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

• EP Patent Application, Publication Number 0,306,228 relates to certain thiazolidinedione derivatives disclosed as having hypoglycaemic and hypolipidaemic activity.
• the compound of example 30 of EP 0,306,228 is 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter also referred to as "Compound (I)").
• Compound (I) forms a novel hydrobromide salt (hereinafter also referred to as the "Hydrobromide”) that is particularly stable and hence is suitable for bulk preparation and handling.
• the Hydrobromide also has a high melting point, shows particularly good aqueous solubility and possesses good bulk flow properties.
• the hydrobromide is therefore surprisingly amenable to large scale pharmaceutical processing and especially to large scale miling.
• the novel form can be prepared by an efficient, economic and reproducible process particularly suited to large-scale preparation.
• the novel Hydrobromide also has useful pharmaceutical properties and in particular it is indicated to be useful for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof. Accordingly, the present invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione hydrobromide or a solvate thereof.
• the hydrobromide is a monohydrobromide.
• the Hydrobromide provides an infrared spectrum substantially in accordance with Figure I. In one favoured aspect, the Hydrobromide provides a Raman spectrum substantially in accordance with Figure II.
• the Hydrobromide provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table I or Figure III.
• the Hydrobromide provides a solid-state 13 C NMR spectrum substantially in accordance with Figure IV.
• the Hydrobromide has a melting point within the range of from 175 to 185°C, especially 180 to 185°C, for example 181°C. Also the Hydrobromide has a T onse t within the range of from 180 to 186°C, for example 182.5°C.
• the Hydrobromide is characterised in that it provides two or more of: (i) an infrared spectrum substantially in accordance with Figure I; (ii) a Raman spectrum substantially in accordance with Figure II; (iii) an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table I or Figure III;
• the present invention encompasses the Hydrobromide or solvate thereof isolated in pure form or when admixed with other materials.
• the Hydrobromide or solvate thereof in isolated form.
• the Hydrobromide or solvate thereof in a purified form.
• the invention provides the Hydrobromide or solvate thereof in a solid pharmaceutically acceptable form, such as a solid dosage form, especially when adapted for oral administration.
• the invention also provides the Hydrobromide or solvate thereof in a pharmaceutically acceptable form, especially in bulk form, such form being particularly capable of being milled. Furthermore, the invention provides the Hydrobromide or solvate thereof in a pharmaceutically acceptable form, especially in bulk form, such form having good flow properties, especially good bulk flow properties.
• a suitable solvate is a hydrate.
• the invention also provides a process for preparing the Hydrobromide or solvate thereof, characterised in that 5-[4-[2-( ⁇ -methyl- ⁇ -(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound(I)), or a salt thereof, preferably dispersed or dissolved in a suitable solvent, is reacted with a source of hydrogen bromide and thereafter, if required, a solvate of the Hydrobromide is prepared; and the Hydrobromide or solvate thereof is recovered.
• Compound(I) 5-[4-[2-( ⁇ -methyl- ⁇ -(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione
• a salt thereof preferably dispersed or dissolved in a suitable solvent
• a suitable reaction solvent is an alkanol, for example propan-2-ol, or a hydrocarbon, such as toluene, a ketone, such as acetone, an ester, such as ethyl acetate, an ether such as tetrahydrofuran, a nitrile such as acetonitrile, or a halogenated hydrocarbon such as dichlor ⁇ methane, water, or an organic acid such as acetic acid; or a mixture thereof.
• a hydrocarbon such as toluene, a ketone, such as acetone, an ester, such as ethyl acetate, an ether such as tetrahydrofuran, a nitrile such as acetonitrile, or a halogenated hydrocarbon such as dichlor ⁇ methane, water, or an organic acid such as acetic acid; or a mixture thereof.
• the source of hydrogen bromide is provided by an aqueous solution of hydrogen bromide, for example a 48% w/w solution in water.
• the source of hydrogen bromide is a solution of hydrogen bromide in an appropriate solvent, optionally the reaction solvent, for example propan-2-ol.
• the hydrogen bromide may be added directly to a solution or suspension of Compound(I) in the chosen reaction solvent.
• An alternative source of hydrogen bromide is provided by a base salt of hydrobromic acid for example ammonium bromide, or the hydrobromic acid salt of an amine, for example ethylamine or diethylamine.
• the reaction is usually carried out at ambient temperature or at an elevated temperature, for example at the reflux temperature of the solvent, although any convenient temperature that provides the required product may be employed.
• Solvates, such as hydrates, of the Hydrobromide are prepared according to conventional procedures.
• Recovery of the required compound generally comprises crystallisation from an appropriate solvent, conveniently the reaction solvent, usually by cooling to a temperature in the range of from 0°C to 60°C, for example 20 to 25°C or from 40 to 50°C.
• the Hydrobromide may be crystallised from an alcohol such as propan-2-ol or a ketone such as acetone.
• the recovery comprises initial cooling to a first temperature, such as in the range of from 40 to 50°C, thereby allowing initiating crystallisation and thereafter cooling to a second temperature, suitably in the range of from 0 to 25°C.
• Crystallisation can also be initiated by seeding with crystals of the Hydrobromide or solvate thereof but this is not essential.
