KR20030007918A - Thiazolidinedione Salt for Treatment of Diabetes Mellitus - Google Patents

Abstract

The present invention is a novel compound for pharmaceuticals, 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvent thereof Cargo, methods for preparing the compound, pharmaceutical compositions comprising the compound, and the use of the compound in medicine.

Description

Thiazolidinedione Salt for Treatment of Diabetes Mellitus}

The present invention relates to novel agents, methods of making the agents and the use of such agents in medicine.

European Patent Application Publication No. 0,306,228 relates to several thiazolidinedione derivatives disclosed as having hypoglycemic activity and hypolipidemic 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 (below) Is also referred to as "Compound I").

International Patent Application Publication No. WO94 / 05659 discloses several salts of the compounds of European Patent No. 0,306,228 (hydrochloric acid, hydrochloric acid and sulfuric acid, and salts formed from organic acids such as mineral acids such as methanesulfonic acid, tartaric acid, in particular maleic acid salts). It includes).

It has now been found that Compound I is particularly stable to form novel hydrobromide salts (also referred to as "hydrobromide" below) suitable for mass production and handling. Hydrobromide has a high melting point, particularly good water solubility, and has good bulk flowability. Thus, hydrobromide is surprisingly easy to handle in large scale pharmaceutical processes, especially large scale milling.

Such new formulations can be prepared by efficient, economical and reproducible methods, which are particularly suitable for large scale preparation.

The new hydrobromide also has useful pharmaceutical properties and is known to be particularly useful for the treatment and / or prevention of diabetes, symptoms associated with diabetes and its various complications.

Accordingly, the present invention provides 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or solvate thereof do.

Suitably, the hydrobromide is monohydrobromide.

In a preferred aspect, hydrobromide provides the infrared spectrum substantially in accordance with FIG. 1.

In a preferred aspect, hydrobromide provides the Raman spectrum substantially in accordance with FIG. 2.

In a preferred aspect, hydrobromide provides an X-ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or FIG. 3.

In a preferred aspect, hydrobromide provides a solid phase ¹³ C NMR spectrum substantially in accordance with FIG. 4.

It is also preferred that the hydrobromide has a melting point of 175 to 185 ° C, in particular 180 to 185 ° C, for example 181 ° C.

Hydrobromide also has a T _onset of 180 to 186 ° C, for example 182.5 ° C.

Thus, in a preferred aspect, hydrobromide is

(i) an infrared spectrum substantially in accordance with FIG. 1;

(ii) substantially the Raman spectrum according to FIG. 2;

(iii) substantially X-ray powder diffraction pattern (XRPD) according to Table 1 or FIG. 3;

(iv) solid phase ¹³ C NMR spectrum substantially in accordance with FIG. 4; And

(v) melting point of 175 to 185 ° C., in particular of 180 to 185 ° C., for example 181 ° C.

It is characterized by providing two or more of them.

The present invention includes hydrobromide or solvate thereof isolated in pure form or mixed with other materials. Thus, in one aspect, an isolated form of hydrobromide or solvate thereof is provided.

In another aspect, hydrobromide or solvate thereof in pure form is provided.

In another aspect, hydrobromide or solvate thereof in crystalline form is provided.

The invention also provides hydrobromide or solvates thereof in solid pharmaceutically acceptable forms, for example solid dosage forms, in particular modified forms for oral administration.

The present invention also provides hydrobromide or solvates thereof in pharmaceutically acceptable form, in particular bulk form, which form is particularly crushable.

The present invention also provides hydrobromide or solvates thereof in pharmaceutically acceptable form, in particular bulk form, which form has good flowability, in particular good bulk flowability.

Suitable solvates are hydrates.

The present invention is also preferably 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4- dispersed or dissolved in a suitable solvent. The hydrobromide of the present invention, characterized by reacting dione (compound I) or a salt thereof with a hydrogen bromide source, and then, if necessary, preparing a solvate of the formed hydrobromide and recovering the hydrobromide or solvate thereof. Provided are methods for preparing the solvates thereof.

Suitable reaction solvents are alkanols such as propan-2-ol, or hydrocarbons such as toluene, ketones such as acetone, esters such as ethyl acetate, ethers such as tetrahydrofuran, nitrile, For example acetonitrile, or halogenated hydrocarbons such as dichloromethane, water, or organic acids such as acetic acid; Or mixtures thereof.

The hydrogen bromide source is advantageously provided in an aqueous hydrogen bromide solution, for example a 48% (w / w) aqueous solution. Alternatively, the hydrogen bromide source is a solution of hydrogen bromide in a suitable solvent, optionally a reaction solvent such as propan-2-ol. Hydrogen bromide can also be added directly to a solution or suspension of compound I in the selected reaction solvent.

