US20040082620A1 - 5'-4-'2-(n-methyl-n-(2-pyridyl)amino)ethoxy!benzyl!thiazolidine-2, 4-dione mesylate salt - Google Patents

5'-4-'2-(n-methyl-n-(2-pyridyl)amino)ethoxy!benzyl!thiazolidine-2, 4-dione mesylate salt Download PDF

Info

Publication number
US20040082620A1
US20040082620A1 US10/451,215 US45121503A US2004082620A1 US 20040082620 A1 US20040082620 A1 US 20040082620A1 US 45121503 A US45121503 A US 45121503A US 2004082620 A1 US2004082620 A1 US 2004082620A1
Authority
US
United States
Prior art keywords
mesylate
solvate
thiazolidine
pyridyl
ethoxy
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US10/451,215
Other languages
English (en)
Inventor
Andrew Craig
Tim Ho
Michael Millan
Deirdre O'Keeffe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
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 GB0031528A external-priority patent/GB0031528D0/en
Priority claimed from GB0031521A external-priority patent/GB0031521D0/en
Priority claimed from GB0031526A external-priority patent/GB0031526D0/en
Priority claimed from GB0031524A external-priority patent/GB0031524D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Assigned to SMITHKLINE BEECHAM P.L.C. reassignment SMITHKLINE BEECHAM P.L.C. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CRAIG, ANDREW SIMON, HO, TIM CHIEN TING, MILLAN, MICHAEL, O'KEEFFE, DEIRDRE
Publication of US20040082620A1 publication Critical patent/US20040082620A1/en
Priority to US11/199,779 priority Critical patent/US7291740B2/en
Abandoned legal-status Critical Current

Links

Images

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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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

