Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-03
2004-10-19
Richter, Johann (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S269700
Reexamination Certificate
active
06806280
ABSTRACT:
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.
International Patent Application, Publication Number WO94/05659 discloses certain thiazolidinedione derivatives having hypoglycaemic and hypolipidaemic activity including 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt (hereinafter also referred to as “Compound (I)”).
International Patent Applications, Publication Numbers WO99/31093, WO99/31094 and WO99/31095 each disclose distinct hydrates of Compound (I).
It has now been discovered that Compound (I) exists in a novel polymorphic form which is particularly suitable for bulk preparation and handling. The novel form can be prepared by an efficient, economic and reproducible process particularly suited to large-scale preparation.
The novel polymorphic form (‘the Polymorph’) 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 a polymorphic form of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt characterised in that it:
(i) provides an infra red spectrum containing peaks at 1763, 912, 856 and 709 cm
−1
; and/or
(ii) provides a Raman spectrum containing peaks at 1762, 1284, 912 and 888 cm
−1
; and/or
(iii) provides a solid-state
13
C nuclear magnetic resonance spectrum containing peaks at 111.0, 113.6, 119.8, 129.1, 130.9, 131.8, 134.7, 138.7, 146.5, 152.7, 157.5, 169.5, 171.0, 178.7 ppm; and/or
(iv) provides an X-ray powder diffraction (XRPD) pattern which gives calculated lattice spacings at 5.87, 5.30, 4.69, 4.09, 3.88, 3.61, 3.53 and 3.46 Angstroms.
In one favoured aspect, the Polymorph provides an infrared spectrum substantially in accordance with FIG. I.
In one favoured aspect, the Polymorph provides a Raman spectrum substantially in accordance with FIG. II.
In one favoured aspect, the Polymorph provides a solid-state nuclear magnetic resonance spectrum substantially in accordance with FIG. III and/or Table I.
In one favoured aspect, the Polymorph provides an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. IV and/or Table II.
The present invention encompasses the Polymorph isolated in pure form or when admixed with other materials, for example the known forms of Compound I (or the “Original Polymorph”) or any other material.
Thus in one aspect there is provided the Polymorph in isolated form.
In a further aspect there is provided the Polymorph in pure form.
In yet a further aspect there is provided the Polymorph in crystalline form.
The invention also provides a process for preparing the Polymorph, characterised in that Compound (I) is suspended in acetone, preferably under an inert atmosphere such as nitrogen, and stirred at an elevated temperature, preferably reflux temperature, for an extended period of time, for example 17 hours, after which time the Polymorph is isolated from the reaction mixture.
In an alternative process a solution of Compound (I) in denatured ethanol at an elevated temperature, for example 50° C., is seeded with crystals of the Polymorph then cooled, preferably to a temperature in the range of from 20-25° C., so as to provide the Polymorph, after which time the Polymorph is recovered from the denatured ethanol. The solution of Compound (I) in the denatured ethanol is conveniently prepared by dissolving Compound (I) in the required amount of denatured ethanol at an elevated temperature, for example 60° C.
Typically the Polymorph is recovered from the reaction by filtration and subsequent drying, usually at an elevated temperature, for example 50° C.
In a further aspect, the invention provides a process for converting Polymorph to Compound (I), wherein a solution of Polymorph in a suitable solvent, such as acetone or ethanol, is seeded with Compound (I). Generally, the solution of Polymorph is obtained by dissolving Polymorph at an elevated temperature in the solvent, such as acetone or ethanol.
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.
For the avoidance of doubt the term “Compound (I)” as used herein refers to the form of 5-[4-[2-(N-methyl-N(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt as disclosed an characterised in International Patent Application, Publication Number WO94/05659.
When used herein “denatured ethanol” means ethanol containing small amounts of methanol, usually up to 5% v/v of methanol, such as from 0.9% v/v to 5% v/v of methanol, for example ethanol containing 4% v/v of methanol.
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.
As mentioned above the compound of the invention has useful therapeutic properties: The present invention accordingly the Polymorph for use as an active therapeutic substance.
More particularly, the present invention provides the Polymorph for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
The Polymorph may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. The formulation of the Polymorph and dosages thereof are generally as disclosed for Compound (I) in International Patent Application, Publication Number WO94/05659 or WO98/55122.
Accordingly, the present invention also provides a pharmaceutical composition comprising the Polymorph and a pharmaceutically acceptable carrier therefor.
The Polymorph 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. For such use, 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, tablet
Blackler Paul David James
Browne Christine Marie
Coakley Timothy G.
Giles Robert Gordon
Morrissey Gillian
Kinzig Charles M.
McCarthy Mary E.
Richter Johann
Robinson Binta
Sieburth Kathryn I.
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