EP1040110A1 - 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt,hydrate as pharmaceutical - Google Patents

5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt,hydrate as pharmaceutical

Info

Publication number
EP1040110A1
EP1040110A1 EP98964510A EP98964510A EP1040110A1 EP 1040110 A1 EP1040110 A1 EP 1040110A1 EP 98964510 A EP98964510 A EP 98964510A EP 98964510 A EP98964510 A EP 98964510A EP 1040110 A1 EP1040110 A1 EP 1040110A1
Authority
EP
European Patent Office
Prior art keywords
hydrate
provides
hydrate according
diabetes mellitus
pyridyl
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.)
Withdrawn
Application number
EP98964510A
Other languages
German (de)
French (fr)
Inventor
Paul David James SmithKline Beecham P BLACKLER
David C. SmithKline Beecham Pharmaceuticals LEE
Michael John SmithKline Beecham Pharma. SASSE
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
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Priority to EP05077331A priority Critical patent/EP1661895A1/en
Publication of EP1040110A1 publication Critical patent/EP1040110A1/en
Withdrawn legal-status Critical Current

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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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.
  • the novel form 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 novel form of 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt (the "Hydrate”) characterised in that the Hydrate: (i) comprises water in the range of from 0.4 to 2.5%w/w; and
  • (iii) provides an X-ray powder diffraction (XRPD) pattern substantially as set out in Table I and /or
  • (iv) provides a Raman spectrum containing peaks at 3106, 3069, 3002, 2961, 1750, 1718, 1684, 1385, 1335, 1229, 1078, 917, 428 and 349 cm '1 and/or
  • (iv) provides a solid-state nuclear magnetic resonance spectrum containing chemical shifts substantially as set out in Table ⁇ .
  • the Hydrate contains water in the range of from 0.5 to 2%w/w, such as from 1.5 to 2.0%w/w or from 1.85 to 2.0%w/w, for example 1.85, 1.86, 1.87 or 1.88%w/w.
  • the Hydrate provides an infra red spectrum substantially as set out in accordance with Figure I.
  • the Hydrate provides an X-ray powder diffraction (XRPD) pattern substantially in accordance with Figure II.
  • the Hydrate provides a Raman spectrum substantially as set out in accordance with Figure HI.
  • the Hydrate provides a solid-state nuclear magnetic resonance spectrum substantially in accordance with Figure IV.
  • the present invention encompasses the Hydrate isolated in pure form or when admixed with other materials, for example the known anhydrous form of Compound I, the above mentioned reversibly rehydratable forms or any other material.
  • the Hydrate in isolated form In a further aspect there is provided the Hydrate in pure form.
  • the Hydrate in crystalline form in yet a further aspect there is provided the Hydrate in crystalline form.
  • the invention also provides a process for preparing the Hydrate, characterised in that 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt is crystallised from ethanol, suitably denatured ethanol, containing 15 to 25% by volume of water, for example 17.5% by volume.
  • aqueous solvents may also be used in the said crystallisation of the Hydrate, for example methanol, acetonitrile or ethyl acetate or mixtures thereof.
  • methanol acetonitrile or ethyl acetate or mixtures thereof.
  • the precise amount of water used in each of the alternative solvents will depend upon the particular solvent chosen, for example approximately 3% by volume in acetonitrile or ethyl acetate.
