EP0844997A1 - Nouvelles formes polymorphes de la troglitazone ayant une activite anti-diabetique augmentee et procede pour leur preparation - Google Patents

Nouvelles formes polymorphes de la troglitazone ayant une activite anti-diabetique augmentee et procede pour leur preparation

Info

Publication number
EP0844997A1
EP0844997A1 EP97915839A EP97915839A EP0844997A1 EP 0844997 A1 EP0844997 A1 EP 0844997A1 EP 97915839 A EP97915839 A EP 97915839A EP 97915839 A EP97915839 A EP 97915839A EP 0844997 A1 EP0844997 A1 EP 0844997A1
Authority
EP
European Patent Office
Prior art keywords
troglitazone
polymorphic form
range
onset
medium
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.)
Ceased
Application number
EP97915839A
Other languages
German (de)
English (en)
Inventor
Krishnamurthi Vyas
Chebiyyam Prabhakar
Sreenivas Dharmaraja Rao
Mamillapalli Ramabadhara Sarma
Om Gaddam Reddy
Rajagopalan Ramanujam
Ranjan Chakrabarti
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 Research Foundation
Reddy Cheminor Inc
Original Assignee
Dr Reddys Research Foundation
Reddy Cheminor Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/665,867 external-priority patent/US5700820A/en
Application filed by Dr Reddys Research Foundation, Reddy Cheminor Inc filed Critical Dr Reddys Research Foundation
Publication of EP0844997A1 publication Critical patent/EP0844997A1/fr
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • This invention relates to a discovery of the preparation of novel polymorphic/pseudopolymorphic forms of Troglitazone and process for the preparation of various polymorphic/pseudopolymorphic forms of Troglitazone.
  • Troglitazone is 5- [ [4- [3 (3,4-dihydro-6- hydroxy-2,5,7,8-tetramethyl-2H-l-benzopyran-2-yl) methoxy] phenyl] methyl] 2,4-thiazolidinedione, having the Formula I shown below.
  • the polymorphic forms prepared by the process of the present invention are more active, as an antidiabetic agent, than the hitherto known Troglitazone.
  • Aldose reductase is the enzyme which reduces aldose present in the humans and animals into corresponding polyols which, in turn, are stored or accumulated in the kidneys, peripheral nerves, eye lens of the diabetic patients and manifest themselves in the above mentioned complications.
  • Troglitazone hitherto known is being considered today as one of the most effective antidiabetic drugs which has a multipurpose 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 Troglitazone is emerging a ⁇ the first drug candidate of euglycemic class of antidiabetic agents.
  • 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 polymorph ⁇ .
  • Sertraline, Frentizole, Ranitidine, Sulfathiazole, Indomethacine etc. are some of the important examples of pharmaceuticals which exhibit polymorphism.
  • EP 490648 and EP 022527 also deal with the subject of polymorphism in drugs.
  • Our observations and results form the subject matter of the present invention.
  • Troglitazone can be prepared in different polymorphic forms possessing anti-diabetic activity.
  • DSC of the polymorphic Form-1 and polymorphic Form-3 have one melting endotherm each at -180°C. and -186°C. (Figs. 1 & 2 ) respectively.
  • Polymorphic Form-2 exhibits an endotherm, in the temperature region 110-120°C. (hereafter referred as Peak 1) before the melting endotherm in the region 165- 190°C. as shown in Fig-3. It was also observed that when the polymorphic Form-2 is heated to 150°C. and cooled, the rerecorded DSC thermogram showed the reduction and absence of the peak 1 as represented by Figs. 4 & 5 respectively, indicating the conversion of the polymorphic Form-2 into another polymorphic form completely/partially.
  • Fig. 15 gives the powder X-ray diffraction pattern of the Forms 1,2,3,5 and 6 to facilitate easy comparison.
  • Fig. 1 is a characteristic differential scanning calorimetric thermogram of Form 1.
  • Fig. 2 is a characteristic differential scanning calorimetric thermogram of Form 3.
  • Fig. 3 is a characteristic differential scanning calorimetric thermogram of Form 2.
  • Fig. 4 is a characteristic differential scanning calorimetric thermogram of Form 2 showing the reduction of peak 1 after heating.
  • Fig. 5 is a characteristic differential scanning calorimetric thermogram of Form 2 showing the absence of peak 1 after heating.
  • Fig. 6 is a characteristic differential scanning calorimetric thermogram of Form 4.
  • Fig. 7 is a characteristic differential scanning calorimetric thermogram of Form 5.
  • Fig. 8 is a characteristic differential scanning calorimetric thermogram of Form .
  • Fig. 9 is a characteristic X-ray powder diffraction pattern of Form 1.
  • Fig. 10 is a characteristic X-ray powder diffraction pattern of Form 2.
  • Fig. 11 is a characteristic X-ray powder diffraction pattern of Form 3.
  • Fig. 12 is a characteristic X-ray powder diffraction pattern of Form 5.
  • Fig. 13 is a characteristic X-ray powder diffraction pattern of Form 6.
  • Fig. 14 is a characteristic X-ray powder diffraction pattern of Form 4.
  • Fig. 15 is the multi-plot of X-ray powder diffraction patterns of Forms 1,2,3,5,6.
  • Fig. 16 is a characteristic infrared absorption spectrum of Form 1 in potassium bromide) . (KBr) .
  • Fig. 17 is a characteristic infrared absorption spectrum of Form 2 in KBr.
  • Fig. 18 is a characteristic infrared absorption spectrum of Form 3 in KBr.
  • Fig. 19 is a characteristic infrared absorption spectrum of Form 4 in KBr.
  • Fig. 20 is a characteristic infrared absorption spectrum of Form 5 in KBr.
  • Fig. 21 is a characteristic infrared absorption spectrum of Form 6 in KBr.
  • Fig.22 is the multi-plot of infrared absorption spectra of Forms 1,2,3,4,5,6 (4000-500 cm " ) .
  • Common color code for Figs. 22-26 Black - Form 1; Orange - Form 2; Red - Form 3; Violet - Form 4; Blue - Form 5; Green - Form 6.
  • Fig. 23 is the multi-plot of infrared absorption spectra of Forms 1,2,3,4,5,6 (3800-2400 cm )
  • Fig. 24 is the multi-plot of infrared absorption spectra of Forms 1,2,3,4,5,6 (1800-1500
  • Fig. 25 is the multi-plot of infrared absorption spectra of Forms 1,2,3,4,5,6 (1500-1100 cm ) .
  • Fig. 26 is the multi-plot of infrared absorption spectra of Forms 1,2,3,4,5,6 (1125-500 cm "1 ) .
  • the present invention provides a process for the preparation of novel polymorphic Form-1 of Troglitazone having the Formula I shown in the drawing accompanying this specification which comprise ⁇ (i) synthesizing Troglitazone, in crude form employing known methods,
  • step (ii) subjecting the crude Troglitazone obtained in step (i) to column chromatography to obtain a partially purified Troglitazone having HPLC purity in the range of 60-70%, (iii) dissolving the partially purified
  • step (ii) subjecting the crude Troglitazone obtained in step (i) to column chromatography to obtain a partially purified Troglitazone having HPLC purity in the range of 60-70%,
  • step (iii) dissolving the partially purified Troglitazone obtained in step (ii) in an organic polar and/or medium polar solvent and heating the resulting solution with a non-polar solvent, and
  • step (ii) subjecting the crude Troglitazone obtained in step (i) to column chromatography to obtain a partially purified Troglitazone having HPLC purity in the range of 60-70%,
  • step (iii) dissolving the partially purified Troglitazone obtained in step (ii) in an organic polar and/or medium polar solvent and heating the resulting solution with a non-polar solvent, and
  • step (v) dissolving the polymorphic Form-2 of Troglitazone so obtained in step (iv) in an organic polar and/or medium polar solvent and heating the resulting solution with a non-polar solvent, and
  • step (iii) dissolving the partially purified Troglitazone obtained in step (ii) in an organic polar and/or medium polar solvent and heating the resulting solution with a non-polar solvent
  • step (iii) dissolving the partially purified Troglitazone obtained in step (ii) in an organic polar and/or medium polar solvent and heating the resulting solution with a non-polar solvent, (iv) scratching the resulting solution, while cooling rapidly to a temperature in the range of 0 to -20°C. at a rate of 2 to 10°C./minute, over a period in the range of 10-30 min. to precipitate the polymorphic Form-2 of Troglitazone,
  • step (v) dissolving the polymorphic Form-2 of Troglitazone so obtained in step (iv) , in an organic polar and/or medium polar solvent and heating the resulting solution with a non-polar solvent, (vi) heating the resulting solution preferably on steam bath and cooling the solution slowly to room temperature at a rate of 0.1 to 1°C./minute, over a period in the range of 24-72 h to crystallize the polymorphic Form-3 of Troglitazone, (vii) filtering the product and melting it by heating,
  • step (ii) subjecting the crude Troglitazone obtained in step (i) to column chromatography to obtain a partially purified Troglitazone having HPLC purity in the range of 60-70%, (iii) dissolving the partially purified
  • step (viii) subjecting the polymorphic Form-4 of Troglitazone so obtained in step (vii) to isothermal heating in the range of 60 to 170°C. preferably at 130°C, for a period in the range of 5 min. to 4 h, cooling to ambient temperature slowly at a rate of 0.1 to 1°C./minute, over a period in the range of 1-4 h, followed by grinding the flake to a fine powder to yield the polymorphic Form 5 of Troglitazone which i ⁇ characterized by the following data.
  • step (ii) subjecting the crude Troglitazone obtained in step (i) to column chromatography to obtain a partially purified Troglitazone having HPLC purity in the range of 60-70%,
  • step (iii) dissolving the partially purified Troglitazone obtained in step (ii) in an organic polar and/or medium polar solvent and heating the resulting solution with a non-polar solvent
  • step (viii) subjecting the polymorphic Form-4 of Troglitazone so obtained in step (vii) to isothermal heating in the range of 60 to 170°C. preferably at 130°C. for a period in the range of 5 min. to 4 h, cooling to ambient temperature at a rate of 0.1 to 1°C./minute, over a period in the range of 1-4 h followed by grinding the flake to a fine powder to yield the polymorphic Form-5 of Troglitazone which is characterized by the data presented in the previous method.
  • step (iii) dissolving the partially purified Troglitazone obtained in step (ii) in an organic polar and/or medium polar solvent and heating the resulting solution with a non-polar solvent
  • step (v) dissolving the polymorphic Form-2 of Troglitazone so obtained in step (iv) in an organic polar and/or medium polar solvent and heating the resulting solution with a non-polar solvent,
  • step (x) subjecting the polymorphic Form-4 of Troglitazone obtained in step (ix) to isothermal heating in the range of 60 to 170°C. preferably at 130°C. for a period in the range of 5 min. to 4 h, cooling to ambient temperature slowly at a rate of 0.1 to 1°C./minute, over a period in the range of 1-4 h followed by grinding the flake to a fine powder to yield the polymorphic Form-5 of Troglitazone which is characterized by the data presented in the previous method.
  • step (iii) dissolving the partially purified Troglitazone obtained in step (ii) in an organic polar and/or medium polar solvent and adding a non-polar solvent to the resulting solution and
  • step (iv) subjecting the polymorphic Form-4 of Troglitazone obtained in step (iii) to isothermal heating in the range of 60 to 170°C. preferably at 130°C. for a period in the range of 5 min. to 4 h, cooling to ambient temperature slowly at a rate of 0.1 to 1 C C./minute, over a period in the range of 1-4 h followed by grinding the flake to a fine powder to yield the polymorphic Form-5 of Troglitazone which is characterized by the data presented in the previous method.
  • the organic polar and/or medium polar solvents are selected from acetonitrile, ethanol, methanol, acetone, 1,4-dioxane, methyl ethyl ketone, ethylacetate, chloroform, tetrahydrofuran, n-propanol, isopropanol, 1,2-dichloroethane, dichloromethane, diethylether, benzene, etc. while the non-polar solvents are selected from hexane, heptane, cyclohexane, carbontetrachloride, toluene, xylene, etc.
  • the present invention is described in detail with examples given below that are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
  • Example-4 5 g of crude Troglitazone obtained by the process as described in Example-1 was taken in -100 ml benzene and heated on steam bath till the solid completely dissolved and the clear solution wa ⁇ allowed to cool to room temperature at a rate of 0.1 to 1°C./minute during a period ⁇ 36 h to give 2.5 g of > 99% pure polymorphic Form-1 of Troglitazone.
  • Examples 5-8 illustrate the process for the preparation of the polymorphic Form-2 of Troglitazone
  • Example-5 5 g of crude Troglitazone obtained by the process as described in Example-1 was taken in -100 ml benzene and heated on steam bath till the solid completely dissolved and the clear solution wa ⁇ allowed to cool to room temperature at a rate of 0.1 to 1°C./minute during a period ⁇ 36 h to give 2.5 g of > 99% pure polymorphic Form-1 of Troglitazone.
  • Examples 5-8 illustrate the process for the preparation of the polymorphic Form-2 of Troglitazone
  • Examples 20-21 illustrate the process for the preparation of the polymorphic Form- of Troglitazone
  • W ⁇ rample-21 15.5g of 5 [4- (6-hydroxy-2,5,7,8-tetramethyl chroman-2yl-methoxy) benzyl] -2-iminothiasolidine-4-one, prepared by the process as described in Example-1, was added to a mixture of 225 ml of acetic acid, 75 ml of cone, hydrochloric acid and 40 ml of water and the mixture was refluxed for 12 hrs. The reaction mixture was cooled to room temperature and 66.2 g of sodium bicarbonate was added and once the evolution of carbondioxide had ceased, the solvent was distilled off applying high vacuum.
  • the polymorphic forms of Troglitazone are more active/bio-available.

