WO2003053963A1

WO2003053963A1 - Novel pharmaceutical

Info

Publication number: WO2003053963A1
Application number: PCT/GB2002/005815
Authority: WO
Inventors: Michael John Millan
Original assignee: Smithkline Beecham Plc
Priority date: 2001-12-20
Filing date: 2002-12-19
Publication date: 2003-07-03
Also published as: GB0130510D0; AU2002361450A1

Abstract

A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione 1-hydroxy-2-naphthoic acid salt whose IR, Raman, X-ray powder diffraction and Solid State13C NMR spectral characteristics are disclosed.

Description

NOVEL PHARMACEUTICAL

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 EP-A 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 WO 94/05659 discloses certain salts of the compounds of EP 0,306,228. The preferred salt of WO 94/05659 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 1-hydroxy- 2-naphthoic acid (hereinafter also referred to as the "l-Hydroxy-2-naphthoate") that is particularly stable and hence is suitable for bulk preparation and handling. The 1- Hydroxy-2-naphthoate is a high melting crystalline material with low solubility. Hence it is amenable to large scale pharmaceutical processing, for example in manufacturing processes which require or generate heat, for example milling, fluid bed drying, spray drying, hot melt processing and sterilisation by autoclaving; or in processes that require wet milling.

Also the novel salt can be prepared by an efficient, economic and reproducible process particularly suited to large-scale preparation.

The novel l-Hydroxy-2-naphthoate 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 l-hydroxy-2-naphthoate salt or a solvate thereof. hi 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 l-hydroxy-2-naphthoate

Figure 2 is a Raman spectrum of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione l-hydroxy-2-naphthoate Figure 3 is an X-Ray Powder Diffractogram for 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione l-hydroxy-2-naphthoate Figure 4 is a Solid State ¹³C NMR spectrum for 5-[4-[2-(N-mefhyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione l-hydroxy-2-naphthoate.

In one favoured aspect of the invention, the l-Hydroxy-2-naphthoate provides an infrared spectrum substantially in accordance with Figure 1. In one favoured aspect of the invention, the l-Hydroxy-2-naphthoate provides a

Raman spectrum substantially in accordance with Figure 2.

In one favoured aspect of the invention, the l-Hydroxy-2-naphthoate 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 l-Hydroxy-2-naρhthoate provides a

Solid State ¹³C ΝMR spectrum substantially in accordance with Figure 4.

In a further favoured aspect the l-Hydroxy-2-naphthoate, provides a melting range in the range of 155 to 175 °C, for example 160.0 - 160.5°C.

In a preferred aspect, the invention provides 5-[4-[2-(Ν-methyl-Ν-(2- pyridyl)amino)etnoxy]benzyl]thiazolidine-2,4-dione, l-hydroxy-2-naphthoate 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 ¹³C MR spectrum substantially in accordance with Figure 4.

Depending on the solvent from which the l-Hydroxy-2-naphthoate is recovered, the l-Hydroxy-2-naphthoate may be obtained as a solvate, and such solvates are a further aspect of the invention. A suitable pharmaceutically acceptable solvate is a hydrate. The present invention encompasses the l-Hydroxy-2-naphthoate or a solvate thereof isolated in pure form or when admixed with other materials.

Thus in one aspect of the invention there is provided the l-Hydroxy-2-naphthoate or a solvate thereof in isolated form.

In a further aspect of the invention there is provided the l-Hydroxy-2-naphthoate or a solvate thereof in pure form.

In yet a further aspect of the invention there is provided the l-Hydroxy-2- naphthoate or a solvate thereof in crystalline form.

Also, the invention provides the l-Hydroxy-2-naphthoate or solvate thereof in a solid pharmaceutically acceptable form, such as a solid dosage form, especially when adapted for oral administration.

Moreover, the invention also provides the l-Hydroxy-2-naphthoate or solvate thereof in a pharmaceutically acceptable form, especially in bulk form, such form being particularly capable of pharmaceutical processing, especially in manufacturing processes which require or generate heat, for example milling; for example heat-drying especially fluid-bed drying or a spray drying; for example hot melt processing; for example heat- sterilisation such as autoclaving; or which require wet milling Examples of manufacturing processes which require or generate heat include milling, heat-drying especially fluid-bed drying, spray drying or hot melt processing and heat-sterilisation such as autoclaving. Particular examples of manufacturing processes which require or generate heat include milling, heat-drying especially fluid-bed drying, spray drying and heat-sterilisation such as autoclaving. Furthermore, the invention provides the l-Hydroxy-2-naphthoate or solvate thereof in a pharmaceutically acceptable form, especially in bulk form, and especially in a form having been processed in a manufacturing process requiring or generating heat, for example in a milled form; for example in heat-dried form, especially a fluid-bed dried formor a spray dried form; for example in a form having being hot melt processed; for example in a form having being heat-sterilised by such as autoclaving; or in a form that has been wet milled

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 and for spray drying and fluid bed drying Advanced Drying Technologies by Kudra, Tadeusz.; Mujumdar, A. S, New York Marcel Dekker, Inc., 2001.