  • Methanol has also been shown to provide the hydrate when the crystallisation is conducted open to the atmosphere. Water can also be used as the crystallization solvent.
  • 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 ⁇ diabetes mellitus.
  • Conditions associated with diabetes include hyperglycaemia and insulin resistance, especially acquired 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 LI 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 the Hydrate for use as an active therapeutic substance.
  • the present invention provides the Hydrate for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
  • the Hydrate may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • the formulation of the Hydrate and dosages thereof are generally as disclosed for Compound (I) in International Patent Application, Publication Number .WO94/05659.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the Hydrate and a pharmaceutically acceptable carrier therefor.
  • the Hydrate 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 g-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate
  • fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the active compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the active compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound.
  • compositions may contain further active agents such as anti-hypertensive agents and diuretics.
  • 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 Hydrate 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 Hydrate may be taken in doses, such as those described above.
  • the present invention provides the use of the Hydrate for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
  • Example 1 Preparation of the Hydrate of 5-[4-[2-(N-methyI-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt.
  • Example 3 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione free base (6.0 g) and maleic acid (2.1 g, 1.05 molar equivalents) were heated in acetonitrile (60 ml) containing water (2ml) to 55°C and held at this temperature for 30 minutes during which time a solution was obtained. The solution was filtered, reheated to 55°C, and then cooled to 0 - 5°C and stirred for two hours. The product was filtered, and dried at 52°C in vacuo for 18 hours to give the title compound (5.7 g, 72%). The water content of the product was 1.86 %w/w.
  • the maleate salt of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione anhydrate (3.0 g) was heated to 80°C in water (200 ml), then filtered hot and cooled to 20-25°C with magnetic stirring. The product was filtered, washed with denatured alcohol (20 ml) and dried at 50°C to give the title compound (1.6 g, 53%), water content 1.87%.
  • the XRPD pattern of the Novel form is shown below in Figure II and a summary of the XRPD angles and calculated lattice spacing characteristic of the Novel form is given in Table I.
  • a PW1710 X-ray powder diffractometer (Cu X-ray source) was used to generate the spectrum using the following acquisition conditions:
  • a Raman spectrum of the Hydrate was recorde from a sample held in a glass vial using a Perkin-Elmer 2000R FT-Raman spectrometer at 4 cm "1 resolution and is shown in Figure III. Data were digitised at 1cm '1 intervals. Excitation was achieved using a Nd:YAG laser (1064 nm) with a power output of 500mW.
  • Peak positions are as follows: 3106, 3069, 3042, 3002, 2961, 2939, 2914, 2872, 1750, 1718, 1684, 1645, 1612, 1586, 1546, 1468, 1445, 1434, 1410, 1385, 1364, 1335, 1304, 1277, 1263, 1246, 1229, 1208, 1192, 1181, 1150, 1121, 1100, 1078, 1039, 1000, 980, 953, 917, 896, 883, 864, 843, 827, 805, 777, 742, 724, 657, 637, 607, 561, 540, 525, 497, 467, 452, 428, 400, 349, 317, and 297 cm "1 .
  • D NMR NMR

