WO2003053962A1 - Sel d'acide malique 5-(4-(2-(n-methyl-n-(2-pyridyl)amino)ethoxy) benzyl) thiazolidine-2, 4-dione et son utilisation contre le diabete sucre - Google Patents

Sel d'acide malique 5-(4-(2-(n-methyl-n-(2-pyridyl)amino)ethoxy) benzyl) thiazolidine-2, 4-dione et son utilisation contre le diabete sucre Download PDF

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Publication number
WO2003053962A1
WO2003053962A1 PCT/GB2002/005814 GB0205814W WO03053962A1 WO 2003053962 A1 WO2003053962 A1 WO 2003053962A1 GB 0205814 W GB0205814 W GB 0205814W WO 03053962 A1 WO03053962 A1 WO 03053962A1
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Prior art keywords
malate
dione
thiazolidine
ethoxy
benzyl
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PCT/GB2002/005814
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English (en)
Inventor
Michael John Millan
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Smithkline Beecham Plc
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Priority claimed from GB0130507A external-priority patent/GB0130507D0/en
Priority claimed from GB0130508A external-priority patent/GB0130508D0/en
Priority claimed from GB0130506A external-priority patent/GB0130506D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to AU2002352479A priority Critical patent/AU2002352479A1/en
Publication of WO2003053962A1 publication Critical patent/WO2003053962A1/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

