WO2003053962A1

WO2003053962A1 - 5- (4- (2- (n-methyl-n- (2-pyridyl) amino) ethoxy) benzyl) thiazolidine-2, 4-dione malic acid salt and use against diabetes mellitus

Info

Publication number: WO2003053962A1
Application number: PCT/GB2002/005814
Authority: WO
Inventors: Michael John Millan
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd
Priority date: 2001-12-20
Filing date: 2002-12-19
Publication date: 2003-07-03
Anticipated expiration: 2004-06-20
Also published as: AU2002352479A1

Abstract

5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (L)-, (D)- and (DL)-malic acid salts whose IR, Raman, X-ray diffraction and Solid State 13C NMR spectral characteristics are disclosed.

Description

_ (4_ ( 2 - (N-METHYL-N- ( 2 -PYRIDYL) AMINO) ETHOXY) BENZYL) THIAZOLIDINE-2 , 4 -DIONE MALIC ACID SALT AND USE AGAINST DIABETES MELLITUS

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 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. We have now prepared and characterised a novel malic acid salt of Compound (I)

[hereinafter also referred to as the "Malate"]. Malic acid is a chiral acid, and we have isolated and characterised separate D, L and DL forms. Hereinafter reference to the

Malate refers generically to any or all of these forms, unless a specific form is explicitly mentioned. The Malate is obtained in a form that is suitably stable for bulk preparation and handling. The Malate also has aqueous solubility that is suitable for intravenous and liquid pharmaceutical formulation.

The novel Malate can be prepared by an efficient, economic and reproducible process particularly suited to large-scale preparation. The novel Malate 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 a malic acid salt of 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione as a novel compound Especially, in one aspect the present invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, (L)-malate salt as a novel compound.

In a further aspect the present invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, (D)-malate salt as a novel compound. In yet a further aspect the present invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, (DL)-malate salt as a novel compound.

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 (L)-malate

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

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)-malate

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 (L)-malate

Figure 5 is an Infrared spectrum of S-^-^^N-methyl-N-^- pyridy aπύno^thoxy^erizylJtWazolidine^^-dione (D)-malate Figure 6 is a Raman spectrum of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione (D)-malate

Figure 7 is an X-Ray Powder Diffractogram for 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (D)-malate

Figure 8 is a Solid State ¹³C ΝMR spectrum for 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (D)-malate

Figure 9 is an Infrared spectrum of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate

Figure 10 is a Raman spectrum of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate Figure 11 is an X-Ray Powder Diffractogram for 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate

Figure 12 is a Solid State ¹³C ΝMR spectrum for 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate.

In one favoured aspect of the invention, the (L)-Malate provides an infrared spectrum substantially in accordance with Figure 1.

In one favoured aspect of the invention, the (L)-Malate provides a Raman spectrum substantially in accordance with Figure 2.

In one favoured aspect of the invention, the (L)-Malate 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)-Malate provides a Solid State ¹³C

ΝMR 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, (L)-Malate 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 NMR spectrum substantially in accordance with Figure 4.

In one favoured aspect of the invention, the (D)-Malate provides an infrared spectrum substantially in accordance with Figure 5.

In one favoured aspect of the invention, the (D)-Malate provides a Raman spectrum substantially in accordance with Figure 6.

In one favoured aspect of the invention, the (D)-Malate provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 2 or Figure 7. In one favoured aspect of the invention, the (D)-Malate provides a Solid State ¹³C

NMR spectrum substantially in accordance with Figure 8.

In a preferred aspect of the invention, the invention provides a 5-[4-[2-(N-methyl- N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, (D)-malate salt, characterised in that it provides: (i) an infrared spectrum substantially in accordance with Figure 5; and (ii) a Raman spectrum substantially in accordance with Figure 6; and (iii) an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table

2 or Figure 7; and

(iv) a Solid State ¹³C NMR spectrum substantially in accordance with Figure 8. In one favoured aspect of the invention, the (DL)-Malate provides an infrared spectrum substantially in accordance with Figure 9.

In one favoured aspect of the invention, the (DL)-Malate provides a Raman spectrum substantially in accordance with Figure 10.

In one favoured aspect of the invention, the (DL)-Malate provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 3 or Figure 11. In one favoured aspect of the invention, the (DL)-Malate provides a Solid State ¹³C NMR spectrum substantially in accordance with Figure 12.

