OA12355A - Tartrate salts of thiazolidinedione derivative. - Google Patents

Tartrate salts of thiazolidinedione derivative. Download PDF

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OA12355A
OA12355A OA1200300029A OA1200300029A OA12355A OA 12355 A OA12355 A OA 12355A OA 1200300029 A OA1200300029 A OA 1200300029A OA 1200300029 A OA1200300029 A OA 1200300029A OA 12355 A OA12355 A OA 12355A
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meso
tartrate
solvaté
accordance
methyl
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OA1200300029A
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Andrew Simon Craig
Tim Chien Ting Ho
Michael Millan
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Smithkline Beecham Plc
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic 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
    • C07D417/02Heterocyclic 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
    • C07D417/12Heterocyclic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/06Antihyperlipidemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system

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Abstract

A novel pharmaceutical compound 5-[4-2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione Meso- Tartrate 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

012355 /
TARTRATE SALTS OP THIAZOLIDINEDIONE DERIVATIVE
This invention relates to a novel phannaceutical, to a process for the préparationof the phannaceutical and to the use of the phannaceutical in medicine.
European Patent Application, Publication Number 0,306,228 relates to certain 5 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-pyridyi)amino)ethoxy]ben2yl]thiazolidine-2,4-dione (hereinafter also referred to as"Compound (I)").
International Patent Application, Publication Number WO94/05659 disclosestO certain salts of the compounds of EP 0,306,228 one of which is the tartrate sait. The preferred sait of WO94/05659 is the maleic acid sait.
It has now been discovered that Compound (T) forms a novel tartrate sait (hereinafter also referred to as the "Meso-Tartrate") .
The novel Meso-Tartrate is a stable, bigh melting crystalline material hence is tj suitable for bulk préparation and handîing. The Meso-Tartrateis amenable to large scalephannaceutical processing, especially in manufacturing processes which require orgenerate heat, for example milling, fluid bed drying, spray drying, hot melt processingand stérilisation by autoclaving. The Meso-Tartrate can also be prepared by an efficient,économie and reproducible process particularly suited to large-scale préparation. 20 The novel Meso-Tartrate also has useful phannaceutical properties and in particular it is indicated to be useful for the treatment and/or prophylaxie of diabètesmellitus, conditions associated with diabètes mellitus and certain complications thereof.
Accordingly, the présent invention provides 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, meso-tartrate sait or a solvaté 25 thereof.
Suitably, the Meso-Tartrate is a mono-tartrate sait.
Mono tartrate salts also optionally comprise another monovalent salting ion suchas an alkali métal or ammonium cation.
In one favoured aspect, the Meso-Tartrate provides an infrared speetnan 30 substantiaUy in accordance with Figure 1.
In one favoured aspect, the Meso-Tartrate provides a Raman speetnan substantially in accordance with Figure 2.
In one favoured aspect, the Meso-Tartrate provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or Figure 3.
35 In one favoured aspect, the Meso-Tartrate provides a Solid State 13C NMR spectrum substantially in accordance with Figure 4. 1 012355
In one favoured aspect, the Meso-Tartrate provides a melting point in the range offfom 147 to 157°C, such as 148 to 155 °C, for exemple 148 °C, 153 °C and 155 °C.
In a preferred aspect, the invention provides 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thia2olidine-2,4-dione, meso-tartrate sait, characterised inthat 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 pattém (XRPD) substantially in accordance with Table1 or Figure 3; and (iv) a Solid State 13C NMR spectrum substantially in accordance with Figure 4.
The présent invention encompasses the Meso-Tartrate or solvaté thereof isolatedin pure form or when admixed with other materiais. Thus in one aspect there is providedthe Meso-T artrate or solvaté thereof in isolated form.
In a funher aspect there is provided the Meso-Tartrate or solvaté thereof in apurified form.
In yet a further aspect there is provided the Meso-Tartrate or solvaté thereof incrystalline form.
Also, the invention provides the Meso-Tartrate or solvaté thereof in a solidphaimaceutically acceptable form, such as a solid dosage form, especially when adaptedfor oral administration.
Moreover, the invention also provides the Meso-Tartrate or solvaté thereof in aphannaceutically acceptable form, especially in bulk form, such form being particularlycapable of pharmaceutical processing, especially in manufacturing processes whichrequire or generate heat, for example milling; for example heat-drying especially fluid-bed drying or a spray drying; for example hot melt processing; for example heat-sterilisation such as autoclaving.