The invention also provides a process for preparing the l-Hydroxy-2-naphthoate 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 l-hydroxy-2-naphthoate ion; and optionally thereafter as required: (i) forming a solvate thereof;

(ii) recovering the l-Hydroxy-2-naphthoate or solvate thereof ; or (iii) further processing the l-Hydroxy-2-naphthoate or solvate thereof in a manufacturing process requiring or generating heat, or in a manufacturing process requiring milling, especially 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 l-hydroxy-2 -naphthoate ion is l-hydroxy-2-naphthoic acid. The l-hydroxy-2-naphthoic 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 l-hydroxy-2-naphthoate ion is provided by a base salt of 1-hydroxy- 2-naphthoic acid for example ammonium l-hydroxy-2-naphthoate, or the l-hydroxy-2- naphfhoic acid salt of an amine, for example efhylamine 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 1-hydroxy- 2-naphthoic acid solutions are preferably in the range of 10 to 75 % % 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.

As indicated above the Toluenesulfonate can exist as a solvate. Suitable solvates are pharmaceutically acceptable solvates, such as non-aqueous solvates Solvates, such as hydrates, of the 1 -Hydroxy-2-naphthoate 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 l-Hydroxy-2- naphthoate to the solvate moiety as a solvent vapour. When the solvate is formed by crystallization methods the nature of the solvate is typically dictated by the solvent from which the l-Hydroxy-2-naphthoate is crystallized.

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 l-Hydroxy-2-naphfhoate may be crystallised from an alcohol such as methanol. 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 maybe used to improve the reproducibility of the product form. Crystallisation may also be initiated by seeding with crystals of the l-Hydroxy-2- naphthoate or a solvate thereof but this is not essential. Compound (ϊ) 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 as if set out in full herein. 1 -Hydroxy-2-naphthoic acid is a commercially available compound.

Suitable manufacturing processes requiring or generating heat include milling, heat-drying, especially a fluid-bed drying, hot melt processing or heat-sterilisation, such as autoclaving. When used herein the term "T_onset" is generally determined by Differential Scanning Calorimetry and 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 l-Hydroxy-2-naphthoate or a solvate thereof for use as an active therapeutic substance.

More particularly, the present invention provides the l-Hydroxy-2-naphthoate 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 l-Hydroxy-2-naphthoate or a solvate thereof may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. Suitable methods for formulating the l-Hydroxy-2-naphthoate 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 l-Hydroxy-2-naphthoate or a solvate thereof and a pharmaceutically acceptable carrier therefor. The 1 -Hydroxy-2-naphthoate 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 ^-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 l-Hydroxy-2-naphthoate or a solvate thereof to a human or non-human mammal in need thereof.

The compositions are formulated according to conventional methods, such as those disclosed in standard reference texts, for example the British and US Pharmacopoeias; Remington's Pharmaceutical Sciences (Mack Publishing Co.); Martindale The Complete Drug Reference (London, The Pharmaceutical Press); and Harry's Cosmeticology (Leonard Hill Books).

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 l-Hydroxy-2- naphthoate 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 l-Hydroxy-2-naphthoate 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, WO 94/05659 or WO

98/55122.

The unit dose compositions of the invention comprise the l-Hydroxy-2- naphthoate 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 l-Hydroxy-2-naphthoate or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier therefor, wherein the l-Hydroxy-2-naphthoate 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 1- Hydroxy-2-naphthoate 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 l-Hydroxy-2-naphthoate 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 l-Hydroxy-2- naphthoate 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 l-Hydroxy-2- naphthoate 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 l-Hydroxy-2-naphfhoate 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 (T), for example 1, 2, 3, 4, 5, 6, 7, 8,