Definitions

  • EP Patent Application, Publication Number 0,306,228 relates to certain thiazolidinedione derivatives disclosed as having hypoglycaemic and hypolipidaemic activity.
  • the compound of Example 30 of EP 0,306,228 is 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter also referred to as
  • Malic acid is a chiral acid, and we have isolated and characterised separate D, L and DL forms. Hereinafter reference to the
  • Malate refers generically to any or all of these forms, unless a specific form is explicitly mentioned.
  • the Malate is obtained in a form that is suitably stable for bulk preparation and handling.
  • the Malate also has aqueous solubility that is suitable for intravenous and liquid pharmaceutical formulation.
  • the novel Malate can be prepared by an efficient, economic and reproducible process particularly suited to large-scale preparation.
  • the novel Malate also has useful pharmaceutical properties and in particular it is indicated to be useful for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
  • the present invention provides a malic acid salt of 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione as a novel compound
  • the present invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, (L)-malate salt as a novel compound.
  • the present invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, (D)-malate salt as a novel compound.
  • the present invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, (DL)-malate salt as a novel compound.
  • Figure 1 is an Infrared spectrum of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (L)-malate
  • Figure 2 is a Raman spectrum of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (L)-malate
  • Figure 3 is an X-Ray Powder Diffractogram for 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (L)-malate
  • Figure 4 is a Solid State 13 C ⁇ MR spectrum for 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (L)-malate
  • Figure 5 is an Infrared spectrum of S- ⁇ - ⁇ N-methyl-N- ⁇ - pyridy a ⁇ no ⁇ thoxy ⁇ erizylJtWazolidine ⁇ -dione (D)-malate
  • Figure 6 is a Raman spectrum of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione (D)-malate
  • Figure 7 is an X-Ray Powder Diffractogram for 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (D)-malate
  • Figure 8 is a Solid State 13 C ⁇ MR spectrum for 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (D)-malate
  • Figure 9 is an Infrared spectrum of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate
  • Figure 10 is a Raman spectrum of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate
  • Figure 11 is an X-Ray Powder Diffractogram for 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate
  • Figure 12 is a Solid State 13 C ⁇ MR spectrum for 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (DL)-malate.
  • the (L)-Malate provides an infrared spectrum substantially in accordance with Figure 1.
  • the (L)-Malate provides a Raman spectrum substantially in accordance with Figure 2.
  • the (L)-Malate provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or Figure 3. In one favoured aspect of the invention, the (L)-Malate provides a Solid State 13 C
  • the invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, (L)-Malate salt, characterised in that it provides:
  • the (D)-Malate provides an infrared spectrum substantially in accordance with Figure 5.
  • the (D)-Malate provides a Raman spectrum substantially in accordance with Figure 6.
  • the (D)-Malate provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 2 or Figure 7.
  • the (D)-Malate provides a Solid State 13 C
  • the invention provides a 5-[4-[2-(N-methyl- N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, (D)-malate salt, characterised in that it provides: (i) an infrared spectrum substantially in accordance with Figure 5; and (ii) a Raman spectrum substantially in accordance with Figure 6; and (iii) an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table
  • the (DL)-Malate provides a Raman spectrum substantially in accordance with Figure 10.
  • the (DL)-Malate provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 3 or Figure 11.
  • the (DL)-Malate provides a Solid State 13 C NMR spectrum substantially in accordance with Figure 12.
  • the invention provides a 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, (DL)-malate salt, characterised in that it provides:
  • the Malate may be obtained as a solvate, and such solvates are a further aspect of the invention.
  • a suitable pharmaceutically acceptable solvate is a hydrate.
  • the present invention encompasses the Malate or a solvate thereof isolated in pure form or when admixed with other materials.
  • the Malate or a solvate thereof in crystalline form provides the Malate or solvate thereof in a solid pharmaceutically acceptable form, such as a solid dosage form, especially when adapted for oral administration.
  • the invention provides the Malate or solvate thereof in a liquid pharmaceutically acceptable form, such as a liquid dosage form, especially when adapted for oral administration.
