JP2003535862A - Thiazolidinedione salts for the treatment of diabetes - Google Patents

Abstract

  (57) [Summary] The present invention relates to a novel compound 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof. , A process for the preparation of the compound, a pharmaceutical composition comprising the compound and the use of the compound in medicine.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to a novel drug, a method for producing the drug, and use of the drug in medicine.

Prior Art European Patent Application Publication No. 0306228 relates to certain thiazolidinedione derivatives disclosed as having hypoglycemic and hypolipidemic activity. E
The compound of Example 30 of P03062228 was 5- [4- [2- (N-methyl-N- (2
-Pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (hereinafter,
"Compound (I)").

International Patent Application Publication No. WO 94/05659 describes salts formed from hydrobromic acid, mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as methanesulfonic acid, tartaric acid,
Disclosed are particular salts of the compounds of EP 0306228, including especially the maleate salt.

DISCLOSURE OF THE INVENTION Compound (I) now forms a novel hydrobromide salt (hereinafter also referred to as “hydrobromide”), which is particularly stable and therefore suitable for mass production and processing. It was found. This hydrobromide also has a high melting point, exhibits particularly good water solubility and has good bulk flow properties. Therefore, this hydrobromide is surprisingly adapted to large-scale pharmaceutical processing, especially large-scale milling operations. This new form can be prepared by efficient, economical and reproducible methods, especially suitable for large scale production. This novel hydrobromide also possesses valuable pharmaceutical properties and is said to be particularly useful for the treatment and / or prevention of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof. Therefore, the present invention provides 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof. provide. Suitably the hydrobromide is the monohydrobromide salt.

In one preferred embodiment, hydrobromide provides an infrared spectrum substantially according to FIG. In one preferred embodiment, hydrobromide provides a Raman spectrum substantially according to Figure II. In one preferred embodiment, the hydrobromide is substantially the same as X according to Figure III.
-Provides a X-ray powder diffraction pattern (XRPD). In one preferred embodiment, hydrobromide provides a solid state ¹³ C-NMR spectrum substantially according to Figure IV. The hydrobromide preferably has a melting point in the range 175 to 185 ° C, in particular 180 to 185 ° C, for example 181 ° C. The hydrobromide is also in the range of 180-186 ° C, for example 18
It has a _Tonset of 2.5 ° C.

Thus, in a preferred embodiment, the hydrobromide comprises two or more: (i) an infrared spectrum substantially according to Figure I; (ii) a Raman spectrum substantially according to Figure II; (iii) substantially. X-ray powder diffraction pattern (XRP) according to Table 1 or FIG.
D); (iv) a solid state ¹³ C NMR spectrum substantially according to Figure IV; and (v) in the range 175 to 185 ° C, in particular 180 to 185 ° C, for example 181.
It is characterized by providing a melting point of ° C.

The present invention includes hydrobromide or its solvates either isolated in pure form or mixed with other substances. Thus, in one aspect, an isolated form of hydrobromide or a solvate thereof is provided. In a further aspect, a pure form of hydrobromide or a solvate thereof is provided. In another further embodiment, a crystalline form of hydrobromide or a solvate thereof is provided. Furthermore, the present invention provides a solid pharmaceutically acceptable form of hydrobromide, such as a solid dosage form, or a solvate thereof, particularly when suitable for oral administration. Moreover, the present invention also provides hydrobromide or a solvate thereof in pharmaceutically acceptable form, especially in bulk form, especially in the form which can be milled. Furthermore, the present invention provides a hydrobromide or a solvate thereof in a pharmaceutically acceptable form, especially in bulk form, which has good flow properties, in particular a form which has good bulk flow properties. A suitable solvate is a hydrate.

The present invention also preferably disperses or dissolves 5- (4- (2- (
N-methyl-N- (2-pyridyl) amino) ethoxy) benzyl) thiazolidine-2,
4-dione (compound (I)) or a salt thereof is reacted with a source of hydrogen bromide,
Then, if necessary, a solvate of hydrobromide is prepared, and the hydrobromide or its solvate is recovered, which provides a method for producing hydrobromide or its solvate.

Suitable solvents are alkanols, for example hydrocarbons such as propan-2-ol or toluene, ketones such as acetone, esters such as ethyl acetate, ethers such as tetrahydrofuran, nitrites such as acetonitrile, or halogenated halogens such as dichloromethane. Hydrocarbon, water, or organic acid such as acetic acid; or a mixture thereof. The source of hydrogen bromide is conveniently provided by an aqueous solution of hydrogen bromide, for example a 48% w / w solution in water. The source of hydrogen bromide is also a solution of hydrogen bromide in a suitable solvent, optionally a reaction solvent such as propan-2-ol. in addition,
Hydrogen bromide can be added directly into a solution or suspension of compound (I) in the reaction solvent of choice.

Another source of hydrogen bromide is provided by basic salts of hydrobromic acid, such as aluminum iodide, or hydrobromic salts of amines such as 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, and any convenient temperature that provides the desired product can be used. Solvates of hydrobromide, such as hydrates, are prepared by conventional procedures.

