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WO2003050115A1 - Citrate de rosiglitazone et son utilisation comme antidiabetique - Google Patents

Citrate de rosiglitazone et son utilisation comme antidiabetique Download PDF

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Publication number
WO2003050115A1
WO2003050115A1 PCT/GB2002/005677 GB0205677W WO03050115A1 WO 2003050115 A1 WO2003050115 A1 WO 2003050115A1 GB 0205677 W GB0205677 W GB 0205677W WO 03050115 A1 WO03050115 A1 WO 03050115A1
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WO
WIPO (PCT)
Prior art keywords
citrate
ethoxy
thiazolidine
dione
benzyl
Prior art date
Application number
PCT/GB2002/005677
Other languages
English (en)
Inventor
Andrew Simon Craig
Tim Chien Ting Ho
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to AU2002352390A priority Critical patent/AU2002352390A1/en
Publication of WO2003050115A1 publication Critical patent/WO2003050115A1/fr

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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

Definitions

  • EP-A-0 306 228 relates to certain thiazolidinedione derivatives disclosed as having hypoglycaemic and hypolipidaemic activity.
  • the compound of Example 30 of EP-A-0 306 228 is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine- 2,4-dione (hereinafter referred to as "Compound (I)").
  • WO 94/05659 discloses certain salts of the compounds of EP-A-0 306 228.
  • the preferred salt of WO 94/05659 is the maleic acid salt.
  • citric acid salt of Compound (I) (hereinafter also referred to as the "Citrate”) specifically as the hydrate (hereinafter also referred to as the “Citrate Hydrate”) that is obtained that are particularly stable and hence suitable for bulk handling and processing, especially wet milling processing.
  • the novel Citrate 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 mellitus and certain complications thereof. Accordingly, in a first aspect the present invention provides a citric acid salt of 5-
  • Citric acid is a triacid, so the citrate salts may theoretically exist in more than one stoichiometry. However at present the Citrate has been isolated only in a form which the ratio of Compound (I) to citric acid is 2: 1 (molar ratio).
  • the present invention provides a 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione 2:1 citrate as a novel compound, preferably as a hydrate.
  • the citrate anion may be associated with a proton (hydrogen atom) in addition to Compound (I) or may be associated with another cation, for example an alkali metal or ammonium cation.
  • the salt may be described as a mixed salt.
  • the preferred aspect of the present invention is a hydrate of the Citrate
  • the present invention provides a hydrate of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione citrate as a novel compound.
  • the present invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione citrate (molar ratio 2: 1) 1 :3 hydrate as a novel compound.
  • Citrate Hydrate 1 characterised by:
  • the Citrate Hydrate 1 provides a Raman spectrum substantially in accordance with Figure 2.
  • the Citrate Hydrate 1 provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or Figure 3. In one favoured aspect, the Citrate Hydrate 1 provides a Solid State 13 C NMR spectrum substantially in accordance with Figure 4.
  • XRPD X-Ray powder diffraction pattern
  • the invention provides a 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione citrate hydrate, characterised in that it provides: (i) an infrared spectrum substantially in accordance with Figure 1 ; and
  • Citrate Hydrate 2 contains approximately 2.6% by weight water, consistent with 1:1.4 hydrate. Additionally a further example contains 0.5% by weight which is consistent with a 1 :0.27 hydrate. Accordingly, the present invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione citrate (molar ratio 2:1) containing approximately 0.4 - 3.8% water.
  • the present invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione citrate (molar ratio 2:1) which is a 1 :0.2 - 1 :2 hydrate.
  • the present invention also provides 5-[4-[2-(N-methyl-N-(2- pvridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione citrate (molar ratio 2:1) 1 :1.4 hydrate as a novel compound.
  • the present invention additionally provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione citrate (molar ratio 2:1) 1:0.25 hydrate as a novel compound.
  • the Citrate Hydrate 2 provides an infrared spectrum substantially in accordance with Figure 5.
  • the Citrate Hydrate 2 provides a Raman spectrum substantially in accordance with Figure 6.
  • the Citrate Hydrate 2 provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Figure 7.
  • XRPD X-Ray powder diffraction pattern
  • the invention provides an 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione citrate hydrate, characterised in that it provides:
  • the Citrate may be obtained as a solvate other than a hydrate. Such solvates form part of the present invention.
  • the present invention encompasses the Citrate preferably as the Citrate Hydrate
  • the Citrate preferably as the Citrate Hydrate, (including Hydrates 1 and 2) in isolated form.
  • the Citrate preferably as the Citrate Hydrate, (including Hydrates 1 and 2) in substantially pure form.
  • the Citrate preferably as the Citrate
  • Hydrate (including Hydrates 1 and 2) in crystalline form.
  • the Citrate preferably as the Citrate Hydrate, (including Hydrates 1 and 2) in non-crystalline form.
  • the invention also provides the Citrate preferably as the Citrate Hydrate (including Hydrates 1 and 2) in a pharmaceutically acceptable form, especially in bulk form, such form being particularly capable of being milled, especially wet-milled.
  • the invention accordingly provides the Citrate, preferably as the Citrate Hydrate, (including Hydrates 1 and 2) thereof in a pharmaceutically acceptable form (especially in a bulk form) in a milled form, especially in a wet-milled form.
  • a suitable text decribing the manufacturing processes referred to herein is "The