9, 10, 11, or 12 mg of Compound (1) 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 1- Hydroxy-2-naphthoate or a pharmaceutically acceptable solvate thereof is present in an amount providing 1 mg of Compound (I); the l-Hydroxy-2-naphthoate or a pharmaceutically acceptable solvate thereof is present in an amount providing 2 mg of Compound (I); the l-Hydroxy-2-naphthoate or a pharmaceutically acceptable solvate thereof is present in an amount providing 3 mg of Compound (I); the l-Hydroxy-2- naphthoate or a pharmaceutically acceptable solvate thereof is present in an amount providing 4 mg of Compound (I); or the l-Hydroxy-2-naphthoate or a pharmaceutically acceptable solvate thereof is present in an amount providing 8mg 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 WO 98/57649, WO 98/57634, WO 98/57635, WO 98/57636, WO 99/03477, WO 99/03476. 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-iV-(2-pyridyl)amino)ethoxy]benzyl]thiazolidme-2,4- dione l-hydroxy-2-naphthoate

A solution of l-hydroxy-2-naphthoic acid (1.58 g) in tetrahydrofuran (10 ml) was added to a stirred solution of 5-[4-[2-(N-memyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine- 2,4-dione (3.0 g) in tetrahydrofuran (30 ml) at 50°C. The clear solution was cooled to 21°C over approximately 30 minutes before the solvent was evaporated under reduced pressure. Methanol (25 ml) was added to the residue and the mixture was stirred for 16 hours at 21°C. The solid precipitate was recovered by filtration, washed with methanol (10 ml) and dried at 50°C for 5 hours to yield 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione l-hydroxy-2-naphfhoate (4.3 g) as a white crystalline solid.

1H-ΝMR (d6-DMSO): consistent with 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione l-hydroxy-2-naphthoate

Water Content (Karl Fischer): 0.07% w/w Example 2 5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazoIidine-2,4- dione l-hydroxy-2-naphthoate

A stirred suspension of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione (3.0 g) in methanol (30 ml) was heated to reflux before a suspension of l-hydroxy-2-naphthoic acid (1.58 g) in methanol (20 ml) was added. The stirred reaction mixture was maintained at reflux until a clear solution was formed and then cooled to 21°C over approximately 1 hour. The solid was collected by filtration, washed with methanol (10 ml) and dried under vacuum at 21°C for 16 hours to afford 5- [4-[2-(N-memyl-N-(2-pyridyl)amino)emoxy]benzyl]thiazolidine-2,4-dione 1 -hydroxy-2- naphthoate (3.9 g) as a white crystalline solid.

Example 3 5-[4-[2-(N-Methyl-N-(2-pyridyl)ami-Qθ)ethoxy]benzyl] thiazolidine-2,4- dione l-hydroxy-2-naphthoate

l-Hydroxy-2-naphthoic acid (12.64 g) was added to a stirred suspension of 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (20.0 g) in methanol (200 ml) at reflux. Methanol (100 ml) was added to facilitate complete addition of the acid. The stirred mixture was maintained at reflux for 50 minutes until all the solids had dissolved and then cooled to 0°C over approximately 90 minutes. The mixture was stirred at 0°C for 45 minutes before the solid was recovered by filtration and washed with methanol (100 ml). The solid was dried under vacuum at 50°C for 16 hours to give 5-[4- [2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione l-hydroxy-2- naphthoate (28.6 g) as a white crystalline solid.

1H-ΝMR (d6-DMSO): consistent with 1:1 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)emoxy]benzyl]thiazolidine-2,4-dione l-hydroxy-2-naphthoate

Water Content (Karl Fischer): 0.03% w/w

Characterising data recorded for the product of Example 1 (5-[4-[2-(N-Methyl-iV-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione l-hydroxy-2-naphthoate

The infrared absorption spectrum of a mineral oil dispersion of the product was obtained using a Νicolet 710 FT-IR spectrometer at 2 cm^-1 resolution (Figure 1). Data were digitised at 1 cm"¹ intervals. Bands were observed at: 3148, 3043, 2659, 1740, 1697, 1645, 1621, 1576, 1546, 1512, 1460, 1427, 1408, 1363, 1325, 1309, 1262, 1249, 1242, 1214, 1182, 1175, 1154, 1148, 1138, 1081, 1055, 1035, 1018, 972, 955, 924, 908, 876, 825, 799, 780, 765, 715, 665, 644, 618, 601, 577, 563, 538, 522, 495, 447, and 426 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: 3149, 3045, 2876, 2647, 1740, 1694, 1645, 1621, 1575, 1547, 1511, 1460, 1427, 1405, 1362, 1324, 1307, 1261, 1242, 1214, 1175, 1149, 1138, 1109, 1081, 1054, 1035, 1016, 972, 954, 924, 907, 876, 825, 799, 779, 762, 713, and 666 cm^"1.