Other sources of hydrogen bromide are provided by base salts of hydrobromic acid, for example ammonium bromide, or hydrobromic acid salts of amines, for example ethylamine or diethylamine.

The reaction is generally carried out at ambient or elevated temperature, for example at the reflux temperature of the solvent, but any convenient temperature can be used which gives the required product.

Solvates, such as hydrates, of hydrobromide are prepared according to conventional methods.

Recovery of the required compound generally comprises crystallization from a suitable solvent, advantageously the reaction solvent, generally by cooling to a temperature of 0 to 60 ° C., for example 20 to 25 ° C., or 40 to 50 ° C. For example, hydrobromide can be crystallized from alcohols such as propan-2-ol, or ketones such as acetone.

In a preferred form, the recovery comprises initiating crystallization by initial cooling to a first temperature, for example 40-50 ° C., and then cooling to a second temperature, suitably 0-25 ° C., to complete the crystallization.

Crystallization may be initiated by seeding crystals of hydrobromide or solvates thereof, but is not required.

Solvates are prepared using appropriate conventional methods.

Compound I is prepared according to known methods, for example the methods disclosed in EP 0,306,228 and WO 94/05659. The disclosures of European Patent Nos. 0,306,228 and WO94 / 05659 are incorporated herein by reference.

As used herein, the term "T _disclosure " is generally determined by differential scanning calorimetry, see, for example, "Pharmaceutical Thermal Analysis, Techniques and Applications", Ford and Timmins, 1989; "The temperature corresponding to the intersection of the pre-transition baseline with the extrapolated leading edge of the transition ".

As used herein for a certain compound, "good fluidity" is suitably characterized in that the compound has a Hausner ratio of 1.5 or less, in particular 1.25 or less.

"Housner ratio" is an acceptable term in the art.

As used herein, the term 'prevention of symptoms associated with diabetes' includes treatment of symptoms such as insulin resistance, impaired glucose tolerance, hyperinsulinemia and diabetes during pregnancy.

Diabetes preferably means type II diabetes.

Symptoms associated with diabetes include hypercalcemia, insulin resistance and obesity. Further symptoms associated with diabetes include hypertension, cardiovascular diseases, in particular atherosclerosis, various relapsing diseases, especially symptoms related to decreased appetite, such as anorexia nervosa, and diseases associated with excessive intake, for example Control of appetite and food intake in subjects suffering from obesity and anorexia bulimia. Additional symptoms associated with diabetes include polycystic ovary syndrome and steroid induced insulin resistance.

Complications of the symptoms associated with diabetes included herein include kidney disease, particularly nephropathy associated with the development of type II diabetes, including diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive neurosis and terminal kidney disease.

As mentioned above, the compounds of the present invention have useful therapeutic properties, and therefore the present invention provides hydrobromide or solvates thereof useful as active therapeutic substances.

More specifically, the present invention provides hydrobromide or a solvate thereof useful for the treatment and / or prevention of diabetes mellitus, symptoms associated with diabetes and its various complications.

The hydrobromide or solvate thereof may be administered on its own or preferably in a pharmaceutical composition comprising a pharmaceutically acceptable carrier. Suitable methods of formulating hydrobromide or solvates thereof are generally as disclosed for compound I in the abovementioned documents.

Accordingly, the present invention also provides a pharmaceutical composition comprising hydrobromide or solvate thereof, and a pharmaceutically acceptable carrier thereof.

Hydrobromide or solvate thereof is generally administered in a single dosage form.

The active compound may be administered by any suitable route, but is generally administered by oral or parenteral route. For such use, the compounds will generally be used in the form of pharmaceutical compositions mixed with pharmaceutical carriers, diluents and / or excipients, although the exact form of the composition will depend upon the mode of administration inherent.

The compositions are prepared in admixture and are suitably modified for oral, parenteral or topical administration, in which case tablets, capsules, liquid oral formulations, powders, granules, lozenges, pastilles, resoluble powders, liquor It may be in the form of solutions or suspensions for use and infusion, suppositories and transdermal devices. Orally administrable compositions, especially shaped oral compositions, are preferred because they are more advantageous for general use.

Tablets and capsules for oral administration are generally provided in unit doses and include conventional excipients such as binders, fillers, diluents, tablets, lubricants, disintegrants, colorants, flavors and wetting agents. Purification can be encoded according to methods well known in the art.

