, needle-shaped crystals. The water content of these crystals remains substantially constant over a broad relative humidity range (RH about 10-90%). The stable water content of Hydrate II represents an advantage of this crystalline form for use in pharmacy.
There is thus provided in a further aspect of the invention 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid in the form of crystals having a low aspect ratio, such as tabular crystals.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
In a further aspect there is provided 5-acetamido-2,3,4,5-tetradeoxy-4guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid in the form of crystals having a high aspect ratio, such as needle-shaped crystals.
Whilst tabular crystals are regarded as typical of Hydrate I and needle-shaped crystals are regarded as typical of Hydrate II, it will be appreciated that the possibility of either Hydrate I or Hydrate II existing in alternative crystal habits under certain circumstances cannot be excluded. It is to be understood that all such alternate crystal habits are within the scope of the present invention.
There is also provided 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid in the form of crystals which have stable water content over a broad humidity range, for example RH 10-90%.
Hydrate I loses substantially all of its water of crystallisation at about 80-90° C. Decomposition occurs at 299° C.
Hydrate II loses one mole of water of crystallisation at about 84-90° C. and a further mole of water of crystallisation of about 135-143° C.
In a yet further aspect the invention provides 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid in the form of a crystalline hydrate which loses substantially all its water of crystallisation at 80-90° C.
In a yet further aspect the invention provides 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranssonic acid in the form of a crystalling hydrate which loses one mole of water of crystallisation at 84-90° C. and a further mole of water of crystallisation at 135-143° C.
In a preferred aspect the invention provides 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic in the form of Hydrate I as herein defined substantially free of Hydrate II as herein defined.
In a further preferred aspect the invention provides 5acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid in the form of Hydrate II as herein defined substantially free of Hydrate I as herein defined.
By “substantially free” is meant containing less than 5% of the alternative hydrate, such as less than 2%, for example less than 1% of the alternative hydrate.
5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranssonic acid may be prepared in crystalline form by crystallisation of the compound from aqueous solution.
Each of Hydrate I and Hydrate II may be prepared substantially free from the alternative Hydrate by controlling the solution concentration and temperature at which crystallisation occurs.
In general, 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid in the form of Hydrate I may be obtained by crystallisation of the compound from aqueous solution at a temperature greater than about 50° C., preferably 50-55° C.
In general, 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid in the form of Hydrate II may be obtained by crystallisation of the compound from aqueous solution at a temperature below about 40° C., preferably about 20-30° C.
Crystallisation of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid from aqueous solution at a temperature in the range of about 40-50° C. typically results in a mixture of tabular and needle-shaped crystals. Such mixtures are disfavoured for the preparation of pharaceutical formulations because of the differing physical properties of Hydrate I and Hydrate II, in particular their flow properties.
Seeding of an aqueous solution of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-Galacto-non-2-enopyranosonic acid with crystals of Hydrate I or Hydrate II may lead to crystallisation of the seeded Hydrate. Preparation of Hydrate I or Hydrate II should therefore be conducted in the absence of seeds of the undesired Hydrate. Conversely, Hydrate I may be prepared by seeding an aqueous solution of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid with crystals of Hydrate I, and Hydrate II may be prepared by seeding an aqueous solution of 5-acetamido-2,3,4,5-tetradeoxy-4guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid with crystals of Hydrate II.
For the preparation of Hydrate II it is preferable to employ a relatively dilute aqueous solution, for example a solution of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid in 15-30 volumes of water, for example 20 volumes of water. Hydrate I may conveniently be crystallised from a relatively concentrated aqueous solution, for example a solution of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid in 12-20 volumes of water, such as 12-15 volumes of water.
We have found that Hydrate II may be converted into Hydrate I in aqueous suspension or saturated solution. Such interconversion may be effected by prolonged ageing of an aqueous suspension or saturated solution of Hydrate II, for example ageing for a period of days, for example more than 10 days, such as about 15 days. Alternatively, interconversion may be effected in the presence of a base, for example an organic base such as imidazole.
Recovery of either Hydrate I or Hydrate II from aqueous solution may be enhanced by the addition to the solution of a suitable counter-solvent. Suitable counter-solvents are water-miscible solven
Patel Vipulkumar
White William James
Williamson Christopher
Biota Scientific Management Pty Ltd.
Foley & Lardner
Stockton Laura L.
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