GB2410948A

GB2410948A - Novel phosphoric acid salt of rosiglitazone

Info

Publication number: GB2410948A
Application number: GB0403254A
Authority: GB
Inventors: Wolf Siegfried; Julia Greil; Johannes Ludescher
Original assignee: Sandoz GmbH; Sandoz AG
Current assignee: Sandoz AG
Priority date: 2004-02-13
Filing date: 2004-02-13
Publication date: 2005-08-17
Also published as: CN1964966A; GB0403254D0

Abstract

5-[[4-[2-(Methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate is a novel salt of rosiglitazone. The invention is also directed to a process for preparation of rosiglitazone phosphate. The compound of the invention is useful for treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

Description

G-33653/P1/9950 24 1 0948 Organic Compounds This invention relates to a

novel compound, to a process for the preparation of such compound, to pharmaceutical compositions containing such compound and to the use of such compound and compositions in medicine.

European Patent Application, Publication Number 0306228 relates to certain thiazolidinedione derivatives disclosed as having hypoglycaemic and hypolipidaemic activity.

The compound of example 30 of EP-A-0306228 is 5-[[4-[2-(methyl-2pyridinylamino) ethoxy]phenyl]methyl]-2,4-thiazolidinedione (according to Merck Index/13th Edition, Monograph number 8346, CAS Registry number: 122320-73-4), i.e. rosiglitazone.

International Application, Publication Number WO 94/05659 discloses certain salts of the compounds of EP-A-0306228. The preferred salt of WO 94/05659 is the maleic acid salt.

There remains a need for alternative salt forms which are straightforward to prepare and which have properties suitable for pharmaceutical processing on a commercial scale.

The present inventors have now prepared and characterized a phosphoric acid salt of 5-[[4-[2(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, hereinafter also referred to as the "Phosphate", and have discovered that the "Phosphate" is particularly stable and hence is suitable for bulk preparation and handling.

The novel Phosphate has also useful pharmaceutical properties and may be used for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

In one aspect therefore, the present invention provides a phosphoric acid salt of 5-[[4-[2 (methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione as a novel compound, preferably as a hydrate.

Phosphoric acid is a triacid, so that the phosphate salts may theoretically exist in more than one stoichiometry. However, the inventors have isolated the Phosphate so far only in the form G- 33653/P1/9950 in which the ratio of 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl] methyl]-2,4- thiazolidinedione to phosphoric acid is or is approximately 1: 1 (molar ratio), which encompasses molar ratios from l: 0.9 to l: 1.2. Theoretically, the molar ratio of 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4thiazolidinedione to phosphoric acid could also be 3: l or 2: 1.

Accordingly, in a further aspect the present invention provides a 5-[[4[2-(methyl-2- pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione 1: 1 phosphate as a novel compound, preferably in a hydrated form.

The Phosphate, preferably as a hydrate, may exist in one of several tautomeric forms, all of which are encompassed by the present invention. It will be appreciated that the present invention encompasses all of the isomeric forms of the Phosphate, preferably as a hydrate, including any stereoisomeric forms thereof, whether as individual isomers or as mixtures of isomers.

Without wishing to be bound by any particular mechanism or theory, the present applicants believe that in the 1: 1 salt the phosphate anion may be associated with a proton (hydrogen atom) in addition to 5-[[4-[2(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4 thiazolidinedione, or may be associated with another cation, for example an alkali metal or ammonium cation. In this case, the salt may be described as a mixed salt.

As indicated above, the preferred aspect of the invention is a hydrate of the Phosphate which hereinafter is also referred to as "Phosphate Hydrate".

The Phosphate in which the ratio of 5-[[4-[2-(methyl-2-pyridirylamino) ethoxy]phenyl] methyl]-2,4-thiazolidinedione to phosphoric acid is (by mole) 1: 1 has been isolated as a Phosphate Hydrate containing approximately 0.1% - 4.5%, e.g. approximately 0.8 % - 4 %, e.g. preferably 1.6% - 3.6% by weight water.

The present invention also encompasses the Phosphate containing less than 0.1 % by weight water, i.e. the anhydrous Phosphate.

