HK1012363B - Substituted thiazolidinedione derivatives - Google Patents

Description

This invention relates to certain novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.

European Patent Applications, Publication Numbers 0,306,228 and 0419035 relate to certain thiazolidinedione derivatives disclosed as having hypoglycaemic and hypolipidaemic activity.

It is now surprisingly indicated that a specific group of compounds from within formula (I) of EP-A-0,306,228 have improved selectivity of action and are therefore of particular use in the treatment of Type II diabetes. These compounds are also indicated to be of particular use for the treatment and/or prophylaxis of other diseases including hyperlipidaemia, hypertension and cardiovascular disease, especially atherosclerosis. In addition these compounds are considered to be useful for treating 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.

These compounds show good aqueous stability and good stability in the solid form, certain of these compounds are indicated to be particularly stable. In addition these compounds are significantly more soluble in water than the corresponding free base.

The surprising and advantageous stability and aqeous solubility of these compounds provides for significant formulation and bulk handling advantages.

Accordingly, the present invention provides 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt or an isomer or tautomeric form thereof and/or a pharmaceutically acceptable solvate thereof.

The compounds of the invention are salts. The present invention extends to all forms of such salts including those provided by association of the salting hydrogen with all possible salt forming parts of the molecule and especially that provided by association with the pyridine nitrogen.

As indicated above a compound of the invention may exist in one of several tautomeric forms, all of which are encompassed by the present invention. It will be appreciated that the present invention encompasses all of the isomeric forms of the compounds of the invention, including any stereoisomeric forms thereof, whether as individual isomers or as mixtures of isomers.

Suitable pharmaceutically acceptable solvates include hydrates.

In a further aspect the present invention also provides a process for the preparation of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt, or an isomer or tautomeric form thereof and/or a pharmaceutically acceptable solvate thereof, which process comprises reacting 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione with a source of maleate ion HOOC.CH=CH.COO^-; and thereafter if required preparing a pharmaceutically acceptable solvate thereof.

The reaction between 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione and the source of maleate ion is generally carried out under conventional salt forming conditions, for example by admixing 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione and the source of maleate ion, suitably in approximately equimolar amounts but preferably using a slight excess of the source of maleate ion, in a solvent, generally a C_1-4 alkanolic solvent such as ethanol, at any temperature which provides a suitable rate of formation of the required product, generally at an elevated temperature for example at the reflux temperature of the solvent and thereafter crystallising the required product.

Pharmaceutically acceptable solvates of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt may be prepared using conventional chemical procedures.

5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione may be prepared according to methods disclosed in EP-A-0306228.

Suitable sources of maleic acid are known commercially available sources or it may be prepared according to known procedures.

Where appropriate the isomeric forms of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt and the pharmaceutically acceptable salts thereof may be prepared as individual isomers using conventional chemical procedures.

The stability of the compounds of the invention may be determined using conventional quantitative analytical methods: For example the stability of the compounds in the solid form may be determined by using accelerated stability tests such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and isothermal testing at elevated temperatures including conventional storage tests wherein the test compounds are stored under controlled conditions of temperature and humidity over known periods of time. Quantitative analysis of the test compounds, against appropriate reference standards before, during and after the storage period allows the stability of the test compound to be determined.

As stated the compounds of the invention are significantly more soluble in water than the corresponding free base. Thus a convenient method for determining the stability of the compounds of the invention in aqueous solution involves determining the degree of precipitation of the parent free base from an aqueous solution of the test compound at known conditions of temperature and over known periods of time. We have found that the compounds of the invention show good aqueous stability. In particular 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt is particularly stable in aqueous solution. Most surprisingly, the compounds of the invention wherein the maleate ion is HOOC.CH=CH.COO^- were found to be particularly stable in aqueous solution.

The quantitative analysis of the test compounds in the above mentioned tests may be carried out using conventional methods, generally chromatographic methods such as high pressure liquid chromatography.

As mentioned above the compounds of the invention are indicated as having useful therapeutic properties:

The present invention accordingly provides 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt or an isomer or tautomeric form thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.

Thus the present invention provides 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt or an isomer or tautomeric form thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of hyperglycaemia.