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A hydrate of 5-[4-[2- (N-methyl-N- (2-pyridyl)amino) ethoxy]benzyl] thiazolidine-2, 4-dione, maleic acid salt, characterised in that it: (i) comprises water in the range of from 0.4 to 2.5 %w/w; and (ii) provides an infra red spectrum containing peaks at 1749, 1703, 1645, 1623, 1365 and 736 cm-1; and/or (iii) provides an X-ray powder diffraction (XRPD) pattern substantially as set out in Figure II and/or (iv) provides a Raman spectrum containing peaks at 3106, 3069, 3002, 2961, 1750, 1718, 1684, 1385, 1335, 1229, 1078, 917, 428 and 349 cm-1 and/or (iv) provides a solid-state nuclear magnetic resonance spectrum containing chemical shifts substantially as set out in Table I; a process for the preparation of such a compound, a pharmaceutical composition containing such a compound and the use of such a compound or composition in medicine.

Description

5-[4-[2-(N- ETHYL-N-(2-PYRIDYL )AMIN0 )ETH0XY ]BENZYL]THIAZ0LIDINE-2 , 4-DIONE , MALEIC ACID SALT , HYDRATE AS PHARMACEUTICAL
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.
International Patent Application, Publication Number WO94/05659 discloses certain thiazolidinedione derivatives having hypoglycaemic and hypolipidaemic activity including 5-[4-[2-(N-methyl-N-(2-pyridyl)arnino)ethoxy]benzyl]thiazolidine- 2,4-dione, maleic acid salt (hereinafter also referred to as "Compound (I)"). Compound (I) is disclosed solely as an anhydrous form. It has now been discovered that Compound (I) exists in a novel form which is particularly suitable for bulk preparation and handling. This can be prepared by an efficient, economic and reproducible process particularly suited to large scale preparation.
The novel form also has useful pharmaceutical properties and in particular it is indicated to be useful for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
Accordingly, the present invention provides a novel form of 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt (the "Hydrate") characterised in that the Hydrate: (i) comprises water in the range of from 0.4 to 2.5%w/w; and
(ii) provides an infra red spectrum containing peaks at 1749, 1703, 1645, 1623, 1365 and 736 cm' ; and/or
(iii) provides an X-ray powder diffraction (XRPD) pattern substantially as set out in Table I and /or (iv) provides a Raman spectrum containing peaks at 3106, 3069, 3002, 2961, 1750, 1718, 1684, 1385, 1335, 1229, 1078, 917, 428 and 349 cm'1 and/or (iv) provides a solid-state nuclear magnetic resonance spectrum containing chemical shifts substantially as set out in Table π.
Suitably the Hydrate contains water in the range of from 0.5 to 2%w/w, such as from 1.5 to 2.0%w/w or from 1.85 to 2.0%w/w, for example 1.85, 1.86, 1.87 or 1.88%w/w.
In one favoured aspect, the Hydrate provides an infra red spectrum substantially as set out in accordance with Figure I.
In one favoured aspect, the Hydrate provides an X-ray powder diffraction (XRPD) pattern substantially in accordance with Figure II.
In a further favoured aspect, the Hydrate provides a Raman spectrum substantially as set out in accordance with Figure HI.
In yet a further favoured aspect, the Hydrate provides a solid-state nuclear magnetic resonance spectrum substantially in accordance with Figure IV. The present invention encompasses the Hydrate isolated in pure form or when admixed with other materials, for example the known anhydrous form of Compound I, the above mentioned reversibly rehydratable forms or any other material. Thus in one aspect there is provided the Hydrate in isolated form. In a further aspect there is provided the Hydrate in pure form.
In yet a further aspect there is provided the Hydrate in crystalline form. The invention also provides a process for preparing the Hydrate, characterised in that 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt is crystallised from ethanol, suitably denatured ethanol, containing 15 to 25% by volume of water, for example 17.5% by volume.
Other aqueous solvents may also be used in the said crystallisation of the Hydrate, for example methanol, acetonitrile or ethyl acetate or mixtures thereof. The precise amount of water used in each of the alternative solvents will depend upon the particular solvent chosen, for example approximately 3% by volume in acetonitrile or ethyl acetate. Methanol has also been shown to provide the hydrate when the crystallisation is conducted open to the atmosphere. Water can also be used as the crystallization solvent.