A particular example of a Phosphate Hydrate contains approximately 0.87% of water, consistent with a 1: 0.23 hydrate. Further particular examples contain approximately 1.6% of water, consistent with a 1: 0.42 hydrate, or approximately 2.3 % of water, consistent with a G-33653/P 1/9950 1: 0.60 hydrate, or 3.3% of water, consistent with a 1: 0.79 hydrate, or 3.58% of water, consistent with a 1: 0.94 hydrate. All percentages are by weight.

Drying of the Phosphate Hydrate under normal conditions e.g. drying at ambient temperatures results in an approximately 1: 0.4 hydrate; drying with the aid of a strong desiccant, e.g. P2Os, at about 45 C results in an approximately l: 0.3 hydrate, and optional further drying at elevated temperatures, e.g. 70 C - 100 C, preferably 80 C, may lead to a water content of less than 0.1 % by weight.

Exposure of the Phosphate Hydrate to high humidity results in an approximately 1: 1 hydrate.

Accordingly, in a further aspect the present invention provides 5-[[4-[2(methyl-2 pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate (molar ratio 1: 1) as a novel compound containing approximately up to 4.5% by weight water.

Alternatively, the present invention provides 5-[[4-[2-(methyl-2pyridinylamino)ethoxy] phenyl]methyl]-2,4-thiazolidinedione phosphate (molar ratio 1: l) which is a hydrate or which is anhydrous, i.e. contains less than 0.1 % water by weight.

In another aspect the present invention comprises a 5-[[4-[2-(methyl-2 pyridinylamino)ethoxy] phenyl]methyl]-2,4-thiazolidinedione phosphate (molar ratio 1: 1) which contains approximately 1.6% water by weight being consistent to a l: 0.42 hydrate.

In an additional aspect the present invention provides 5-[[4-[2-(methyl-2 pyridinylamino)ethoxy] phenyl]methyl]-2,4-thiazolidinedione phosphate (molar ratio 1: 1) which contains approximately 3.6% water by weight being consistent to a 1: 0.94 hydrate.

However, since the water content cannot be fixed to exactly to a molar ratio as mentioned above, in one suitable embodiment, there is provided a Phosphate Hydrate characterized by: i) an infrared spectrum substantially in accordance with Figure 1, and / or ii) an X-ray powder diffraction (XRPD) pattern substantially in accordance with Table l and Figure 2.

Figure I shows the infrared spectrum of the Phosphate Hydrate wherein the scale of the abscissa is the wave number in emu, and the ordinate is transmittance in %.

G-33653/Pt/9950 Figure 2 shows the X-ray powder diffraction (XRPD) pattern of the Phosphate Hydrate, wherein the scale of the abscissa is in degrees 2O, and the ordinate is the linear intensity in counts per second (cps) Table 1 shows the interplanar spacings (d, given in A, i.e. Angstroem), characteristic XRPD angles (2 thetas) and relative intensities (in %).

In one favoured aspect, the Phosphate Hydrate provides an infrared spectrum substantially in accordance with Figure 1.

to In another favoured aspect, the Phosphate Hydrate provides a X-Ray powder diffraction (XRPD) pattern substantially in accordance with Table 1 and Figure 2.

In a preferred aspect, the invention provides a 5-[[4-[2-(methyl-2pyridinylarnino)ethoxy] phenyl]methyl]-2,4-thiazolidinedione phosphate hydrate characterized by: i) an infrared spectrum substantially in accordance with Figure 1, and ii) an X-ray powder diffraction (XRPD) pattern substantially in accordance with Table 1 and Figure 2.

Depending on the solvent from which the Phosphate is recovered, the Phosphate may be obtained as a solvate other than a hydrate. Such solvates form part of the present invention.

References to the Phosphate hereinafter include solvates thereof.

The present invention encompasses the Phosphate, preferably as the Phosphate Hydrate, when isolated in pure form or when admixed with other materials, e.g. pharmaceutically acceptable carriers.

Thus in one aspect there is provided the Phosphate, preferably as the Phosphate Hydrate, in isolated form.

In a further aspect there is provided the Phosphate, preferably as the Phosphate Hydrate, in substantially pure form.

In yet a further aspect there is provided the Phosphate, preferably as the Phosphate Hydrate, in crystalline form.