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

Abstract

L'invention concerne de nouvelles formes polymorphes de la Troglitazone et des procédés pour préparer des formes polymorphes de la Troplitazone. Les formes polymorphes de la Troplitazone peuvent servir à traiter des maladies d'origine diabétique.
EP97915839A 1996-06-19 1997-02-18 Nouvelles formes polymorphes de la troglitazone ayant une activite anti-diabetique augmentee et procede pour leur preparation Ceased EP0844997A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/665,867 US5700820A (en) 1996-02-20 1996-06-19 Polymorphic forms of troglitazone having enhanced anti-diabetic activity and a process for their preparation
US665867 1996-06-19
PCT/US1997/002577 WO1997027191A1 (fr) 1996-06-19 1997-02-18 Nouvelles formes polymorphes de la troglitazone ayant une activite anti-diabetique augmentee et procede pour leur preparation

Publications (1)

Publication Number Publication Date
EP0844997A1 true EP0844997A1 (fr) 1998-06-03

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EP97915839A Ceased EP0844997A1 (fr) 1996-06-19 1997-02-18 Nouvelles formes polymorphes de la troglitazone ayant une activite anti-diabetique augmentee et procede pour leur preparation

Country Status (4)

Country Link
EP (1) EP0844997A1 (fr)
JP (1) JP2000511875A (fr)
CN (1) CN1196730A (fr)
WO (1) WO1997027191A1 (fr)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ20011524A3 (cs) 1998-10-29 2002-01-16 Board Of Regents, The University Of Texas System Pouľití thiazolidindionových derivátů pro prevenci děloľních stahů u předčasného porodu nebo laktace
AU3957800A (en) * 1999-04-16 2000-11-02 Dr. Reddy's Research Foundation Crystalline r- guanidines, arginine or (l) -arginine (2(s)) -2- ethoxy -3-(4- (2-(10(h) -phenoxazin -10-yl)ethoxy}phenyl)propanoate
MXPA01010472A (es) * 1999-04-16 2002-05-06 Reddy Research Foundation Formas polimorficas novedosas de un agente contra la diabetes; procedimiento para su preparacion y composiciones farmaceuticas que las contienen.
WO2000063191A1 (fr) * 1999-04-16 2000-10-26 Dr. Reddy's Research Foundation Nouvelles formes polymorphes d'un agent antidiabetique: procede de preparation et composition pharmaceutique contenant ces dernieres
US6528507B1 (en) 1999-04-16 2003-03-04 Dr. Reddy's Laboratories Limited Polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
CA2383347A1 (fr) 1999-08-31 2001-03-08 Maxia Pharmaceuticals, Inc. Benzelidene-thiazolidinediones et leurs analogues, utilises dans le traitement du diabete
US7241895B2 (en) 2000-09-26 2007-07-10 Dr. Reddy's Laboratories Limited Polymorphic forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)amino[ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation
NZ525498A (en) * 2000-09-26 2004-11-26 Reddys Lab Ltd Dr Novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation
IL157740A0 (en) 2001-03-07 2004-03-28 Incyte San Diego Inc Heterocyclic derivatives and pharmaceutical compositions containing the same
US7265139B2 (en) 2001-03-08 2007-09-04 Incyte San Diego Inc. RXR activating molecules
CA2439310C (fr) * 2001-03-23 2009-09-29 Richter Gedeon Vegyeszeti Gyar Rt. Methode de preparation de fluconazole et de ses modifications cristallines
AU2002352706A1 (en) 2001-11-15 2003-06-10 Maxia Pharmaceuticals, Inc. N-substituted heterocycles for the treatment of hypercholesteremia, dyslipidemia and other metabolic disorders, cancer, and other diseases
US7196108B2 (en) 2002-03-08 2007-03-27 Incyte San Diego Inc. Bicyclic heterocycles for the treatment of diabetes and other diseases
US7102000B2 (en) 2002-03-08 2006-09-05 Incyte San Diego Inc. Heterocyclic amide derivatives for the treatment of diabetes and other diseases
GB2405403A (en) * 2003-08-29 2005-03-02 Cipla Ltd Rosiglitazone maleate of particular polymorphic forms and methods of preparing rosiglitazone free base

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JPS6051189A (ja) * 1983-08-30 1985-03-22 Sankyo Co Ltd チアゾリジン誘導体およびその製造法
JPS62234085A (ja) * 1985-12-18 1987-10-14 Sankyo Co Ltd チアゾリジン誘導体を有効成分とする糖尿病性合併症治療剤
IL86330A0 (en) * 1987-06-22 1988-11-15 Marga Investigacion Famotidine polymorphic forms and their preparation

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Also Published As

Publication number Publication date
CN1196730A (zh) 1998-10-21
JP2000511875A (ja) 2000-09-12
WO1997027191A1 (fr) 1997-07-31

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