WO2003050116A1 - Sel d'acide 10-camphorsulphonique de 5(-4-(2-(n-methyl-n-(2-pyridil)amino)ethoxy)benzyl)thiazolidine-2,4-dione et son utilisation contre le diabete sucre - Google Patents

Sel d'acide 10-camphorsulphonique de 5(-4-(2-(n-methyl-n-(2-pyridil)amino)ethoxy)benzyl)thiazolidine-2,4-dione et son utilisation contre le diabete sucre Download PDF

Info

Publication number
WO2003050116A1
WO2003050116A1 PCT/GB2002/005678 GB0205678W WO03050116A1 WO 2003050116 A1 WO2003050116 A1 WO 2003050116A1 GB 0205678 W GB0205678 W GB 0205678W WO 03050116 A1 WO03050116 A1 WO 03050116A1
Authority
WO
WIPO (PCT)
Prior art keywords
camphorsulfonate
thiazolidine
dione
amino
methyl
Prior art date
Application number
PCT/GB2002/005678
Other languages
English (en)
Inventor
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
Priority claimed from GB0129877A external-priority patent/GB0129877D0/en
Priority claimed from GB0129850A external-priority patent/GB0129850D0/en
Priority claimed from GB0129849A external-priority patent/GB0129849D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to AU2002352391A priority Critical patent/AU2002352391A1/en
Publication of WO2003050116A1 publication Critical patent/WO2003050116A1/fr