G-33653/P1/9950 In an alternative aspect there is provided the Phosphate, preferably as the Phosphate Hydrate, in non-crystalline fomm.

In a further aspect, the present invention also provides the Phosphate, preferably as the Phosphate Hydrate, in a pharmaceutically acceptable form, especially in bulk form, such form being capable of being further processed, e.g. milled, according to known processes. The invention further provides the Phosphate, preferably as the Phosphate Hydrate, in a pharmaceutically acceptable form, e.g. in a milled form.

lo In another aspect, the invention provides a process for preparing the Phosphate, preferably the Phosphate Hydrate, comprising reacting 5-[[4-[2(methyl-2-pyridinylamino)ethoxy]phenyl] methyl]-2,4-thiazolidinedione or a salt thereof, preferably dispersed or suspended or dissolved in a suitable solvent medium, with a suitable source of a phosphate ion, e.g. phosphoric acid, and thereafter, if required, carrying out one or more of the following optional steps: Is i) forming a solvate thereof; ii) recovering the Phosphate, preferably the Phosphate Hydrate; iii) drying the product obtained, especially under vacuum.

Optionally, the Phosphate, preferably the Phosphate Hydrate, may be further processed in known manufacturing processes, e.g. in a milling process.

Altematively, 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy] phenyl] methyl]-2, 4- thiazolidinedione or a salt thereof, may be added as a powder to the suitable source of the phosphate ion.

In general Phosphates may be prepared by contacting stoichiometric amounts, for example l: l, of phosphoric acid and 5-[[4-[2-(methyl-2pyridinylamino)ethoxy]phenyl]methyl]-2,4 thiazolidinedione, or alternatively using an excess of phosphoric acid, e.g. a ratio of 2: I to 2.5: l of phosphoric acid and 5-[[4-[2-(methyl-2-pyridinylamino) ethoxy]phenyl] methyl]-2,4-thiazolidinedione.

The concentration of 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl] methyl]-2,4- thiazolidinedione is preferably in the range of 1 to 50% weight/volume, more preferably 1 - 10% weight/volume related to the total amount of solvent medium used in the reaction G-33653/P1/9950 A suitable solvent medium for the solution or dispersion or suspension of 5-[[4-[2-(methyl-2pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione or a salt thereof, and the reaction with a suitable source of the phosphate ion, as described above, is an organic solvent medium, e.g. a ketone, e.g. acetone, or an alcohol, e.g. a C' - C4 alcohol, e.g. ethanol, or a nitrite, e.g. acetonitrile, or an ether, e.g. tetrahydrofuran, or mixtures thereof, or water, or mixtures of said organic solvent media with water.

Preferably, water is used as a cosolvens. Preferred amounts of water are 1 to 100% (v/v), preferably l to 20 % (v/v) of water related to the organic solvent medium.

A suitable source of the phosphate ion is phosphoric acid, for example 85% (w/w) phosphoric acid or less concentrated phosphoric acid, e.g. diluted from 1: 1 to 1: 10 w/v with water or with an organic solvent medium such as a ketone, e.g. acetone, or an alcohol, e.g. a Cal - C4 alcohol, e.g. ethanol, or mixtures of a ketone and an alcohol. The phosphoric acid is preferably added as such, or as a solution, for example a solution in one of the above mentioned organic solvent media.

An alternative source of the phosphate ion may be metaphosphoric acid, preferably in combination with water, or sodium or potassium dihydrogenphosphate, disodium or dipotassium hydrogenphosphate or trisodium or tripotassium phosphate in combination with a mineral acid, preferably phosphoric acid.

Formation of the Phosphate Hydrate requires the presence of water at some stage. The water may be present m the source of the phosphate ion, e.g. in the phosphoric acid used, e.g. by using 85% (w/w) or less concentrated phosphoric acid, or the water may be present as a cosolvens in the process, e.g. l to 100% (v/v), preferably l - 20%, of water related to the organic solvent medium.

However, it is also possible to provide sufficient water for the formation of the Phosphate Hydrate by carrying out the reaction with exposure to atmospheric moisture, or by the use of a non-antydrous solvent medium, e.g. aqueous acetone, or of a non-anhydrous source of the phosphate ion, e.g. 85% (w/w) phosphoric acid.