  • This invention relates to a novel pharmaceutical, to a process for the preparation of the pharmaceutical and to the use of the pharmaceutical in medicine.
  • 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.
  • Methanesulfonic acid is mentioned as a potential counter-ion but the preparation of a methanesulfonic acid salt is not exemplified.
  • methanesulfonate salt of Compound (I) we have now prepared and characterised a methanesulfonate salt of Compound (I) and discovered that a novel form of methanesulfonate salt (hereinafter also referred to as the “Mesylate”) is formed that is particularly stable and hence is suitable for bulk preparation and handling.
  • the Mesylate also has a high melting point, shows particularly good aqueous solubility and possesses good bulk flow properties. The Mesylate is therefore surprisingly amenable to large scale pharmaceutical processing and especially to large scale milling.
  • novel salt can be prepared by an efficient and economic process particularly suited to large-scale preparation.
  • novel Mesylate 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 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione mesylate salt, or solvate thereof.
  • the Mesylate exists in more than one novel polymorphic form.
  • the present invention extends to all such forms whether in a pure polymorphic form or when admixed with any other material, such as another polymorphic form.
  • the novel polymorpic forms of the Mesylate are referred to as Form I, Form II, Form III and Form IV.
  • Each of the said forms may also be referred to herein as the Mesylate as appropriate.
  • the invention provides the Mesylate, or a solvate thereof, suitably as characterised by data provided by at least one of the following: infrared, Raman, X-ray powder diffraction or nuclear magnetic resonance and melting point data as provided herein, including partial spectral data provided herein
  • the invention provides Mesylate Form I, or solvate thereof.
  • the invention provides Mesylate Form II, or solvate thereof.
  • the invention provides Mesylate Form m, or solvate thereof.
  • the invention provides Mesylate Form IV, or solvate thereof.
  • the present invention provides 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione mesylate salt (Form I), characterised by
  • the Mesylate may be obtained as a solvate, and such solvate is a favoured aspect of the invention.
  • the Mesylate provides an infrared spectrum substantially in accordance with FIG. 1.
  • the Mesylate provides a Raman spectrum substantially in accordance with FIG. 2.
  • the Mesylate provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or FIG. 3.
  • the present invention provides 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione mesylate salt (Form II), characterised by
  • the Mesylate may be obtained as a solvate, and such solvate is a favoured aspect of the invention.
  • the Mesylate provides an infrared spectrum substantially in accordance with FIG. 4.
  • the Mesylate provides a Raman spectrum substantially in accordance with FIG. 5.
  • the Mesylate provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 2 or FIG. 6.
  • the present invention provides 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione mesylate salt (Form III), characterised by
  • the Mesylate may be obtained as a solvate, and such solvate is a favoured aspect of the invention.
  • the Mesylate provides an infrared spectrum substantially in accordance with FIG. 7.
  • the Mesylate provides a Raman spectrum substantially in accordance with FIG. 8.
  • the Mesylate provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 3 or FIG. 9.
  • the present invention provides 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione mesylate salt (Form IV), characterised by
  • the Mesylate may be obtained as a solvate, and such solvate is a favoured aspect of the invention.
  • the Mesylate provides an infrared spectrum substantially in accordance with FIG. 10.
  • the Mesylate provides a Raman spectrum substantially in accordance with FIG. 11.
  • the Mesylate provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 4 or FIG. 12.
  • the Mesylate provides a Solid State 13 C NMR spectrum substantially in accordance with FIG. 13.
  • the Mesylate Form IV provides a melting range in the range of 142 to 152° C., for example 148.9-150.3° C.
  • the invention provides 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, Mesylate salt Form IV, characterised in that it provides:
  • the present invention encompasses the Mesylate or a solvate thereof isolated in pure form or when admixed with other materials.
  • the invention provides the Mesylate or solvate thereof in a solid pharmaceutically acceptable form, such as a solid dosage form, especially when adapted for oral administration.
  • the invention also provides the Mesylate or solvate thereof in a pharmaceutically acceptable form, especially in bulk form, such form being particularly capable of being milled.
  • the invention therefor also provides the Mesylate or solvate thereof in a milled form.
  • the invention provides the Mesylate or solvate thereof in a pharmaceutically acceptable form, especially in bulk form, such form having good flow properties, especially good bulk flow properties.
  • a suitable solvate is a a pharmaceutically acceptable solvate, such as a hydrate.
  • the invention also provides a process for preparing the Mesylate or a solvate thereof, characterised in that 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (1)), or a salt thereof, preferably dispersed or dissolved in a suitable solvent, is reacted with a suitable source of mesylate ion and thereafter, if required, a solvate of the resulting Mesylate is prepared; and the Mesylate or a solvate thereof is recovered.
  • Compound (1) 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione
  • a suitable source of mesylate ion preferably dispersed or dissolved in a suitable solvent
  • the source of Mesylate ion is methanesulfonic acid.
  • the methanesulfonic acid is preferably added as a liquid or in solution.
  • Suitable solvents include for example water, an ether such as tetrahydrofuran, a ketone such as acetone, a lower alcohol such as methanol, ethanol, or propan-2-ol, or a mixture of solvents.