  • the invention provides the Malate or solvate thereof in a liquid pharmaceutically acceptable form, such as a liquid dosage form, especially when adapted for intravenous administration.
  • the invention also provides a process for preparing the Malate or a solvate thereof, characterised in that 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)), preferably dispersed or dissolved in a suitable solvent, is reacted with a suitable source of malate ion; and optionally thereafter as required: (i) forming a solvate thereof; (ii) recovering the Malate or solvate thereof ; (iii) separating (L) or (D) forms of the Malate; or (iv) further processing the Malate or solvate thereof in a pharmaceutical manufacturing process.
  • Compound (I) preferably dispersed or dissolved in a suitable solvent
  • a suitable reaction solvent is an alkanol, for example propan-2-ol, or a hydrocarbon, such as toluene, a ketone, such as acetone, an ester, such as ethyl acetate, an ether such as tetrahydrofuran, a nitrile such as acetonitrile, or a halogenated hydrocarbon such as dichloromethane or water, or an organic acid such as acetic acid; or a mixture thereof.
  • a hydrocarbon such as toluene, a ketone, such as acetone, an ester, such as ethyl acetate, an ether such as tetrahydrofuran, a nitrile such as acetonitrile, or a halogenated hydrocarbon such as dichloromethane or water, or an organic acid such as acetic acid; or a mixture thereof.
  • the source of malate ion is malic acid.
  • the malic acid is preferably added as a solid or in solution, for example in water or a lower alcohol such as methanol, ethanol, or propan-2-ol, or a ketone, such as acetone, or a mixture of solvents.
  • An alternative source of malate ion is provided by a suitably soluble base salt of malic acid for example ammonium malate, or the malic acid salt of an amine, for example ethylamine or diethylamine.
  • the concentration of Compound (I) is preferably in the range 2 to 25% weight/volume, more preferably in the range 5 to 20%.
  • the concentration of malic acid solutions are preferably in the range of 2 to 200% weight/volume.
  • the reaction is usually carried out at ambient temperature or at an elevated temperature, for example at the reflux temperature of the solvent, although any convenient temperature that provides the required product may be employed.
  • Solvates, such as hydrates, of the Malate may be prepared according to conventional procedures, for example by crystallising or recrystallising from a solvent which provides or contains the solvate moiety, or by exposing the Malate to the solvate moiety as a vapour.
  • the solvate is formed by crystallization methods the nature of the solvate is typically dictated by the solvent from which the Malate is crystallized.
  • Recovery of the required compound generally comprises crystallisation from an appropriate solvent, conveniently the reaction solvent, usually assisted by cooling.
  • the Malate may be crystallised from acetone.
  • An improved yield of the salt can be obtained by evaporation of some or all of the solvent or by crystallisation at elevated temperature followed by controlled cooling, preferably in stages. Careful control of precipitation temperature and seeding may be used to improve the reproducibility of the product form.
  • Crystallisation can also be initiated by seeding with crystals of the Malate or a solvate thereof but this is not essential.
  • Compound (I) is prepared according to known procedures, such as those disclosed in EP 0,306,228 and WO 94/05659. The disclosures of EP 0,306,228 and WO 94/05659 are incorporated herein by reference.
  • 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 Malate or a solvate thereof for use as an active therapeutic substance.
  • the present invention provides the Malate or a solvate thereof for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
  • the Malate or a solvate thereof may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. Suitable methods for formulating the Malate or a solvate thereof are generally those disclosed for Compound (I) in the above mentioned publications.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the Malate or a solvate thereof and a pharmaceutically acceptable carrier therefor.
  • the Malate or a solvate thereof is normally administered in unit dosage form.
  • the active compound may be administered by any suitable route but usually by the oral or parenteral routes.
  • the compound will normally be employed in the form of a pharmaceutical composition in association with a pharmaceutical carrier, diluent and/or excipient, although the exact form of the composition will naturally depend on the mode of administration.
  • Compositions are prepared by admixture and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles, reconstitutable powders, injectable and infusable solutions or suspensions, suppositories and transdermal devices.
  • Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • Solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p_-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • 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 monoole