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

(i) an inf ared spectrum substantially in accordance with Figure 9; and (ii) a Raman spectrum substantially in accordance with Figure 10; and (iii) an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table

3 or Figure 11 ; and

(iv) a Solid State ¹³C NMR spectrum substantially in accordance with Figure 12.

Depending on the solvent from which the Malate is recovered, the Malate 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 Malate 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 Malate or a solvate thereof in isolated form.

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

In yet a further aspect of the invention there is provided the Malate or a solvate thereof in crystalline form. Also, the invention provides the Malate 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 Malate or solvate thereof in a liquid pharmaceutically acceptable form, such as a liquid dosage form, especially when adapted for oral administration.

Also, the invention provides the Malate or solvate thereof in a liquid pharmaceutically acceptable form, such as a liquid dosage form, especially when adapted for intravenous administration.

Suitable texts describing manufacturing processes for obtaining the above- mentioned pharmaceutically acceptable forms include "The Theory and Practice of Industrial Pharmacy" edited by Leon Lachman, Herbert A. Lieberman and Joseph L. Kanig, published by Lea & Febiger.

The invention also provides a process for preparing the Malate or a solvate thereof, characterised in that 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)), preferably dispersed or dissolved in a suitable solvent, is reacted with a suitable source of malate ion; and optionally thereafter as required: (i) forming a solvate thereof; (ii) recovering the Malate or solvate thereof ; (iii) separating (L) or (D) forms of the Malate; or (iv) further processing the Malate or solvate thereof in a pharmaceutical manufacturing process.

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 malate ion is malic acid. The malic acid is preferably added as a solid or in solution, for example in water or a lower alcohol such as methanol, ethanol, or propan-2-ol, or a ketone, such as acetone, or a mixture of solvents. An alternative source of malate ion is provided by a suitably soluble base salt of malic acid for example ammonium malate, or the malic 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 malic acid solutions are preferably in the range of 2 to 200% weight/volume.

The reaction is usually carried out at ambient temperature or at an elevated temperature, for example at the reflux temperature of the solvent, although any convenient temperature that provides the required product may be employed. Solvates, such as hydrates, of the Malate 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 Malate to the solvate moiety as a vapour. When the solvate is formed by crystallization methods the nature of the solvate is typically dictated by the solvent from which the Malate is crystallized. Recovery of the required compound generally comprises crystallisation from an appropriate solvent, conveniently the reaction solvent, usually assisted by cooling. For example, the Malate may be crystallised from acetone. An improved yield of the salt can be obtained by evaporation of some or all of the solvent or by crystallisation at elevated temperature followed by controlled cooling, preferably in stages. Careful control of precipitation temperature and seeding may be used to improve the reproducibility of the product form.

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

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.

(L)-, (D)- and (DL)-malic acid are commercially available compounds. 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 Malate or a solvate thereof for use as an active therapeutic substance.

More particularly, the present invention provides the Malate 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 Malate 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 Malate 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 Malate or a solvate thereof and a pharmaceutically acceptable carrier therefor.

The Malate 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 the Malate 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 the Malate 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 Malate 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 Malate 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 Malate or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier therefor, wherein the Malate 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 Malate 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 Malate 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 Malate 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 Malate 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 Malate or a pharmaceutically acceptable solvate thereof is present in an amount providing up to 12mg, including l-12mg, such as 2-12mg 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 Malate or a pharmaceutically acceptable solvate thereof is present in an amount providing 1 mg of Compound (I); the Malate or a pharmaceutically acceptable solvate thereof is present in an amount providing 2 mg of Compound (I); the Malate or a pharmaceutically acceptable solvate thereof is present in an amount providing 3 mg of Compound (I); the Malate or a pharmaceutically acceptable solvate thereof is present in an amount providing 4 mg of Compound (I); or the Malate 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-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione (L)-malate

A solution of (L)-malic acid (1.13 g) in tetrahydrofuran (10 ml) was added to a stirred solution of 5-[4-[2-(N-methyl-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 20 minutes before the solvent was removed under vacuum. Acetone (20 ml) was added to the residue to produce a clear solution after 5 minutes stirring. After approximately 20 minutes a precipitate began to form. The mixture was stirred for 16 hours before the solid was collected by filtration, washed with acetone (10 ml) and dried under vacuum for 16 hours to afford the (L)-Malate (3.3 g) as a white crystalline solid.