  • Suitable solvents include toluene, acetonitrile, ethyl acetate or diethyl ether. As indicated, suitable solvents also include mixtures of the above-mentioned solvents.
  • An alternative source of Mesylate ion is provided by a suitably soluble base salt of methanesulfonic acid for example ammonium methanesulfonate, or the methanesulfonic acid salt of an amine, for example ethylamine or diethylamine.
  • the concentration of Compound (1) is preferably in the range 2 to 50% weight/volume, more preferably in the range 5 to 20%.
  • concentration of methanesulfonic acid solutions are preferably in the range of 5 to 150% weight/volume.
  • the reaction is usually carried out at ambient temperature or at an elevated temperature, for example 50-60° C. or 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 Mesylate are prepared according to conventional procedures.
  • Recovery of the required compound generally comprises crystallisation from an appropriate solvent, conveniently the reaction solvent, usually assisted by cooling.
  • the Mesylate may be crystallised from an ether such as tetrahydrofuran, a nitrile such as acetonitrile, an ester such as ethyl acetate, or a lower alcohol such as propan-2-ol.
  • 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, optionally in stages. Careful control of precipitation temperature and seeding may be used to improve the reproducability of the product form.
  • Crystallisation can also be initiated by seeding with crystals of the Mesylate, especially Mesylate Form IV, or a solvate thereof but this is not essential, although it is preferred as mentioned for consistency of product form.
  • Compound (I) is prepared according to known procedures, such as those disclosed in EP-A-0 306 228 and WO 94/05659. The disclosures of EP-A-0 306 228 and WO 94/05659 are incorporated herein by reference.
  • Methanesulfonic acid is a commercially available compound.
  • 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”.
  • good flow properties is suitably characterised by the said compound having a Hausner ratio of less than or equal to 1.5, especially of less than or equal to 1.25.
  • proliferaxis 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 compound of the invention has useful therapeutic properties:
  • the present invention accordingly provides the Mesylate or a solvate thereof for use as an active therapeutic substance.
  • the present invention provides the Mesylate 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 Mesylate 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 Mesylate 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 Mesylate or a solvate thereof and a pharmaceutically acceptable carrier therefor.
  • the Mesylate 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 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 Mesylate 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 Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Complete Drug Reference (London, The Pharmaceutical Press) and Harry's Cosmeticology (Leonard Hill Books).
  • 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 Mesylate 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 Mesylate or a solvate thereof 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.
  • the X-Ray Powder Diffractogram pattern of the product 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. TABLE 1 Angle Rel.
  • solubility of the material was determined by adding water in aliquots from 0.1 to 1 ml to approximately 15 mg of drug substance until the powder had dissolved Solubility: >100 mg/ml.
  • the X-Ray Powder Diffractogram pattern of the product 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 2. TABLE 2 Angle Rel.
  • Methanesulfonic acid (1.69 g) was added to a suspension of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (6.0 g) and ethanol (50 ml) and the mixture was stirred and heated to give a clear solution.
  • Diethyl ether 50 ml was added and the mixture was heated to reflux and then cooled to 21° C. over a period of 1 hour. The product was collected by filtration, washed with diethyl ether (50 ml) and dried under vacuum for 2 hours at 21° C.
  • the Raman spectrum of the product (FIG. 8) 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 Nd:YAG laser (1064 nm) with a power output of 400 mW. Bands were observed at: 3099, 3008, 2935, 1747, 1610, 1546, 1441, 1386, 1332, 1266, 1205, 1179, 1079, 1042, 985, 920, 820, 776, 740, 657, 636, 618, 603, 557, 544, 522, 469, 407, 392, 339, 226 cm ⁇ 1 .
  • the X-Ray Powder Diffractogram pattern of the product 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. TABLE 1 Angle Rel.
  • the solubility of the material was determined by adding water in aliquots from 0.5 to 1 ml to approximately 100 mg of drug substance until the powder had dissolved
  • Methanesulfonic acid (0.54 ml) was added to a mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (3.0 g) and ethyl acetate (60 ml) and the reaction mixture stirred and heated to reflux to give a suspension. After cooling to 21° C.
  • the X-Ray Powder Diffractogram pattern of the product 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 4. TABLE 4 Angle Rel.
  • the solid-state NMR spectrum of the product (FIG. 13) 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 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.
  • the 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.
  • the ratio between the bulk density and the tapped bulk density (Hausner Ratio) of the Mesylate was determined using standard methods (“Pharmaceutics—The Science of Dosage Form Design”, editor M. Aulton, 1988, published by: Churchill Livingstone).
  • T onset of the drug substance was determined by Differential Scanning Calorimetry using a Perkin-Elmer DSC7 apparatus.
  • T onset (10° C./minute, closed pan): 147° C.
  • the melting range of the Mesylate was determined according to the method described in the U.S. Pharmacopoeia, USP 23, 1995, ⁇ 741> “Melting range or temperature, Procedure for Class Ia”, using a Buchi 545 melting point instrument.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US10/451,215 2000-12-22 2001-12-21 5'-4-'2-(n-methyl-n-(2-pyridyl)amino)ethoxy!benzyl!thiazolidine-2, 4-dione mesylate salt Abandoned US20040082620A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/199,779 US7291740B2 (en) 2000-12-22 2005-08-09 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione Mesylate salt

