WO2003053965A1

WO2003053965A1 - Salicylate salt of a thiazolidinedione derivative

Info

Publication number: WO2003053965A1
Application number: PCT/GB2002/005822
Authority: WO
Inventors: Tim Chien Ting Ho
Original assignee: Smithkline Beecham Plc
Priority date: 2001-12-20
Filing date: 2002-12-19
Publication date: 2003-07-03
Also published as: AU2002350978A1; GB0130509D0

Abstract

A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate salt whose IR, Raman, X-ray powder diffraction and Solid State 13C NMR spectral characteristics are disclosed.

Description

SALICY ATE SALT OF A THIAZOLIDINEDIONE DERIVATIVE

This invention relates to a novel pharmaceutical, to a process for the preparation of the pharmaceutical and to the use of the pharmaceutical in medicine.

European Patent Application, Publication Number 0,306,228 relates to certain thiazolidinedione derivatives disclosed as having hypoglycaemic and hypolipidaemic activity. The compound of Example 30 of EP 0,306,228 is 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter also referred to as "Compound (I)").

International Patent Application, Publication Number WO94/05659 discloses certain salts of the compounds of EP 0,306,228. The preferred salt of WO94/05659 is the maleic acid salt.

There remains a need for alternative salt forms which have properties suitable for pharmaceutical processing on a commercial scale.

It has now been discovered that Compound (I) forms a novel salt with salicylic acid (hereinafter also referred to as the "Salicylate").

The Salicylate is indicated to be a stable crystalline material with good flow properties, and hence is suitable for bulk preparation and handling. Further, the novel salt has low solubility and so is amenable to processing by wet milling. Also the novel salt can be prepared by an efficient, economic and reproducible process particularly suited to large-scale preparation. Therefore the Salicylate is amenable to large scale pharmaceutical processing.

The novel Salicylate also has useful pharmaceutical properties and in particular it is indicated to be useful for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

Accordingly, the present invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione as a salicylate salt or a solvate thereof.

In the accompanying drawings:

Figure 1 is an Infrared spectrum of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate;

Figure 2 is a Raman spectrum of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate;

Figure 3 is an X-Ray Powder Diffractogram for 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate;

Figure 4 is a Solid State ¹³C ΝMR spectrum for 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate. In one favoured aspect of the invention, the Salicylate provides an infrared spectrum substantially in accordance with Figure 1.

In one favoured aspect of the invention, the Salicylate provides a Raman spectrum substantially in accordance with Figure 2.

In one favoured aspect of the invention, the Salicylate provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or Figure 3.

In one favoured aspect of the invention, the Salicylate provides a Solid State ¹³C NMR spectrum substantially in accordance with Figure 4.

In a preferred aspect, the invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate salt, characterised in that it provides:

(i) an infrared spectrum substantially in accordance with Figure 1 ; and (ii) a Raman spectrum substantially in accordance with Figure 2; and (iii) an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or Figure 3; and (iv) a Solid State ^,3C NMR spectrum substantially in accordance with Figure 4.

The present invention encompasses the Salicylate or a solvate thereof when isolated in pure form or when admixed with other materials.

Thus in one aspect of the invention there is provided the Salicylate or a solvate thereof in isolated form.

In a further aspect of the invention there is provided the Salicylate or a solvate thereof in pure form.

In yet a further aspect of the invention there is provided the Salicylate or a solvate thereof in crystalline form.

Also, the invention provides the Salicylate or solvate thereof in a solid pharmaceutically acceptable form, such as a solid dosage form, especially when adapted for oral administration.

Also, the invention provides the Salicylate or solvate thereof in a solid pharmaceutically acceptable form, especially in bulk flowable form, such form being particularly capable of pharmaceutical processing.

Also, the invention provides the Salicylate or solvate thereof in a solid pharmaceutically acceptable form, especially in a form having been processed in a manufacturing process requiring wet milling.

Suitable texts describing the manufacturing processes referred to herein include "The Theory and Practice of Industrial Pharmacy" edited by Leon Lachman, Herbert A. Lieberman and Joseph L. Kanig, published by Lea & Febiger Depending on the solvent from which the Salicylate is recovered, the Salicylate may be obtained as a solvate, and such solvates are a favoured aspect of the invention. A suitable solvate is a hydrate.