The reaction may be carried out at ambient temperature, e.g. at approximately 20 - 35 C, or at elevated temperatures of e.g. 35 to 60 C, preferably at 30 to 50 C, or at the reflux temperature G-33653/P1/9950 of the solvent medium, although any convenient temperature that provides the required product may be employed.

Solvates, preferably the hydrates, of the Phosphate are to be prepared, e. g. by crystallizing from a solvent medium as described above which may provide or contain the solvate moiety, or by exposing the Phosphate to the solvate moiety as a vapour.

Recovery of the required compound, e.g. the Phosphate, preferably the Phosphate Hydrate, before drying comprises isolation from an appropriate solvent medium, which is optionally the above mentioned solvent medium used for the above described reaction, preferably with water as a cosolvens, or which is a mixture of said solvent media, or alternatively a different solvent medium or mixture thereof, e.g. a Cal - C4 alkyl acetate, or e.g. a hydrogenated carbon, e.g. hexane.

Alternatively the required compound may be isolated by crystallization from the appropriate solvent medium or mixture of solvent media as described above which may be initiated by the use of seed crystals. Careful control of precipitation temperature from approximately - 30 C to about 0 - 20 C, and/or the use of seed crystals are useful to improve the reproducibility of the Phosphate, preferably the Phosphate Hydrate.

Optionally, the required compound, e.g. the Phosphate, preferably the Phosphate Hydrate, may be further processed without being isolated from the mixture of the reaction as described above.

Preferably the isolated Phosphate Hydrate is dried under vacuum at ambient temperature, e.g. - 35 C or at elevated temperatures, e.g. 35 - 80 C. The drying is optionally carried out over a desiccant, e.g. phosphorus pentoxide. Drying is continued until the water content is below approximately 4.5%, e.g. 3.58%, e.g. less than 0.1 % by weight.

5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4thiazolidinedione may be prepared according to known procedures, such as the method disclosed in EP-A-0306228.

G-33653/P1/9950 As mentioned above the compound of the invention has useful therapeutic properties. The present invention accordingly provides a Phosphate, preferably as the Phosphate Hydrate, for use as an active therapeutic substance.

Particularly, the present invention provides the Phosphate, preferably the Phosphate Hydrate, for use in the treatment and/or prophylaxis hyperglycaemia.

More particularly, the present invention provides the Phosphate, preferably the Phosphate Hydrate, for use in the treatment of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

When used herein, the term "prophylaxis of conditions associated with diabetes mellitus" includes treating conditions such as insulin resistance, impaired glucose tolerance, hyperinsulinaemia and gestational diabetes. Diabetes mellitus preferably means Type II diabetes mellitus.

Conditions associated with diabetes mellitus include hyperglyeaemia, hyperlipidaemia, obesity, hypertension, cardiovascular disease, certain eating disorders, polycystic ovarian syndrome and steroid induced insulin resistance.

Complications of conditions associated with diabetes mellitus encompassed herein include renal disease, especially renal disease associated with the development of Type II diabetes mellitus including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.

The Phosphate, preferably the Phosphate Hydrate, may be administered per se, or preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.

Accordingly, the present invention also provides a pharmaceutical composition comprising the Phosphate, preferably the Phosphate Hydrate, and a pharmaceutically acceptable carrier thereof.

As used herein, the term "pharmaceutically acceptable" embraces compounds, compositions and ingredients for both human and veterinary use.

In accordance with conventional pharmaceutical practice the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.

G-33653/P1/9950 The compound of the present invention may be administered by any suitable route, but usually by the oral or parenteral routes.

Pharmaceutical compositions are prepared by admixture and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles, reconstitutable powders, injectable and infusable solutions or suspensions, suppositories and transdermal devices.

Suitable methods for formulating the pharmaceutical compositions of the Phosphate, preferably the Phosphate Hydrate, are known.

The present invention further provides a method for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof, in a human or non-human mammal which comprises administering an effective, non toxic, amount of the Phosphate, preferably the Phosphate Hydrate, to a human or non-human mammal in need thereof.