Compound I is prepared according to known procedures, such as those disclosed in WO94/05659. The disclosures of WO94/05659 are incorporated herein by reference.
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 π diabetes mellitus. Conditions associated with diabetes include hyperglycaemia and insulin resistance, especially acquired 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 LI diabetes including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease. As mentioned above the compound of the invention has useful therapeutic properties: The present invention accordingly the Hydrate for use as an active therapeutic substance.
More particularly, the present invention provides the Hydrate for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
The Hydrate may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. The formulation of the Hydrate and dosages thereof are generally as disclosed for Compound (I) in International Patent Application, Publication Number .WO94/05659.
Accordingly, the present invention also provides a pharmaceutical composition comprising the Hydrate and a pharmaceutically acceptable carrier therefor.
The Hydrate 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. For such use, 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 g-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
For parenteral administration, 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. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, 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. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound.
In addition such compositions may contain further active agents such as anti-hypertensive agents and diuretics.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
As used herein 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 Hydrate to a human or non-human mammal in need thereof. Conveniently, the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.
In the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof the Hydrate may be taken in doses, such as those described above.
Similar dosage regimens are suitable for the treatment and/or prophylaxis of non-human mammals.
In a further aspect the present invention provides the use of the Hydrate for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
No adverse toxicological effects are indicated in the above mentioned treatments for the compounds of the invention. The following examples illustrate the invention but do not limit it in any way.
Example 1: Preparation of the Hydrate of 5-[4-[2-(N-methyI-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt.
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione free base (6.0 g) and maleic acid salt (2.1 g, 1.05 molar equivalents) were heated in methanol (40 ml) to 55°C and held at this temperature for 30 minutes during which a solution was obtained. The solution was filtered, re-heated to 55°C, and then cooled to 0 - 5°C and stirred for two hours. The product was filtered, and dried at 52°C in vacuo for 18 hours to give the title compound (6.7 g, 84%). The water content of the product was 0.54%w/w.
The Hydrate of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt was also prepared by means of the following procedures:
Example 2
5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione ( 1.5 g, 4.2 mmole) and maleic acid (0.525 g @ 97.6% assay, 4.4 mmole, 1.05 mole equivalents) were heated in methanol (15 ml) and the temperature was held at 60°C. The resulting solution was filtered and then cooled to 0°C with magnetic stirring at which point a thick suspension was formed. The product, 5-[4-[2-(N-Methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine -2,4-dione maleate, was isolated, washed with methanol and dried, in vacuo, at 52°C (Yield 1.4 g, 70.5%). Water content of the product was 2.0%.