The invention also provides a process for preparing the Salicylate or a solvate thereof, characterised in that 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (1)), or a salt thereof, preferably dispersed or dissolved in a suitable solvent, is reacted with a suitable source of salicylate ion and optionally thereafter as required: (i) forming a solvate thereof; (ii) recovering the Salicylate or solvate thereof ; or

(iii) further processing the Salicylate or solvate therof in a manufacturing process requiring wet milling.

A suitable reaction solvent is an alkanol, for example propan-2-ol, or a hydrocarbon, such as toluene, a ketone, such as acetone, an ester, such as ethyl acetate, an ether such as tetrahydrofuran, a nitrile such as acetonitrile, or a halogenated hydrocarbon such as dichloromethane or water, or an organic acid such as acetic acid; or a mixture thereof.

Conveniently, the source of salicylate ion is salicylic acid. The salicylic acid may be added per se or in solution, for example in a lower alcohol such as methanol, ethanol, or propan-2-ol, or a mixture of solvents. An alternative source of salicylate ion is provided by a base salt of salicylic acid for example ammonium salicylate, or the salicylic acid salt of an amine, for example ethylamine or diethylamine.

The concentration of Compound (I) is preferably in the range 2 to 25% weight/volume, more preferably in the range 5 to 20%. The concentration of salicylic acid solutions are preferably in the range of 5 to 50 % weight/volume.

The reaction is usually carried out at ambient temperature or at an elevated temperature, for example 50 - 60°C or at the reflux temperature of the solvent, although any convenient temperature that provides the required product may be employed.

Recovery of the required compound comprises isolation from an appropriate solvent, optionally the reaction solvent, or alternatively a different solvent or solvent mixture. For example, the Salicylate is prepared by treating Compound (I) with salicylic acid in tetrahydrofuran, followed by evaporation or partial evaporation of the solvent, and subsequent treatment with water. Alternatively, recovery of the required compound generally comprises crystallisation from an appropriate solvent or mixture of solvents, conveniently the reaction solvent, usually assisted by cooling. For example, the Salicylate may be crystallised from water. An improved yield of the salt may be obtained by evaporation of some or all of the solvent or by crystallisation at elevated temperature followed by controlled cooling, optionally in stages. Careful control of precipitation temperature and seeding may be used to improve the reproducibility of the product form.

Crystallisation may also be initiated by seeding with crystals of the Salicylate or a solvate thereof but this is not essential.

As indicated above the Salicylate may exist as a solvate. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates.

Solvates, such as hydrates, of the Salicylate may be prepared according to conventional procedures, for example by crystallising or recrystallising from a solvent which provides or contains the solvate moiety, or by exposing the Salicylate to the solvate moiety as a vapour. When the solvate is formed by crystallisation methods the nature of the solvate is typically dictated by the solvent from which the Salicylate is crystallised.

Compound (I) is prepared according to known procedures, such as those disclosed in EP 0,306,228 and WO 94/05659. The disclosures of EP 0,306,228 and WO 94/05659 are incorporated herein by reference. Salicylic acid is a commercially available compound.

When used herein in respect of certain compounds the term "good flow properties" is suitably characterised by the said compound having a Hausner ratio of less than or equal to 1.5 "Hausner ratio" is an art accepted term.

When used herein the term "T_onsel" is generally determined by Differential

Scanning Calorimetry and each has a meaning generally understood in the art, as for example expressed in "Pharmaceutical Thermal Analysis, Techniques and Applications", Ford and Timmins, 1989 as "The temperature corresponding to the intersection of the pre-transition baseline with the extrapolated leading edge of the transition".

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

Conditions associated with diabetes include hyperglycaemia and insulin resistance and obesity. Further conditions associated with diabetes include hypertension, cardiovascular disease, especially atherosclerosis, certain eating disorders, in particular the regulation of appetite and food intake in subjects suffering from disorders associated with under-eating, such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia. Additional conditions associated with diabetes include polycystic ovarian syndrome and steroid induced insulin resistance.

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

As mentioned above the compound of the invention has useful therapeutic properties: The present invention accordingly provides the Salicylate or a solvate thereof for use as an active therapeutic substance.

More particularly, the present invention provides the Salicylate or a solvate thereof for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

The salicylate or a solvate thereof may be administered/?-??- se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. Suitable methods for formulating the Salicylate or a solvate thereof are generally those disclosed for Compound (I) in the above mentioned publications.

Accordingly, the present invention also provides a pharmaceutical composition comprising the Salicylate or a solvate thereof and a pharmaceutically acceptable carrier therefor.

The Salicylate or a solvate thereof is normally administered in unit dosage form.

