OA12284A - Thiazolidinedione salt for treatment of diabetes mellitus. - Google Patents

Thiazolidinedione salt for treatment of diabetes mellitus. Download PDF

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OA12284A
OA12284A OA1200200370A OA1200200370A OA12284A OA 12284 A OA12284 A OA 12284A OA 1200200370 A OA1200200370 A OA 1200200370A OA 1200200370 A OA1200200370 A OA 1200200370A OA 12284 A OA12284 A OA 12284A
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hydrobromide
solvaté
methyl
amino
pyridyl
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OA1200200370A
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Andrew Simon Craig
Tim Chien Ting Ho
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Smithkline Beechamp P L C
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Endocrinology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

A novel pharmaceutical compound 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione hydrobromide or a solvate thereof, a process for preparing such a compound, a pharmaceutical composition comprising such a compound and the use of such a compound in medicine.

Description

012284
THIAZOLIDINEDIONE SAIT FOR TREATMENT OF DIABETES MELLITUS
This invention relates to a noveî pharmaceutical, to a process for the préparationof the pharmaceutical and to the use of the pharmaceutical in medicine. 5 European Patent Application, PublicationNumber 0,306,228 relates to certain thiazolidinedione dérivatives disclosed as having hypoglycaemic and hypolipidaemicactivity. The compound of example 30 of EP 0,306,228 is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidme-2,4-dione (hereinafter also referred to as"Compound ([)"). 10 International Patent Application, Publication Number WO94/05659 discloses certain salts of the compounds of EP 0,306,228 including salts formed from minerai acidssuch as hydrobromic, hydrochloric and sulphuric acids, and organic acids, such asmethanesulphonic, tartane and, in particular, maleic acid salts.
Ithas now been discovered thaï Compound (I) forms a novel hydrobromide sait -15—- (hereinafter also referred to as the "Hydrobromide") that is particularly stable and hence issuitable for bulk préparation and handling. The Hydrobromide also has a high meîtingpoint, shows particularly good aqueous solubility and possesses good bulk flowproperties. The hydrobromide is therefore surprisingly amenahle to large scalepharmaceutical processing and especially to large scale miling. 20 The novel form can be prepared by an efficient, économie and reproducible process particularly suited to large-scale préparation.
The novel Hydrobromide also has useful pharmaceutical properties and inparticular it is indicated to be useful for the treatment and/or prophylaxis of diabètesmellitus, conditions associated with diabètes mellitus and certain complications thereof. 25 Accordingly, the présent mention provides 5-[4-[2-(N~methyl-N-(2- pyridyl)ammo)ethoxy3benzyl]thiazolidine-2,4-dione hydrobromide or a solvaté thereof.
Suitably, the hydrobromide is a monohydrobromide.
In one favoured aspect, the Hydrobromide provides an infrared spectrumsubstantially in accordance with Figure I. 30 In one favoured aspect, the Hydrobromide provides a Raman spectrum
substantially in accordance with Figure IL
In one favoured aspect, the Hydrobromide provides an X-Ray powder diffractionpattern (XRPD) substantially in accordance with Table I or Figure III.
In one favoured aspect, the Hydrobromide provides a solid-staie 13C NMR35 spectrum substantially in accordance with Figure IV.
It is also favoured that the Hydrobromide has a melting point within tire range offrom 175 to 185°C, especially 180 to 185°C, for example 181°C. 012284 10 - - --------15 20 25 30
Al’so the Hydrobromide bas a Tonset within the range of from 180 to 186°C, forexample 182.5°C.
Thus in a prefenred aspect, 1he the Hydrobromide is characterised ïn that itprovides two or more of: (i) an infrared spectrum substantially in accordance with Figure I; (ii) a Raman spectrum substantially in accordance with Figure H; (iii) an X-Ray powder diffraction pattern (XRPD) substantially in accordance withTable I or Figure IH; (iv) a solid-state 13C NMR spectrum substantially in accordance with Figure IV; and (v) a melting point within the range of from 175 to 185°C, especially 180 to 185°C,for example 181°C.