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
GB0031528A GB0031528D0 (en) 2000-12-22 2000-12-22 Novel pharmaceutical
GB0031521A GB0031521D0 (en) 2000-12-22 2000-12-22 Novel pharmaceutical
GB0031521.8 2000-12-22
GB0031524.2 2000-12-22
GB0031528.3 2000-12-22
GB0031526A GB0031526D0 (en) 2000-12-22 2000-12-22 Novel pharmaceuticals
GB0031526.7 2000-12-22
GB0031524A GB0031524D0 (en) 2000-12-22 2000-12-22 Novel pharmaceutical
PCT/GB2001/005751 WO2002051839A1 (en) 2000-12-22 2001-12-21 5-'4-'2-(n-methyl-n- (2-pyridyl)amino)ethoxy!benzyl!thiazolidine-2, 4-dione mesylate salt

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/199,779 Continuation US7291740B2 (en) 2000-12-22 2005-08-09 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione Mesylate salt

Publications (1)

Publication Number Publication Date
US20040082620A1 true US20040082620A1 (en) 2004-04-29

Family

ID=27447913

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/451,215 Abandoned US20040082620A1 (en) 2000-12-22 2001-12-21 5'-4-'2-(n-methyl-n-(2-pyridyl)amino)ethoxy!benzyl!thiazolidine-2, 4-dione mesylate salt
US11/199,779 Expired - Fee Related US7291740B2 (en) 2000-12-22 2005-08-09 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione Mesylate salt

Family Applications After (1)

Application Number Title Priority Date Filing Date
US11/199,779 Expired - Fee Related US7291740B2 (en) 2000-12-22 2005-08-09 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione Mesylate salt

Country Status (12)

Country Link
US (2) US20040082620A1 (ko)
EP (1) EP1349855B1 (ko)
JP (1) JP2004520326A (ko)
KR (1) KR100840846B1 (ko)
CN (1) CN1310912C (ko)
AT (1) ATE337313T1 (ko)
CY (1) CY1106226T1 (ko)
DE (1) DE60122580T2 (ko)
DK (1) DK1349855T3 (ko)
ES (1) ES2270955T3 (ko)
PT (1) PT1349855E (ko)
WO (1) WO2002051839A1 (ko)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050136031A1 (en) * 2003-12-16 2005-06-23 Bentley Michael D. Chemically modified small molecules
US20060182692A1 (en) * 2003-12-16 2006-08-17 Fishburn C S Chemically modified small molecules
US20070265313A1 (en) * 2006-05-09 2007-11-15 Teva Pharmaceutical Industries, Ltd. 2-N butanedioic acid, methods of preparation and compositions with rosiglitazone maleate
US9012469B2 (en) 2010-09-30 2015-04-21 Astrazeneca Ab Crystalline naloxol-peg conjugate

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE39384E1 (en) 1993-09-01 2006-11-07 Smithkline Beecham P.L.C. Substituted thiazolidinedione derivatives
DK1448559T3 (da) * 2001-11-21 2007-04-30 Smithkline Beecham Plc 5-(4-(2-(N-methyl-N-(2-pyridyl)amino)ethoxy)benzyl)thiazolodin-2,4-dionbenzensulfat; fremgangsmåde til dets fremstilling; polymorf i, II og III deraf; og dets anvendelse som farmaceutisk aktiv bestenddel
DE102005034406A1 (de) * 2005-07-22 2007-02-01 Ratiopharm Gmbh Neue Salze von Rosiglitazon
EP2062880A1 (en) 2007-11-22 2009-05-27 Bayer Schering Pharma Aktiengesellschaft 5-[(3,3,3-Trifluoro-2-hydroxy-1-arylpropyl)amino]-1H-quinolin-2-ones, a process for their production and their use as anti-inflammatory agents

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5741803A (en) * 1992-09-05 1998-04-21 Smithkline Beecham Plc Substituted thiazolidinedionle derivatives
US5910592A (en) * 1992-09-05 1999-06-08 Smithkline Beecham Plc Substituted thiazolidinedione derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0842925A1 (en) * 1987-09-04 1998-05-20 Beecham Group Plc Substituted thiazolidinedione derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5741803A (en) * 1992-09-05 1998-04-21 Smithkline Beecham Plc Substituted thiazolidinedionle derivatives
US5910592A (en) * 1992-09-05 1999-06-08 Smithkline Beecham Plc Substituted thiazolidinedione derivatives

