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.)
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Application number
EP01971336A
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German (de)
French (fr)
Inventor
Prabhakar Chebiyyam
Ramabhadra Sarma Mamillapalli
Vyas Krishnamurthi
Vishnuvardhan Reddy Seella
Om Reddy Gaddam
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Dr Reddys Laboratories Ltd
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Dr Reddys Research Foundation
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Publication of EP1322647A1 publication Critical patent/EP1322647A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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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Abstract

This invention relates to novel polymorphic/pseudopolymorphic forms of 5-[4-[2[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate having formula (I). 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-(2-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate.

Description

NONEL POLYMORPHIC FORMS OF 5-[4-[2-[Ν-METHYL-Ν-(2-
PYRJDYL)AMINO]ETHOXY]BENZYL] THIAZOLj_D]-NE-2,4-DIONE MALEATE
AND PROCESS FOR THEIR PREPARATION
Field of the Invention
This invention relates to novel polymorphic/pseudopolymorphic forms of 5-[4-[2-
[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate and its stereo- isomers having formula (I). 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.
The 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.
Out of the many drags available for the treatment of diabetic ailments, the thiazolidine dione derivatives are very prominent and are considered as much superior effective constituents compared to the sulphonyl ureas. 5-[4-[2-[N-methyl-N-(2- pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, one such thiazolidmedione which exhibited euglycemic effect, was reported in the year 1988 by Beecham group England (EP 0306228A1) and created interest in the field, ever since.
The 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. The 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. The novel polymorphic Forms of 5-[4-[2-[N-methyl-
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. These 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. The 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.
Background of the invention The latest trend that has, of late, crept into the pharmaceutical industry is the studies on polymorphism in drugs and the difference in the activity of different polymorphic forms of a given drug. By the term 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.
5,700,820 discloses six polymorphic forms of Troglitazone, 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 also deal with the subject of polymorphism in drugs.
European Patent No.0306338, International publication No. WO 94/25026 and
U.S. Patent Application No. 5,646,169 describe that the relative configurations of the diastereomers have been determined by x-ray crystallographic analysis and that the crystal and molecular structure of the 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate is under preparation. The report does not touch upon the possibility/observation that 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]thoxy]enzyl] thiazolidine-2,4-dione maleate exists in different polymorphic forms. There is no published literature regarding such an observation till date. 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. The fact that polymorphism in 5-[4-[2-[N-methyl-N-(2-pyridyl) amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate has not been studied earlier coupled with the current interest in the field of polymorphism in drugs prompted us to take-up this investigation our observations and results from the subject matter of the present invention.
With a view to prevent/cure the chronic complications of diabetes, research is being conducted round the world in recent times. 5-[4-[2-[N-methyl-N-(2-pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate is being considered today as one of the most effective anti-diabetic drugs which as a multi-purpose activity not only acting on diabetes itself but also on the reduction of the triglycerides and also on the accompanying complications mentioned above. Indeed the said 5-[4-[2-[N-methyl-N-(2-pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate is emerging as the second drug candidate of euglycemic class of antidiabetic agents.
With an objective to develop novel polymorphic forms for lowering cholesterol and reducing body weight with beneficial effects in the treatment and/or prophylaxis of diseases related to increased levels of lipids, atherosclerosis, coronary artery diseases,
Syndrome-X, impaired glucose tolerance, insulin resistance, insulin resistance leading to type 2 diabetes and diabetes complications thereof, for the treatment of diseases wherein insulin resistance is the pathophysiological mechanism and for the treatment of hypertension, with better efficacy, potency and lower toxicity, we focused our research to develop new polymorphic forms effective in the treatment of the above mentioned diseases. Effort in this direction has led to polymorphic forms having the formula (I).
Another objective of the present invention is to provide polymorphic forms of 5-
[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, their stereoisomers, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures which may have agonist activity against
PPARα and/or PPARγ, and optionally inhibit HMG CoA reductase, in addition to having agonist activity against PPARα and/or PPARγ.
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.
Summary of the Invention
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 polymoφhism, 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.
All these polymorphic forms were proved to be identical in solution as evident from Nuclear Magnetic Resonance (NMR), Ultra Niolet (UN) & Mass spectral data. On the other hand, solid state techniques like Differential Scanning Calorimetry (DSC),
Powder X-Ray Diffractometry (XRD) and Infra Red spectroscopy (IR) revealed the difference among these forms.
