Title of Invention

"A CRYSTALLINE HYDRATED FORM OF 5-[4-[2-N-METHYL-N-(2-PYRIDYL)AMINO)ETHOXY]BENZYL]THIAZOLIDINE-2, 4-DIONE, MALEIC ACID SALT"

Abstract

A hydrate of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione, maleic acid., characterised in that it: (i) comprises water in the range of from 0.3 to 0.6 molar equivalents; and (ii) provides an infrared spectrum containing peaks at 1757, 1331, 1290, 1211 and 767 cm-1; and/or (iii) provides a Raman spectrum containing peaks at 1758,1610,1394, 1316 and 1289 cm-1; and/or (iv) provides a solid state nuclear magnetic resonance spectrum containing chemical shifts substantially as set out in Table I herein; and/or (v) provides an X-ray powder diffraction (XRPD) pattern substantially as set out in Figure IV herein; a process for the preparation of such a compound, a pharmaceutical composition containing such a compound and the use of such a compound or composition in medicine.

Full Text

The present invention relates to a crystalline hydrated form of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2 ,4-dione, maleic acid salt. 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. International Patent Application, ' Publication Number W094/05659 discloses certain thiazolidinedione derivatives having hypoglycaemic and hypolipidaemic activity including 5-[4-[2-(N-methyl-N-(2-ridyl)amino)ethoxy]benzyl] thiazolidine- 2,4-dione, maleic acid salt (hereinafter also referred to as "Compound (0')- Compound (I) is disclosed solely as an anhydrous form. It has now been discovered that Compound (I) exists in a novel hydrated form which is particularly suitable for bulk preparation and handling. This can be prepared by an efficient, economic and reproducible process particularly suited to large scale preparation. The novel hydrate 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- mdilitus-and-certain- Accordingly, the present invention provides a hydrate of 5-[4-[2-(N-methyl-N- (2-pyridyflamino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic ac4f$ie "Hydrate") characterised in that the Hydrate: (i) comprises water in the range of from 0.3 to 0.6 molar equivalents; and (ii) provides aninfra red spectrum containing peaks at 1757, 1331, 1290, 1211 and 767 cnrl and/or (iii) provides a Raman spectrum containing peaks at 1758, 1610, 1394, 1316 and 1289 cm'; and/or (iv) provides a solid state nuclear magnetic resonance spectrum containing chemical shifts substantially as set out in Table I; and/or (v) provides an X-ray powder diffraction (XRPD) pattern substantially as set out in Figure IV, Suitably, the water content of the Hydrate is in the range of from 0.3 to 0.5 0 molar equivalents, for example 0.4 molar equivalents In one favoured aspect, the Hydrate provides an infra red spectrum substantially in accordance with Figure I. In one favoured aspect, the Hydrate provides a Raman spectrum substantially in accordance with Figure II. In one favoured aspect, the Hydrate provides a solid state nuclear magnetic resonance spectrum substantially in accordance with Figure III. Brief Description of the Accompanying Drawings Figure I illustrates infrared (ir) absorption spectrum of the hydrate salt of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic • acid, in accordance with the present invention. Figure II illustrates Raman spectrum of the hydrate salt of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolicline-2,4-dione,maleic acid, in accordance with the present invention. Figure III illustrates nuclear magnetic resonance (nmr) spectrum of the hydrate salt of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid, in accordance with the present invention. Figure IV illustrates X-ray powder diffraction (XRPD) pattern of the hydrate salt of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid, in accordance with the present invention. The Hydrate can exist in certain dehydrated forms which reversibly convert to the Hydrate when contacted with water, either in liquid or vapour form. The present invention encompasses all such reversibly rehydratable forms of the Hydrate. The present invention encompasses the Hydrate isolated in pure form or when admixed with other materials, for example the known anhydrous form of Compound I, the above mentioned reversibly rehydratable forms or any other material. Thus in one aspect there is provided the Hydrate in isolated form. In a further aspect there is provided the Hydrate in pure form. In yet a further aspect there is provided the Hydrate in crystalline form. The invention also provides a process for preparing the Hydrate, characterised in that 5- [4-[2-(N-methyl-N-(2-pyridyr)amino)ethoxyjbenzyljthiazolidine-2,4-dione, maleic acicfis crystallised from aqueous ethanol, conveniently aqueous denatured ethanol. Suitably, the aqueous ethanol contains from 2% to 15% of water by volume, such as 5% to 15% of water by volume, favourably 7% to 12% of water by volume, preferably 10 to 12%, for example 10%. Other aqueous solvents may also be used to prepare the Hydrate, for example isopropanol, acetonftrile, tetrahydrofuran, methyl ethyl ketone, ethyl acetate or acetic acid, or mixtures thereof. The precise amount of water used in each of the alternative solvents will depend upon the particular solvent chosen but tyvically it is in the range of from 2 to 15% of water by volume of water, for example 3%. For certain solvents, such as in ethyl acetate, water levels as low as 1% by volume can provide the Hydrate (thus providing a suitable range of 1 to 15% of water by volume in the appropriate solvent). Alternatively, the Hydrate can be obtained by crystallization from water containing a small amount (for example 2 to 5% by volume) of an organic acid such as acetic acid. Crystallisation and any recrystallization is generally carried out at low to ambient temperature, such as in the range of between 0 to 30°C for example 25°C; alternatively crystallisation may be initiated at an elevated temperature, such as in the range of between 30°C and 60°C for example 50°C, and then completed by allowing the temperature of the solvent to cool to ambient or low temperature, such as in the range of between 0 to 30°C for example 20°C. The crystallisation can be initiated by seeding with crystals of the Hydrate but this is not essential. Compound I is prepared according to known procedures, such as those disclosed in WO94/05659 Ind. P.A. No. 2504/DEL/98. The disclosures of WO94/05659 2504/DEL/98are incorporated herein by reference. 