EP1322647A1 - Novel polymorphic forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt and process for their preparation - Google Patents

Novel polymorphic forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt and process for their preparation

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Publication number
EP1322647A1
EP1322647A1 EP01971336A EP01971336A EP1322647A1 EP 1322647 A1 EP1322647 A1 EP 1322647A1 EP 01971336 A EP01971336 A EP 01971336A EP 01971336 A EP01971336 A EP 01971336A EP 1322647 A1 EP1322647 A1 EP 1322647A1
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EP
European Patent Office
Prior art keywords
pyridyl
thiazolidine
ethoxy
benzyl
methyl
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Withdrawn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
EP01971336A
Other languages
German (de)
English (en)
French (fr)
Inventor
Prabhakar Chebiyyam
Ramabhadra Sarma Mamillapalli
Vyas Krishnamurthi
Vishnuvardhan Reddy Seella
Om Reddy Gaddam
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.)
Dr Reddys Laboratories Ltd
Original Assignee
Dr Reddys Research Foundation
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 Dr Reddys Research Foundation filed Critical Dr Reddys Research Foundation
Publication of EP1322647A1 publication Critical patent/EP1322647A1/en
Withdrawn legal-status Critical Current

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic 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
    • C07D417/02Heterocyclic 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
    • C07D417/12Heterocyclic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/06Antihyperlipidemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives

Definitions

  • This invention relates to novel polymorphic/pseudopolymorphic forms of 5-[4-[2-
  • the invention also relates to a pharmaceutical composition comprising the novel polymorphic form or their mixture and a pharmaceutically acceptable carrier.
  • the polymorphic forms of the present invention are more active, as antidiabetic agent, than the hitherto known 5-[4-[2-[N-methyl-N-(2- pyridyl)amino]ethoxy] benzyl] thiazolidine-2,4-dione maleate.
  • the present invention also relates to a process for the preparation of various polymorphic/pseudopolymorphic 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate, having the formula (I) shown below.
  • the polymorphic forms prepared by the process of the present invention are more active, as an antidiabetic agent.
  • polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, of formula (I) defined above of the present invention reduce blood glucose and has beneficial effect on coronary heart disease and atherosclerosis.
  • novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate, of formula (I) defined above of the present invention are useful in reducing body weight and for the treatment and or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders.
  • novel polymorphic forms of 5-[4-[2-[N- methyl-N-(2-pyridyl) amino]ethoxy]benzyl]thiazolidin ' e-2,4-dione maleate, of formula (I) of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomeralosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy.
  • N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, of formula (I) are also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders.
  • novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2- pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, of formula (I) may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia, treating diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy, pancreatitis, arteriosclerosis, retinopathy, xanthoma, inflammation and for the treatment of cancer.
  • PCOS polycystic ovarian syndrome
  • novel polymorphic forms of 5-[4-[2-[N-methyl-N- (2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate, of formula (I) of the present invention are useful in the treatment and or prophylaxis of the above said diseases in combination/con-comittant with one or more HMG CoA reductase inhibitors, hypolipidemic hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol.
  • polymorphism we mean to include different physical forms, crystal forms, crystalline / liquid crystalline / non-crystalline (amorphous) forms. This has especially become very interesting after observing that many antibiotics, antibacterials, tranquilizers etc., exhibit polymorphism and some/one of the polymorphic forms of a given drug exhibit superior bio-availability and consequently show much higher activity compared to other polymorphs.
  • Sertraline, Frentizole, Ranitidine, Sulfathiazole, Indomethacine etc. are some of the important examples of pharmaceuticals which exhibit polymorphism.
  • Polymorphism in drugs is a topic of current interest and is evident from the host of patents being granted. To cite a few, U.S.
  • Polymorphism in drugs is a topic of current interest and is evident from the host of patents being granted to cite a few U.S. 5,248,699 discusses about five polymorphic forms of Sertraline hydrochloride while EP 014590, describes four polymorphic forms of Frentizole EP 490648 and EP 022527, six polymorphic forms of Troglitazone WO 97/27191 also deal with the subject of polymorphism in drugs.
  • Another objective of the present invention is to provide polymorphic forms of 5-
  • PPAR ⁇ and/or PPAR ⁇ optionally inhibit HMG CoA reductase, in addition to having agonist activity against PPAR ⁇ and/or PPAR ⁇ .
  • Another objective of the present invention is to provide novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, their stereoisomers, pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activities, without toxic effect or with reduced toxic effect.
  • Yet another objective of the present invention to provide a process for the preparation of novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate, their stereoisomers, pharmaceutically acceptable solvates.
  • Still another objective of the present invention is to provide pharmaceutical compositions containing novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
  • the present invention relates to an observation that 5-[4-[2-[N-methyl-N-(2- pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate exhibits polymo ⁇ hism, which has not been reported till date.
  • the polymorphic Forms I, II, III and IN are obtained from different solvents like ethanol, acetone, methanol and 1,4-dioxane respectively. From powder X-ray diffraction studies Forms I, II, LU and IN are found to be crystalline in nature.
  • DSC of the polymorphic Form I shows melting endotherm at 100.53°C.
  • Form II dislays endotherm at 127.67°C.
  • Form LU exhibits melting endotherm at 126.41 °C and
  • Form TV exhibits endotherm at 125.39°C.
  • X-ray powder diffraction pattern has been obtained on a Rigaku D Max 2200 model diffractometer equiped with horizontal gonimometer in ⁇ /2 ⁇ geometry.
  • the copper K ⁇ C ⁇ l .5418A) radiation was used and the sample was scanned between 3-45 degrees 2 ⁇ .
  • the samples weighed in aluminum cells were heated from room temperature to 220°C at a heating rate of 5°C /min.
  • the empty aluminum cell was used as a reference. Dry nitrogen gas was purged through DSC cell continuously throughout the analysis at a flow rate of 30 ml/min.
  • Fig 1 is a characteristic differential scanning calorimetric thermogram of Form I
  • Fig 2 is a characteristic differential scanning calorimetric thermogram of Form II
  • Fig 3 is a characteristic differential scanning calorimetric thermogram of Form III
  • Fig 4 is a characteristic differential scanning calorimetric thermogram of Form IN
  • Fig 5 is a characteristic X-ray diffraction pattern of Form I
  • Fig 6 is a characteristic X-ray diffraction pattern of Form II
  • Fig 7 is a characteristic X-ray diffraction pattern of Form III
  • Fig 8 is a characteristic X-ray diffraction pattern of Form IN
  • Fig 9 is the multi-plot of X-ray diffraction patterns of Forms I, II, III and IN
  • Fig 10 is a characteristic infrared absorption spectrum of Form I in potassium bromide.
  • Fig 11 is a characteristic infrared absorption spectrum of Form II in potassium bromide.
  • Fig 12 is a characteristic infrared absorption spectrum of Form III in potassium bromide.
  • Fig 13 is a characteristic infrared abso ⁇ tion spectrum of Form IN in potassium bromide.
  • LR (cm -1 ) 3435 (m), 2997 (w), 2773 (m), 1750 (m), 1701 (s), 1620 (m), 1510 (m), 1362 (m), 1332 (m), 1237 (s), 1165 (m), 864 (s), 764 (s), 717 (m), 654 (m), 540 (w), Fig. (10).
  • LR 3424 (w), 3040 (w), 2947 (m), 2720 (m), 1751 (m), 1702 (s), 1641 (m), 1618 (m), 1574 (w), 1541 (w), 1412 (w), 1382 (w), 1359 (m), 1326 (m), 1265 (w), 1242 (s), 1213 (w), 1162 (s), 1067 (w), 1031 (w), 865 (s), 773 (s), 713 (s), 667 (m), 576 (w), 539 (m), (Fig. 11).
  • LR 3429 (m), 2949 (m), 2738 (m), 1747 (w), 1704 (s), 1641 (m), 1617 (m), 1513 (s), 1464 (m), 1352 (m), 1244 (s), 1178 (s), 1069 (m), 862 (w), 777 (s), 717 (m), 657 (m), 589 (w) (Fig. 12).
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as bracine, cinchona alkaloids and their derivatives and the like.
  • chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as bracine, cinchona alkaloids and their derivatives and the like.
  • Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981. Conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula (I) may be prepared by hydrolyzing the pure diastereomeric amide.
  • the present invention also envisages a pharmaceutical composition comprising any of the polymo ⁇ hic Forms I to IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] benzyl] thiazolidine-2,4-dione maleate, of the formula (I) and a pharmaceutically acceptable carrier .
  • the present invention also envisages a pharmaceutical composition comprising a mixture of any of polymo ⁇ hic Forms I to FV of 5-[4-[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]benzyl] thiazo ⁇ dine-2,4-dione maleate, of the formula (I) and a pharmaceutically acceptable carrier .
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavourants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • Such compositions typically contain from 1 to 25%, preferably 1 to 15% by weight of active ingredient, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
  • polymo ⁇ hic forms of the formula (I) as defined above are clinically administered to mammals, including man, via either oral, nasal, pulmonary, transdermal or parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment.
  • Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection.
  • the patient cannot swallow the medication, or abso ⁇ tion following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be admimstered parenterally.
  • the dosage is in the range of about 0.01 to about 100 mg/kg body weight of the subject per day or preferably about 0.01 to about 30 mg/kg body weight per day admimstered singly or as a divided dose.
  • the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active ingredient will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the polymo ⁇ hic form can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like.
  • the polymo ⁇ hic form can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds.
  • Aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil may also be used for injectable solutions.
  • the injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the preparation may contain the polymo ⁇ hic forms of the present invention dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, such as propylene glycol, surfactants, abso ⁇ tion enhancers such as lecithin (phosphatidylcholine) or cyclodextrin or preservatives such as parabenes.
  • Tablets, dragees or capsules having talc and/or a carbohydrate carried binder or the like are particularly suitable for any oral application.
  • carriers for tablets, dragees or capsules include lactose, corn starch and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet production method is exemplified below:
  • ingredients 1-4 are uniformly moistened with an aqueous solution of 5 and granulated after drying under reduced pressure.
  • Ingredient 6 is added and granules are compressed by a tabletting machine to prepare 1000 tablets containing 30 mg of ingredient 1.
  • Example - 2 1 g of the 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4- dione maleate obtained by the process as described in Example- 1 was taken in 10 ml EtOH and heated on a steam bath till the solid completely dissolved. The clear solution was allowed to cool to RT over a period of 18 h to yield 80% of >99% pure polymo ⁇ hic Form I of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate.
  • Example - 3 1 g of the 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4- dione maleate obtained by the process as described in Example-1 was taken in 50 ml acetone and heated on a steam bath till the solid completely dissolved. The solution was allowed to cool to RT over a period of 18 h to yield 60%> of > 99% pure polymo ⁇ hic Form II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate.
  • Example - 4 1 g of the 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4- dione maleate obtained by the process as described in Example-1 was dissolved in 10 ml of methanol and heated on a steam bath till the solid completely dissolved. The clear solution was filtered and allowed to cool to RT over a period of 18 h to yield 75% of > 99% pure polymo ⁇ hic Form III of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] benzyl] thiazolidine-2,4-dione maleate.
  • Example - 5 1 g of the 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate obtained by the process as described in Example-1 was dissolved in 10 ml of m