In the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof, the Phosphate, preferably the Phosphate Hydrate, may be taken in amounts so as to provide 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl] methyl]-2, 4-thiazolidinedione in suitable doses, e.g. such as disclosed in EP-A0306228.

In a further aspect, the present invention provides the use of the Phosphate, preferably the Phosphate Hydrate, for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

Additionally, the present invention provides the use of the Phosphate, preferably the Phosphate Hydrate, in combination with one or more other anti-diabetic agents, e.g. biguanidines, sulfonylureas and alpha glucosidase inhibitors, for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

G-33653/P1/9950 The following examples illustrate the invention but do not limit it in any way. All temperatures are given in degree Celsius and are uncorrected. The water content is determined by the Karl Fisher method.

Example 1:

Preparation of 5-[l4-12-(methYl-2-pvridinYlaminolethoxYlPhenyllmethyll-24 thiazolidinedione phosphate hydrate g of 5 -[[4-[2-(methyl-2pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione are dissolved in a mixture of 250 ml acetone and 20 ml of H2O at approximately 30 C. The solution is stirred and 1.89 ml of 85% phosphoric acid are added with stirring. Seed crystals of the title compound are added, stirring is stopped and the suspension is allowed to stand at ambient temperature for about 3 hours with stirring for 2 to 3 minutes in 30 minute intervals.

The title compound is isolated by suction, washed with 25 ml of acetone and dried in vacuo for approximately 15 hours at ambient temperature, and obtained as white crystalline solid.

Yield (5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4thiazolidinedione phosphate hydrate): 5.54 g Water content (Karl Fisher): 1.6 % w/w Content Phosphoric acid: 21.7% (by ion chromatography)

Example 2:

Preparation of 5-14-l 2-(methYl-2-pvridinvlamino)ethoxvlphenvllmethyll294 thiazolidnedione phosphate hydrate g of 5-[[4-[2-(methyl-2pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione are dissolved in a mixture of 1250 ml of acetone and 100 ml of H2O at approximately 30 C. The solution is stirred, and 9.45 ml of 85% phosphoric acid are added with stirring. Stirring is stopped, and the suspension is allowed to stand at ambient temperature for about 18 hours.

The suspension is then gently stirred for about 1 hour. The white crystals are then isolated by suction, washed with a mixture of 95 ml of acetone and 5 ml H2O and dried in vacuo for approximately 3 hours at ambient temperature.

Yield (5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4thiazolidinedione phosphate hydrate): 28.56 g Water content (Karl Fisher) : 3.3 % w/w G-33653/P1/9950 Characterising data for the product of Example 2: Infrared absorption spectrum The infrared spectrum of the solid product as obtained by Example 2 (Figure 1) was recorded using a BRUKER FTIR-Tensor 27. Bands were observed at 2704 (broad), 1748, 1701 (broad), 1643, 1611, 1546, 1513, 1469, 1420, 1391, 1330, 1302, 1244, 1110, 1028, 928, 821, 767, 716 cm a.

X-Rav Powder Diffraction (XRPD) pattern The X-Ray Powder Diffraction (XRPD) pattern of the solid product as obtained by Example 2 is shown in Figure 2 (scale of the abscissa in degrees 23, and the ordinate is the linear intensity in counts per second, i.e. cps) and was recorded under the following conditions: Equipment: X-Ray Powder Diffractometer D-8 (AXSBRUKER), theta-theta-goniometer, sample changer, target: Copper, Kal+Ka2 = 1.5406 A, parallel beam optics (receiving soller-slit: 0.07 mm), Scintillation counter, standard sample holders.

Data collection: Tube anode: Cu; Generator tension: 40kV; Generator current: 40mA; Start angle: 2.0 2D, End angle: 40.0 20; Step size: O.Ol 2H; Time per step: 2 seconds; 20 may vary l to 3% absolutely.

Interplanar spacings (d, given in A, i.e. Angstroem), characteristic XRPD angles (2 theta ) and relative intensities (in TO) are recorded in Table 1.