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, parenterai 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 g-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. For parenterai 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. Parenterai 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. In addition such compositions may contain further active agents such as anti-hypertensive agents and diuretics. 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 acceptable1 embraces compounds, compositions and ingredients for both human and veterinary use: for example the term 'pharmaceutically acceptable salt1 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 Hydrate 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 the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof Hydrate may be taken in doses, such as those described above. Similar dosage regimens are suitable for the treatment and/or prophylaxis of non-human mammals. In a further aspect the present invention provides the use of Hydrate for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof. 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: Preparation of Hydrate of 5-[4-[2-(N-methyI-N-(2- ^pyridyl)amino)ethoxy] benzyl] thiazo!idine-2,4-dione, maleic acid£ 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione free base (6.0 g) and maleic acid (2.1 g) were heated to 60°C in denatured ethanol (60 ml) containing additional water (6.1 ml, i.e. a total water content of approximately 10% (v/v)), and stirred at this temperature for 30 minutes during which a solution was obtained. The solution was filtered, re-heated to 55°C, and then cooled to 20-25°C and stirred for eighteen hours. The product was filtered and dried at 50°C in vacuo to give the title compound (4.62 g, 58%). CHARACTERISING DATA: The following characterising data were generated for the Hydrate: A Water content This was determined as 1.55% w/w (0.41 molar equivalents) using a Karl Fischer apparatus. B Infrared The infrared absorption spectrum of a mineral oil dispersion of the Hydrate was obtained using a Nicolet 710 FT-IR spectrometer at 2 cnr1 resolution. Data were digitised at 1 cm~l intervals. The spectrum obtained is shown in Figure I. Peak positions are as follows: 3574, 3458, 3377, 3129,2776, 1757,1743, 1708, 1691,1640,1620,1585,1542, 1512, 1414,1350, 1331, 1306, 1290, 1249,1238,1211, 1183,1163,1143,1107,1078,1063, 1031,1002,974,954,927,902,865,836,830, 817, 809, 767, 735,717,663, 616, 585, 558, 520 and 508 cm'1. C Raman A Raman spectrum of the Hydrate was recorded through glass vials using a Perkin Elmer 2000R spectrometer at 4 cm'1 resolution and is shown in Figure II (1800 - 200 cm'1). Excitation was achieved using a Nd:YAG laser (1064 run) with a power output of 500 mW. Data were digitised at 1 cm'l intervals. Peak positions are as follows: 1758,1743, 1703, 1610,1586,1544,1468,1435,1394, 1330,1316, 1289,1265, 1238,1206, 1185, 1148,1095,1032,1003, 976, 923, 903, 843, 825, 780,741,722, 664, 637, 606, 526,471,403, 331 and 293 cm'1. D NMR The 90.55MHz 13C CP-MAS NMR spectrum for the Hydrate is shown below in Figure III. Chemical shifts are tabulated in Table I. Data were recorded at ambient temperature and 10 kHz spinning frequency, without prior grinding of the sample, on a Bruker AMX360WB spectrometer, with 1.6ms cross polarization, and a repetition rate of 20 s. Chemical shifts were referenced to the high-field resonance of solid adamantane (38.4 ppm relative to tetramethylsilane), and are judged accurate to within +/- 0.5ppm. Peaks were not assigned. Table I. 13C Chemical Shifts of the Hydrate Chemical Shift (ppm) 32.4 59.3 117.6 152.8 177.5 38.8 65.6 119.8 154.9 179.2 42.1 67.0 133.1 159.4 42.9 68.4 135.2 160.2 43.8 111.5 138.5 168.1 53.0 113.8 139.9 171.3 54.7 115.3 148.5 174.4 57.2 116.4 149.0 175.0 E X-Ray Powder Diffraction (XRPD) The XRPD pattern of the Hydrate is shown below in Figure IV and a summary of the XRPD angles and calculated lattice spacing characteristic of the Hydrate is given in Table II. A PW1710 X-ray powder diffractometer (Cu X-ray source) was used to generate the spectrum using the following acquisition conditions: Tube anode: Cu Generator tension: 40 kV Generator current: 30 mA Start angle: 3.5 °20 End angle: 35.0 °20 Step size: 0.020 Time per step: 4.550 s X-Ray Powder Diffraction Angles and Calculated Lattice Spacing Characteristic of the Hydrate. Example 2 The maleate salt of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]ben2yl] thiazolidine-2,4,-dione anhydrate (3.0 g) was stirred and heated at 55-60°C in acetonitrile (30 ml) containing water (1 ml) until complete dissolution was achieved. The resultant solution was stirred and cooled to 20-25 °C and the product was filtered, washed with acetonitrile (5 ml) and dried at 50°C in vacua to give the title compound (1.8 g, 60%). The water content of the product was 1.77%. Example 3 The procedure of Example 2 was repeated using tetrahydrofuran (15 ml) containing water (0.5 ml) as solvent. Yield 1.8 g (60%), water content 1.60%. Example 4 The procedure of Example 2 was repeated using methyl ethyl ketone (30 ml) containing water (1 ml) as solvent. Yield 2.05 g (68%), water content 1.58%. Example 5 The procedure of Example 2 was followed using 2.0 g maleate salt, heating to 65°C in ethyl acetate (150 ml) containing water (1.5 ml) as solvent. Yield 1.34 g (67%), water content 1.61%. Example 6 The procedure of Example 2 was followed, heating to 65-70°C in isopropanol (33 ml) containing water (1 ml) as solvent. Yield 2.4 g (80%), water content 1.58%. Example 7 The procedure of Example 2 was repeated using a mixture of water (20 ml) and acetic acid (1.0 g) as solvent. Yield 0.76 g (38%), water content 1.78%. We Claim: 1. A crystalline hydrated form of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2 ,4-dione, maleic acid salt, which has a water content of from 0.3 to 0.5 molar equivalents; and which is identifiable by one or more of the following spectral data sets: infrared spectrum containing peaks at 1757, 1331, 1290, 1211 and 767 cm-1; Raman spectrum containing peaks at 1758, 1610, 1394, 13 16 and 1289cm-1; solid state nuclear magnetic resonance (NMR) spectrum containing 13C chemical shifts of 32.4, 38.8, 42.1, 42.9, 43.8, 53.0, 54.7, 57.2, 59.3, 65.6, 67.0, 68.4, 111.5, 113.8, 115.3, 116.4, 117.6, 119.8, 133.1, 135.2, 138.5, 139.9, 148.5, 149.0, 152.8, 154.9, 159.4, 160.2, 168.1, 171.3, 174.4, 175.0, 177.5, 179.2 (ppm); X-ray powder diffraction (XRPD) pattern containing peaks at diffraction angles of 7.5, 9.8, 15.2, 17.2, 17.9, 19.3, 20.4, 20.7, 22.3, 24.8, 25.6, 26.6, 27.1, 28.1, 29.3, 30.2, 31.6(◦2θ) 2. A hydrate as claimed in claim 1 which has been obtained by crystallising 5-[4-[2-(N-methyl-N-(2-pyridyl) amino) ethoxy]benzyl] thiazolidine-2,4-dione, maleic acid salt from ethanol to which water has been added in an amount of from 7% to 12 % of water by volume.