Example 3: 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione free base (6.0 g) and maleic acid (2.1 g, 1.05 molar equivalents) were heated in acetonitrile (60 ml) containing water (2ml) to 55°C and held at this temperature for 30 minutes during which time a solution was obtained. The solution was filtered, reheated to 55°C, and then cooled to 0 - 5°C and stirred for two hours. The product was filtered, and dried at 52°C in vacuo for 18 hours to give the title compound (5.7 g, 72%). The water content of the product was 1.86 %w/w.
Example 4
The maleate salt of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione anhydrate (3.0 g) was heated to 80°C in water (200 ml), then filtered hot and cooled to 20-25°C with magnetic stirring. The product was filtered, washed with denatured alcohol (20 ml) and dried at 50°C to give the title compound (1.6 g, 53%), water content 1.87%.
Example 5
The maleate salt of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidione-2,4-dione anhydrate (2.0 g) was heated to 75°C in ethyl acetate (100 ml) containing water (3 ml), then filtered hot and cooled with magnetic stirring to 20- 25°C. The product was filtered and dried at 50 °C to give the title compound (1.43 g, 72%), water content 1.88%.
Example 6
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione free base (6.0 g) and maleic acid (2.1 g, 1.05 molar equivalents) were heated in denatured ethanol (60 ml) containing water (17.5% by volume) to 60°C and held at this temperature for 30 minutes during which a solution was obtained. The solution was filtered, re-heated to 55°C , and then cooled to 5 - 10°C and stirred for four hours.. The product was filtered, and dried at 52°C in vacuo for 18 hours to give the title compound (5.05 g, 62%), water content 1.85%.
CHARACTERISING DATA: The following characterising data was generated for the Hydrate from example 2:
A Infrared
The infrared absorption spectrum of a mineral oil dispersion of the Novel form was obtained using a Nicolet 710 FT-IR spectrometer at 2 cm-1 resolution. Data were digitised at 1cm"1 intervals. The spectrum obtained is shown in Figure I. Peak positions are: 3428, 3139, 3054, 1749, 1703, 1645, 1623, 1584, 1566, 1539,
1510,1411, 1365, 1333, 1318,1302, 1275, 1264, 1247, 1238, 1187, 1178, 1166, 1143, 1109, 1098, 1078, 1060, 1039, 1006, 979, 972, 956, 929, 924, 917, 896, 885, 864, 843, 810, 775, 764, 736, 718, 656, 604, 598, 587, 562 and 542 cm-1
B X-Ray Powder Diffraction (XRPD)
The XRPD pattern of the Novel form is shown below in Figure II and a summary of the XRPD angles and calculated lattice spacing characteristic of the Novel form is given in Table I. A PW1710 X-ray powder diffractometer (Cu X-ray source) was used to generate the spectrum using the following acquisition conditions:
Tube anode: Cu
Generator tension: 40 kV
Generator current: 30 mA
Start angle: 3.5 °2Θ
End angle: 35.0 °2Θ
Step size: 0.02
Time per step: 4.550 s Table I.
X-Ray Powder Diffraction Angles and Calculated Lattice Spacing Characteristic of the Novel form.
C Raman
A Raman spectrum of the Hydrate was recorde from a sample held in a glass vial using a Perkin-Elmer 2000R FT-Raman spectrometer at 4 cm"1 resolution and is shown in Figure III. Data were digitised at 1cm'1 intervals. Excitation was achieved using a Nd:YAG laser (1064 nm) with a power output of 500mW. Peak positions are as follows: 3106, 3069, 3042, 3002, 2961, 2939, 2914, 2872, 1750, 1718, 1684, 1645, 1612, 1586, 1546, 1468, 1445, 1434, 1410, 1385, 1364, 1335, 1304, 1277, 1263, 1246, 1229, 1208, 1192, 1181, 1150, 1121, 1100, 1078, 1039, 1000, 980, 953, 917, 896, 883, 864, 843, 827, 805, 777, 742, 724, 657, 637, 607, 561, 540, 525, 497, 467, 452, 428, 400, 349, 317, and 297 cm"1. D NMR
The 90.55 MHz "C-CP-MAS NMR spectrum for the Hydrate is shown below in Figure IV. Chemical shifts are tabulated in Table II. Data were recorded at ambient temperature and 10kHz spinning frequency, with minimal prior grinding of the sample, using a Bruker AMX360WB spectrometer, with 1.6 ms cross-polarisation and a repetition time of 15s. Chemical shfts were referenced to the carboxylate signal of a glycine test sample at 176.4 ppm relative to tetramethylsilane and are judged accurate to within +/- 0.5 ppm. Peaks were not assigned.
Table II
13C Chemical Shifts of the Hydrate
Chemical Shift (ppm)
35.7 112.9 (2 resonances) 136.8 173.6
37.9 119.7 143.0 176.6
50.3 129.1 153.2
57.0 133.2 157.4
65.6 134.0 168.6
109.3 136.1 171.7