The présent invention encompasses the Hydrobromide or solvaté thereof isolatedin pure form or when admixed with other materials. Thus in one aspect there is providedthe Hydrobromide or solvaté thereof in isolated form. a-fljjtjjg,. aspect there is provided the Hydrobromide or solvaté thereof in apurified fonn.
In yet a further aspect there is provided the Hydrobromide or solvaté thereof incrystalline form.
Also, the invention provides the Hydrobromide or solvaté thereof in a solidpharmaceutically acceptable form, such as a solid dosage form, especially whenadapted for oral administration.
Moreover, the invention also provides the Hydrobromide or solvaté thereof in apharmaceutically acceptable form, especially in buik form, such form being particularlycapable of being milled.
Furthermore, the invention provides the Hydrobromide or solvaté thereof in apharmaceutically acceptable form, especially in bulk form, such form having good flowproperties, especially good bulk flow properties. A suitable solvaté is a hydrate.
The invention also provides a process for preparing the Hydrobromide or solvatéthereof, characterised in that 5-[4-[2-(N-methyl-N-(2- pyridyi)amino)ethoxy]benzyI]thiazolidine-2,4-dione (Compound(î)), or a sait thereof,preferably dispersed or dissolved in a suitable solvent, is reacted with a source ofhydrogen bromide and thereafter, if required, a solvaté of the Hydrobromide is prepared;and the Hydrobromide or solvaté thereof is recovered. A suitable reaction solvent is an alkanol, for example propan-2-ol, or ahydrocarbon, such as toluene, a ketone, such as acétone, an ester, such as ethyl acetate, anether such as tetrahydrofuran, a nitrile such as acetonitrile, or a halogenated hydrocarbon 35 012284 such as dichlorômethane, water, or an organic acid such as acetic acid; or a mixturethereof.
Conveniently, the source of hydrogen bromide is provided by an aqueous solutionof hydrogen bromide, for example a 48% w/w solution in water. Altematively, the source 5 of hydrogen bromide is a solution of hydrogen bromide in an appropriate solvent, optionally the reaction solvent, for example propan-2-ol. In addition, the hydrogenbromide may be added directly to a solution or suspension of Compound(I) in the chosenreaction solvent.
An alternative source of hydrogen bromide is provided by a base sait of 10 hydrobromic acid for example ammonium bromide, or the hydrobromic acid sait of anamine, for example ethylamine or diethylamine.
The réaction is usually carried oui at ambient température or at an elevatedtempérature, for example at the reflux température of the solvent, although anyconvenient température that provides the required product may be employed. 15 Solvatés, such as hydrates, of the Hydrobromide are prepared according to conventional procedures.
Recovery of the required compound generally comprises crystallisation ffom an appropriate solvent, conveniently the reaction solvent, usually by cooling to a température in the range of from 0°C to 60°C, for example 20 to 25°C or from 40 to 50°C. For20 example the Hydrobromide may be crystallised ffom an alcohol such as propan-2-ol or a ketone such as acetone.
In one preferred form the recovery comprises initial cooling to a first température,such as in the range of ffom 40 to 50°C, thereby allowing initiating crystallisation andthereafter cooling to a second température, suïtably in the range of ffom 0 to 25°C. 25 Crystallisation can also be initiated by seeding with crystals of the Hydrobromide or solvaté thereof but this is not essential.
Solvatés are prepared by use of appropriate conventional methods.
Compound (I) is prepared according to known procedures, such as those disclosedin EP 0,306,228 and WO94/05659. The disclosures of EP 0,306,228 and WO94/05659 30 are incorporated herein by reference.
When used herein the term "Tonsef is generally determined by Differential
Scanning Calorimetry and has a meaning generally understood in the art, as forexample expressed in Pharmaceutical Thermal Analysis, Techniques andApplications", Ford and Timmins, 1989 as "The température corresponding to the 35 intersection of the pre-transition baseline with the extrapolated leading edge of thetransition”. 012284
When used herein in respect of certain compounds the terni "good flowproperties" is suitably characterised by the said compound having a Hausner ratio of lessthan or equal to 1.5, especiaîîy of less than or equal to 1.25. "Hausner ratio" is an art accepted term.
When used herein the term 'prophylaxie of conditions associated with diabètesmellitus' includes the treatment of conditions such as insulin résistance, impaired glucosetolérance, hyperinsulinaemia and gestational diabètes.
Diabètes mellitus preferably means Type II diabètes mellitus.
Conditions associated with diabètes include hyperglycaemia and insulin résistanceand obesity. Further conditions associated with diabètes include hypertension,cardiovascular disease, especially athéroscléroses, certain eating disorders, in parücularthe régulation of appetite and food intake in subjects suffering from disorders associatedwith under-eating, such as anorexia nervosa, and disorders associated with over-eating,such as obesity and anorexia bulimia. Additional conditions' associated with diabètesinclude polycystic ovarian syndrome and steroid induced insulin résistance.
The complications of conditions associated with diabètes mellitus encompassedherein includes rénal disease, especially rénal disease associated with the development ofType II diabètes including diabetic nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage rénal disease.
As mentioned above the compound of the invention has useful therapeuticproperties: The présent invention accordingly provides the Hydrobromide or solvatéthereof for use as an active therapeutic substance.
More parti cularly, the présent invention provides the Hydrobromide or solvatéthereof for use in the treatment and/or prophylaxie of diabètes mellitus, conditionsassociated with diabètes mellitus and certain complications thereof.
The Hydrobromide or solvaté thereof may be administered per se or, preferably,as a pharmaceutical composition aiso comprising apharmaceutically acceptable carrier.Suitable methods for formulating the Hydrobromide or solvaté thereof are generally thosedisclosed for Compound (I) in the above mentioned publications.
Accordingly, the présent invention also provides a pharmaceutical compositioncomprising the Hydrobromide or solvaté thereof and a pharmaceutically acceptablecarrier therefor.
The Hydrobromide or solvaté thereof is normaiiy administered in unit dosage form.
The active compound may be administered by any suitable route but usually bythe oral or parentéral routes. For such use, the compound will normaiiy be employed inthe form of a pharmaceutical composition in association with a pharmaceutical carrier, 012284 5 diluent and/or excipient, although the exact form of the composition will naturally dépendon the mode of administration.
Compositions are prepared by admixture and are suitably adapted for oral,parentéral or topical administration, and as such may be in the form of tablets, capsules,oral liquid préparations, 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, tablettingagents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tabletsmay be coated according to well known methods in the art.
Suitable fillers for use include cellulose, mannitol, lactose and other similaragents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch dérivativessuch as sodium starch glycollate. Suitable lubricants include, for example, magnésiumstéarate. Suitable pharmaceutically acceptable wetting agents include sodium laurylsulphate.
Solid oral compositions may be prepared by conventional methods of blending,filling, tabletting or the like. Repeated blending operations may be used to distribuie theactive agent throughout those compositions employing large quantifies of fillers. Suchoperations are, of course, conventional in the art.
Oral liquid préparations may be in the form of, for example, aqueous or oilysuspensions, solutions, émulsions, syrups, or élixirs, or may be presented as a dry productfor reconstitution with water or other suitable vehicle before use. Such liquidpréparations may contain conventional additives such as suspending agents, for examplesorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose,aluminium stéarate gel or hydrogenated edible fats, emulsifying agents, for examplelecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edibleoiis), for example, almond oiî, fractionated coconut oil, oily esters such as esters ofglycérine, propylene gîycol, or ethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouringagents.
For parentéral administration, fluid unit dose forms are prepared containing acompound of the présent invention and a stérile vehicle. The compound, depending onthe vehicle and the concentration, can be either suspended or dissolved. Parentéralsolutions are normally prepared by dissolving the active compound in a vehicle and filtersterilising before filling into a suitable vial or ampoule and sealing. Advantageously,adjuvants such as a local anaesthetic, preservatives and buffering agents are also 012284 6 dissolvedinthevehicle. Toenhancethestability,thecompositioncanbefrozenafterfilling into the viai and the water removed under vacuum.
Parentéral suspensions are prepared in substantially the same manner except thatthe active compound is suspended in the vehicle instead of being dissolved and sterilised 5 by exposure to ethylene oxide before suspending in the stérile vehicle. Advantageously, asurfactant or wetting agent is included in the composition to facilitate uniformdistribution of the active compound.
As is common practice, the compositions will usually be accompanied by writtenor printed directions for use in the medical treatment concemed. 10 As used herein the term 'pharmaceutically acceptable' embraces compounds, compositions and ingrédients for both human and veterinary use: for example the term'pharmaceutically acceptable sait' embraces a veterinarily acceptable sait.
The présent invention further provides a method for the treatment and/orprophylaxie of diabètes mellitus, conditions associated with diabètes mellitus and certain 15 complications thereof, in a human or non-human mammal which comprises administeringan effective, non-toxic, amount of Hydrobromide or solvaté thereof to a human ornon-human mammal in need thereof.
Conveniently, the active ingrédient may be administered as a pharmaceuticalcomposition hereinbefore defined, and this forms a particular aspect of the présent 20 invention.
In a further aspect the présent invention provides the use of Hydrobromide orsolvaté thereof for the manufacture of a médicament for the treatment and/or prophylaxisof diabètes mellitus, conditions associated with diabètes mellitus and certaincomplications thereof. 25 In the treatment and/or prophylaxis of diabètes mellitus, conditions associated with diabètes mellitus and certain complications therêof the Hydrobromide or solvatéthereof may be taken in amounts so as to provide Compound (I) in suitable doses, such asthose disclosed in EP 0,306,228, WO94/05659 or WO98/55122. ,
No adverse toxicological effects are indicated in the above mentioned treatments 30 for the compounds of the invention.
The following examples illustrate the invention but do not limit it in any way. 012284
Example 1: 5-(4-[2-(N-methyl-N-(2-pyridyI)amino)ethoxy]benzylîthiazolidine-2,4-dione hydrobromide A mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione (1.0 g) and propan-2-oI (50 ml) was stirred and heated to reflux for a period of10 minutes at which point a clear solution was observed. Hydrobromic acid (48% w/wsolution in water, 0.31ml) was then added dropwise, and the reaction mixture stirredfor 10 minutes at reflux then allowed to cool to 21°C. The product was collected byfiltration and washed with propan-2-ol (10 ml) to give the 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione hydrobromide (0.41 g) as a whitecrystalline solid.
Example 2: 5-[4-[2-(N-methyl-N-(2-pyridyl)ainino)ethoxy]benzyl]thiazolidine-2,4-dione hydrobromide A mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidiner2,4-dione (3.0 g) and acetone (100 ml) was stirred and heated to reflux for a period of 15minutes at which point a clear solution was observed.
Hydrobromic acid (48% w/w solution in water, 0.95 ml ) was added and the reactionmixture stirred at reflux for 15 minutes and then cooled to 21°C. After standing for120 hours the mother liquor was decanted and the crystalline product washed withacetone (10 ml) and dried under vacuum for 3 hours to give 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy3benzyl]thiazolidine-2,4-dionehydrobromide (3.7 g). 1H-NMR (d6-DMSO): consistent with 5-[4-[2-(N-methyl-N-(2- pyridyi)amino)ethoxy]benzyl]thiazolidine~2,4-dione hydrobromide containing acetone,0.5% wt/wt.