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EP01971336A 2000-09-26 2001-09-25 Novel polymorphic forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt and process for their preparation Withdrawn EP1322647A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN805CH2000 2000-09-26
INMA080500 2000-09-26
PCT/US2001/029896 WO2002026737A1 (en) 2000-09-26 2001-09-25 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

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EP1322647A1 true EP1322647A1 (en) 2003-07-02

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EP (1) EP1322647A1 (no)
JP (1) JP2004509961A (no)
AU (1) AU9123201A (no)
BR (1) BR0114196A (no)
CA (1) CA2426117A1 (no)
CZ (1) CZ2003864A3 (no)
HU (1) HUP0301161A3 (no)
IL (1) IL155036A0 (no)
MX (1) MXPA03002580A (no)
NO (1) NO324968B1 (no)
NZ (1) NZ525498A (no)
PL (1) PL360661A1 (no)
SK (1) SK3752003A3 (no)
WO (1) WO2002026737A1 (no)
ZA (1) ZA200303223B (no)

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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
DZ3155A1 (fr) 1999-04-23 2000-11-02 Smithkline Beecham Plc Nouvelle composition pharmaceutique.
US20040248945A1 (en) 1999-04-23 2004-12-09 Smithkline Beecham P.L.C. Thiazolidinedione derivative and its use as antidiabetic
CO5170421A1 (es) 1999-04-23 2002-06-27 Smithkline Beecham Plc Nuevo compuesto farmaceutico maleico
WO2004062667A1 (en) * 2003-01-08 2004-07-29 Dr. Reddy's Laboratories Limited Amorphous form of rosiglitazone maleate and process for preparation thereof
GB0307259D0 (en) * 2003-03-28 2003-05-07 Glaxo Group Ltd Process
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GB2405403A (en) * 2003-08-29 2005-03-02 Cipla Ltd Rosiglitazone maleate of particular polymorphic forms and methods of preparing rosiglitazone free base
UA83504C2 (en) 2003-09-04 2008-07-25 Селджин Корпорейшн Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
AR047541A1 (es) * 2004-02-13 2006-01-25 Sandoz Ag Fosfato de 5-[[4-[2-metil-2-piridinil-amino-etoxi]fenil]metil]-2,4 tiazolidinadiona (rosiglitazona) y sus formas polimorficas
EP1753759A2 (en) * 2004-03-31 2007-02-21 Sandoz AG Novel co-precipitate of amorphous rosiglitazone
KR20070011497A (ko) * 2004-05-11 2007-01-24 산텐 세이야꾸 가부시키가이샤 각결막 장해 치료제
JP2005350451A (ja) * 2004-05-11 2005-12-22 Santen Pharmaceut Co Ltd 角結膜障害治療剤
CZ296472B6 (cs) * 2004-07-27 2006-03-15 Zentiva, A. S Sul kyseliny stavelové s 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidin-2,4-dionu azpusob její prípravy a její pouzití
ITMI20041537A1 (it) * 2004-07-28 2004-10-28 Chemi Spa Nuova forma polimorfa del rosiglitazone maleato
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JP2004509961A (ja) 2004-04-02
PL360661A1 (en) 2004-09-20
IL155036A0 (en) 2003-10-31
HUP0301161A2 (hu) 2003-11-28
NZ525498A (en) 2004-11-26
AU9123201A (en) 2002-04-08
BR0114196A (pt) 2003-07-22
WO2002026737A8 (en) 2003-11-06
SK3752003A3 (sk) 2005-03-04
NO20031356L (no) 2003-05-26
NO324968B1 (no) 2008-01-14
CA2426117A1 (en) 2002-04-04
CZ2003864A3 (cs) 2004-01-14
MXPA03002580A (es) 2003-10-15
ZA200303223B (en) 2004-07-26
NO20031356D0 (no) 2003-03-25
HUP0301161A3 (en) 2005-04-28

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