Suitable fillers for use include cellulose, mannitol, lactose and other similar materials. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

Solid oral compositions can be prepared by conventional methods such as blending, filling or tableting. The blending operation can be repeated to distribute the active agent throughout the composition with a large amount of filler. Such manipulation is, of course, common in the art.

Oral liquid preparations can be provided, for example, in the form of aqueous or oil suspensions, solutions, emulsions, syrups or elixirs, or as dry products which are dissolved in water or other suitable vehicle prior to use. Such liquid preparations are conventional additives, for example suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifiers, for example lecithin Sorbitan monooleate or acacia; Non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oil esters such as esters of glycerin, propylene glycol or ethyl alcohol; Preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.

For parenteral administration, fluid unit dosage forms are prepared to include a compound of the invention and a sterile vehicle. The compound may be suspended or dissolved depending on the vehicle and concentration. Parenteral solutions are typically prepared by dissolving the active compound in the vehicle, filtering and sterilizing, then filling into a suitable vial or ampoule and sealing. Adjuvants such as local anesthetics, preservatives and buffers are also advantageously dissolved in the vehicle. To increase stability, the composition can be filled into a vial and the water removed in vacuo and then frozen.

Parenteral suspensions are prepared in substantially the same manner except that the active compound is exposed to ethylene oxide to dissolve, sterilize and then suspend in a sterile vehicle, instead of suspending in a vehicle. It is advantageous to include surfactants or wetting agents in the compositions to promote uniform distribution of the active compounds.

As in normal practice, compositions generally involve handwritten or printed instructions for use in related medical treatments.

As used herein, the term 'pharmaceutically acceptable' includes compounds, compositions and components for use in both humans and animals, for example the term 'pharmaceutically acceptable salts' is veterinary acceptable. Salts.

The present invention comprises the administration of a nontoxic effective amount of hydrobromide or a solvate thereof to a human or non-human mammal in need of treatment and / or prevention of diabetes mellitus, symptoms associated with diabetes and various complications thereof. And / or methods of prevention.

Advantageously, the active ingredient may be administered in a pharmaceutical composition as defined above, which forms a particular aspect of the present invention.

In a further aspect, the present invention provides the use of hydrobromide or a solvate thereof in the manufacture of a medicament for the treatment and / or prevention of diabetes mellitus, symptoms associated with diabetes and various complications thereof.

In the treatment and / or prophylaxis of diabetes mellitus, diabetes related symptoms and various complications thereof, hydrobromide or solvate thereof may be prepared using Compound I at a suitable dosage such as disclosed in European Patent Nos. 0,306,228, WO94 / 05659 and WO98 / 55122. It may be administered in an amount provided.

The treatment mentioned above did not show any toxicologically adverse effects on the compounds of the present invention.

The following examples are merely to illustrate the invention and do not limit the invention in any way.

Example 1:

5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide

5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (1.0 g) and propan-2-ol (50 ml ) Was stirred and heated to reflux for 10 minutes at which point a clear solution was observed. Hydrobromic acid (48% (w / w) solution in water, 0.31 ml) was then added dropwise and the reaction mixture was stirred at reflux for 10 minutes and then cooled to 21 ° C. The product was collected by filtration and washed with propan-2-ol (10 ml) to give 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] as a white crystalline solid. Benzyl] thiazolidine-2,4-dione hydrobromide (0.41 g) was obtained.

Example 2:

5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide

A mixture of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (3.0 g) and acetone (100 ml) Stirred and heated to reflux for 15 minutes at which point a clear solution was observed. Hydrobromic acid (48% (w / w) solution in water, 0.95 ml) was added and the reaction mixture was stirred at reflux for 15 minutes and then cooled to 21 ° C. After standing for 120 hours, the mother liquor was decanted and the crystalline product was washed with acetone (10 ml) and vacuum dried for 3 hours to give 5- [4- [2- (N-methyl-N- (2-pyridyl) Amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide (3.7 g) was obtained.

1H-NMR (d6-DMSO): 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] containing acetone (0.5% (wt / wt)) Matches thiazolidine-2,4-dione hydrobromide.

Example 3:

5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide

A mixture of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (15.0 g) and acetone (230 ml) Stirred and heated to reflux for 15 minutes at which point a clear solution was observed. Hydrobromic acid (48% (w / w) aqueous solution, 4.75 ml) was then added and the mixture was cooled to 45 ° C., stirred for 1 hour and then cooled to 21 ° C. The white solid was collected by filtration and washed with acetone (100 ml) to give the white crystalline solid 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thia Zolidine-2,4-dione hydrobromide (17.7 g) was obtained.