Brief Description of the Figures
X-ray powder diffraction pattern has been obtained on a Rigaku D Max 2200 model diffractometer equiped with horizontal gonimometer in Θ/2 Θ geometry. The copper K αCλ^l .5418A) radiation was used and the sample was scanned between 3-45 degrees 2Θ.
Differential scanning calorimeter was performed on a Shimadzu DSC-50 equipped with a controller. The data was collected on to a Pentium PC using a Shimadzu
TA-50 software. 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 absoφtion spectrum of Form IN in potassium bromide.
Detailed Description of the invention According to a feature of the present invention, there is provided a novel polymoφhic Form-I of 5-[4-[2-[Ν-methyl-Ν-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2, 4-dione maleate, and its stereoisomers having the formula I which is characterized by the following data:
DSC endotherm at 100.53°C (on set at 88.65°C) (Fig. 1). X Ray powder diffraction (2Θ) : 10.90, 14.54, 15.96, 18.46, 18.60, 19.76, 20.72, 21.84, 22.36, 22,46, 23.90, 24.04, 24.72, 25.30, 25.98, 27.44, 29.70 (Fig. 5).
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).
According to another feature of the present invention, there is provided a novel polymoφhic Form-II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, and its stereoisomers having the formula I which is characterized by the following data:
DSC : Endotherm at 127.67°C (on set at 123.17°C) Fig. 2. XRD (2Θ): 8.90, 15.40, 18.06, 19.20, 22.30, 23.40, 23.62, 24.80, 25.10, 25.84, 26.72, 27.18, 29.30, 29.54, 29.84, 33.26 (Fig. 6).
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).
According to yet another feature of the present invention, there is provided a novel polymoφhic Form-Ill of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino] ethoxy]benzyl] thiazolidine-2,4-dione maleate and its stereoisomers having the formula I which is characterized by the following data:
DSC : Endotherm at 126.4PC (on set at 122.06°C) (Fig. 3). XRD (2Θ): 4.60, 8.46, 9.24, 14.98, 15.86, 17.02, 18.60, 21.92, 23.50, 25.00,
25.44, 26.00, 26.38, 28.34, 33.90 (Fig. 7).
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).
According to yet another feature of the present invention, there is provided a novel polymoφhic Form-IN of 5-[4-[2-[Ν-methyl-Ν-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, and its stereoisomers having the formula I which is characterized by the following data: DSC : Endotherm at 125.39°C (on set at 121.03°C) (Fig. 4).
XRD (2Θ): 7.4, 8.8, 9.54, 14.98, 15.32, 15.82, 16.90, 17.70, 18.40, 18.54, 19.08, 19.72, 20.22, 20.48, 21.36, 21,66, 22.18, 22.58, 23.32, 23.96, 24.52, 25.38, 26.48, 27.00, 27.58, 27.94, 28.34, 28.54, 28.84, 29.10, 29.86, 30.02, 30.40, 30.52, 30.84, 31.40, 31.94 (Fig. 8). IR : 3433 (m), 2930 (m), 1753 (w), 1705 (s), 1642 (w), 1617 (m), 1512 (s), 1467
(w), 1351 (m), 1244 (m), 1162 (m), 1061 (w), 864 (s), 765 (s), 714 (w), 658 (m), 526 (w) (Fig. 13). c
According to another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form-I of 5-[4-[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, of the formula I, having the characteristics described earlier, which comprises:
(i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, employing known methods and dissolving in ethanol,
(ii) heating the solution in a steam bath till the solid completely dissolved, (iii) filtering the clear solution and cooling to room temperature over a period of l8 h,
(iv) isolating the Form I of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate formed.
According to another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form-II of 5-[4-[2-[N-methyl-N-(2- pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate, of the formula I, having the characteristics described earlier, which comprises: (i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, employing known methods and dissolving in acetone,
(ii) heating the solution in a steam bath till the solid completely dissolved,
(iii) filtering the clear solution and cooling to room temperature over a period of l8 h,
(iv) isolating the Form II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate formed.
According to another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form-Ill of 5-[4-[2-[N-methyl-N-(2- pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate, of the formula I, having the characteristics described earlier, which comprises:
(i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine- 2,4-dione maleate, employing known methods and dissolving in methanol,
(ii) heating the solution in a steam bath till the solid completely dissolved, (iii) filtering the clear solution and cooling to room temperature over a period of l8 h,
(iv) isolating the Form III of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate formed.
According to yet another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form-IN of 5-[4-[2-[Ν-methyl-Ν-(2- pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate of the formula I, having the characteristics described earlier, which comprises:
(i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, employing known methods and dissolving in 1,4-dioxane, (ii) heating the solution in a steam bath till the solid completely dissolved,
(iii) filtering the clean solution and cooling to room temperature over a period of l8 h,
(iv) isolating the Form IN of 5 - [4- [2- [Ν-methyl-Ν-(2-pyridyl)amino] ethoxy] benzyl]thiazolidine-2,4-dione maleate formed. The 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. 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 polymoφhic 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 polymoφhic Forms I to FV of 5-[4-[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]benzyl] thiazoϋdine-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. The polymoφhic 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. However, in circumstances where the patient cannot swallow the medication, or absoφtion following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be admimstered parenterally. By either route, 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. However, 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. Thus, for oral administration, the polymoφhic 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. For parenteral administration, the polymoφhic form can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, 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.
For nasal administration, the preparation may contain the polymoφhic forms of the present invention dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, such as propylene glycol, surfactants, absoφtion 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. Preferably, 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:
Tablet Production Example: a) 1) Active ingredient 30 g
2) Lactose 95 g
3) Corn starch 30 g
4) Carboxymethyl cellulose 44 g
5) Magnesium stearate i g
200 g for 1000 tablets The ingredients 1 to 3 are uniformly blended with water and granulated after drying under reduced pressure. The ingredient 4 and 5 are mixed well with the granules and compressed by a tabletting machine to prepare 1000 tablets each containing 30 mg of active ingredient. b) 1) Active ingredient 30 g
2) Calcium phosphate 90 g
3) Lactose 40 g
4) Corn starch 35 g
5) Polyvinyl pyrrolidone 3.5 g
6) Magnesium stearate 1.5 g
200 g for 1000 tablets The 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.
The present invention is described in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
EXAMPLES Example- 1
A mixture of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine- 2,4-dione (69 g, 0.19 M) and maleic acid (22.8 g, 0.19 M) was heated under reflux while stirring in iso-propanol (1.0 L) until a clear solution was obtained (1-2 h). The reaction mass was allowed to cool to RT while stirring for 15-20 h. The white to off- white crystalline compound was filtered, washed with iso-propanol (3 x 100 ml) and pet. ether (2 x 100 ml) dried to furnish white to off-white product (84.5 g; Yield : 92%).
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 polymoφhic 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 polymoφhic 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 polymoφhic 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 taken in 10 ml 1,4- dioxane 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 70% of > 99% pure polymoφhic Form IN of 5-[4-[2-[Ν-methyl-Ν-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate.

Claims

C L A I M S
1. A novel polymoφhic Form-I of 5-[4-[2-[N-methyl-N-(2-pyridyl) amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate, and its stereoisomers having the formula I
which is characterized by the following data:
DSC endotherm at 100.53°C (on set at 88.65°C),
X Ray powder diffraction (2Θ) : 10.90, 14.54, 15.96, 18.46, 18.60, 19.76, 20.72, 21.84, 22.36, 22,46, 23.90, 24.04, 24.72, 25.30, 25.98, 27.44, 29.70,
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).
2. A novel polymoφhic Form-II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate, and its stereoisomers having the formula I
which is characterized by the following data:
DSC : Endotherm at 127.67°C (on set at 123.17°C),
XRD (2Θ): 8.90, 15.40, 18.06, 19.20, 22.30, 23.40, 23.62, 24.80, 25.10, 25.84, 26.72, 27.18, 29.30, 29.54, 29.84, 33.26,
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).
3. A novel polymoφhic Form-Ill of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate and its stereoisomers having the formula I which is characterized by the following data:
DSC : Endotherm at 126.41°C (on set at 122.06°C),
XRD (2Θ): 4.60, 8.46, 9.24, 14.98, 15.86, 17.02, 18.60, 21.92, 23.50, 25.00, 25.44, 26.00, 26.38, 28.34, 33.90,
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).
4. A novel polymoφhic Form-IN of 5-[4-[2-[Ν-methyl-Ν-(2-pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate, and its stereoisomers having the formula I
which is characterized by the following data:
DSC : Endotherm at 125.39°C (on set at 121.03°C),
XRD (2Θ): 7.4, 8.8, 9.54, 14.98, 15.32, 15.82, 16.90, 17.70, 18.40, 18.54, 19.08, 19.72, 20.22, 20.48, 21.36, 21,66, 22.18, 22.58, 23.32, 23.96, 24.52, 25.38, 26.48, 27.00, 27.58, 27.94, 28.34, 28.54, 28.84, 29.10, 29.86, 30.02, 30.40, 30.52, 30.84, 31.40, 31.94,
LR : 3433 (m), 2930 (m), 1753 (w), 1705 (s), 1642 (w), 1617 (m), 1512 (s), 1467 (w), 1351 (m), 1244 (m), 1162 (m), 1061 (w), 864 (s), 765 (s), 714 (w), 658 (m), 526 (w).
5. A process for the preparation of novel polymoφhic Form I of 5-[4-[2-[N-methyl- N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, which comprises
(i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine- 2,4-dione maleate, employing known methods and dissolving in ethanol,
(ii) heating the solution in a steam bath till the solid completely dissolved,
(iii) filtering the clean solution and cooling to room temperature over a period of 18 h and (iv) isolating the Form I of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate formed.
6. A process for the preparation of novel polymoφhic Form II of 5-[4-[2-pSf-methyl- N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, which comprises: (i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, employing known methods and dissolving in acetone, (ii) heating the solution in a steam bath till the solid completely dissolved, (iii) filtering the clean solution and cooling to room temperature over a period of 18 h and (iv) isolating the Form II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate formed.
7. A process for the preparation of novel polymoφhic Form III of 5-[4-[2-[N- methyl-N-(2-pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate, which comprises: (i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, employing known methods and dissolving in methanol, (ii) heating the solution in a steam bath till the solid completely dissolved, (iii) filtering the clean solution and cooling to room temperature over a period of 18 h and (iv) isolating the Form LU of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate formed.
8. A process for the preparation of novel polymoφhic Form IN of 5-[4-[2-[Ν- methyl-N-(2-pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate, which comprises: (i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, employing known methods and dissolving in 1,4-dioxane, (ii) heating the solution in a steam bath till the solid completely dissolved, (iii) filtering the clean solution and cooling to room temperature over a period of 18 h and (iv) isolating the Form IN of 5-[4-[2-[Ν-methyl-Ν-(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate formed.
9. A pharmaceutical composition comprising a mixture of any of polymoφhic Forms I to IN of 5-[4-[2-[Ν-methyl-Ν-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, of the formula (I) and a pharmaceutically acceptable carrier, diluent, excipient or solvate.
10. A pharmaceutical composition as claimed in claim 9, in the form of a tablet, capsule, powder, syrup, solution or suspension.
11. A method of preventing or treating hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism comprising administering a polymoφhic Form selected from Form I to IN of 5-[4-[2-[Ν-methyl-Ν-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10 to a patient in need thereof.
12. A method according to claim 11, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperhpidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomeralonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma and cancer.
13. A method of reducing plasma glucose, triglycerides, total cholesterol, LDL, NLDL and free fatty acids in the plasma comprising admimstering a polymoφhic Form selected from Form I to IN of 5-[4-[2-[Ν-methyl-Ν-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10.
14. A method of preventing or treating hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism comprising administering a polymoφhic Form selected from Form I to IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10 in combination / concomittant with HMG Co A reductase inhibitors or fibrates or nicotinic acid or cholestyramine or colestipol or probucol which maybe administered together or within such a period as to act synergistically together to a patient in need thereof.
15. A method according to claim 14, wherein the disease is type II diabetes, impaired
" glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperhpidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomeralonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma and cancer.