Table 1

d-value Angle Rel.Intensity (A) 2 theta (%) 22.66 3.90 13 20.63 4.28 21 16.42 5.38 18 14.20 6.22 7 10.51 8.41 16 10.26 8.61 19 9.879 8.94 7 8.911 9.92 18 8.170 10.82 6 7.514 l 1.77 7 7.111 12.44 24 6.828 12.96 10 6.748 13.11 9 6.497 13.62 13 6.301 14.04 31 G-33653/P1/9950 (continued) d-value Angle Rel.Intensity (A) 2 thetas 5.667 15.63 65 5.622 15.75 100 5.514 16.06 16 5.239 16.91 19 5.123 17.30 42 4.924 18.00 17 4.855 18.26 9 4.663 19.02 15 4.524 19.61 35 4.342 20.44 14 4.135 21.47 40 4.100 21.66 33 4.037 22.00 16 3.941 22.54 30 3.876 22.93 12 3.817 23.29 13 3.803 23.37 15 3.777 23.54 t6 3.741 23.77 15 3.690 24.10 18 3.641 24.43 18 3.591 24.77 18 3.550 25.06 18 3.449 25.81 19 3.389 26.28 23 3.279 27.17 8 3.227 27.62 14 3.201 27.85 14 3.128 28.51 9 3.066 29.11 10 3.025 29.51 14 2.957 30.20 9 2.922 30.57 12

_

2.910 30.70 13 2.829 31.60 10 2.807 31.86 9 2.774 32.25 9 2.759 32.42 9 2.711 33.01 7 2.674 33.49 7 2.617 34.24 10 2.608 34.36 11 2.568 34.91 8

_ _

2.556 35.08 8 2.452 36.61 7 G-33653/P1/9950 (continued) d-valu e An gl e Rel. In ten s ity (A) 2 thetas (%) 2.421 37.11 7 2.367 37.98 6 2.330 38.60 7 2.302 39.10 8 2.273 39.62 8

Example 3:

Preparation of 5-LL4-l2-(methYl-2-ovridinylamino)ethoxylphenYllmethYll-24 thiazolidinedione phosphate hydrate g of 5-[[4-[2-(methyl-2pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione are l O dissolved in a mixture of 500 ml 96% ethanol and 50 ml of H2O at approximately 60 C.

2.1 ml of 85% phosphoric acid are added. With stirring seed crystals of 5[[4-[2-(methyl-2 pyridinylamino)ethoxy]phenyl]methyl]-2,4thiazolidinedione phosphate are added, and the stirring is stopped. The suspension is allowed to stand at ambient temperature for about 3 hours with stirring for 2 to 3 minutes in 30 minute intervals. The title compound is isolated by suction, washed in 2 portions with a total of 50 ml of ethanol and dried at ambient temperature in vacuo for about 4 days, and obtained as white crystalline solid.

Yield (5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4thiazolidinedione phosphate hydrate): 10.32 g Water content (Karl Fisher) : 2.3 % w/w Content Phosphoric acid: 20.1 % (by ion chromatography)

Example 4:

Drvine of 5-l[4-2-(methYl-2-ovridinvlamino)ethoxvlPhenYllmethyll-2.4 thiazolidinedione phosphate hydrate with phosphorus pentoxide g of 5-[[4[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate hydrate, water content (Karl Fisher) 2.8% w/w, are dried at a temperature of about 45 C for about 24 hours in vacuo in presence of P2Os.

Water content (Karl Fisher): 0.87% w/w G-33653/P1/9950

Example 5:

Exposure of 5-14-l2-(methYI-2-ovridinYlamino)ethoxYlphenylLmethyll-294 thiazolidinedione phosphate hydrate to humidity 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4thiazolidinedione phosphate hydrate was exposed to different relative humidities for about 24 hours. Results are given

below in Table 2:

Table 2

Water content (Karl Fisher) (%) wlw Initial 2.8 45% relative humidity 3.42 63% relative humidity 3.37 86% relative humidity 3.58 The Phosphate, preferably the Phosphate Hydrate, as herein described, shows high stability.

After a stress test according to known methods, which was performed at 80 C for about 160 hours in a closed vial, no degradation has been observed as determined by HPLC using standard methods.