Furthennore, the invention provides the Meso-Tartrate or solvaté thereof in aphannaceutically acceptable form, especially in bulk form.and especially in form havingbeen processed in a manufacturing process requiring or generating heat, for example ina milled form; for example inheat-dried form, especially a fiuid-bed dried form or aspray dried form; for example in a form having being hot melt processed; for example ina form having being heat-sterilised by such as autoclaving. A suitable solvaté is a hydrate.
The invention also provides a process for preparing the Meso-Tartrate or a solvatéthereof, characterised in that 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)) or a sait thereof,preferably dispersed or dissolved in a suitable solvent, is reacted with a source of meso- 2 012355 tartrate ion and thereafter, if required, a solvaté of the resulting Meso-Tartrate isprepared; and the Meso-Tartrate or a solvaté thereof is recovered. A suitable reaction solvent is a ketone for example acetone, or an ether forexample tetrahydrofuran, an alkanol, such as propan-2-ol, a hydrocarbon, such astoluene, an ester, such as ethyl acetate, a nitrile such as acetonitrile, or a halogenatedhydrocarbon such as dichloromethane or water, or an organic acid such as acetic acid; ora mixture thereof. • Conveniently, the source of meso-tartrate ion is meso-tartaric acid. The meso-tartaric acid is preferably added as a solid or in solution, for example in water or a loweralcohol such as methanol, éthanol, or propan-2-ol, or a mixture of solvents. An alternativesource of meso-tartrate ion is provided by a suitabîy soluble base sait of meso-tartaricacid for example ammonium meso-tartrate, or the meso-tartaric acid sait of an amine, forexample 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 the tartaricacid solutions are preferably in the range of 5 to 125% weight/volume.
The reaction is usually carried out 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.
Solvatés, such as hydrates, of the Meso-Tartrate are prepared according toconventional procedures.
Recovery of the required compound generally comprises crystallisation from anappropriate solvent or mixture of solvents, conveniently the reaction solvent, usuallyassisted by cooling. For example, the Meso-Tartrate may be crystalhsed from a ketonesuch as acetone, or an ether such as tetrahydrofuran or water or a mixture thereof.. Animproved yield of the sait may be obtained by évaporation of some or ail of the solventor by crystallisation at elevated température followed by controlled cooling, optionally instages. Careful control of précipitation température may be used to improve thereproducability of the product form.
Crystallisation can also be initiated by seeding with crystals of the Meso-Tartrateor a solvaté thereof but this is not essential.
When the mono tartrate sait comprise another monovalent salting ion such as analkali métal or ammonium catiomthe said ion is conveniently formed by reacting themono tartrate sait with a solution of the chosen monovalent salting ion for example amétal or ammonium ion. Altematively Compound (I) may be treated with a mono tartratesait of the said monovalent salting ion. 3 012355
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 WO94/05659are incoiporated herein by reference.
Meso-tartaric acid is a commercially available compound.
When used herein the tenu "TonseÎ" is generaliy determined by DifîerentialScanning Calorimetry and has a meaning generaliy understood in the art, as forexample expressed in Pharmaceutical Thermal Analysis, Techniques andApplications", Ford and Timmins, 1989 as "The température corresponding to theintersection of the pre-transition baseline with the extrapolated leading edge of thetransition".
When used herein in respect of certain compounds the term "good flowproperties" is suitably characterised by the said compound having a Hausner ratio of lessthan or equal to 1.5, especially of less than or equal to 1.25.. "Hausner ratio" is an art accepted tenn.
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 Π diabètes mellitus.
Conditions associated with diabètes include hyperglycæmia and insulin résistanceand obesity. Further conditions associated with diabètes include hypertension,cardiovascular disease, especially atherosclerosis, certain eating disorders, inparticularthe 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 buhmia. Additional conditions associated with diabètesinclude polycystic ovarian syndrome and steroid induced insulin résistance.
The complications of conditions associated with diabètes mellitus encoœpassedherein includes rénal disease, especially rénal disease associated with the development ofType Π 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 therapeuïicproperties: The présent invention accordingly provides the Meso-Tartrate or a solvatéthereof for use as an active therapeutic substance.