  • 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 Malate or a solvate thereof to a human or non-human mammal in need thereof.
  • 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 Malate or a solvate thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
  • the Malate or a solvate thereof may be taken in amounts so as to provide Compound (I) in suitable doses especially unit doses, such as those disclosed in EP 0,306,228, WO 94/05659 or WO 98/55122.
  • the unit dose compositions of the invention comprise the Malate or a pharmaceutically acceptable solvate thereof in an amount providing up to 12 mg, including 1-12 mg such as 2-12 mg of Compound (I), especially 2-4 mg, 4-8 mg or 8-12 mg of Compound (I), for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of Compound (I).
  • a pharmaceutical composition comprising the Malate or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier therefor, wherein the Malate or a pharmaceutically acceptable solvate thereof is present in an amount providing 1, 2, 4, 8, 12, 4 to 8 or 8 to 12 mg of Compound (I); such as lmg of Compound (I); such as 2 mg of Compound (I); such as 4 mg of Compound (I); such as 8 mg of Compound (I); such as 12 mg of Compound (I).
  • the invention also provides a pharmaceutical composition comprising the Malate or a pharmaceutically acceptable solvate thereof in combination with one or more other anti-diabetic agents and optionally a pharmaceutically acceptable carrier therefor.
  • the invention also provides a method for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof, in a human or non-human mammal which comprises administering an effective, non-toxic, amount of the Malate or a pharmaceutically acceptable solvate thereof in combination with one or more other anti-diabetic agents.
  • the present invention provides the use of the Malate or a pharmaceutically acceptable solvate thereof in combination with one or more other anti- diabetic agents, for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
  • the administration of the Malate or a pharmaceutically acceptable solvate thereof and the other anti-diabetic agent or agents includes co-administration or sequential administration of the active agents.
  • the Malate or a pharmaceutically acceptable solvate thereof is present in an amount providing up to 12mg, including l-12mg, such as 2-12mg of Compound (I), especially 2- 4 mg, 4-8 mg or 8-12 mg of Compound (I), for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 mg of Compound (I) or 4 to 8 or 8 to 12 mg of Compound (I).
  • the Malate or a pharmaceutically acceptable solvate thereof is present in an amount providing 1 mg of Compound (I); the Malate or a pharmaceutically acceptable solvate thereof is present in an amount providing 2 mg of Compound (I); the Malate or a pharmaceutically acceptable solvate thereof is present in an amount providing 3 mg of Compound (I); the Malate or a pharmaceutically acceptable solvate thereof is present in an amount providing 4 mg of Compound (I); or the Malate or a pharmaceutically acceptable solvate thereof is present in an amount providing 8mg of Compound (I).
  • the other antidiabetic agents are suitably selected from biguanides, sulfonylureas and alpha glucosidase inhibitors.
  • the other antidiabetic agent is suitably a biguanide.
  • the other antidiabetic agent is suitably a sulfonylurea.
  • the other antidiabetic agent is suitably a alpha glucosidase inhibitor.
  • Suitable antidiabetic agents are those disclosed in WO 98/57649, WO 98/57634, WO 98/57635, WO 98/57636, WO 99/03477, WO 99/03476. The contents of the above mentioned publications are incorporated herein by reference as if set out in full herein.
  • the infrared abso ⁇ tion spectrum of a mineral oil dispersion of the product was obtained using a ⁇ icolet 710 FT-IR spectrometer at 2 cm -1 resolution ( Figure 1). Data were digitised at 1 cm -1 intervals. Bands were observed at: 1729, 1718, 1697, 1639, 1555, 1518, 1463, 1414, 1327, 1301, 1246, 1220, 1184, 1102, 1084, 1066, 1054, 1033, 1003, 902, 830, 815, 786, 740, 721 657, 616, 607, 546, 529 cm '1 .
  • the infrared spectrum of the solid product was recorded using Perkin-Elmer Spectrum One FT-IR spectrometer fitted with a universal ATR accessory. Bands were observed at: 3108, 2940, 1729, 1719, 1694, 1638, 1627, 1553, 1518, 1463, 1414, 1362, 1327, 1302, 1245, 1220, 1183, 1102, 1084, 1066, 1054, 1033, 1003, 924, 902, 830, 815, 785, 740, 720, 656, 635, 615, 606, 543, 526 cm "1 .
  • the X-Ray Powder Diffractogram pattern of the product ( Figure 3) was recorded using the following acquisition conditions: Tube anode: Cu, Generator tension: 40 kV, Generator current: 40 mA, Start angle: 2.0 °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.lO kHz.
  • the 13 C MAS spectrum was acquired by cross-polarisation from Hartmann-Hahn matched protons (CP contact time 3 ms, repetition time 15 s) and protons were decoupled during acquisition using a two-pulse phase modulated (TPPM) composite sequence.
  • TPPM phase modulated