The active compound may be administered by any suitable route but usually by the oral or parenteral routes. For such use, the compound will normally be employed in the form of a pharmaceutical composition in association with a pharmaceutical carrier, diluent and/or excipient, although the exact form of the composition will naturally depend on the mode of administration.

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. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the active compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.

Parenteral suspensions are prepared in substantially the same manner except that the active compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound.

As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.

As used herein the term 'pharmaceutically acceptable' embraces compounds, compositions and ingredients for both human and veterinary use: for example the term 'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt.

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 Salicylate or a solvate thereof to a human or non-human mammal in need thereof.

Conveniently, the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.

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

In the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof the salicylate or a solvate thereof may be taken in amounts so as to provide Compound (I) in suitable doses, especially unit doses, such as those disclosed in EP 0,306,228, WO94/05659 or WO98/55122.

The unit dose compositions of the invention comprise the Salicylate or a pharmaceutically acceptable solvate thereof in an amount providing up to 12 mg, including 1-12 mg such as 2-12 mg of Compound (I), especially 2-4 mg, 4-8 mg or 8-12 mg of Compound (I), for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of Compound (I). Thus in particular there is provided a pharmaceutical composition comprising the Salicylate or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier therefor, wherein the Salicylate or a pharmaceutically acceptable solvate thereof is present in an amount providing 1, 2, 4, 8, 12, 4 to 8 or 8 to 12 mg of Compound (I); such as lmg of Compound (I); such as 2 mg of Compound (I); such as 4 mg of Compound (I); such as 8 mg of Compound (I); such as 12 mg of Compound (I).

The invention also provides a pharmaceutical composition comprising the Salicylate or a pharmaceutically acceptable solvate thereof in combination with one or more other anti-diabetic agents and optionally a pharmaceutically acceptable carrier therefor.

The invention also 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 Salicylate or a pharmaceutically acceptable solvate thereof in combination with one or more other anti-diabetic agents.

In a further aspect the present invention provides the use of the Salicylate or a pharmaceutically acceptable solvate thereof in combination with one or more other anti- diabetic agents, for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof. In the above mentioned treatments the administration of the Salicylate or a pharmaceutically acceptable solvate thereof and the other anti-diabetic agent or agents includes co-administration or sequential administration of the active agents.

Suitably in the above mentioned compositions, including unit doses, or treatments the Salicylate or a pharmaceutically acceptable solvate thereof is present in an amount providing up to 12 mg, including 1-12 mg, such as 2-12 mg of Compound (I), especially 2-4 mg, 4-8 mg or 8-12 mg of Compound (I), for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 mg of Compound (I) or 4 to 8 or 8 to 12 mg of Compound (I). Thus for example in the above mentioned compositions, including unit doses, or treatments the Salicylate or a pharmaceutically acceptable solvate thereof is present in an amount providing 1 mg of Compound (I); the Salicylate or a pharmaceutically acceptable solvate thereof is present in an amount providing 2 mg of Compound (I); the Salicylate or a pharmaceutically acceptable solvate thereof is present in an amount providing 3 mg of Compound (I); the Salicylate or a pharmaceutically acceptable solvate thereof is present in an amount providing 4 mg of Compound (I); or the Salicylate or a pharmaceutically acceptable solvate thereof is present in an amount providing 8 mg of Compound (I).

The other antidiabetic agents are suitably selected from biguanides, sulfonylureas and alpha glucosidase inhibitors. The other antidiabetic agent is suitably a biguanide. The other antidiabetic agent is suitably a sulfonylurea. The other antidiabetic agent is suitably a alpha glucosidase inhibitor. Suitable antidiabetic agents are those disclosed in WO98/57649, WO98/57634, WO98/57635, WO98/57636, WO99/03477, WO99/03476. The contents of the above mentioned publications are incorporated herein by reference as if set out in full herein.

No adverse toxicological effects are indicated in the above mentioned treatments for the compounds of the invention.

The following Examples illustrate the invention but do not limit it in any way.

Example 1: 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy)benzyI] thiazolidine-2,4- dione salicylate

5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (4.0 g) in tetrahydrofuran (40 ml) was heated to reflux until a clear solution was observed. A solution of salicylic acid (1.55 g) in tetrahydrofuran (10 ml) was added and the reaction mixture stirred at reflux for 10 minutes and then cooled to 21°C. The solvent was removed under reduced pressure to give a glassy solid. Water (100 ml) was added, and the entire mixture stirred for 3.75 hours at reflux, then cooled to 21 °C. The white solid was collected by filtration, washed with water (100 ml) then dried under vacuum for 1.5 hours at 21°C to afford 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate (5.3 g, 96%) as a white crystalline solid.