Claims

1. A hydrate of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt., characterised in that it:
(i) comprises water in the range of from 0.4 to 2.5%w/w; and
(ii) provides an infra red spectrum containing peaks at 1749, 1703, 1645, 1623,
1365 and 736 cm~l; and/or
(iii) provides an X-ray powder diffraction (XRPD) pattern substantially as set out in Table I and /or
(iv) provides a Raman spectrum containing peaks at 3106, 3069, 3002, 2961, 1750, 1718, 1684, 1385, 1335, 1229, 1078, 917, 428 and 349 cm"1 and/or (iv) provides a solid-state nuclear magnetic resonance spectrum containing chemical shifts substantially as set out in Table II.
2. A hydrate according to claim 1, wherein the water content is in the range of from 1.5 to 2.0% w/w.
3. A hydrate according to claim 1 or claim 2, which provides an infra red spectrum substantially in accordance with Figure I.
4. A hydrate according to any one of claims 1 to 3, which provides an X-ray powder diffraction (XRPD) pattern substantially as set out in accordance with Figure II.
5. A hydrate according to any one of claims 1 to 4, which provides a Raman spectrum substantially as set out in Figure HI.
6. A hydrate according to any one of claims 1 to 5, which provides a solid state nuclear magnetic resonance spectrum substantially in accordance with Figure IV.
7. A hydrate according to any one of claims 1 to 6, in isolated form.
8. A hydrate according to any one of claims 1 to 7, in pure form.
9. A hydrate according to any one of claims 1 to 8, in crystalline form.
10. A compound in the form of a rehydratable form of a hydrate according to any one of claims 1 to 9.
11. A process for preparing a hydrate according to claim 1, characterised in that 5- [4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt is crystallised from ethanol containing 15 to 25% by volume of water.
12 A pharmaceutical composition comprising an effective, non-toxic amount of a hydrate according to claim 1 and a pharmaceutically acceptable carrier therefor.
13. A hydrate according to claim 1, for use as an active therapeutic substance.
14. A hydrate according to claim 1, for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
15. The use of Hydrate for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
16. 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 Hydrate to a human or non-human mammal in need thereof.
EP98964510A 1997-12-16 1998-12-14 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt,hydrate as pharmaceutical Withdrawn EP1040110A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP05077331A EP1661895A1 (en) 1997-12-16 1998-12-14 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt,hydrate as pharmaceutical