  • the invention also provides a process for preparing the Citrate, preferably the Citrate Hydrate, 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 citrate ion, such as citric acid or a citric acid hydrate; and optionally thereafter as required:
  • a suitable source of citrate ion such as citric acid or a citric acid hydrate
  • Formation of the Hydrate requires the presence of water at some stage; the water may be added as a cosolvent in the process e.g. 5 to 100 % water. However, it is also possible to provide sufficient water for hydrate formation by carrying out the reaction with exposure to atmospheric moisture, or by use of non-anhydrous solvents.
  • the isolated Citrate Hydrate is dried under vacuum at ambient temperature, for example 18-25°C, especially 21 °C.
  • the drying is optionally carried out over a dessicant such as phosphorus pentoxide, and optionally for an extended period for example 10-150 hours. Drying is continued until the water content becomes stable at about 5 - 7%, for example 5.7 - 6.2%.
  • a dessicant such as phosphorus pentoxide
  • the isolated Citrate Hydrate may be also be dried, or Hydrate 1 further dried, under vacuum at elevated temperature, for example 50-80°C, especially 60-70 °C.
  • the drying is optionally carried out over a dessicant such as phosphorus pentoxide, and also preferably for a period of 10-30 hours. In this way we have reproducibly isolated the hydrate form characterised above as Hydrate 2.
  • citrates may be prepared by contacting stoichiometric amounts (for example 1 : 1 or 1 :2) of citric acid and Compound (I); alternatively an excess of the acid may be used.
  • Mixed salts may be prepared by forming a precursor 1 : 1 salt in situ or using it pre-formed; and contacting the precursor salt with a solution containing the metal, ammonium ion, or other cation; or treating a citric acid salt such as a metal or ammonium citrate with Compound (I).
  • a suitable reaction solvent is a ketone, such as acetone, an ether such as tetrahydrofuran or a nitrile such as acetonitrile.
  • the source of citrate ion is citric acid or a hydrate thereof, for example citric acid monohydrate.
  • the citric acid is preferably added as a solid or in solution or as a suspension, for example in water, ether, ketone, nitrile or a lower alcohol such as methanol, ethanol, or propan-2-ol, or a mixture of solvents.
  • solid citric acid monohydrate may be added to a solution of Compound (I) in solution, or as a suspension in, for example tetrahydrofuran.
  • citrate ion is provided by a suitably soluble base salt of citric acid, for example ammonium citrate, or the citrate salt of an amine, for example ethylamine ofdiethylamine.
  • a suitably soluble base salt of citric acid for example ammonium citrate
  • the citrate salt of an amine for example ethylamine ofdiethylamine.
  • the concentration of Compound (I) is preferably in the range 3 to 50% weight/volume, more preferably in the range 5 to 20%.
  • the concentration of citric acid solutions are preferably in the range of 5 to 75% 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, preferably the hydrates, of the Citrate are to be prepared for example by crystallising or recrystallising from a solvent which provides or contains the solvate moiety, or by exposing the Citrate to the solvate moiety as a vapour. Recovery of the required compound before drying comprises isolation from an appropriate solvent, optionally the reaction solvent, or alternatively a different solvent or solvent mixture.
  • the Citrate is prepared by treating Compound (I) with citric acid or citric acid monohydrate in tetrahydrofuran, followed by evaporation or partial evaporation of the solvent, and subsequent treatment with water.
  • the required compound may be isolated by crystallisation from an appropriate solvent or solvent mixture which may be initiated by use of seed crystals. Careful control of precipitation temperature and/or the use of seeding may be used to improve the reproducibility of the product form.
  • Formation of a hydrate requires the presence of water at some stage. This may be added as water as the solvent, or as a co-solvent, or by exposure to atmospheric moisture.
  • Citric acid and citric acid monohydrate are commercially available compounds.
  • diabetes mellitus 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.
  • the present invention accordingly provides the Citrate, preferably as the Citrate Hydrate (including Hydrates 1 and 2), for use as an active therapeutic substance.
  • the present invention provides the Citrate, preferably the Citrate Hydrate (including Hydrates 1 and 2), for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
  • the Citrate preferably the Citrate Hydrate (including Hydrates 1 and 2), may be administered er se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • Suitable methods for formulating the Citrate, preferably the Citrate Hydrate (including Hydrates 1 and 2) are generally those disclosed for Compound (I) in the above mentioned publications.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the Citrate preferably the Citrate Hydrate (including Hydrates 1 and 2), and a pharmaceutically acceptable carrier therefor.
  • the Citrate preferably the Citrate Hydrate (including Hydrates 1 and 2), 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.
  • 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 sulfate.
  • 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.
  • 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
  • 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.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • 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.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound.
  • compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
  • 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 Citrate, preferably the Citrate Hydrate (including Hydrates 1 and 2), to a human or non-human mammal in need thereof.
  • an effective, non-toxic, amount of the Citrate preferably the Citrate Hydrate (including Hydrates 1 and 2)