More particularly, the présent invention provides the Meso-Tartraté or a solvatéthereof for use in the treatment and/or prophylaxis of diabètes mellitus, conditionsassociated with diabètes mellitus and certain complications thereof.
The Meso-Tartrate or a solvaté thereof may be administered per se or, preferably,as a pharmaceutical composition also comprising a phannaceuücally acceptable carrier. 4 0 1235ξ
Suitable methods for formulating the Meso-Tartrate or a solvaté thereof are generally those disclosed for Compound (I) in the above mentioned publications.
Accordingly, the présent invention also provides a pharmaceutical composition comprising the Meso-Tartrate or a solvaté thereof and apharmaceutically acceptable carrier therefor.
The Meso-Tartrate or a solvaté thereof is normally 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 normally be employed inthe form of a pharmaceutical composition in association with a pharmaceutical carrier,diluent and/or excipient, although the exact fonn of the composition will naturally dépendon the mode of administration.
Compositions are prepared by admixture and are suitabîy 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 ar.e 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, fabricants, 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 fabricants 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 distribute 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, hydroxyethyicelfalose, carboxymethyl cellulose,aluminium stéarate gel or hydrogenated edible fats, emulsifying agents, for example 5 012355 lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edibleoils), for exemple, almond oil, fractionated coconut oil, oily esters such as esters ofglycérine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propylg-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring 5 agents.
For parentéral administration, fluid unit dose fonns are prepared confaining 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 fîlling into a suitable vial or ampoule and sealing. Advantageously,adjuvants such as a local anaesthetic, preservatives and buffering agents are alsodissolved in the vehicle. To enhance the stability, the composition can be frozen afterfîlling into the vial and the water removed under vacuum.
Parentéral suspensions are prepared in substantially the same manner except that15 the active compound is suspended in the vehicle instead of being dissolved and sterilisedby exposure to ethylene oxide before suspending in the stérile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniformdistribution of the active compound.
As is common practice, the compositions will usually be accompaniedby written20 or printed directions for use in the medical treatment concemed.
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/or25 prophylaxis of diabètes mellitus, conditions associated with diabètes mellitus and certain complications thereof, in a human or non-human mammal which comprises administeringan effective, non-toxic, amount of Meso-Tartrate or a solvaté thereof to a human ornon-human mammal in need thereof.
Conveniently, the active ingrédient may be administered as a pharmaceutical30 composition hereinbefore defîned, and this forms a particular aspect of the présent invention.
In a further aspect the présent invention provides the use of Meso-Tartrate or asolvaté thereof for the manufacture of a médicament for the treatment and/or prophylaxisof diabètes mellitus, conditions associated with diabètes mellitus and certain 35 complications thereof.
In the treatment and/or prophylaxis of diabètes mellitus, conditions associatedwith diabètes mellitus and certain complications thereof the Meso-Tartrate or a solvaté 6 012355 thereof 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 efîects are indicated in the above mentioned treatroentsfor 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-dionemeso-tartrate A mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]ben2yl]thiazolidme -2,4-dione (8.0 g) and tetrahydroforan (160 ml) was stirred and heated to 50°C. A solution ofwe^o-tartaric acid (3.84 g) in water (20 ml) was added and the mixture stirred at 50°C for 15minutes, filtered and the clear filtrate cooled to 21 °C. The solvent was evaporated underreduced pressure at 40°C, acetone (40 ml) was added and the mixture stirred at 21 °C to give awhite suspension. The product was collected by filtration, washed with acetone and dried undervacuum to give 5-(4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]ben2yl]thiazolidine-2,4-dionemeso-tartrate (10.6 g) as a white, crystalline solid.
Example 2 5-[4-[2-(N-MethyI-N-(2-pyridyI)amino)ethoxyïbenzylJthiazoIidine-2,4-dione meso-tartrate A mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyI]thiazolidine-2,4-dione (3.0 g, 8.4 mmol), acetone (40 ml) and tetrahydrofuran (5 ml) washeated at reflux for 2.5 hours with stirring. To this was added a solution of meso-tartaricacid monohydrate (1.41 g, 8.4 mmol) in water (2 ml). The reaction mixture was heated atreflux with stirring for 2.5 hours, then cooled to 21°C and stirred for 16 hours at 21 °C.
The white solid was collected by filtration, washed with acetone (40 ml) then dried underreduced pressure for 2.5 hours at 21°C to afford 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione meso-tartrate (3.25 g) as a whitecrystalline solid.