Found: C: 53.47, H: 5.09, Ν: 8.35: Expect: C: 53.76, H: 5.13, Ν: 8.55.

1H-ΝMR (d6-DMSO): Consistent with 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (L)-malate (1:1).

Example 2 5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4- dione (L)-malate

A solution of (L)-malic acid (1.13 g) in acetone (5 ml) was added to a stirred mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (3.0 g) in acetone (20 ml) at reflux. The suspension was maintained at reflux for 45 minutes before the stirred mixture was cooled to 21°C over approximately 30 minutes. The product was collected by filtration, washed with acetone (2 x 5 ml), and dried under vacuum at 21°C for 16 hours to yield the (L)-Malate (3.3 g) as a white crystalline solid.

Example 3 5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyI] thiazolidine-2,4- dione (L)-malate A stirred suspension of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione (25.0 g) in acetone (170 ml) was heated to reflux before a solution of (L)-malic acid (9.37 g) in acetone (40 ml) was added. The mixture was maintained at reflux for 45 minutes and then cooled to 21°C over approximately 1 hour. The solid was collected by filtration, washed with acetone (50 ml) and dried at 50°C under vacuum for 16 hours to afford the (L)-Malate as a white crystalline solid (27.2 g).

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

The infrared absoφtion 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: 1729, 1718, 1697, 1639, 1555, 1518, 1463, 1414, 1327, 1301, 1246, 1220, 1184, 1102, 1084, 1066, 1054, 1033, 1003, 902, 830, 815, 786, 740, 721 657, 616, 607, 546, 529 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: 3108, 2940, 1729, 1719, 1694, 1638, 1627, 1553, 1518, 1463, 1414, 1362, 1327, 1302, 1245, 1220, 1183, 1102, 1084, 1066, 1054, 1033, 1003, 924, 902, 830, 815, 785, 740, 720, 656, 635, 615, 606, 543, 526 cm^"1.

The Raman spectrum of the product (Figure 2) was recorded with the sample in an ΝMR tube using a Νicolet 960 E.S.P. FT-Raman spectrometer, at 4 cm"l resolution with excitation from a Νd:V04 laser (1064 nm) with a power output of 400mW. Bands were observed at: 3107, 3063, 3045, 2941, 2908, 2886, 1742, 1720, 1612, 1583, 1549, 1463, 1446, 1434, 1417, 1393, 1363, 1328, 1300, 1278, 1264, 1246, 1220, 1208, 1180, 1035, 980, 925, 903, 831, 746, 658, 638, 608, 471, 430, 404, 343, 281, 221 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: 35.7, 39.8, 40.8, 48.8, 50.6, 53.5, 56.7, 64.1, 69.6, 112.1, 115.4, 118.4, 119.7, 125.8, 130.3, 131.8, 139.0, 144.5, 146.5, 151.2, 158.8, 169.9, 172.3, 173.8, 178.8, 181.1 ppm.

Properties of the (L)-Malate, recorded for the product of Example 3

Solid State Stability of the (L)-Malate

The solid state stability of the (L)-Malate 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 101% initial). b) 50°C: No significant degradation observed (HPLC assay 96% initial).

Solubility of the (L)-Malate

The solubility of the (L)-Malate salt was determined by an HPLC assay of a saturated solution of the (L)-Malate. Solubility: 5.6 mg/ml.

Example 4 5-[4-[2-(N-Methyl-N-(2-pyridyI)amino)ethoxy]benzyl]thiazolidine-2,4- dione (D)-malate

A stirred suspension of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione (3.0 g) in acetone (20 ml) was heated to reflux before a solution of (D)-malic acid (1.13 g) in acetone (5 ml) was added. The stirred mixture was maintained at reflux for 1 hour and then cooled to 21°C over approximately 1 hour. The solid was collected by filtration, washed with acetone (10 ml) and dried under vacuum for 16 hours at 21 °C to afford the (D)-Malate (3.2 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 (D)-malate (1:1).

Example 5 5-[4-[2-(N-MethyI-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione (D)-malate A solution of (D)-malic acid (8.25 g) in acetone (35 ml) 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 acetone (135 ml) at reflux. The suspension was held at reflux for 1 hour then cooled to 21°C over approximately 1 hour. The solid was collected by filtration, washed with acetone (40 ml) and dried under vacuum at 50°C for 16 hours to yield the (D)-Malate (21.1 g) as a white crystalline solid.