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9726566.4A GB9726566D0 (en) 1997-12-16 1997-12-16 Novel pharmaceutical
GB9726566 1997-12-16
PCT/EP1998/008155 WO1999031095A1 (en) 1997-12-16 1998-12-14 5-[4-[2- (n-methyl-n- (2-pyridyl)amino) ethoxy]benzyl] thiazolidine-2, 4-dione, maleic acid salt, hydrate as pharmaceutical

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP05077331A Division EP1661895A1 (en) 1997-12-16 1998-12-14 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt,hydrate as pharmaceutical

Publications (1)

Publication Number Publication Date
EP1040110A1 true EP1040110A1 (en) 2000-10-04

Family

ID=10823692

Family Applications (2)

Application Number Title Priority Date Filing Date
EP05077331A Withdrawn EP1661895A1 (en) 1997-12-16 1998-12-14 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt,hydrate as pharmaceutical
EP98964510A Withdrawn EP1040110A1 (en) 1997-12-16 1998-12-14 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt,hydrate as pharmaceutical

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP05077331A Withdrawn EP1661895A1 (en) 1997-12-16 1998-12-14 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt,hydrate as pharmaceutical

Country Status (35)

Country Link
EP (2) EP1661895A1 (en)
JP (1) JP2002508373A (en)
KR (1) KR100549142B1 (en)
CN (3) CN1281453A (en)
AP (1) AP1365A (en)
AR (1) AR017214A1 (en)
AU (1) AU1967999A (en)
BG (1) BG64988B1 (en)
BR (1) BR9813600A (en)
CA (1) CA2314107A1 (en)
CO (1) CO4980880A1 (en)
CZ (1) CZ299965B6 (en)
DZ (1) DZ2681A1 (en)
EA (1) EA004260B1 (en)
EG (1) EG22337A (en)
GB (1) GB9726566D0 (en)
HR (1) HRP20000408B1 (en)
HU (1) HUP0100509A3 (en)
IL (1) IL136424A (en)
IN (1) IN192487B (en)
MA (1) MA26580A1 (en)
MY (1) MY135612A (en)
NO (1) NO317254B1 (en)
OA (1) OA11766A (en)
PE (1) PE20000058A1 (en)
PL (1) PL341146A1 (en)
RS (1) RS50126B (en)
SA (1) SA99191115B1 (en)
SK (1) SK286618B6 (en)
TR (2) TR200001799T2 (en)
TW (1) TW509690B (en)
UA (1) UA72198C2 (en)
UY (2) UY25308A1 (en)
WO (1) WO1999031095A1 (en)
ZA (1) ZA9811506B (en)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6664278B2 (en) 1997-12-16 2003-12-16 Smithkline Beecham P.L.C. Hydrate of 5-[4-[2-(N-methyl-N-(2-pyridil)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt
GB9726568D0 (en) 1997-12-16 1998-02-11 Smithkline Beecham Plc Novel pharmaceutical
GB9909041D0 (en) * 1999-04-20 1999-06-16 Smithkline Beecham Plc Novel pharmaceutical
PL351684A1 (en) * 1999-04-23 2003-06-02 Smithkline Beecham Plc Polymorph of 5−[4−[2− (n−methyl−n−( 2−pyridyl)amino) ethoxy]benzyl] thiazolidine−2,4−dione, maleic acid salt
BR0009934A (en) * 1999-04-23 2002-06-04 Smithkline Beecham Plc Pharmaceutical
EP1175418A2 (en) * 1999-04-23 2002-01-30 Smithkline Beecham Plc Thiazolidinedione derivative and its use as antidiabetic
YU80302A (en) * 2000-04-25 2005-11-28 Kyorin Pharmaceutical Co. Ltd. Novel stable crystal of thiazolidinedione derivatives and process for producing the same
GB0014005D0 (en) * 2000-06-08 2000-08-02 Smithkline Beecham Plc Novel pharmaceutical
GB0021784D0 (en) * 2000-09-05 2000-10-18 Smithkline Beecham Plc Novel pharmaceutical
GB0021978D0 (en) * 2000-09-07 2000-10-25 Smithkline Beecham Plc Novel pharmaceutical
NZ525498A (en) * 2000-09-26 2004-11-26 Reddys Lab Ltd Dr Novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation
GB0129872D0 (en) * 2001-12-13 2002-02-06 Smithkline Beecham Plc Novel pharmaceutical
GB0129876D0 (en) * 2001-12-13 2002-02-06 Smithkline Beecham Plc Novel pharmaceutical
AU2002350965A1 (en) * 2001-12-13 2003-06-23 Smithkline Beecham Plc Toluenesulfonate hydrates of a thiazolidinedione derivative
GB2405403A (en) * 2003-08-29 2005-03-02 Cipla Ltd Rosiglitazone maleate of particular polymorphic forms and methods of preparing rosiglitazone free base
ITMI20041537A1 (en) * 2004-07-28 2004-10-28 Chemi Spa NEW POLYMORPHIC SHAPE OF EVIL ROSIGLITAZONE
CZ298424B6 (en) * 2005-05-24 2007-09-26 Zentiva, A. S. Crystallization process of rosiglitazone and derivatives thereof from mixed solutions
EP2184055A1 (en) 2008-11-07 2010-05-12 LEK Pharmaceuticals d.d. Process for preparing solid dosage forms of rosiglitazone maleate

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE186724T1 (en) * 1987-09-04 1999-12-15 Beecham Group Plc SUBSTITUTED THIAZOLIDINEDIONE DERIVATIVES
GB8820389D0 (en) * 1988-08-26 1988-09-28 Beecham Group Plc Novel compounds
GB9218830D0 (en) 1992-09-05 1992-10-21 Smithkline Beecham Plc Novel compounds
SG47100A1 (en) * 1994-02-10 1998-03-20 Smithkline Beecham Plc Use of insulin sensitisers for treating renal diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9931095A1 *