Water content (Karl Fisher): 0.44% wt/wt

DSC: T_onSet = 119.0°C, T_peak = 125.5°C

Elemental Analysis

Found: C; 60.45 H; 5.04 N; 8.45

Theory: (C₂₅H₂₅N₃O₆S) C; 60.59 H; 5.08 N; 8.48

Example 2: 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazoIidine-2,4- dione salicylate

5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (20.0 g) in tetrahydrofuran (200 ml) was heated to reflux for 30 minutes when a clear solution was observed. A solution of salicylic acid (7.73 g) in tetrahydrofuran (50 ml) was added and the reaction mixture stirred at an oil bath temperature of 70°C for 10 minutes, then cooled to 21°C. The solvent was removed under reduced pressure to give a glassy solid. Water (500 ml) was added, and the entire mixture stirred for 100 minutes at reflux, cooled to 21°C, then stirred for 17 hours at 21°C. The white solid was collected by filtration, washed with water (100 ml) then dried under vacuum for 7 hours 25 minutes at 45°C to afford 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate (26.5 g, 96%) as a white crystalline solid.

1H-NMR (d₆-DMSO): consistent with a 5-[4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy]benzyl]thiazolidine-2,4-dione salicylate (1 :1 salt)

Water content (Karl Fisher): 0.12% wt/wt

DSC: T_onset = 122.1°C, T_peak = 126.9°C

Elemental Analysis

Found: C; 60.61 H; 5.09 N; 8.43

Theory: (C₂₅H₂₅N₃O₆S) C; 60.59 H; 5.08 N; 8.48

Characterising data for the Salicylate recorded for the product of Example 1

The infrared absorption spectrum of a mineral oil dispersion of the product was obtained using a Nicolet 710 FT-IR spectrometer at 2 cm^-1 resolution (Figure 1). Data were digitised at 1 cm^"1 intervals. Bands were observed at: 3120, 3040, 2925, 2853, 2707, 1775, 1735, 1698, 1641, 1630, 1613, 1586, 1566, 1544, 1512, 1484, 1462, 1440, 1413, 1391, 1384, 1357, 1331, 1298, 1267, 1245, 1218, 1184, 1178, 1170, 1141, 1111, 1097, 1081, 1062, 1033, 1027, 1012, 1002, 971, 962, 936, 922, 898, 871, 856, 820, 806, 763, 755, 738, 723, 705, 667, 638, 614, 607, 595, 560, 535, 525, 507, 475, and 452 cm^"1.

The infrared spectrum of the solid product was recorded using Perkin-Elmer Spectrum One FT-IR spectrometer fitted with a universal ATR accessory. Bands were observed at:

2923, 2694, 1735, 1694, 1626, 1611, 1586, 1564, 1543, 1511, 1483, 1461, 1439, 1412, 1390, 1329, 1297, 1268, 1243, 1178, 1169, 1140, 1097, 1082, 1061, 1027, 1000, 936, 897, 871, 855, 819, 805, 705, 753, 738, 722, and 666 cm^"1

The Raman spectrum of the product (Figure 2) was recorded with the sample in an NMR tube using a Nicolet 960 E.S.P. FT-Raman spectrometer, at 4 cm^"1 resolution with excitation from a Nd:V04 laser (1064 nm) with a power output of 400mW. Bands were observed at:

3106, 3076, 3062, 3013, 2938, 2924, 2877, 1742, 1682, 1612, 1589, 1565, 1545, 1484, 1460, 1441, 1413, 1391, 1332, 1298, 1279, 1269, 1249, 1224, 1208, 1181, 1152, 1141, 1098, 1029, 987, 937, 897, 843, 805, 779, 740, 719, 666, 638, 608, 565, 526, 475, 450, 438, 399, 383, 335, 298, 258, and 86 cm^"1.

The X-Ray Powder Diffractogram pattern of the product (Figure 3) was recorded using the following acquisition conditions: Tube anode: Cu, Generator tension: 40 kV, Generator current: 40 mA, Start angle: 2.0 °2Θ, End angle: 35.0 °2Θ, Step size: 0.02 °2Θ , Time per step: 2.5 seconds. Characteristic XRPD angles and relative intensities are recorded in Table 1.