• Solvates are prepared by use of appropriate conventional methods.
• Compound (I) is prepared according to known procedures, such as those disclosed in EP 0,306,228 and WO94/05659. The disclosures of EP 0,306,228 and WO94/05659 are incorporated herein by reference.
• T onset is generally determined by Differential Scanning Calorimetry and has a meaning generally understood in the art, as for example expressed in Pharmaceutical Thermal Analysis, Techniques and Applications", Ford and Timmins, 1989 as "The temperature corresponding to the intersection of the pre-transition baseline with the extrapolated leading edge of the transition” .
• good flow properties is suitably characterised by the said compound having a Hausner ratio of less than or equal to 1.5, especially of less than or equal to 1.25.
• Diabetes ratio is an art accepted term. When used herein the term 'prophylaxis of conditions associated with diabetes mellitus' includes the treatment of conditions such as insulin resistance, impaired glucose tolerance, hyperinsulinaemia and gestational diabetes.
• Diabetes mellitus preferably means Type II diabetes mellitus.
• Conditions associated with diabetes include hyperglycaemia and 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.
• the compound of the invention has useful therapeutic properties: The present invention accordingly provides the Hydrobromide or solvate thereof for use as an active therapeutic substance.
• the present invention provides the Hydrobromide or solvate thereof for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
• the Hydrobromide or solvate thereof may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. Suitable methods for formulating the Hydrobromide or solvate thereof are generally those disclosed for Compound (I) in the above mentioned publications. Accordingly, the present invention also provides a pharmaceutical composition comprising the Hydrobromide or solvate thereof and a pharmaceutically acceptable carrier therefor.
• the Hydrobromide or solvate thereof is normally administered in unit dosage form.
• the active compound may be administered by any suitable route but usually by the oral or parenteral routes.
• the compound will normally be employed in the form of a pharmaceutical composition in association with a pharmaceutical carrier, diluent and/or excipient, although the exact form of the composition will naturally depend on the mode of administration.
• compositions are prepared by admixture and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles, reconstitutable powders, injectable and infusable solutions or suspensions, suppositories and transdermal devices.
• Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
• Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
• the tablets may be coated according to well known methods in the art.
• Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
• Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
• Suitable lubricants include, for example, magnesium stearate.
• Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
• Solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl
• 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
• almond oil fractionated
• 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 theNehicle.
• 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 will usually be accompanied by written or printed directions for use in the medical treatment concerned.
• 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 Hydrobromide or solvate thereof to a human or non-human mammal in need thereof.
• the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.
• the present invention provides the use of Hydrobromide or solvate thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
• the Hydrobromide or solvate thereof may be taken in amounts so as to provide Compound (I) in suitable doses, such as those disclosed in EP 0,306,228, WO94/05659 or WO98/55122.
• Example 1 5-[4-[2-(N-methyl-N-(2-pyridyI)amino)ethoxy]benzyl]thiazolidine-2,4- dione hydrobromide
• the solid state stability of the drug substance was determined by storing approximately 1.0 g of the material in a glass bottle at i) 40°C / 75% Relative Humidity (RH), open exposure, for 1 month and b) at 50°C, closed, for 1 month. The material was assayed by HPLC for final content and degradation products in both cases. a) 40°C / 75% RH: No significant degradation observed (HPLC assay 98% initial). b) 50°C: No significant degradation observed (HPLC assay 98% initial).
• the ratio between the bulk density and the tapped bulk density (Hausner Ratio) of the Hydrobromide was determined using standard methods ("Pharmaceutics - The Science of Dosage Form Design", editor M. Aulton, 1988, published by:Churchill Livingstone). Hausner Ratio: 1.3
• T onse t of the drug substance was determined by Differential Scanning Calorimetry using a Perkin-Elmer DSC7 apparatus. T onS e t : 182.5 o C
• the melting point of the drug substance was determined visually by hot stage microscopy. Mpt: 181 °C
• the IR spectrum of the solid product was recorded using a universal ATR accessory. Bands were observed at: 2929, 2859, 2749, 1745, 1694, 1641, 1608, 1543, 1514, 1445, 1419, 1382, 1358, 1326, 1311, 1287, 1255, 1240, 1202, 1184, 1148, 1070, 1053, 1031, 1014, 985, 906, 862, 844, 802, 768, 737, 710, 657 cm-l.
• the Raman spectrum of the product ( Figure II) was recorded with the sample in an NMR tube using a Nicolet 960 E.S.P.
• the XRPD pattern of the product ( Figure III) was recorded using the following acquisition conditions: Tube anode: Cu, Generator tension: 40 kN, Generator current: 40 mA, Start angle: 2.0 °2 ⁇ , End angle: 35.0 °2 ⁇ , Step size: 0.02 °2 ⁇ , Time per step: 2.5 seconds. Characteristic XRPD angles and relative intensities are recorded in Table 1.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (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)
• Plural Heterocyclic Compounds (AREA)
• Thiazole And Isothizaole Compounds (AREA)

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• 2000
  • 2000-06-08 GB GBGB0014006.1A patent/GB0014006D0/en not_active Ceased
• 2001
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