Also Published As

Publication number Publication date
JP2002508373A (en) 2002-03-19
AP1365A (en) 2005-01-26
EA200000654A1 (en) 2000-12-25
WO1999031095A1 (en) 1999-06-24
IN192487B (en) 2004-04-24
CO4980880A1 (en) 2000-11-27
HRP20000408B1 (en) 2008-04-30
BG64988B1 (en) 2006-11-30
BG104603A (en) 2001-03-30
EG22337A (en) 2002-12-31
TR200001799T2 (en) 2001-01-22
TR199802625A3 (en) 1999-10-21
NO20003069L (en) 2000-06-15
CN101302215A (en) 2008-11-12
CA2314107A1 (en) 1999-06-24
UA72198C2 (en) 2005-02-15
BR9813600A (en) 2000-10-10
MA26580A1 (en) 2004-12-20
NO20003069D0 (en) 2000-06-15
EP1661895A1 (en) 2006-05-31
ZA9811506B (en) 2000-11-06
UY25308A1 (en) 1999-07-19
PL341146A1 (en) 2001-03-26
TR199802625A2 (en) 1999-10-21
SK9172000A3 (en) 2001-01-18
HUP0100509A3 (en) 2002-06-28
AR017214A1 (en) 2001-08-22
SA99191115B1 (en) 2006-10-11
PE20000058A1 (en) 2000-02-26
RS50126B (en) 2009-03-25
KR100549142B1 (en) 2006-02-03
GB9726566D0 (en) 1998-02-11
YU36300A (en) 2004-03-12
SK286618B6 (en) 2009-02-05
CZ20002204A3 (en) 2000-11-15
DZ2681A1 (en) 2004-06-20
HRP20000408A2 (en) 2000-08-31
HUP0100509A2 (en) 2002-05-29
NO317254B1 (en) 2004-09-27
AU1967999A (en) 1999-07-05
TW509690B (en) 2002-11-11
CN1281453A (en) 2001-01-24
UY25304A1 (en) 2000-12-29
EA004260B1 (en) 2004-02-26
IL136424A0 (en) 2001-06-14
CZ299965B6 (en) 2009-01-07
OA11766A (en) 2005-07-19
AP2000001831A0 (en) 2000-06-30
CN101381367A (en) 2009-03-11
MY135612A (en) 2008-05-30
IL136424A (en) 2003-12-10
KR20010033141A (en) 2001-04-25

Similar Documents

Publication Publication Date Title
US7368574B2 (en) Substituted thiazolidinedione derivative, process for its preparation and its pharmaceutical use
US20070203200A1 (en) 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt, hydrate as pharmaceutical
EP1173434B1 (en) Thiazolidinedione derivative and its use as antidiabetic
EP1040110A1 (en) 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt,hydrate as pharmaceutical
WO2000064896A9 (en) Polymorph of 5-[4-[2- (n-methyl-n-( 2-pyridyl)amino) ethoxy]benzyl] thiazolidine-2,4-dione, maleic acid salt
EP1045847A1 (en) Hydrate of 5- 4- 2- (n-methyl-n- (2-pyridil)amino) ethoxy]benzyl] thiazolidine-2, 4-dione maleic acid salt
WO2000064893A2 (en) Thiazolidinedione derivative and its use as antidiabetic
AU2001276509A1 (en) Tartrate salts of thiazolidinedione derivative
WO2002020520A1 (en) A thiazolidinedione derivative and its use as antidiabetic
AU770817B2 (en) 5-(4-(2-(N-methyl-N-(2-pyridyl)amino)ethoxy)benzyl) thiazolidine-2,dione,maleic acid salt, hydrate as pharmaceutical
EP1305310B1 (en) Tartrate salts of thiazolidinedione derivative
AU774613B2 (en) Hydrate of 5-(4-(2- (N-methyl-N- (2-pyridil)amino) ethoxy)benzyl) thiazolidine-2,4-dione maleic acid salt
ZA200108722B (en) Thiazolidinedione derivative and its use as antidiabetic.

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20000613

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL PAYMENT 20000613;LT PAYMENT 20000613;LV PAYMENT 20000613;MK PAYMENT 20000613;RO PAYMENT 20000613;SI PAYMENT 20000613

17Q First examination report despatched

Effective date: 20010525

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: SMITHKLINE BEECHAM PLC

APBX Invitation to file observations in appeal sent

Free format text: ORIGINAL CODE: EPIDOSNOBA2E

APBX Invitation to file observations in appeal sent

Free format text: ORIGINAL CODE: EPIDOSNOBA2E

APAF Appeal reference modified

Free format text: ORIGINAL CODE: EPIDOSCREFNE

APBT Appeal procedure closed

Free format text: ORIGINAL CODE: EPIDOSNNOA9E

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20051014

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1032905

Country of ref document: HK

RTI1 Title (correction)

Free format text: 5-??4-??2-(N-METHYL-N-(2-PYRIDYL)AMINO)ETHOXY BENZYL THIAZOLIDINE-2,4-DIONE,MALEIC ACID SALT,HYDRATE AS PHARMACEUTICAL