In a further aspect the present invention also provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment and/or prophylaxis of hyperlipidaemia.

As indicated hereinbefore the present invention also provides a compound of formula (I) or a tautomeric form thereof and/or a pharmaceutically acceptable solvate thereof for use in the treatment of hypertension and cardiovascular disease.

Cardiovascular disease includes in particular atherosclerosis.

5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt or an isomer or tautomeric form thereof and/or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.

Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.

As used herein the term 'pharmaceutically acceptable' embrases compounds, compositions and ingredients for both human and veterinary use: for example the term 'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt.

The composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.

Usually the pharmaceutical compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged.

Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as powders presented in sachets, may also be used.

In accordance with conventional pharmaceutical practice the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.

Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate.

Most suitably the composition will be formulated in unit dose form. Such unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more especially 0.1 to 250 mg.

Conveniently, the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.

In the treatment and/or prophylaxis of hyperglycaemic humans, and/or the treatment and/or prophylaxis of hyperlipidaemic human, the compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable solvate thereof, may be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg.

In the treatment and/or prophylaxis of hyperglycaemic non-human mammals, especially dogs, the active ingredient may be adminstered by mouth, usually once or twice a day and in an amount in the range of from about 0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg. Similar dosage regimens are suitable for the treatment and/or prophylaxis of hyperlipidaemia in non-human mammals.

The dosages regimens for the treatment of hypertension and cardiovascular disease will generally be those mentioned above in relation to hyperglycaemia.

In a further aspect the present invention provides the use of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt or an isomer or tautomeric form thereof and/or a pharmaceutically acceptable solvate thereof for the manufacture of a medicament for the treatment and/or prophylaxis of hyperglycaemia.

The present invention also provides the use of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of hyperlipidaemia, hypertension or cardiovascular disease.

The following Example illustrates the invention but does not limit it in any way.

Example 1 5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt

5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (470g) and maleic acid (137g) were dissolved in ethanol (41.) at boiling. The hot solution was filtered via diatomaceous earth and was then allowed to cool slowly with gentle agitation. After leaving in a refrigerator at 0-5°C for several hours, the maleate salt was filtered off, washed with ethanol and dried in vacuo at 50° to give 446g (73%) of product, m.p. 120-121°C.

1H NMR δ (d₆-DMSO): 3.0-3.35 (2H, complex); 3.10 (3H, s); 3.95 (2H, t); 4.15 (2H, t); 4.85 (1H, complex); 6.20 (2H, s); 6.65 (1H, t); 6.85 (3H, complex); 7.15 (2H, d) 7.65 (1H, t); 8.05 (1H, complex); 11.85-12.1 (1H, broad, exchanges with D₂0).

A very broad signal was observed in the range 2-5ppm which is thought to be due to residual water from the solvent and the exchangeable carboxylic acid protons.

Example 2 5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt

5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt (294.6g, 0.825M) and maleic acid (95.8g 0.825m) were stirred in refluxing ethanol (2.71) until all the solid had dissolved. Decolourising charcoal was added and the hot solution filtered through celite, allowed to cool to room temperature with stirring. After cooling in a refrigerator at 0-5°C for several hours, the title compound was filtered, collected and dried at 50°C under vacuum overnight to give 364.1g (87%) of product, m.p. 119 - 119.5°C.

The 1H NMR spectra was as for Example 1.

Claims (6)

1. A compound 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt or an isomer or tautomeric form thereof and/or a pharmaceutically acceptable solvate thereof.
2. A process for preparing 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt, or an isomer or tautomeric form thereof and/or a pharmaceutically acceptable solvate thereof, which process comprises reacting 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione with a source of maleate ion HOOC.CH=CH.COO^-; and thereafter if required preparing a pharmaceutically acceptable solvate thereof.
3. A pharmaceutical composition, comprising 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt or an isomer or tautomeric form thereof, and/or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.
4. 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt or an isomer or tautomeric form thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.
5. 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt or an isomer or tautomeric form thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of hyperglycaemia, hyperlipidaemia, hypertension and cardiovascular disease.
6. The use of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt or an isomer or tautomeric form thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of hyperglycaemia, hyperlipidaemia, hypertension and cardiovascular disease.