Characteristic data for hydrobromide

(1) Recording of the product of Example 3

Solubility of Hydrobromide

Water solubility was measured by adding water to about 100 mg of drug substance in fractions of 1 to 1,000 ml until the powder dissolved. Visible solubility was confirmed by HPLC analysis of the saturated solution. Solubility: 6 mg / ml

Solid Phase Stability of Hydrobromide

About 1.0 g of drug substance is stored in a glass jar under conditions of a) 40 ° C./RH 75%, open exposure, 1 month, and b) 50 ° C., closed, 1 month to determine the solid phase stability of the drug substance. It was. In both cases the material was analyzed for final content and degradation products by HPLC.

a) 40 ° C./75% RH: No significant degradation was observed (HPLC analysis 98% initial)

b) 50 ° C .: No significant degradation was observed (HPLC analysis 98% initial)

Hydrobromide Fluidity

The ratio between the bulk density of the hydrobromide and the tapped bulk density (Housner ratio) using standard methods ("Pharmaceutics-The Science of Dosage Form Design", editor M. Aulton, 1988, published by Churchill Livingstone) Was determined. Hausner ratio: 1.3

T of hydrobromide _Start

T _initiation of drug substance was determined by differential scanning calorimetry using a Perkin-Elmer DSC7 device. T _start : 182.5 ℃

Melting Point of Hydrobromide

The melting point of the drug substance was visually determined by hot stage microscopy. Mpt: 181 ℃

(2) Recording of the product of Example 2

An infrared absorption spectrum of the mineral oil dispersion of the product was obtained using a Nicolet 710 FT-IR spectrometer at 2 cm ⁻¹ resolution (FIG. 1). Data was quantified at 1 cm ⁻¹ intervals. Bands are 2923, 2854, 2749, 1745, 1698, 1643, 1610, 1544, 1515, 1459, 1419, 1378, 1327, 1313, 1287, 1256, 1240, 1228, 1203, 1185, 1151, 1071, 1054, 1032, It was observed at 1014, 985, 906, 803, 771, 738, 712 and 524 cm ^-1 .

The IR spectrum of the solid product was recorded using a conventional ATR accessory. Bands are 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 and 657 cm ⁻¹ . Raman spectra of the product as a sample in an NMR tube using a Nicolet 960 ESP FT-Raman spectrometer at a resolution of 4 cm ⁻¹ , excited with a 400 mW Nd: V04 laser (1064 nm) (FIG. 2) Recorded. The bands are 3067, 2997, 2926, 2884, 2860, 1747, 1611, 1588, 1545, 1445, 1382, 1360, 1315, 1287, 1240, 1213, 1185, 1070, 1016, 986, 917, 826, 769, 740, 712, 659, 636, 620, 605, 506, 470, 405, 332, 303, 134 and 99 cm ⁻¹ .

The XRPD pattern of the product (Figure 3) was recorded using the following acquisition conditions: tube anode: Cu, generator voltage: 40 kV, generator current: 40 mA, start angle: 2.0 ° 2θ, end angle: 35.0 ° 2θ , Step size: 0.02 ° 2θ, time per step: 2.5 seconds. Characteristic XRPD angles and relative intensities are shown in Table 1 below.

Claims (10)

5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide compound or solvate thereof. The method of claim 1, (i) an infrared spectrum substantially in accordance with FIG. 1; (ii) substantially the Raman spectrum according to FIG. 2; (iii) substantially X-ray powder diffraction pattern (XRPD) according to Table 1 or FIG. 3; (iv) solid phase ¹³ C NMR spectrum substantially in accordance with FIG. 4; And (v) melting point of 175 to 185 ° C., in particular of 180 to 185 ° C., for example 181 ° C. A compound characterized by providing two or more of them. The compound according to claim 1 or 2, which is in purified form. The compound of any one of claims 1-3, which is in a solid dosage form. 4. A compound according to any one of claims 1 to 3 in crushable pharmaceutically acceptable form. 4. A compound according to any one of claims 1 to 3 in a pharmaceutically acceptable form with good fluidity. 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione or a salt thereof is reacted with a hydrogen bromide source and then If so prepared for the solvate of the hydrobromide formed, and recovering the hydrobromide or solvate thereof, 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) Methoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof. 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof, and pharmaceutically acceptable thereof A pharmaceutical composition comprising a carrier. 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide compound or solvate thereof used as therapeutically active substance . 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or solvate thereof, associated with diabetes, diabetes Use in the manufacture of a medicament for the treatment and / or prevention of symptoms and various complications thereof.