  • compositions are formulated according to conventional methods, such as those disclosed in standard reference texts, for example the British and US
  • the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.
  • the present invention provides the use of the Citrate, preferably the Citrate Hydrate (including Hydrates 1 and 2), for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
  • the Citrate preferably the Citrate Hydrate (including Hydrates 1 and 2)
  • the Citrate Hydrate may be taken in amounts so as to provide Compound (I) in suitable doses, such as those disclosed in EP-A-0 306 228, WO 94/05659 or WO 98/55122, preferably as unit doses.
  • suitable doses such as those disclosed in EP-A-0 306 228, WO 94/05659 or WO 98/55122, preferably as unit doses.
  • the unit dose compositions of the invention comprise the Citrate, preferably the
  • Citrate Hydrate (including Hydrates 1 and 2), 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).
  • a pharmaceutical composition comprising the Citrate, preferably the Citrate Hydrate (including Hydrates 1 and 2), and a pharmaceutically acceptable carrier therefor, wherein the Citrate, preferably the Citrate Hydrate (including Hydrates 1 and 2), is present in an amount providing 1, 2, 4, 8, 12, 4 to 8 or 8 to 12 mg of Compound (I); such as 1 mg of Compound (I); such as 2 mg of Compound (I); such as 4 mg of Compound (I); such as 8mg of Compound (I); such as 12 mg of Compound (I).
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the Citrate, preferably the Citrate Hydrate (including Hydrates 1 and 2), 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 Citrate, preferably the Citrate Hydrate (including Hydrates 1 and 2), in combination with one or more other anti-diabetic agents.
  • the present invention provides the use of the Citrate, preferably the Citrate Hydrate (including Hydrates 1 and 2), 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.
  • the administration of the Citrate preferably the Citrate Hydrate (including Hydrates 1 and 2), 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.
  • the administration of the Citrate preferably the
  • Citrate Hydrate (including Hydrates 1 and 2), and the other anti-diabetic agent or agents includes co-administration or sequential administration of the active agents.
  • the Citrate preferably the Citrate Hydrate (including Hydrates 1 and 2), is present in an amount providing up to 12mg, 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) or 4 to 8 or 8 to 12 mg of Compound (I).
  • the Citrate preferably the Citrate Hydrate (including Hydrates 1 and 2), thereof is present in an amount providing lmg of Compound (I);
  • the Citrate preferably the Citrate Hydrate (including Hydrates 1 and 2), is present in an amount providing 2 mg of Compound (I);
  • the Citrate preferably the Citrate Hydrate (including Hydrates 1 and 2), is present in an amount providing 4 mg of Compound (I); or the Citrate, preferably the Citrate Hydrate (including Hydrates 1 and 2), thereof is present in an amount providing 8 mg of Compound (I).
  • the other antidiabetic agents are suitably selected from biguanides, sulphonylureas and alpha glucosidase inhibitors.
  • the other antidiabetic agent is suitably a biguanide.
  • the other antidiabetic agent is suitably a sulphonylureas.
  • the other antidiabetic agent is suitably a alpha glucosidase inhibitor.
  • Suitable antidiabetic agents are those disclosed in WO98/57649, WO98/57634, WO98/57635, WO98/57636, WO99/03477, WO99/03476. The contents of the above mentioned publications are incorporated herein by reference as if set out in full herein.
  • 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: 3134, 2922, 1743, 1699, 1641, 1610, 1542, 1512, 1467, 1440, 1419, 1386, 1357, 1326, 1297, 1246, 1172, 1158, 1111, 1052, 1030, 1009, 930, 906, 821, 767, 739, 716, 659 cm "1 .
  • the X-Ray Powder Diffraction (XRPD) 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 °2 ⁇ , End angle: 35.0 °2 ⁇ , Step size: 0.02 °2 ⁇ , Time per step: 2.5 seconds. Characteristic XRPD angles and relative intensities are recorded in 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.10 kHz.
  • the 13 C MAS spectrum was acquired by cross-polarisation from Hartmann-Hahn matched protons (CP contact time 3ms, repetition time 15 s) and protons were decoupled during acquisition using a two-pulse phase modulated (TPPM) composite sequence.
  • TPPM phase modulated
  • the solid state stability of the drug substance 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 material was determined by adding water in aliquots from 1 to 1000 ml to approximately 100 mg of drug substance until the powder had dissolved. The visual solubility was confirmed by an HPLC assay of a saturated solution. Solubility: 1.1 mg/ml.
  • Example 4 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione citrate hydrate 2 5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione citrate hydrate 1, product of example 1 (0.38 g) was dried under vacuum over phosphorus pentoxide at 64°C for 26 hours to give 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione citrate hydrate 2 as a white, non- crystalline solid.
  • the infrared absorption spectrum of a mineral oil dispersion of the product was obtained using a Nicolet 710 FT-IR spectrometer at 2 cm '1 resolution ( Figure 5). Data were digitised at 1 cm "1 intervals. Bands were observed at: 2925, 1747, 1694, 1643, 1609, 1510, 1462, 1377, 1303, 1245, 1161, 1032, 999, 932, 832, 766, 721, 663, 603, 525 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: 2927, 2765, 1747, 1690, 1643, 1609, 1510, 1415, 1385, 1303, 1241, 1158, 1032, 997, 930, 898, 830, 763, 737, 714, 660 cm "1 .
  • the Raman spectrum of the product ( Figure 6) was recorded with the sample in an NMR tube using a Nicolet 960 E.S.P. FT-Raman spectrometer, at 4 cm "1 resolution with excitation from a Nd:V04 laser (1064 nm) with a power output of 400mW. Bands were observed at: 3102, 3067, 2931, 1747, 1611, 1548, 1411, 1389, 1329, 1264, 1209, 1180, 1100, 1055, 983, 921, 896, 825, 742, 666, 638, 605, 473, 399, 310, 94 cm '1 .
  • XRPD X-Ray Powder Diffraction