16. A method according to claim 14 for the treatment and / or prophylaxis of disorders related to Syndrome X, which comprises administering a polymoφhic Form selected from Form I to IN of 5-[4-[2-[Ν-methyl-Ν-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine- 2,4-dione maleate, having the formula I as defined in claims 1-4 in combination with HMG CoA reductase inhibitors or fibrates or nicotinic acid or cholestyramine or colestipol or probucol which may be administered together or within such a period as to act synergistically together.
17. A method of reducing plasma glucose, triglycerides, total cholesterol, LDL, NLDL and free fatty acids in the plasma, which comprises administering a polymoφhic Form selected from Form I to IN of 5-[4-[2-[Ν-methyl-Ν-(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10 in combination / concomittant with HMG CoA reductase inhibitors or fibrates or nicotinic acid or cholestyramine or colestipol or probucol which may be administered together or within such a period as to act synergistically together to a patient in need thereof.
18. Use of a polymoφhic Form selected from Form I to IN of 5-[4-[2-[Ν-methyl-Ν- (2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10 for preventing or treating hyperhpidemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism.
19. Use of a polymoφhic Form according to claim 18, wherein the disease is type.LI diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperhpidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.
20. Use of a polymoφhic Form selected from Form I to LV of 5-[4-[2-[N-methyl-N- (2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10 for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in the plasma.
21. Use of a polymoφhic Form selected from Form I to IN of 5-[4-[2-[Ν-methyl-Ν- (2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10 in combination concomittant with HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol which may be administered together or within such a period as to act synergistically together for preventing or treating hyperhpidemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism to a patient in need thereof.
22. Use of a polymoφhic Form according to claim 21, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperhpidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.
23. Use of a polymoφhic Form selected from Form I to IN of 5-[4-[2-[Ν-methyl-Ν- (2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10 in combination/concomittant with HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL or free fatty acids in the plasma.
24. Use of a polymoφhic Form selected from Form I to IV of 5-[4-[2-[N-methyl-N-(2- pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10 for preparing a medicament for preventing or treating hyperhpidemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism.
25. Use of a polymoφhic form according to claim 24, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hyper-tension, obesity, atherosclerosis, hyperhpidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomeralosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.
26. Use of a polymoφhic Form selected from Form I to LV of 5-[4-[2-[N-methyl-N- (2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10 for preparing a medicament for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in the plasma.
27. Use of a polymoφhic Form selected from Form I to IN of 5-[4-[2-[Ν-methyl-Ν- (2-pyridyl)arnino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10 for preparing a medicament in combination/concomittant with HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol for preventing or treating hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism.
28. Use of a polymoφhic form according to claim 27, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperhpidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomeralosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.
29. Use of a polymoφhic Form selected from Form I to IN of 5-[4-[2-[Ν-methyl-Ν- (2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10 for preparing a medicament in combination/concomittant with HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL or free fatty acids in the plasma.
30. A medicine for preventing or treating hyperhpidemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism comprising administering an effective amount of a polymoφhic Form selected from Form I to IN of 5-[4-[2-[Ν-methyl-Ν-(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10.
31. A medicine according to claim 30, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomeralosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.
32. A medicine for reducing plasma glucose, triglycerides, total cholesterol, LDL,
NLDL and free fatty acids in the plasma comprising an effective amount of a polymoφhic Form selected from Form I to IN of 5-[4-[2-[Ν-methyl-Ν-(2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10.
33. A medicine for preventing or treating hyperhpidemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the underlying pathophysiological mechanism comprising a polymoφhic Form selected from Form I to IN of 5-[4-[2-[Ν- methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10 and HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol.
34. A medicine according to claim 33, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperhpidemia, coronary artery disease and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomeralosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose reductase inhibitors, for improving cognitive functions in dementia and treating diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.
35. A medicine for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in the plasma, which comprises a polymoφhic Form selected from Form I to IN of 5-[4-[2-[Ν-methyl-Ν-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine- 2,4-dione maleate, having the formula I as defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10 and HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol.
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)

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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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ZA200303223B (en) 2004-07-26
NO324968B1 (en) 2008-01-14
PL360661A1 (en) 2004-09-20
IL155036A0 (en) 2003-10-31
CA2426117A1 (en) 2002-04-04
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HUP0301161A2 (en) 2003-11-28
AU9123201A (en) 2002-04-08
NZ525498A (en) 2004-11-26
JP2004509961A (en) 2004-04-02
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