Example 3: 5-[4-[2-(N-methyl-N-(2-pyridyI)amino)ethoxy]benzyl]thiazoIidine-2,4-dione hydrobromide A mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]ben2yl] thiazolidine-2,4-dione (15.0 g) and acetone (230 ml) was stirred and heated to reflux for 15 minutes atwhich point a clear solution was observed. Hydrobromic acid (48% w/w aqueoussolution, 4.75 ml) was then added and the mixture was cooled to 45 °C and stirred for 1hour, and then cooled to 21 °C. The white solid was collected by filtration, and washedwith acetone (100 ml) to give 5-[4-[2-(N~methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione hydrobromide (17.7 g) as a whitecrystalline solid.
CHARACTERISLNG DATA FOR THE HYDROBROMIDE (1) RECORDED FOR THE PRODUCT OF EXAMPLE 3
Solubility of the Hydrobromide 012284
The solubility ôf the material was detennined by adding water in aliquots ffom 1 to1000ml to approximately lOOmgof drug substance until the powder had dissolved. TheVisual solubility was confirmed by an HPLC assay of a saturated solution.
Solubility: 6mg/ml.
Solid State Stahility of the Hydrobromide
The solid State stability of the drug substance was detennined by storing approximately1.0 g of the material in a glass botüe at i) 40°C / 75 % Relative Humidity (RH), openexposure, for 1 month and b) at 50°C, closed, for 1 month. The material was assayedby HPLC for final content and dégradation products in both cases. a) 40°C /75% RH: No significant dégradation observed (HPLC assay 98% initial). b) 50°C: No significant dégradation observed (HPLC assay 98% initial).
Flow Properties of the Hydrobromide:
The ratio between the bulk density and the tapped bulk density (Hausner Ratio) of theHydrobromide was detennined using standard methods ("Pharmaceutics - The Scienceof Dosage Form Design”, editor M. Aulton, 1988, published by:ChurchillLivingstone).
Hausner Ratio: 1.3
Tonset of the Hydrobromide
The Tonset of the drug substance was detennined by Differential Scanning Calorimetryusing a Perkin-Elmer DSC7 apparatus.
Tonset·’ 182.5 OC
Melting Point of the Hydrobromide
The melting point of the drug substance was detennined visually by hot stagemicroscopy.
Mpt: 181 oc (2) RECORDED FOR THE PRODUCT OF EXÂMPLE 2
The infrared absorption spectrum of a minerai oil dispersion of the product was obtainedusing aNicoIet 710 FT-IR spectrometer at 2 cm-1 resolution (Figure I). Data weredigitised at 1 cm-1 intervals. Bands were observed at: 2923, 2854, 2749, 1745, 1698, 1643, 1610, 1544, 1515, 1459, 1419, 1378, 1327, 1313, 1287, 1256, 1240, 1228, 1203, 1185, 1151, 1071, 1054, 1032, 1014, 985, 906,803, 771, 738, 712, 524 cm"1.
The IR spectrum of the solid product was recorded using a universal ATR accessory.Bands were observed at: 2929, 2859, 2749, 1745, 1694, 1641, 1608, 1543, 1514, 1445, 1419, 1382, 1358, 1326, 1311, 1287, 1255, 1240, 1202, 1184, 1148, 1070, 1053, 1031, 1014, 985, 906, 862, 844, 802, 768, 737, 710, 657 cm"1.The Ramanspectrum of the product (Figure II) was recorded with the sample in an NMR tube usingaNicolet 960 E.S.P. FT-Raman spectrometer, at 4 cm'1 resolution with excitation from aNd:V04 laser (1064 nm) with a power output of 400mW. Bands were observed at: 3067,2997,2926,2884,2860,1747,1611,1588,1545,1445,1382,1360, 1315,1287,1240, 012284 * 1213,1185, 1070,1016,986,917, 826,769, 740,712, 659,636, 620, 605, 506,470,405, 332,303,134, 99 cm'1. « 5 The XRPD pattern of the product (Figure ΠΙ) was recorded using the following acquisition conditions: Tube anode: Cu, Generator tension: 40 kV, Generator current: 40mA, Start angle: 2.0 °2Θ, End angle: 35.0 °2Ô, Step size: 0.02 °20 , Time per step: 2.5seconds. Characteristic XRPD angles and relative intensities are recorded in Table 1. 10 Table 1