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
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Abstract

L'invention concerne un sel de citrate de 5-[4-[2-(N-méthyl-N-(2-pyridyl)amino)éthoxy]benzyl]thiazolidine-2,4-dione et un solvate correspondant, de préférence l'hydrate. L'invention concerne également un procédé de préparation de ce composé, une composition pharmaceutique contenant ce composé ainsi que l'utilisation dudit composé à des fins médicales.
PCT/GB2002/005677 2001-12-13 2002-12-13 Citrate de rosiglitazone et son utilisation comme antidiabetique WO2003050115A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002352390A AU2002352390A1 (en) 2001-12-13 2002-12-13 Rosiglitazone citrate and its use as antidiabetic

Applications Claiming Priority (2)

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GB0129851.2 2001-12-13
GBGB0129851.2A GB0129851D0 (en) 2001-12-13 2001-12-13 Novel compounds

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WO2003050115A1 true WO2003050115A1 (fr) 2003-06-19

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007009799A1 (fr) * 2005-07-22 2007-01-25 Ratiopharm Gmbh Sels d'acides amines de rosiglitazone
JP2007522172A (ja) * 2004-02-13 2007-08-09 サンド・アクチエンゲゼルシヤフト リン酸ロシグリタゾン及び多形体形態

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0306228A1 (fr) * 1987-09-04 1989-03-08 Beecham Group Plc Thiazolidinediones substituées
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WO1994005659A1 (fr) * 1992-09-05 1994-03-17 Smithkline Beecham Plc Derives substitues de la thiazolidenedione
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JP2007522172A (ja) * 2004-02-13 2007-08-09 サンド・アクチエンゲゼルシヤフト リン酸ロシグリタゾン及び多形体形態
WO2007009799A1 (fr) * 2005-07-22 2007-01-25 Ratiopharm Gmbh Sels d'acides amines de rosiglitazone
EA012594B1 (ru) * 2005-07-22 2009-10-30 Рациофарм Гмбх Аминокислые соли росиглитазона

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