  • the solid state stability of the (L)-Malate salt was determined by storing approximately 1.0 g of the material in a glass bottle at a) 40°C / 75% Relative Humidity (RH), open exposure, for 1 month and b) at 50°C, closed, for 1 month. The material was assayed by
  • HPLC for final content and degradation products in both cases a) 40°C / 75% RH: No significant degradation observed (HPLC assay 101% initial). b) 50°C: No significant degradation observed (HPLC assay 96% initial).
  • the solubility of the (L)-Malate salt was determined by an HPLC assay of a saturated solution of the (L)-Malate. Solubility: 5.6 mg/ml.
  • Example 5 5-[4-[2-(N-MethyI-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione (D)-malate
  • a solution of (D)-malic acid (8.25 g) in acetone (35 ml) was added to a stirred suspension of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (20.0 g) in acetone (135 ml) at reflux.
  • the suspension was held at reflux for 1 hour then cooled to 21°C over approximately 1 hour.
  • the solid was collected by filtration, washed with acetone (40 ml) and dried under vacuum at 50°C for 16 hours to yield the (D)-Malate (21.1 g) as a white crystalline solid.
  • the infrared absorption spectrum of a mineral oil dispersion of the product was obtained using a ⁇ icolet 710 FT-IR spectrometer at 2 cm -1 resolution ( Figure 5). Data were digitised at 1 cm" 1 intervals. Bands were observed at: 1729, 1718, 1695, 1639, 1556, 1518, 1462, 1414, 1327, 1302, 1246, 1220, 1183, 1102, 1084, 1067, 1055, 1033, 1003, 903, 830, 815, 786, 739, 721, 656, 616, 607, 546, 502 cm "1 .
  • the infrared spectrum of the solid product was recorded using Perkin-Elmer Spectrum One FT-IR spectrometer fitted with a universal ATR accessory. Bands were observed at: 3108, 1729, 1719, 1694, 1638, 1628, 1553, 1518, 1463, 1413, 1392, 1363, 1327, 1302, 1245, 1220, 1183, 1101, 1084, 1066, 1054, 1033, 1003, 924, 902, 830, 815, 785, 740, 720, 656 cm "1 .
  • the solid-state NMR spectrum of the product ( Figure 8) was recorded on a Bruker AMX360 instrument operating at 90.55 MHz: The solid was packed into a 4 mm zirconia MAS rotor fitted with a Kel-F cap and rotor spun at ca.lO kHz.
  • the 13 C MAS spectrum was acquired by cross-polarisation from Hartmann-Hahn matched protons (CP contact time 3 ms, repetition time 15 s) and protons were decoupled during acquisition using a two-pulse phase modulated (TPPM) composite sequence.
  • TPPM phase modulated
  • the solid state stability of the (D)-Malate salt was determined by storing approximately 1.0 g of the material in a glass bottle at a) 40°C / 75% Relative Humidity (RH), open exposure, for 1 month and b) at 50°C, closed, for 1 month. The material was assayed by HPLC for final content and degradation products in both cases. a) 40°C / 75% RH: No significant degradation observed (HPLC assay 100% initial). b) 50°C: No significant degradation observed (HPLC assay 100% initial).
  • the solubility of the (D)-Malate salt was determined by an HPLC assay of a saturated solution of the (D)-Malate. Solubility: 5.5 mg/ml.
  • the infrared spectrum of the solid product was recorded using Perkin-Elmer Spectrum One FT-IR spectrometer fitted with a universal ATR accessory. Bands were observed at: 3347, 2928, 2761, 1750, 1694, 1646, 1609, 1545, 1509, 1467, 1417, 1391, 1359, 1321, 1303, 1267, 1232, 1212, 1166, 1114, 1059, 1030, 998, 929, 902, 835, 764, 739, 716, 660 cm- 1 .
  • the Raman spectrum of the product ( Figure 10) was recorded with the sample in a glass vial using a Perkin-Elmer 2000R FT-Raman spectrometer, at 4 cm "1 resolution with excitation from a ⁇ d:YAG laser (1064 nm) with a power output of 400mW. Bands were observed at: 3099, 3064, 3043, 2970, 2923, 1748, 1610, 1583, 1546, 1472, 1439, 1415, 1390, 1360, 1321, 1295, 1266, 1234, 1209, 1177, 1035, 982, 931, 903, 827, 774, 742, 660, 638, 603, 510, 470, 422, 397, 351, 281 cm" 1 .
  • the X-Ray Powder Diffractogram pattern of the product (Figure 11) was recorded using the following acquisition conditions: Tube anode: Cu, Generator tension: 40 kV, Generator current: 40 mA, Start angle: 2.0 °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 3.
  • the solid-state NMR spectrum of the product (Figure 12) was recorded on a Bruker AMX360 instrument operating at 90.55 MHz: The solid was packed into a 4 mm zirconia MAS rotor fitted with a Kel-F cap and rotor spun at ca.lO kHz.
  • the 13 C MAS spectrum was acquired by cross-polarisation from Hartmann-Hahn matched protons (CP contact time 3 ms, repetition time 15 s) and protons were decoupled during acquisition using a two-pulse phase modulated (TPPM) composite sequence.
  • TPPM phase modulated
  • Solid State Stability of the (DL)-Malate salt was determined by storing approximately 1.0 g of the material in a glass bottle at a) 40°C / 75% Relative Humidity (RH), open exposure, for 1 month and b) at 50°C, closed, for 1 month. The material was assayed by HPLC for final content and degradation products in both cases. a) 40°C / 75% RH: No significant degradation observed (HPLC assay 101% initial). b) 50°C: No significant degradation observed (HPLC assay 98% initial).
  • solubility of the material was determined by an HPLC assay of a saturated solution of the (DL)-Malate. Solubility: 4.7 mg/ml.