Links

Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl

Definitions

  • European 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 "Compound (I)").
  • International Patent Application, Publication Number WO 94/05659 discloses certain salts of the compounds of EP 0,306,228.
  • the preferred salt of WO 94/05659 is the maleic acid salt.
  • the novel Camphorsulfonate is a high melting crystalline material hence is amenable to large scale pharmaceutical processing, especially in manufacturing processes which require or generate heat, for example milling, fluid bed drying, spray drying, hot melt processing and sterilisation by autoclaving.
  • the novel Camphorsulfonate can be prepared by an efficient, economic and reproducible process particularly suited to large-scale preparation.
  • the novel Camphorsulfonate exists in several stereochemical forms, each of which forms a separate aspect of this invention.
  • the novel Camphorsulfonate 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 camphorsulfonic acid salt of 5-[4- [2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione.
  • 10-Camphorsulfonic acid is a chiral molecule and hence can exist in one or more stereochemical forms, for example ( ⁇ R)-(-), (lS)-(+) or ( ⁇ ).
  • the Camphorsulphonate can therefore exist in one or more stereochemical forms.
  • the present invention encompasses all forms of the Camphorsulfonate.
  • the present invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (1 R)-(-)- 10-camphorsulfonate salt (the (li?)-(-)-10-Camphorsulfonate).
  • the present invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione ( 1 S)-(+)- 10-camphorsulfonate salt (the (lS)-(+)-10-Camphorsulfonate).
  • the present invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (+)-l O-camphorsulfonate salt (the ( ⁇ )- 10-Camphorsulfonate).
  • the (li?)-(-)-10-Camphorsulfonate provides an infrared spectrum substantially in accordance with Figure 1.
  • the (li?)-(-)-10-Camphorsulfonate provides a Raman spectrum substantially in accordance with Figure 2.
  • the (li?)-(-)-10-Camphorsulfonate provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or Figure 3.
  • the (lfl)-(-)-10-Camphorsulfonate provides a Solid State 13 C NMR spectrum substantially in accordance with Figure 4.
  • the (lJ?)-(-)-10-Camphorsulfonate has a melting point in the range of from 145 to
  • 165 c such as 150 to 160 O C, for example 154.8 -155.6 °C.
  • the invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, ( 1 R)-(-)- 10-Camphorsulfonate salt, characterised in that 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 pattern (XRPD) substantially in accordance with Table 1 or Figure 3; and
  • the (lS)-(+)-10-Camphorsulfonate provides a Raman spectrum substantially in accordance with Figure 6.
  • the (lS)-(+)-10-Camphorsulfonate provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 2 or Figure 7.
  • the (lS)-(+)-10-Camphorsulfonate provides a Solid State 13 C NMR spectrum substantially in accordance with Figure 8.
  • the (lS)-(+)-10-Camphorsulfonate has a melting point in the range of from 145 to 165 °C, such as 150 to 160°C, for example 153.7-154.9 °C .
  • the invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (lS)-(+)-10-Camphorsulfonate salt, characterised in that it provides: (i) an infrared spectrum substantially in accordance with Figure 5; and
  • the ( ⁇ )-lO-Camphorsulfonate provides a Raman spectrum substantially in accordance with Figure 10.
  • the ( ⁇ )- 10-Camphorsulfonate provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 3 or Figure 11.
  • the ( ⁇ )-lO-Camphorsulfonate provides a Solid State 13 C NMR spectrum substantially in accordance with Figure 12.
  • the (+)-10-Camphorsulfonate provides a melting point in the range of from 160 to 180 °C, such as 165 to 173°C, for example 168.3-169.7 °C .
  • the invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (+)- 10-Camphorsulfonate salt, characterised in that it provides:
  • Camphorsulfonate or a solvate thereof in pure form In yet a further aspect there is provided the Camphorsulfonate or a solvate thereof in crystalline form.
  • the invention provides the Camphorsulfonate or solvate thereof in a solid pharmaceutically acceptable form, such as a solid dosage form, especially when adapted for oral administration. Moreover, the invention also provides the Camphorsulfonate, or a solvate thereof, in a pharmaceutically acceptable form, especially in bulk form, such form being particularly capable of pharmaceutical processing, especially in manufacturing processes which require or generate heat.
  • Examples of manufacturing processes which require or generate heat include milling, heat-drying especially fluid-bed drying, spray drying or hot melt processing and heat-sterilisation such as autoclaving.
  • Particular examples of manufacturing processes which require or generate heat include milling, heat-drying especially fluid-bed drying, spray drying or heat-sterilisation such as autoclaving.
  • the invention provides the Camphorsulfonate, or a solvate thereof, in a pharmaceutically acceptable form, especially in a bulk form.and especially in a form having been processed in a manufacturing process requiring or generating heat, for example in a milled form; for example in a heat-dried form, especially a fluid-bed dried form or a spray dried form; for example in a form having being hot melt processed; for example in a form having being heat-sterilised by such as autoclaving.
  • the invention also provides a process for preparing the Camphorsulfonate 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 10- camphorsulfonate ion; and optionally thereafter as required:
  • 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 10-camphorsulfonate ion is 10-camphorsulfonic acid.
  • the 10-camphorsulfonic 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 an ether such as tetrahydrofuran, or a mixture of solvents.
  • An alternative source of 10-camphorsulfonate ion is provided by a suitably soluble base salt of 10-camphorsulfonic acid for example ammonium tartrate, or the 10-camphorsulfonic 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 10- camphorsulfonic acid solutions are preferably in the range of 2 to 25% 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.
  • Camphorsulfonate can exist as a solvate.
  • Suitable solvates are pharmaceutically acceptable solvates, such as hydrates.
  • a favoured solvate is a hydrate.
  • Solvates, such as hydrates, of the Camphorsulfonate 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 Camphorsulfonate 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 Camphorsulfonate is crystallized.
  • a Camphorsulfonate solvate is a one aspect of the present invention.
  • Recovery of the required compound generally comprises crystallisation from an appropriate solvent, conveniently the reaction solvent, usually assisted by cooling.
  • the Camphorsulfonate may be crystallised from an ester such as ethyl acetate.
  • An improved yield of the salt may 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 reproducability product form.
  • Suitable manufacturing processes requiring or generating heat include milling, heat-drying, especially a fluid-bed drying, hot melt processing or heat-sterilisation, such as autoclaving.
  • Suitable manufacturing processes requiring or generating heat include milling, heat-drying, especially a fluid-bed drying or heat-sterilisation, such as autoclaving.
  • Crystallisation can also be initiated by seeding with crystals of the Camphorsulfonate 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.
  • T onset is generally determined by Differential Scanning Calorimetry and has a meaning generally understood in the art, as for example expressed in "Pharmaceutical Thermal Analysis, Techniques and Applications", Ford and Timmins, 1989 as "The temperature corresponding to the intersection of the pre- transition baseline with the extrapolated leading edge of the transition".
  • 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.
  • Camphorsulfonate can refer to a single stereoisomer of the salt or to a mixture of stereoisomers.
  • '10-camphorsulfonic acid' can refer to a single stereoisomer the acid or a mixture of stereoisomers of the acid.
  • 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 compound of the invention has useful therapeutic properties:
  • the present invention accordingly provides the Camphorsulfonate or a pharmaceutically acceptable solvate thereof for use as an active therapeutic substance.
  • the present invention provides the Camphorsulfonate or a pharmaceutically acceptable solvate thereof for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
  • the Camphorsulfonate or a pharmaceutically acceptable solvate thereof may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. Suitable methods for formulating the Camphorsulfonate or a pharmaceutically acceptable solvate thereof are generally those disclosed for Compound (I) in the above mentioned publications. Accordingly, the present invention also provides a pharmaceutical composition comprising the Camphorsulfonate or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier therefor.
  • the Camphorsulfonate or a pharmaceutically acceptable 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 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 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 Camphorsulfonate or a pharmaceutically acceptable solvate thereof to a human or non-human mammal in need thereof.
  • 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 Camphorsulfonate or a pharmaceutically acceptable 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.
  • Camphorsulfonate or a pharmaceutically acceptable solvate thereof may be taken in amounts so as to provide Compound (I) in suitable doses, such as those disclosed in EP 0,306,228, WO94/05659 or WO98/55122.
  • compositions of the invention comprise the Camphorsulfonate 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 Camphorsulfonate or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier therefor, wherein the Camphorsulfonate 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 1 mg 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
  • 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 Camphorsulfonate or a pharmaceutically acceptable solvate thereof in combination with one or more other anti-diabetic agents.
  • the present invention provides the use of the Camphorsulfonate 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 Camphorsulfonate 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 Camphorsulfonate or a pharmaceutically acceptable solvate thereof is present 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) or 4 to 8 or 8 to 12 mg of Compound (I).
  • the Camphorsulfonate or a pharmaceutically acceptable solvate thereof is present in an amount providing 1 mg of Compound (I); the Camphorsulfonate or a pharmaceutically acceptable solvate thereof is present in an amount providing 2 mg of Compound (I); the Camphorsulfonate or a pharmaceutically acceptable solvate thereof is present in an amount providing 3 mg of Compound (I); the Camphorsulfonate or a pharmaceutically acceptable solvate thereof is present in an amount providing 4 mg of Compound (I); or the Camphorsulfonate or a pharmaceutically acceptable solvate 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 sulphonylurea.
  • 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: at 2956, 2776, 1733, 1694, 1645, 1626, 1544, 1514, 1484, 1416, 1392, 1330, 1235, 1209, 1147, 1036, 1000, 969, 928, 824, 788, 760, 719, 665 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 raA, 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 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 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), 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 T onse t of the drug substance was determined by Differential Scanning Calorimetry using a Perkin-Elmer DSC7 apparatus. ⁇ onset (10°C/minute, closed pan): 156.7°C
  • the melting range of the Sulfate was determined according to the method described in the U.S. Pharmacopoeia, USP 23, 1995, ⁇ 741> "Melting range or temperature, Procedure for Class la", using a Buchi 545 melting point instrument. Melting range: 154.8 -155.6°C
  • 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 ⁇ l intervals. Bands were observed at: 3423, 3111, 2922, 2853, 2778, 1734, 1696, 1644, 1626, 1544, 1514, 1462, 1416, 1376, 1330, 1236, 1209, 1150, 1040, 1000, 968, 824, 762, 720, 664, 618, 602, 584, 570, 524, 509 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: 2955, 2776, 1733, 1694, 1644, 1625, 1543, 1513, 1484, 1416, 1392, 1330, 1235, 1209, 1147, 1036, 1000, 969, 927, 824, 787, 761, 719, 664 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.
  • the X-Ray Powder Diffractogram pattern of the product ( Figure 7) was recorded using the following acquisition conditions: Tube anode: Cu, Generator tension: 40 kN, 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 2.
  • 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.10 kHz.
  • the l3 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 drug substance was determined by storing approximately
  • the T onse t of the drug substance was determined by Differential Scanning Calorimetry using a Perkin-Elmer DSC7 apparatus. ⁇ onset (10°C/minute, closed pan): 151.5°C
  • the melting range of the Sulfate was determined according to the method described in the U.S. Pharmacopoeia, USP 23, 1995, ⁇ 741> "Melting range or temperature, Procedure for Class la", using a Buchi 545 melting point instrument. Melting range: 153.7 - 154.9°C
  • 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: 2956, 2776, 1733, 1693, 1645, 1625, 1543, 1513, 1484, 1415, 1392, 1330, 1312, 1235, 1209, 1169, 1146, 1070, 1041, 1000, 969, 928, 824, 788, 758, 718, 664 cm "1 .
  • the Raman spectrum of the product ( Figure 10) was recorded with the sample in an NMR tube using a Nicolet 960 E.S.P.
  • 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 T onset of the drug substance was determined by Differential Scanning Calorimetry using a Perkin-Elmer DSC7 apparatus. ⁇ onset (10°C/minute, closed pan): 166.9°C
  • the melting range of the Sulfate was determined according to the method described in the U.S. Pharmacopoeia, USP 23, 1995, ⁇ 741> "Melting range or temperature, Procedure for Class la", using a Buchi 545 melting point instrument. Melting range: 168.3 - 169.7°C