Characterising data recorded for the product of Example 4 (5-[4-[2-(N-Methyl-JV-(2- pyridyl)amino)ethoxy] benzyl] thiazolidine-2,4-dione (D)-malate)

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 5). Data were digitised at 1 cm"¹ intervals. Bands were observed at: 1729, 1718, 1695, 1639, 1556, 1518, 1462, 1414, 1327, 1302, 1246, 1220, 1183, 1102, 1084, 1067, 1055, 1033, 1003, 903, 830, 815, 786, 739, 721, 656, 616, 607, 546, 502 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: 3108, 1729, 1719, 1694, 1638, 1628, 1553, 1518, 1463, 1413, 1392, 1363, 1327, 1302, 1245, 1220, 1183, 1101, 1084, 1066, 1054, 1033, 1003, 924, 902, 830, 815, 785, 740, 720, 656 cm^"1.

The Raman spectrum of the product (Figure 6) was recorded with the sample in an ΝMR tube using a Νicolet 960 E.S.P. FT-Raman spectrometer, at 4 cm^"1 resolution with excitation from a Νd:V04 laser (1064 nm) with a power output of 400mW. Bands were observed at: 3107, 3065, 2941, 2908, 1741, 1612, 1463, 1328, 1264, 1246, 1220, 1178, 980, 903, 831, 746, 658, 639, 608, 470, 404, 343 cm^"1.

The X-Ray Powder Diffractogram pattern of the product (Figure 7) 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 2.

Table 2

Angle I Rel. Intensity

The solid-state NMR spectrum of the product (Figure 8) 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: 39.9, 40.8, 50.7, 56.8, 64.2, 69.7, 112.1, 115.5, 118.3, 119.7, 121.8, 125.8, 130.4, 131.9, 139.0, 146.6, 151.2, 158.8, 172.5, 173.9, 178.8, 181.1 ppm.

Properties of the (D)-Malate, recorded for the product of Example 5

Solid State Stability of the (D)-Malate

The solid state stability of the (D)-Malate 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 100% initial). b) 50°C: No significant degradation observed (HPLC assay 100% initial).

Solubility of the (D)-Malate

The solubility of the (D)-Malate salt was determined by an HPLC assay of a saturated solution of the (D)-Malate. Solubility: 5.5 mg/ml.

Example 6 5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione (DL)-malate

A suspension of (DL)-malic acid (1.13 g) in acetone (10 ml) was warmed until a clear solution was observed. This solution was added to a stirred, refluxing suspension of 5-[4- [2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (3.0 g) in acetone (20 ml). The stirred mixture was maintained at reflux for 1 hour and then cooled to 21°C over a further hour. The solid was recovered by filtration, washed with acetone (10 ml) and dried at 21°C for 48 hours to afford 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate (3.7 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 (DL)-malate (1:1), containing 0.2% acetone.

Found: C: 53.67, H: 5.12, Ν 8.43; Expect: C: 53.76, H: 5.13, Ν: 8.55. Example 7 5-[4-[2-(N-Methyl-N-(2-pyridyI)amino)ethoxy]benzyl]thiazolidine-2,4- dione ( L)-malate

A hot, clear solution of (DL)-malic acid (8.25 g) in acetone (70 ml) 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 acetone (135 ml) at reflux. The mixture was maintained at reflux until all of the solid had dissolved and then cooled to 40°C over approximately 45 minutes. The solution was stirred for 1 hour at 40°C and then cooled to 21°C over a further 30 minutes. The suspension was then heated to reflux for 2 hours, cooled to 21°C and the solid collected by filtration and washed with acetone (50 ml). The solid was dried at 50°C under vacuum to afford 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate (3.7 g) as a white, crystalline solid.

Characterising data recorded for the product of Example 6 (5-[4-[2-(N-methyl- N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate)

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 9). Data were digitised at 1 cm"¹ intervals. Bands were observed at: 3339, 2727, 1750, 1696, 1645, 1610, 1545, 1510, 1465, 1417, 1359, 1322, 1304, 1267, 1232, 1211, 1176, 1166, 1114, 1078, 1060, 1030, 1013, 998, 969, 952, 929, 903, 836, 765, 732, 716, 661, 618, 602, 556, 528, 510, 469 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: 3347, 2928, 2761, 1750, 1694, 1646, 1609, 1545, 1509, 1467, 1417, 1391, 1359, 1321, 1303, 1267, 1232, 1212, 1166, 1114, 1059, 1030, 998, 929, 902, 835, 764, 739, 716, 660 cm-¹.

The Raman spectrum of the product (Figure 10) was recorded with the sample in a glass vial using a Perkin-Elmer 2000R FT-Raman spectrometer, at 4 cm^"1 resolution with excitation from a Νd:YAG laser (1064 nm) with a power output of 400mW. Bands were observed at: 3099, 3064, 3043, 2970, 2923, 1748, 1610, 1583, 1546, 1472, 1439, 1415, 1390, 1360, 1321, 1295, 1266, 1234, 1209, 1177, 1035, 982, 931, 903, 827, 774, 742, 660, 638, 603, 510, 470, 422, 397, 351, 281 cm"¹. The X-Ray Powder Diffractogram pattern of the product (Figure 11) 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 3.

Table 3

The solid-state NMR spectrum of the product (Figure 12) 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: 38.5, 40.9, 43.8, 51.0, 56.2, 64.7, 69.0, 110.2, 113.5, 118.3, 131.5, 132.3, 137.2, 144.2, 150.8, 158.6, 173.3, 174.6, 176.5, 181.7 ppm.

Properties of the (DL)-Malate, recorded for the product of Example 7

Solid State Stability of the (DL)-Malate The solid state stability of the (DL)-Malate 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 101% initial). b) 50°C: No significant degradation observed (HPLC assay 98% initial).

Solubility of the (DL)-Malate

The solubility of the material was determined by an HPLC assay of a saturated solution of the (DL)-Malate. Solubility: 4.7 mg/ml.

Claims

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

2. 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (L)- malate.

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

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

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

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

7. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (L)-malate 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.

8. 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (D)- malate.

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

10. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (D)-malate salt, characterised by: a Raman spectrum substantially in accordance with Figure 6.

11. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (D)-malate salt, characterised by: an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 2 or Figure 7.

12. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (D)-malate salt, characterised by: a Solid State ¹³C NMR spectrum substantially in accordance with Figure 8.

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

(i) an infrared spectrum substantially in accordance with Figure 5; and (ii) a Raman spectrum substantially in accordance with Figure 6; and (iii) an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 2 or Figure 7; and (iv) a Solid State ¹³C NMR spectrum substantially in accordance with Figure 8.

14. 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate.

15. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate salt, characterised by: an infrared spectrum substantially in accordance with Figure 9.

16. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate salt, characterised by: a Raman spectrum substantially in accordance with Figure 10.

17. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate salt, characterised by: an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 3 or Figure 11.

18. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate salt, characterised by: a Solid State ¹³C NMR spectrum substantially in accordance with Figure 12.

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

(i) an infrared spectrum substantially in accordance with Figure 9; and (ii) a Raman spectrum substantially in accordance with Figure 10; and (iii) an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 3 or Figure 11; and (iv) a Solid State ¹³C NMR spectrum substantially in accordance with Figure 12.

20. A compound according to any one of claims 1 to 19, or a solvate thereof, in isolated form.

21. A compound according to any one of claims 1 to 19, or a solvate thereof, in substantially pure form.

22. A compound according to any one of claims 1 to 19, or a solvate thereof, in crystalline form.

23. A compound according to any one of claims 1 to 19, or a solvate thereof, in a solid pharmaceutically acceptable form, such as a solid dosage form, especially when adapted for oral administration..

24. A compound according to any one of claims 1 to 19, or a solvate thereof, in a liquid pharmaceutically acceptable form, such as a liquid dosage form, especially when adapted for oral administration.

25. A compound according to any one of claims 1 to 19, or a solvate thereof, in a liquid pharmaceutically acceptable form, such as a liquid dosage form, especially when adapted for intravenous administration.

26. A process for preparing a compound according to any one of claims 1 to 19, 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 malate ion; and optionally thereafter as required: (i) forming a solvate thereof; (ii) recovering the Malate or solvate thereof ; (iii) separating (L) or (D) forms of the Malate; or

(iv) further processing the Malate or solvate thereof in a pharmaceutical manufacturing process.

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

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

29. A pharmaceutical composition according to claim 27 or claim 28, wherein the Malate 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)).

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

31. A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione malate 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.

32. A use of a 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione malate, 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.

33. 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 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione malate, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.