The Raman spectrum (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: 3074, 3053, 2960, 2917, 1742, 1613, 1582, 1546, 1465, 1427, 1393, 1366, 1330, 1307, 1279, 1264, 1250, 1204, 1179, 1141, 1019, 997, 921, 877, 839, 821, 795, 742, 729, 646, 639, 605, 534, 496, 470, 430, 412, 341, 303, and 284 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: 36.1, 37.2, 46.8, 50.8, 55.4, 63.2, 111.2, 113.4, 114.6, 117.1, 124.7, 125.7, 126.2, 127.6, 128.2, 128.9, 136.0, 140.6, 152.7, 157.3, 162.6, 173.0, 176.2, 179.1 ppm.

Properties of the l-Hydroxy-2-naphthoate, recorded for the product of Example 3

Solubility of the l-Hydroxy-2-naphthoate

The solubility of the salt was determined by adding water in aliquots from 1 to 1000 ml to approximately 100 mg of drug substance until the powder had dissolved. The visual solubility was confirmed by an HPLC assay of a saturated solution. Solubility: 0.03 mg/ml.

Tonset of the l-Hydroxy-2-naphthoate The T_onset of the salt was determined by Differential Scanning Calorimetry using a

Perkin-Elmer DSC7 apparatus. ^τonset (10°C/minute, closed pan): 164 °C

Melting Range of the l-Hydroxy-2-naphthoate The melting range of the salt was dete-trnined according to the method described in the U.S. Pharmacopoeia, USP 23, 1995, <741> "Melting range or temperature, Procedure for Class la", using a Buchi 545 melting point instrument. Melting range: 160.0 -160.5°C

Claims

1. A salt of 5-[4-[2-(N-memyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione and l-hydroxy-2-naphthoic acid.

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

3. A 5-[4-[2-(N-memyl-N-(2-ρyridyl)ammo)emoxy]benzyl]thiazolidine-2,4-dione 1- hydroxy-2-naphthoate 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 1- hydroxy-2-naphthoate 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)ammo)ethoxy]bei-syl]thiazolidine-2,4-dione 1- hydroxy-2-naphthoate 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 1- hydroxy-2-naphthoate 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 6, or a solvate thereof, in a form having been processed in a manufacturing process requiring or generating heat.

11. A compound according to claim 10, or a solvate thereof, in a bulk form.

12 A compound according to claim 10 or 11, or a solvate thereof, wherein the processed form is selected from: a dry-milled form, a heat-dried form, a hot melt processed form and a heat-sterilised form.

13 A compound according to any one of claims 10 to 12, or a solvate thereof, in a wet-milled form.

14. A process for preparing a compound according to any one of claims 1 to 13, or a solvate thereof, characterised in that 5-[4-[2-(N-mefhyl-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 l-hydroxy-2-naphthoate ion; and optionally thereafter as required:

(i) forming a solvate thereof;

(ii) recovering the l-Hydroxy-2-naphfhoate or solvate thereof ; or (iii) further processing the l-Hydroxy-2-naphthoate or solvate thereof in a manufacturing process requiring or generating heat, or in a manufacturing process requiring milling, especially wet milling.

15. A pharmaceutical composition comprising a 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione l-hydroxy-2-naphthoate salt, (the 1- Hydroxy-2-naphthoate) or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.

16. A pharmaceutical composition comprising a 5-[4-[2-(N-methyl-N-(2- ρyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione l-hydroxy-2-naphthoate salt, (the 1- Hydr xy-2-naphthoate) or a pharmaceutically acceptable solvate thereof, in combination with one or more other anti-diabetic agents and optionally a pharmaceutically acceptable carrier therefor.

17. A pharmaceutical composition according to claim 14 or claim 15, wherein the 1- Hydroxy-2-naphthoate 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)).

18. A compound 5-[4-[2-(N-methyl-N-(2-pyridyl)a-mino)ethoxy]be-nzyl]thiazolidine- 2,4-dione l-hydroxy-2-naphthoate salt, or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.

19. A compound 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine- 2,4-dione l-hydroxy-2-naphthoate 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.

20. A use of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)emoxy]benzyl]thiazolidine-2,4- dione l-hydroxy-2-naphthoate, 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.

21. 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 13, or a solvate thereof, to a human or non-human mammal in need thereof.