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8067431B2 (en) 2003-12-16 2011-11-29 Nektar Therapeutics Chemically modified small molecules
US20060182692A1 (en) * 2003-12-16 2006-08-17 Fishburn C S Chemically modified small molecules
US12016952B2 (en) 2003-12-16 2024-06-25 Nektar Therapeutics Methods of preparing a monodisperse oligo(ethylene glycol) reagent composition
US11129794B2 (en) 2003-12-16 2021-09-28 Nektar Therapeutics Chemically modified small molecules
US20050136031A1 (en) * 2003-12-16 2005-06-23 Bentley Michael D. Chemically modified small molecules
US9388104B2 (en) 2003-12-16 2016-07-12 Nektar Therapeutics Chemically modified small molecules
US20100210676A1 (en) * 2003-12-16 2010-08-19 Nektar Therapeutics Chemically Modified Small Molecules
US7786133B2 (en) 2003-12-16 2010-08-31 Nektar Therapeutics Chemically modified small molecules
US20100305147A1 (en) * 2003-12-16 2010-12-02 Nektar Therapeutics Chemically modified small molecules
US8034825B2 (en) 2003-12-16 2011-10-11 Nektar Therapeutics Chemically modified small molecules
US7632841B2 (en) 2006-05-09 2009-12-15 Teva Pharmaceutical Industries, Ltd. 2-N{5-[[4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl]methyl]-2,4-thiazolidinedione} butanedioic acid, methods of preparation and compositions with rosiglitazone maleate
US20100081695A1 (en) * 2006-05-09 2010-04-01 Teva Pharmaceutical Industries, Ltd. 2-N-{5-[ [4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl]methyl]-2,4-thiazolidinedione) butanedioic acid, methods of preparation and compositions with rosiglitazone maleate
US7435741B2 (en) 2006-05-09 2008-10-14 Teva Pharmaceutical Industries, Ltd. 2-N{5-[[4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl]methyl]-2,4-thiazolidinedione} butanedioic acid, methods of preparation and compositions with rosiglitazone maleate
US20070265313A1 (en) * 2006-05-09 2007-11-15 Teva Pharmaceutical Industries, Ltd. 2-N butanedioic acid, methods of preparation and compositions with rosiglitazone maleate
US9012469B2 (en) 2010-09-30 2015-04-21 Astrazeneca Ab Crystalline naloxol-peg conjugate
US9149539B1 (en) 2010-09-30 2015-10-06 Astrazeneca Ab Crystalline naloxol-PEG conjugate

Also Published As

Publication number Publication date
ATE337313T1 (de) 2006-09-15
KR100840846B1 (ko) 2008-06-23
CY1106226T1 (el) 2011-06-08
DE60122580T2 (de) 2007-08-30
US20060040993A1 (en) 2006-02-23
PT1349855E (pt) 2006-12-29
JP2004520326A (ja) 2004-07-08
KR20030064855A (ko) 2003-08-02
US7291740B2 (en) 2007-11-06
DK1349855T3 (da) 2006-12-27
DE60122580D1 (de) 2006-10-05
CN1310912C (zh) 2007-04-18
ES2270955T3 (es) 2007-04-16
EP1349855A1 (en) 2003-10-08
CN1491224A (zh) 2004-04-21
EP1349855B1 (en) 2006-08-23
WO2002051839A1 (en) 2002-07-04

Similar Documents

Publication Publication Date Title
US7291740B2 (en) 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione Mesylate salt
US20070191435A1 (en) Hydrochloride salt of 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione
EP1305312B1 (en) Tartrate salts of thiazolidinedione derivative
EP1446404B1 (en) Rosiglitazone edisylates and their use as antidiabetics
EP1315724B1 (en) A thiazolidinedione derivative and its use as antidiabetic
US20040014791A1 (en) Thiazolidinedione derivative and its use as antidiabetic
AU2001284284A1 (en) The hydrochloride salt of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione
US20040014790A1 (en) Tartrate salt of thiazolidinedione derivative
EP1305310B1 (en) Tartrate salts of thiazolidinedione derivative
US20040024027A1 (en) 5(4-(2-(n-methyl-n-(2-pyridyl)amino)ethoxy)benzyl)thiazolidine-2,4-dione hydriodide as pharmaceutical
EP1448559B1 (en) 5-(4-(2-(n-methyl-n-(2-pyridyl)amino)ethoxy)benzyl)thiazolidine-2,4-dione benzenesulfonate; process for its preparation; polymorphs i, ii and iii thereof; and its use as pharmaceutical active ingredient
US20040029926A1 (en) Thiazolidinone nitrate salt
US20040038968A1 (en) Thiazolidinedione derivative and its use as antidiabetic
US20040102485A1 (en) Tartrate salt of thiazolidinedione derivative
WO2003050111A1 (en) Toluenesulfonate salts of a thiazolidinedione derivative

Legal Events

Date Code Title Description
AS Assignment

Owner name: SMITHKLINE BEECHAM P.L.C., GREAT BRITAIN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CRAIG, ANDREW SIMON;HO, TIM CHIEN TING;MILLAN, MICHAEL;AND OTHERS;REEL/FRAME:014175/0937;SIGNING DATES FROM 20031118 TO 20031202

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION