US20020133016A1 - Substituted thiazolidined derivative, process for its preparation and its pharmaceutical use - Google Patents

Substituted thiazolidined derivative, process for its preparation and its pharmaceutical use Download PDF

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Publication number
US20020133016A1
US20020133016A1 US10/071,339 US7133902A US2002133016A1 US 20020133016 A1 US20020133016 A1 US 20020133016A1 US 7133902 A US7133902 A US 7133902A US 2002133016 A1 US2002133016 A1 US 2002133016A1
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Prior art keywords
hydrate
provides
hydrate according
diabetes mellitus
water
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Abandoned
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US10/071,339
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English (en)
Inventor
Ian Lynch
Michael Sasse
Bernadette Choudary
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Priority to US10/071,339 priority Critical patent/US20020133016A1/en
Publication of US20020133016A1 publication Critical patent/US20020133016A1/en
Priority to US10/354,365 priority patent/US20030139604A1/en
Priority to US11/205,426 priority patent/US20050288513A1/en
Priority to US11/536,313 priority patent/US7368574B2/en
Abandoned legal-status Critical Current

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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
    • 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
    • A61P3/06—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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • This invention relates to a novel pharmaceutical, to a process for the preparation of the pharmaceutical and to the use of the pharmaceutical in medicine.
  • Compound (I) is disclosed solely as an anhydrous form. It has now been discovered that Compound (I) exists in a novel hydrated form which is particularly suitable for bulk preparation and handling. This can be prepared by an efficient, economic and reproducible process particularly suited to large scale preparation.
  • novel hydrate also has useful pharmaceutical properties and in particular it is indicated to be useful for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
  • the present invention provides a hydrate of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt (the “Hydrate”) characterised in that the Hydrate:
  • (i) comprises water in the range of from 0.3 to 0.6 molar equivalents
  • (ii) provides an infrared spectrum containing peaks at 1757, 1331, 1290, 1211 and 767 cm ⁇ 1 ;
  • (iii) provides a Raman spectrum containing peaks at 1758, 1610, 1394, 1316 and 1289 cm ⁇ 1 ;
  • (v) provides an X-ray powder diffraction (XRPD) pattern substantially as set out in FIG. IV.
  • XRPD X-ray powder diffraction
  • the water content of the Hydrate is in the range of from 0.3 to 0.5 molar equivalents, for example 0.4 molar equivalents
  • the Hydrate provides an infra red spectrum substantially in accordance with FIG. I.
  • the Hydrate provides a Raman spectrum substantially in accordance with FIG. II.
  • the Hydrate provides a solid state nuclear magnetic resonance spectrum substantially in accordance with FIG. III.
  • the Hydrate can exist in certain dehydrated forms which reversibly convert to the Hydrate when contacted with water. either in liquid or vapour form.
  • the present invention encompasses all such reversibly rehydratable forms of the Hydrate.
  • the present invention encompasses the Hydrate isolated in pure form or when admixed with other materials, for example the known anhydrous form of Compound I. the above mentioned reversibly rehydratable forms or any other material.
  • the invention also provides a process for preparing the Hydrate, characterised in that 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt is crystallised from aqueous ethanol, conveniently aqueous denatured ethanol.
  • the aqueous ethanol contains from 2% to 15% of water by volume. such as 5% to 15% of water by volume, favourably 7% to 12% of water by volume, preferably 10 to 12%, for example 10%.
  • aqueous solvents may also be used to prepare the Hydrate, for example isopropanol, acetonitrile, tetrahydrofuran, methyl ethyl ketone, ethyl acetate or acetic acid, or mixtures thereof.
  • the precise amount of water used in each of the alternative solvents will depend upon the particular solvent chosen but typically it is in the range of from 2 to 15% of water by volume of water, for example 3%.
  • water levels as low as 1% by volume can provide the Hydrate (thus providing a suitable range of 1 to 15% of water by volume in the appropriate solvent).
  • the Hydrate can be obtained by crystallization from water containing a small amount (for example 2 to 5% by volume) of an organic acid such as acetic acid.
  • Crystallisation and any recrystallization is generally carried out at low to ambient temperature, such as in the range of between 0 to 30° C. for example 25° C.; alternatively crystallisation may be initiated at an elevated temperature, such as in the range of between 30° C. and 60° C. for example 50° C., and then completed by allowing the temperature of the solvent to cool to ambient or low temperature, such as in the range of between 0 to 30° C. for example 20° C.
  • the crystallisation can be initiated by seeding with crystals of the Hydrate but this is not essential.
  • Compound I is prepared according to known procedures, such as those disclosed in WO94/05659. The disclosures of WO94/05659 are incorporated herein by reference.
  • proliferaxis of conditions associated with diabetes mellitus includes the treatment of conditions such as insulin resistance, impaired glucose tolerance, hyperinsulinemia and gestational diabetes.
  • Diabetes mellitus preferably means Type II diabetes mellitus.
  • Conditions associated with diabetes include hyperglycaemia and insulin resistance, especially acquired insulin resistance and obesity. Further conditions associated with diabetes include hypertension, cardiovascular disease, especially atherosclerosis, certain eating disorders, in particular the regulation of appetite and food intake in subjects suffering from disorders associated with under-eating ,such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia. Additional conditions associated with diabetes include polycystic ovarian syndrome and steroid induced insulin resistance.
  • the complications of conditions associated with diabetes mellitus encompassed herein includes renal disease, especially renal disease associated with the development of Type II diabetes including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.
  • aqueous with reference to a given solvent or solvent mixture refers to a solvent which contains sufficient water to provide Hydrate i.e having from 0.3 to 0.6 molar equivalents of water.
  • the compound of the invention has useful therapeutic properties:
  • the present invention accordingly the Hydrate for use as an active therapeutic substance.
  • the present invention provides the Hydrate for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
  • the Hydrate may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • the formulation of the Hydrate and dosages thereof are generally as disclosed for Compound (I) in International Patent Application, Publication Number WO94/05659.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the Hydrate and a pharmaceutically acceptable carrier therefor.
  • the Hydrate is normally administered in unit dosage form.
  • the active compound may be administered by any suitable route but usually by the oral or parenteral routes.
  • the compound will normally be employed in the form of a pharmaceutical composition in association with a pharmaceutical carrier, diluent and/or excipient. although the exact form of the composition will naturally depend on the mode of administration.
  • compositions are prepared by admixture and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules. oral liquid preparations, powders, granules, lozenges, pastilles. reconstitutable powders, injectable and infusable solutions or suspensions, suppositories and transdermal devices. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers. diluents, tabletting agents, lubricants, disintegrants, colorants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • Solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or coloring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate,
  • fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the active compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the active compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound.
  • compositions may contain further active agents such as anti-hypertensive agents and diuretics.
  • compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
  • the term ‘pharmaceutically acceptable’ embraces compounds, compositions and ingredients for both human and veterinary use: for example the term ‘pharmaceutically acceptable salt’ embraces a veterinarily acceptable salt.
  • the present invention further provides a method for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof, in a human or non-human mammal which comprises administering an effective, non-toxic, amount of Hydrate to a human or non-human mammal in need thereof.
  • the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.
  • conditions associated with diabetes mellitus and certain complications thereof Hydrate may be taken in doses, such as those described above.
  • the present invention provides the use of Hydrate for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
  • Peak positions are as follows: 3574, 3458, 3377, 3129, 2776, 1757, 1743, 1708, 1691, 1640, 1620, 1585, 1542, 1512, 1414, 1350, 1331, 1306, 1290, 1249, 1238, 1211, 1183, 1163, 1143, 1107, 1078, 1063, 1031, 1002, 974, 954, 927, 902, 865, 836, 830, 817, 809, 767, 735, 717, 663, 616, 585, 558, 520 and 508 cm ⁇ 1 .
  • a Raman spectrum of the Hydrate was recorded through glass vials using a Perkin Elmer 2000R spectrometer at 4 cm ⁇ 1 resolution and is shown in FIG. II (1800-200 cm ⁇ 1 ). Excitation was achieved using a Nd:YAG laser (1064 nm) with a power output of 500 mW. Data were digitised at 1 cm ⁇ 1 intervals.
  • Peak positions are as follows: 1758, 1743, 1703, 1610, 1586, 1544, 1468, 1435, 1394, 1330, 1316, 1289, 1265, 1238, 1206, 1185, 1148, 1095, 1032, 1003, 976, 923, 903, 843, 825, 780, 741, 722, 664, 637, 606, 526, 471, 403, 331 and 293 cm ⁇ 1 .
  • a PWI1710 X-ray powder diffractometer (Cu X-ray source) was used to generate the spectrum using the following acquisition conditions: Tube anode: Cu Generator tension: 40 kV Generator current: 30 mA Start angle: 3.5° 2 ⁇ End angle: 35.0° 2 ⁇ Step size: 0.020 Time per step: 4.550 s
  • Example 2 The procedure of Example 2 was repeated using tetrahydrofuran (15 ml) containing water (0.5 ml) as solvent. Yield 1.8 g (60%), water content 1.60%.
  • Example 2 The procedure of Example 2 was repeated using methyl ethyl ketone (30 Ml) containing water (1 ml) as solvent. Yield 2.05 g (68%), water content 1.58%.
  • Example 2 The procedure of Example 2 was followed using 2.0 g maleate salt, heating to 65° C. in ethyl acetate (150 ml) containing water (1.5 ml) as solvent. Yield 1.34 g (67%), water content 1.61%.
  • Example 2 The procedure of Example 2 was followed, heating to 65-70° C. in isopropanol (33 ml) containing water (1 ml) as solvent. Yield 2.4 g (80%), water content 1.58%.
  • Example 2 The procedure of Example 2 was repeated using a mixture of water (20 ml) and acetic acid (1.0 g) as solvent. Yield 0.76 g (38%), water content 1.78%.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
US10/071,339 1997-12-16 2002-02-08 Substituted thiazolidined derivative, process for its preparation and its pharmaceutical use Abandoned US20020133016A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US10/071,339 US20020133016A1 (en) 1997-12-16 2002-02-08 Substituted thiazolidined derivative, process for its preparation and its pharmaceutical use
US10/354,365 US20030139604A1 (en) 1997-12-16 2003-01-30 Substituted thiazolidinedione derivative, process for its preparation and its pharmaceutical use
US11/205,426 US20050288513A1 (en) 1997-12-16 2005-08-17 Substituted thiazolidinedione derivative, process for its preparation and its pharmaceutical use
US11/536,313 US7368574B2 (en) 1997-12-16 2006-09-28 Substituted thiazolidinedione derivative, process for its preparation and its pharmaceutical use