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un sel d'acide 10-camphorsulphonique de 5(-4-(2-(n-méthyl-n-(2-pyridil)amino)éthoxy)benzyl)thiazolidine-2,4-dione, un procédé d'élaboration d'un tel sel, une composition contenant un tel sel, et l'utilisation médicale de ce sel.
PCT/GB2002/005678 2001-12-13 2002-12-13 Sel d'acide 10-camphorsulphonique de 5(-4-(2-(n-methyl-n-(2-pyridil)amino)ethoxy)benzyl)thiazolidine-2,4-dione et son utilisation contre le diabete sucre WO2003050116A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002352391A AU2002352391A1 (en) 2001-12-13 2002-12-13 A 5(-4-(2-(n-methyl-n-(2-pyridil)amino)ethoxy)benzyl)thiazolidine-2,4-dione (i) 10-camphorsulphonic acid salt and use against diabetes mellitus

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB0129877A GB0129877D0 (en) 2001-12-13 2001-12-13 Novel pharmaceutical
GB0129849.6 2001-12-13
GB0129850A GB0129850D0 (en) 2001-12-13 2001-12-13 Novel pharmaceutical
GB0129877.7 2001-12-13
GB0129850.4 2001-12-13
GB0129849A GB0129849D0 (en) 2001-12-13 2001-12-13 Novel pharmaceutical

Publications (1)

Publication Number Publication Date
WO2003050116A1 true WO2003050116A1 (fr) 2003-06-19

Family

ID=27256353

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2002/005678 WO2003050116A1 (fr) 2001-12-13 2002-12-13 Sel d'acide 10-camphorsulphonique de 5(-4-(2-(n-methyl-n-(2-pyridil)amino)ethoxy)benzyl)thiazolidine-2,4-dione et son utilisation contre le diabete sucre

Country Status (2)

Country Link
AU (1) AU2002352391A1 (fr)
WO (1) WO2003050116A1 (fr)

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 (4)

* 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
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

Patent Citations (4)

* 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
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
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 (3)

* 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

Also Published As

Publication number Publication date
AU2002352391A1 (en) 2003-06-23

Similar Documents

Publication Publication Date Title
EP1315723B1 (fr) Sel hydrochloride de 5- 4- 2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione
EP1446404B1 (fr) Edisylates de rosiglitazone et leur utilisation en tant qu'antidiabetiques
EP1305312A1 (fr) Tartrates de derive de thiazolidinedione
EP1305311B1 (fr) Tartrate de derive de thiazolidinedione
WO2003050113A1 (fr) Sel d'hydrogene sulfate de 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione
US20040014791A1 (en) Thiazolidinedione derivative and its use as antidiabetic
AU2001292028B2 (en) Sodium salts of 5-'4-'2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione
WO2003050116A1 (fr) Sel d'acide 10-camphorsulphonique de 5(-4-(2-(n-methyl-n-(2-pyridil)amino)ethoxy)benzyl)thiazolidine-2,4-dione et son utilisation contre le diabete sucre
WO2002012233A1 (fr) Sels de tartrate de derive de thiazolidinedione
AU2001292034B2 (en) A thiazolidinedione derivative and its use as antidiabetic
WO2003053962A1 (fr) 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
WO2003050111A1 (fr) Sels de type toluenesulfonate issus d'un derive de la thiazolidinedione
WO2003050112A1 (fr) Hydrates de toluenesulfonate d'un derive de thiazolidinedione
WO2003053963A1 (fr) Nouveau produit pharmaceutique
WO2003053964A1 (fr) Sel de 2-naphtalenesulfonate 5-(4-(2-(n-methyl-n-(2-pyridil)amino)ethoxy)benzyl)thiazolidine-2, 4-dione et son utilisation contre le diabete sucre
US20040087629A1 (en) Tartrate salts of thiazolidinedione derivative
WO2003053965A1 (fr) Sel de salicylate d'un derive de thiazolidinedione
WO2003050114A1 (fr) Sel de sulfate d'un derive de thiazolidinedione
US20040102485A1 (en) Tartrate salt of thiazolidinedione derivative
AU2001292034A1 (en) A thiazolidinedione derivative and its use as antidiabetic

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP