Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-15
2004-11-09
Davis, Zinna Northington (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
06815457
ABSTRACT:
This invention relates 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 1360, 1326, 1241, 714 and 669 cm
−1
; and/or
(ii) provides a Raman spectrum containing peaks at 1581, 768, 670, 271 and 226 cm
−1
; and/or
(iii) provides a solid-state nuclear magnetic resonance spectrum containing peaks at chemical shifts substantially as set out in Table I; and/or
(iv) provides an X-ray powder diffraction (XRPD) pattern containing peaks substantially as set out in Table II.
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.
In one favoured aspect, the Polymorph provides an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. IV.
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 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 a slurry of Compound (I) in aqueous ethanol containing up to about 2.5% w/v water, preferably aqueous denatured ethanol containing up to about 2.5% w/v water, for example 2.5% w/v water, is heated, suitably to a temperature in the range of from 35° C. and 60° C., such as 40° C. to 50° C., for example to 45° C., for an extended period of time, for example 65 hours, after which time the Polymorph is recovered from the denatured ethanol. Optionally, the reaction mixture is seeded with the Polymorph.
In a further process of the invention, Compound (I) is admixed with denatured ethanol, heated to an elevated temperature, preferably a temperature in the range of from 35° C. and 60° C., such as 40° C. to 50° C., for example from 45° to 47° C., over an extended period of time, for example 65 hours, after which time the Polymorph is recovered from the solvent. Optionally, the reaction mixture is seeded with Polymorph.
In a further process a solution of Compound (I) in denatured ethanol containing up to 2.5% w/v water, for example 0.8 to 2.5% w/v water, at 55° C. is seeded with the Polymorph then cooled to a temperature in the range of from 20° C. to 25° C. to provide the Polymorph. The Polymorph is then 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. In our hands this latter process is also effectively carried out using Compound (I) containing up to 25% w/w of the hydrate disclosed in WO99/31093 mentioned above
Conveniently the Polymorph is recovered from the reaction solvent, such as denatured ethanol, by filtration and subsequent drying, preferably at an elevated temperature, for example 45° C.
In a further aspect the present invention also provides a process for preparing Compound (I) (also for convenience referred to as the “Original Polymorph”) from the Polymorph of the invention, which process comprises first preparing a solution of the Polymorph in a mixture (100:1 v/v) of absolute ethanol and methanol, at an elevated temperature, suitably in the range of from 60° C. to 75° C. for example at 68° C., and then allowing the solution to cool to ambient temperature, for example 20-25° C., thereby allowing the Original Polymorph to crystallise.
In a preferred form of the said process to prepare the Original Polymorph, the solution of the Polymorph in the absolute ethanol/methanol mixture is filtered, usually once complete dissolution of the Polymorph is attained and the resulting solution is reheated to an elevated temperature, for example to 65° C., which solution is then allowed to cool to ambient temperature, for example 20 to 25° C.
In the above mentioned processes for preparing the Original Polymorph the solution may be seeded with the Original Polymorph 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.
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 accep
Blackler Paul David James
Giles Robert Gordon
Sasse Michael
Davis Zinna Northington
Kinzig Charles M.
McCarthy Mary E.
Sieburth Kathyrn L.
SmithKline Beecham p.l.c.
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