Angle Intensity 2-Theta 0 % 10.0 2.9 11.7 2.7 12.4 0.8 13.2 S.9 13.4 9.6 13.8 1.1 14.4 1.8 14.8 5.6 15.9 7.4 16.3 23.5 17.1 17.2 17.6 15.5 18.1 21.1 19.4 15.1 20.3 6.8 20.7 2.4 21.3 7.3 22.1 36.3 22.5 20.8 22.8 3 23.4 100 23.7 18 24.0 19.7 24.5 18.1 24.9 25.2 25.7 10.6 26.3 12 26.8 11.8 27.0 15.8 27.3 6.6 012294 41 10 27.8 15.4 28.2 5 29.2 12.4 29.4 6.8 29.9 5.9 30.4 11.5 30.7 21.9 31.1 2.9 31.8 7.2 32.2 8.3 32.3 8.8 32.5 11.9 33.0 7.3 33.9 7 34.3 9 34.7 5.5

Claims (10)

  1. 012284 11 CLAIMS:
    1. A compound 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy3benzyl]thia2olidine- 2,4-dione hydrobromide or a solvaté thereof.
  2. 2. A compound according to claim 1, characterised in that it provides two or moreof: (i) an infrared spectrum substantially in accordance with Figure I; (ii) a Raman spectrum substantially in accordance with Figure II; (iii) an X-Ray powder diffraction pattern (XRPD) substantially in accordance withTable I or Figure III; (iv) a solid-state 13C NMR spectrum substantially in accordance with Figure IV; and (v) a melting point within the range of from 175 to 185°C, especially 180 to 185°C,for example 181°C.
  3. 3. A compound according to claim 1 or claim 2, in purified form.
  4. 4. A compound according to any one of daims 1 to 3, in a solid dosage form.
  5. 5. A compound according to any one of daims 1 to 3, in a pharmaceuticalîyacceptable form capable of being milled.
  6. 6. A compound according to any one of daims 1 to 3, in a pharmaceuticalîyacceptable form having good flow properties.
  7. 7. A process for preparing the 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione hydrobromide or a solvaté thereof.characterised in that 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]ben2yl]thiazolidine- 2,4-dione or a sait thereof is reacted with a source of hydrogen bromide and thereafter, ifrequired, a solvaté of the Hydrobromide is prepared; and the Hydrobromide or solvatéthereof is recovered.
  8. 8. A pharmaceutical composition comprising 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione hydrobromide or a solvaté thereof.and a pharmaceuticalîy acceptable carrier therefor.
  9. 9. A compound 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine- 2,4-dione hydrobromide or a solvaté thereof for use as an active therapeutic substance. οι 2284 12
  10. 10. A use of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4 dione hydrobromide or a solvaté thereof, for the manufacture of a médicament for the 5 treatment and/or prophylaxis of diabètes mellitus, conditions associated with diabètesmellitus and certain complications thereof.
OA1200200370A 2000-06-08 2001-06-08 Thiazolidinedione salt for treatment of diabetes mellitus. OA12284A (en)

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USRE39384E1 (en) 1993-09-01 2006-11-07 Smithkline Beecham P.L.C. Substituted thiazolidinedione derivatives
DE102005034406A1 (en) * 2005-07-22 2007-02-01 Ratiopharm Gmbh New salts of rosiglitazone
WO2008091624A2 (en) * 2007-01-22 2008-07-31 Teva Pharmaceutical Industries Ltd. Polymorphic forms of rosiglitazone hydrobromide and processes for preparation thereof
EP1956018A1 (en) * 2007-02-06 2008-08-13 Boehringer Ingelheim Pharma GmbH & Co. KG Method of preparing a derivative of benzimidazole
WO2010021745A2 (en) * 2008-08-21 2010-02-25 Teva Pharmaceutical Industries Ltd. Polymorphic forms of rosiglitazone hydrobromide and processes for their preparation

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