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Abstract

L'invention concerne des sels d'acides maliques-(DL) et-(D), des sels d'acide malique (L)-5-[4-[2-(N-méthyl-N-(2-pyridyl)amino)éthoxy]benzyl]thiazolidine-2,4-dione ainsi que leurs caractéristiques spectrales infrarouges, Raman, de sa diffraction de ryons X sur poudre et de sa RMN 13C en phase solide.
PCT/GB2002/005814 2001-12-20 2002-12-19 Sel d'acide malique 5-(4-(2-(n-methyl-n-(2-pyridyl)amino)ethoxy) benzyl) thiazolidine-2, 4-dione et son utilisation contre le diabete sucre WO2003053962A1 (fr)

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AU2002352479A AU2002352479A1 (en) 2001-12-20 2002-12-19 5- (4- (2- (n-methyl-n- (2-pyridyl) amino) ethoxy) benzyl) thiazolidine-2, 4-dione malic acid salt and use against diabetes mellitus

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB0130506.9 2001-12-20
GB0130507.7 2001-12-20
GB0130507A GB0130507D0 (en) 2001-12-20 2001-12-20 Novel compounds
GB0130508.5 2001-12-20
GB0130508A GB0130508D0 (en) 2001-12-20 2001-12-20 Novel compounds
GB0130506A GB0130506D0 (en) 2001-12-20 2001-12-20 Novel compounds

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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
WO2009102226A1 (fr) * 2008-02-12 2009-08-20 Adamed Sp. Z O.O. Sel d'acide malonique de la 5-[[4-[2-(méthyl-2-pyridinylamino)éthoxy]phényl]méthyl]-2,4-thiazolidinedione

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EP0306228A1 (fr) * 1987-09-04 1989-03-08 Beecham Group Plc Thiazolidinediones substituées
WO1994005659A1 (fr) * 1992-09-05 1994-03-17 Smithkline Beecham Plc Derives substitues de la thiazolidenedione
WO1999031094A1 (fr) * 1997-12-16 1999-06-24 Smithkline Beecham Plc Produit pharmaceutique consistant en un hydrate, sel de l'acide maleique, de formule 5-[4-[2- (n-methyl-n- (2-pyridyl)amino) ethoxy]benzyl] thiazolidine-2, 4-dione
WO2000064892A2 (fr) * 1999-04-23 2000-11-02 Smithkline Beecham P.L.C. Nouvelle composition pharmaceutique

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EP0306228A1 (fr) * 1987-09-04 1989-03-08 Beecham Group Plc Thiazolidinediones substituées
WO1994005659A1 (fr) * 1992-09-05 1994-03-17 Smithkline Beecham Plc Derives substitues de la thiazolidenedione
WO1999031094A1 (fr) * 1997-12-16 1999-06-24 Smithkline Beecham Plc Produit pharmaceutique consistant en un hydrate, sel de l'acide maleique, de formule 5-[4-[2- (n-methyl-n- (2-pyridyl)amino) ethoxy]benzyl] thiazolidine-2, 4-dione
WO2000064892A2 (fr) * 1999-04-23 2000-11-02 Smithkline Beecham P.L.C. Nouvelle composition pharmaceutique

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Title
BARRIE C C CANTELLO ET AL: "Facile biocatalytic reduction of the carbon-carbon double bond of 5-benzylidenethiazolidine-2,4-diones.Synthesis of(+,-)-5-(4-{2-[methyl(2-pyridylamino]ethoxy}benzyl)thiazolidine-2,4 -dione(BRL49653),its (R)-(+)-enantiomer and analogues", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, CHEMICAL SOCIETY. LETCHWORTH, GB, 1994, pages 3319 - 3324, XP002099539, ISSN: 0300-922X *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2009102226A1 (fr) * 2008-02-12 2009-08-20 Adamed Sp. Z O.O. Sel d'acide malonique de la 5-[[4-[2-(méthyl-2-pyridinylamino)éthoxy]phényl]méthyl]-2,4-thiazolidinedione

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