Example 3 5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyI)thiazoIidine-2,4-dione meso-Tartrate A mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl3thiazolidine-2,4-dione (10.0 g, 28 mmol), acetone (120 ml) and tetrahydrofuran (15 mi)was heated at reflux for 50 minutes with stirring. To this was added a solution of meso-tartaric acid monohydrate (4.7 g, 28 mmol) in water (6.0 ml). The reaction mixture washeated at reflux with stirring for 1 hour, then cooled to 21°C and stirred for 16 hours at21°C. The white solid was collected by filtration, washed with acetone (50 ml) then driedunder reduced pressure for 3 hours at 21°C to afford 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)e1hoxy]benzyl]fhiazoiidine-2,4-dione meso-tartrate (11.7 g) as a whitecrystalline solid. 7 Ο 12355
Characterising data recorded for the product of Example 1
The infrared absorption spectrum of a minerai oil dispersion of the product was obtained using a Nicolet 710 FT-IR spectrometer at 2 cnr1 resolution (Figure 1). Data were digitised at 1 cm-1 intervals. Bands were observed at: 3405, 1738, 1694, 1629, 5 1556, 1537, 1505, 1459, 1436, 1418, 1330, 1268, 1249, 1223, 1182, 1167, 1143, 1104, 1074, 1057, 1033, 1000, 949, 916, 887, 853, 818, 771, 717, 668, 619, 568, 528, 515 cm'1.
The infrared spectrum of the solid product was recorded using Perkin-ElmerSpectrum One FT-IR spectrometer fitted with a universal ATR accessory. Bands were 10 observed at: 3407, 2937, 2750,1739, 1693, 1628, 1555, 1535, 1504, 1476, 1459, 1412, 1388, 1358, 1330, 1261, 1248, 1222, 1182, 1167, 1143, 1101, 1074, 1056, 1033, 999, 948, 916, 887, 853, 818, 771, 744, 717, 667 cm'l.
The Raman spectrum of the product (Figure 2) was recorded with the sample inan NMR tube using a Nicolet 960 E.S.P. FT-Raman spectrometer, at 4 cm-1 resolution 15 with excitation from a Nd:V04 laser (1064 nm) with a power output of 400mW. Bandswere obserbed at: 3101, 3059, 2952, 2922, 2877, 1739, 1604, 1544,1458,1438, 1394, 1331, 1270, 1222, 1203, 979, 887, 827, 739, 668, 638, 605, 472, 344 cm'1
The X-Ray Powder Diffractogram pattern of the product (Figure 3) was recorded usingthefollowing acquisition conditions: Tube anode: Cu, Generator tension: 40 kV, Generator 20 current: 40 mA, Start angle: 2.0 °20, End angle: 35.0 °2Θ, Step size: 0.02 °2Q, Time per step:2.5 seconds.Characteristic XRPD angles and relative intensities are recorded in Table 1.
Table 1.
Angle Rel. Intensity 2-Theta ° % 4.9 11.4 9.3 12.4 9.9 3.1 12.2 1.9 14.3 3.3 14.9 7 15.2 19 15.9 23.8 16.2 13.9 17.0 8.6 17.3 17.5 18.1 25.9 18.5 31.3 19.1 10.7 19.9 18.4 8 012355 20.4 100 21.6 26 22.2 23.7 22.7 6.1 23.6 23.1 24.5 5.7 25.2 23 25.8 9.2 26.2 17.8 26.8 11.5 27.4 14.7 28.1 6.8 28.4 8.7 29.7 5.7 30.2 9.7 30.6 9.3 31.1 23.6 31.4 13.4 32.2 14 32.6 19.7 32.9 15.2 33.6 11.4 33.8 12.4 34.4 8.7 34.7 9
The solid-state NMR spectrum of the product (Figure 4) was recorded ou a Broker AMX360instrument operating at 90.55 MHz: The solid was packed into a 4 mm zirconia MAS rotorfitted with a Kel-F cap and rotor spun at ca.10 kHz. The 10 * * I3C MAS spectrum was acquiredhy cross-polarisation from Hartmann-Hahn matched protons (CP contact time 3ms, répétition 5 time 15 s) and protons were decoupled during acquisition using a two-pulse phase modulated(TPPM) composite sequence. Chemical shifts were exteroally referenced to the carboxylatesignal of glycine at 176.4 ppm relative to TMS and were observed at: 183.0, 177.2, 175.4, 173.0, 160.0,159.0,151.8,144.2, 138.9,134.3, 130.8, 128.2, 123.6, 113.7, 112.8, 77.4, 76.7, 74.5, 55.5, 53.5, 50.0, 42.4, 36.6, 33.8 ppm. 10 Properties of the Meso-Tartrate
Solid State Stability of the Meso-Tartrate, recorded for the product of Example 1
The solid State stability of the drug substance was determined by storing approximately 1.0 g of the material in a glass bottle at i) 40°C /75% Relative Humidity (RH), ppen 9 012355 exposure, 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 97% initial). 5 b) 50°C: No significant dégradation observed (HPLC assay 98% initial).