Furthermore, the present applicants have observed that the 5-[[4-[2(methyl-2- pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate, preferably the hydrate thereof, according to the present invention, exhibits a more expressed solubility in water when compared to rosiglitazone maleate which is the main form in which rosiglitazone is currently marketed as active substance in pharmaceutical preparations. This enhanced solubility in water, being e.g. about twice as high as that of the maleate form, is useful and interesting for industrial application.

Additionally, the process for the production of the Phosphate, preferably the Phosphate Hydrate, is relatively simple.

Claims

G-33653/P1/9950 Claims: 1. A salt of

5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4 thiazolidinedione and phosphoric acid, or a solvate thereof.
2. A salt as claimed in claim l, being 5-[[4-[2-(methyl-2-pyridinylamino) ethoxy]phenyl] methyl]-2,4-thiazolidinedione phosphate (molar ratio 1: 1), or a solvate thereof.
3. A salt as claimed in claim 1, being 5-[[4-[2-(nethyl-2-pyridinylanino) ethoxy]phenyl] methyl]-2,4-thiazolidinedione (1: 1) phosphate containing up to approximately 4.5 % water by weight.
4. A salt as claimed in claim 1, being 5-[[4-[2-(methyl-2-pyridinylamino) ethoxy]phenyl] methyl]-2,4-thiazolidinedione (1: 1) phosphate hydrate containing approximately 0.1% to 4.5 % wafer by weighs.
5. A salt as claimed in claim 1, being 5-[[4-[2-(methyl-2-pyridinylamino) ethoxy]phenyl] methyl]-2,4-thiazolidinedione (1: 1) phosphate hydrate containing approximately 1.5% to 4% water by weight.
6. A salt as claimed in claim 1, being 5-[[4-[2-(methyl-2-pyridinylamino) ethoxy]phenyl] methy1]-2,4-thiazolidinedione (1: 1) phosphate hydrate, characterized by i) an infrared spectrum substantially in accordance with Figure 1; and/or ii) an X-ray powder diffraction (XRPD) pattern substantially in accordance with

Table 1 and Figure 2
7. A salt as claimed in claim 1, being 5-[[4-[2-(methyl-2-pyridinylamino) ethoxy]phenyl] methyl]-2,4-thiazolidinedione (1: 1) phosphate hydrate, characterized by an infrared spectrum substantially in accordance with Figure I
8. A salt as claimed in claim 1, being 5-[[4-[2-(methyl-2-pyridinylamino) ethoxy]phenyl] methyl]-2,4-thiazolidinedione (1: 1) phosphate hydrate, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Table l and Figure 2 G-33653/P 1/9950
9. A salt as claimed in claim 1, being 5-[[4-[2-(methyl-2-pyridinylamino) ethoxy]phenyl] methyl]-2,4-thiazolidinedione (1: 1) phosphate hydrate, characterized by i) an infrared spectrum substantially in accordance with Figure I, and ii) an X-ray powder diffraction (XRPD) pattern substantially in accordance with

Table 1 and Figure 2
10. A compound as claimed in any of claims 1 to 9 in crystalline form
1 1. A compound as claimed in any of claims 1 to 9 in isolated form
12. A compound as claimed in any of claims 1 to 9 in substantially pure form
13. A compound as claimed in any of claims 1 to 9 in non-crystalline form
14. A process for preparing a compound as claimed in any of claims 1 to 9, comprising reacting 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl] methyl]-2,4 thiazolidinedione or a salt thereof, preferably dispersed or suspended or dissolved in a suitable solvent medium, with a suitable source of a phosphate ion, e.g. phosphoric acid, and thereafter, if required, carrying out one or more of the following optional steps: i) forming a solvate thereof, ii) recovering the Phosphate, preferably the Phosphate Hydrate, iii) drying the product obtained, especially under vacuum iv) further processing the Phosphate, preferably the Phosphate Hydrate.
15. A process as claimed in claim 14, wherein the suitable source of the phosphate ion is phosphoric acid.
16. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 13, and a pharmaceutically acceptable carrier therefor.

G-33653/P1/9950
17. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 13, in combination with one or more other anti-diabetic agents, and optionally a pharmaceutically acceptable carrier therefor.
18. A compound as claimed in any of claims I to l 3, for use as an active therapeutic substance.
19. The use of a compound as claimed in claim 1 to 13, for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.