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB9726563.1 1997-12-16
GBGB9726563.1A GB9726563D0 (en) 1997-12-16 1997-12-16 Novel pharmaceutical
US58181600A 2000-06-16 2000-06-16
US10/071,339 US20020133016A1 (en) 1997-12-16 2002-02-08 Substituted thiazolidined derivative, process for its preparation and its pharmaceutical use

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PCT/EP1998/008153 Continuation WO1999031093A1 (en) 1997-12-16 1998-12-14 Substituted thiazolidinedione derivative, process for its preparation and its pharmaceutical use
US09581816 Continuation 1998-12-14
US58181600A Continuation 1997-12-16 2000-06-16

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US10/354,365 Abandoned US20030139604A1 (en) 1997-12-16 2003-01-30 Substituted thiazolidinedione derivative, process for its preparation and its pharmaceutical use
US11/205,426 Abandoned US20050288513A1 (en) 1997-12-16 2005-08-17 Substituted thiazolidinedione derivative, process for its preparation and its pharmaceutical use
US11/536,313 Expired - Fee Related US7368574B2 (en) 1997-12-16 2006-09-28 Substituted thiazolidinedione derivative, process for its preparation and its pharmaceutical use

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US11/205,426 Abandoned US20050288513A1 (en) 1997-12-16 2005-08-17 Substituted thiazolidinedione derivative, process for its preparation and its pharmaceutical use
US11/536,313 Expired - Fee Related US7368574B2 (en) 1997-12-16 2006-09-28 Substituted thiazolidinedione derivative, process for its preparation and its pharmaceutical use

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US (4) US20020133016A1 (hu)
EP (1) EP1042321A1 (hu)
JP (1) JP2002508371A (hu)
KR (1) KR100549141B1 (hu)
CN (3) CN101318956A (hu)
AP (1) AP1363A (hu)
AR (2) AR017211A1 (hu)
AU (2) AU2272299A (hu)
BG (1) BG64850B1 (hu)
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CZ (1) CZ300081B6 (hu)
DZ (1) DZ2679A1 (hu)
EA (1) EA002833B1 (hu)
EG (1) EG22250A (hu)
GB (1) GB9726563D0 (hu)
HR (1) HRP20000404A2 (hu)
HU (1) HUP0102292A3 (hu)
ID (1) ID24714A (hu)
IL (2) IL136425A (hu)
MA (1) MA26581A1 (hu)
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NO (1) NO317255B1 (hu)
NZ (1) NZ504703A (hu)
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PE (1) PE20000125A1 (hu)
PL (1) PL341213A1 (hu)
RS (1) RS50080B (hu)
SA (1) SA99200200B1 (hu)
SK (1) SK286422B6 (hu)
TR (2) TR200001793T2 (hu)
TW (1) TW487709B (hu)
UA (1) UA66821C2 (hu)
UY (2) UY25309A1 (hu)
WO (1) WO1999031093A1 (hu)
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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
US6815457B1 (en) 1999-04-23 2004-11-09 Smithkline Beecham P.L.C. Thiazolidinedione derivative and its use as antidiabetic
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US20050163842A1 (en) * 2003-12-31 2005-07-28 Garth Boehm Rosiglitazone and metformin formulations
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USRE39384E1 (en) 1993-09-01 2006-11-07 Smithkline Beecham P.L.C. Substituted thiazolidinedione derivatives
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US20040248945A1 (en) 1999-04-23 2004-12-09 Smithkline Beecham P.L.C. Thiazolidinedione derivative and its use as antidiabetic
ES2203453T3 (es) * 1999-04-23 2004-04-16 Smithkline Beecham Plc Polimorfo de sal del acido maleico de 5-(4-(2-(n-metil-n-(2-piridil)amino)etoxi)bentil)tiazolidina-2,4-diona.
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EP1468997A3 (en) * 2003-04-18 2004-11-03 CHEMI S.p.A. Polymorphous forms of rosiglitazone maleate
GB2405403A (en) * 2003-08-29 2005-03-02 Cipla Ltd Rosiglitazone maleate of particular polymorphic forms and methods of preparing rosiglitazone free base
ITMI20041537A1 (it) * 2004-07-28 2004-10-28 Chemi Spa Nuova forma polimorfa del rosiglitazone maleato
CZ298424B6 (cs) * 2005-05-24 2007-09-26 Zentiva, A. S. Zpusob krystalizace rosiglitazonu a jeho derivátuze smesných rozpouštedel
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