Documents:

554-DEL-2003-Abstract-(27-12-2007).pdf

554-del-2003-abstract.pdf

554-DEL-2003-Claims-(27-12-2007).pdf

554-DEL-2003-Claims-08-05-2008.pdf

554-del-2003-claims.pdf

554-DEL-2003-Correspondence-Others-(27-12-2007).pdf

554-DEL-2003-Correspondence-Others-08-05-2008.pdf

554-del-2003-correspondence-others.pdf

554-del-2003-description (complete)-08-05-2008.pdf

554-del-2003-description (complete).pdf

554-del-2003-drawings.pdf

554-DEL-2003-Form-1-(27-12-2007).pdf

554-DEL-2003-Form-1-08-05-2008.pdf

554-del-2003-form-1.pdf

554-del-2003-form-18.pdf

554-DEL-2003-Form-2-(27-12-2007).pdf

554-DEL-2003-Form-2-08-05-2008.pdf

554-del-2003-form-2.pdf

554-DEL-2003-Form-3-(27-12-2007).pdf

554-del-2003-form-3.pdf

554-del-2003-form-5.pdf

554-DEL-2003-GPA-(27-12-2007).pdf

554-del-2003-gpa.pdf

554-DEL-2003-Other Document-08-05-2008.pdf

554-del-2003-pct-220.pdf

554-del-2003-pct-409.pdf

554-del-2003-pct-search report.pdf

554-DEL-2003-petition-137-(27-12-2007).pdf

554-DEL-2003-petition-138-(27-12-2007).pdf