Table 1

The solid-state NMR spectrum of the product (Figure 4) was recorded on a Bruker AMX360 instrument operating at 90.55 MHz: The solid was packed into a 4 mm zirconia MAS rotor fitted with a Kel-F cap and rotor spun at ca.lO kHz. The ¹³C MAS spectrum was acquired by cross-polarisation from Hartmann-Hahn matched protons (CP contact time 3 ms, repetition time 15 s) and protons were decoupled during acquisition using a two-pulse phase modulated (TPPM) composite sequence. Chemical shifts were externally referenced to the carboxylate signal of glycine at 176.4 ppm relative to TMS and were observed at: 38.8, 41.1, 53.8, 55.9, 69.9, 112.6, 113.5, 117.0, 119.4, 128.5, 130.2, 132.6, 134.3, 138.4, 145.0, 151.9, 156.7, 162.6, 175.6, 178.2 ppm.

Properties of the Salicylate, recorded for the product of Example 2

Solid State Stability of the Salicylate

The solid state stability of the salt was determined by storing approximately 1.0 g of the material in a glass bottle at a) 40°C / 75% Relative Humidity (RH), open exposure, for 1 month and b) at 50°C, closed, for 1 month. The material was assayed by HPLC for final content and degradation products in both cases. a) 40°C / 75% RH: No significant degradation observed (HPLC assay 99% initial). b) 50°C: No significant degradation observed (HPLC assay 99% initial).

Solubility of the Salicylate

The solubility of the material was determined by an HPLC assay of a saturated solution of the Salicylate

Solubility: 0.8 mg/ml.

Flow Properties of the Salicylate

The ratio between the bulk density and the tapped bulk density (Hausner Ratio) of the Salicylate was determined using standard methods ("Pharmaceutics - The Science of Dosage Form Design", editor M. Aulton, 1988, published by:Churchill Livingstone). Hausner Ratio: 1.45

Claims

1. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate salt.

2. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate salt, characterised by: an infrared spectrum substantially in accordance with Figure 1.

3. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate salt, characterised by: a Raman spectrum substantially in accordance with Figure 2.

4. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate salt, characterised by: an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or Figure 3.

5. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate salt, characterised by: a Solid State ¹³C NMR spectrum substantially in accordance with Figure 4.

6. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate salt, characterised by:

(i) an infrared spectrum substantially in accordance with Figure 1 ; and

(ii) a Raman spectrum substantially in accordance with Figure 2; and

(iii) an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table

1 or Figure 3; and

(iv) a Solid State ¹³C NMR spectrum substantially in accordance with Figure 4.

7. A compound according to any one of claims 1 to 6, or a solvate thereof, in isolated form.

8. A compound according to any one of claims 1 to 6, or a solvate thereof, in substantially pure form.

9. A compound according to any one of claims 1 to 6, or a solvate thereof, in crystalline form.

10. A compound according to any one of claims 1 to 9, or a solvate thereof, in a pharmaceutically acceptable form.

11. A compound according to any one of claims 1 to 10, or a solvate thereof, in bulk flowable form.

12. A compound according to any one of claims 1 to 11, or a solvate thereof, in a wet- milled form.

13. A process for preparing a compound according to any one of claims 1 to 9, or a solvate thereof, characterised in that 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] benzyl]thiazolidine-2,4-dione (Compound (I))or a salt thereof, preferably dispersed or dissolved in a suitable solvent, is reacted with a suitable source of salicylate ion; and optionally thereafter as required:

(i) forming a solvate thereof;

(ii) recovering the salicylate salt or solvate thereof ; or

(iii) further processing the salicylate salt or solvate thereof in a manufacturing process requiring wet milling.

14. A pharmaceutical composition comprising 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate salt (the Salicylate) or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.

15. A pharmaceutical composition comprising the 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate salt (the Salicylate) or a pharmaceutically acceptable solvate thereof, in combination with one or more other antidiabetic agents and optionally a pharmaceutically acceptable carrier therefor.

16. A pharmaceutical composition according to claim 14 or claim 15, wherein the Salicylate or the pharmaceutically acceptable solvate thereof, is present in an amount providing 1, 2, 4, 8, 12, 4 to 8 or 8 to 12 mg of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)).

17. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate salt, or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.

18. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione salicylate salt, or a pharmaceutically acceptable solvate thereof, for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

19. A use of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione salicylate salt, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

20. 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 a compound according to any one of claims 1 to 12, or a solvate thereof, to a human or non-human mammal in need thereof.