Melting Point of the Meso-Tartrate
The melting point of the Meso-Tartrate was detennined according to the method described inthe U.S. Pharmacopoeia, USP 23, 1995, <741> "Melting range or température, Procedurefor Class la", using a Buchi 545 melting point instrument.
10 Product of example 1, Melting Point: 149°CProduct of example 2, Melting Point: 153°CProduct of example 3, Melting Point: 155°C
Tonset fhe Meso-Tartrate
The Tonset of the drug substance was detennined by Differential Scanning Calorimetry ,5 using a Perkin-Elmer DSC apparatus.
Product of example 1, Tonset (10°C/minute, closed pan): 146°CProduct of example 2,Tonset (10°C/minute, openpan): 153°C
Product of example 3, T0Ijset (10°C/minute, open pan): 154°C 10

Claims (12)

  1. 012355 CLAIMS:
    1. A compound 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thia2olidine- 2,4-dione, Meso-Tartrate sait or a solvaté thereof.
  2. 2. A compound according to claim 1, characterised in that it provides: (i) an infrared spectrum substantially in accordance with Figure 1; (ii) a Raman spectrum substantially in accordance with Figure 2; (iii) an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table1 or Figure 3; or (iv) a Solid State 13C NMR spectrum substantially in accordance with Figure 4.
  3. 3. A compound according to claim 1, characterised in that it provides two or moreof: (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 Table1 or Figure 3; and (iv) a Solid State 13C NMR spectrum substantially in accordance with Figure 4.
  4. 4. A compound according to any one of claims 1 to 3, in puiifîed form.
  5. 5. A compound according to any one of claims 1 to 3, in a solid dosage form.
  6. 6. A compound according to any one of claims 1 to 3, in a form being capable ofpharmaceutical processing in amanufacturing process that requires or générâtes heat,for example milling; for example heat-drying especially fluid-bed drying or a spraydiying; for example hot melt processing; for example heat-sterilisation such asautoclaving.
  7. 7. A compound according to any one of claims 1 to 3, in a form having beenprocessed in a manufacturing process requiring or generating heat, for example in amilled form; for example inheat-dried form, especially a fluid-bed dried form or a spraydried form; for example in a form having being hot melt processed; for example in aform having being heat-sterilised by such as autoclaving. 11 012355 .JE
  8. 8. A compound according to any one of daims 1 to 3, in a pharmaceuticallyacceptable form having good flow properties.
  9. 9. A process for preparing the Meso-Tartrate or a solvaté thereof, characterised inthat5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyi]thiazolidine-2,4-dione(Compound (I)) or a sait thereof, is reacted with a source of meso- tartarate ion andthereafter, if required, a solvaté of the resulting Meso-Tartrate is prepared; and the Meso-Tartrate or a solvaté thereof is recovered.
  10. 10. A phannaceutical composition comprising 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]ben2yl]thia2olidine-2,4-dione meso- tartrate or a solvaté thereof.and a pharmaceutically acceptable carrier therefor.
  11. 11. A compound 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine- 2,4-dione meso- tartrate or a solvaté thereof, for use as an active therapeutic substance.
  12. 12. A use of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]ben2yl]thiazoIidine-2,4-dione meso- tartrate or a solvaté thereof, for the manufacture of a médicament for thetreatment and/or prophylaxie of diabètes mellitus, conditions associated with diabètesmellitus and certain complications thereof. 12
OA1200300029A 2000-08-04 2001-08-03 Tartrate salts of thiazolidinedione derivative. OA12355A (en)

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