Recovery of the desired compound is generally generally 0 ° C. to 60 ° C., eg 20 ° C. to 25 ° C.
Alternatively it consists in crystallizing from a suitable solvent, conveniently the reaction solvent, by cooling to a temperature in the range 40 ° C to 50 ° C. For example, hydrobromide can be crystallized from alcohols such as propan-2-ol or ketones such as acetone. In one preferred form, the recovery is first cooled to a first temperature, for example a temperature in the range of 40 to 50 ° C, thereby initiating crystallization, and then to a second temperature, suitably 0 to 25 ° C. Including cooling to a range of temperatures.

Crystallization can also be initiated by seeding with crystals of hydrobromide or a solvate thereof, although this operation is not essential. Compound (I) can be prepared according to known procedures such as EP0306228 and WO94 / 0.
Prepared according to the procedure as disclosed in 5659. The contents of EP 0306228 and WO 94/05659 are incorporated herein by reference. The term “T _onset ” as used herein is generally measured by differential scanning calorimetry, eg, “temperature at the intersection of the pretransition baseline and the transitioned extrapolated leading end”. As, Pharmaceutical Thermal Analysis, Techniq
ues and Applications, Ford and Timmins, 1989, with their generally recognized significance.

The term “good flow properties” as used herein for a particular compound refers to a compound having a Hausner ratio of 1.5 or less, especially 1.25 or less. Characterized "Hausner ratio" is a term understood in the art. The term "prevention of conditions associated with diabetes mellitus" as used herein includes treatment of conditions such as insulin resistance, impaired glucose tolerance, hyperinsulinemia and gestational diabetes.

Preferably, diabetes mellitus is type II diabetes. Conditions associated with diabetes include hyperglycemia and insulin resistance and obesity. Further diabetes-associated conditions are hypertension, cardiovascular diseases, in particular atherosclerosis, certain eating disorders, especially diseases associated with reduced eating such as anorexia nervosa, and obesity, bulimia nervosa. Including regulation of appetite and food intake in subjects suffering from disorders related to overeating such as. Additional symptoms associated with diabetes include polycystic ovary syndrome and steroid-induced insulin resistance. The complications of conditions associated with diabetes mellitus included herein are renal diseases, especially I
Includes kidney disease related to the development of type I diabetes, diabetic nephropathy, glomerulonephritis,
It includes glomerulosclerosis, nephrotic syndrome, hypertensive nephropathy and end-stage renal disease.

As mentioned above, the compounds of the present invention have useful therapeutic properties: Therefore, the present invention provides hydrobromide salts or solvates thereof for use as active therapeutic substances. More particularly, the present invention provides hydrobromide salts or solvates thereof for use in the treatment and / or prevention of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof. The hydrobromide salt or solvate thereof may be administered per se or, preferably, as a pharmaceutical composition with a pharmaceutically acceptable carrier. In general, suitable methods for formulating the hydrobromide salt or its solvates are those disclosed for compound (I) in the above publications.

Accordingly, the present invention also provides a pharmaceutical composition comprising a hydrobromide salt or a solvate thereof and a pharmaceutically acceptable carrier. Hydrobromide or its solvates will usually be administered in a unit dosage form. The active compound can be administered by any suitable route, but is usually administered by the oral or parenteral route. For said use, the compound is usually used in the form of a pharmaceutical composition with pharmaceutically acceptable carriers, diluents and / or excipients, but necessarily the exact form of the composition is It will depend on the method of administration.

The composition is prepared by mixing and is suitably adapted for oral, parenteral or topical administration, tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles,
It may also be in the form of reconstituted powders, injection and infusion solutions or suspensions, suppositories and transdermal devices. Orally administrable compositions, especially shaped oral compositions, are preferred, as they are more advantageous for general use. Tablets and capsules for oral administration are usually presented in unit doses, and conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavors and humectants. including. The tablets can be coated according to methods well known in the art. Fillers suitable for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable humectants include sodium lauryl sulfate.

Solid oral compositions can be prepared by conventional methods of blending, filling, tabletting and the like.
Repeated mixing operations can be used to disperse the active agent in compositions that use large amounts of filler. The operation is, of course, routine in the art. Oral liquid formulations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or as a dry product for reconstitution with water or other suitable vehicle before use. May be given. The liquid formulations may be formulated with conventional additives such as suspending agents such as sorbitol, syrups, methylcellulose,
Gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hardened edible fats, emulsifiers such as lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may be wrapped in edible oils) such as almond oil, coconut oil, Oily 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,
It may contain conventional flavors or colorants.

For parenteral administration, liquid unit dosage forms are prepared containing a compound of the invention and a sterile vehicle. The compound, depending on the vehicle and concentration, can be either suspended or dissolved. Parenteral solutions are usually prepared by dissolving the active compound in the vehicle, filter sterilizing, then filling into suitable vials or ampoules and sealing. Advantageously, adjuvants such as local anesthetics, preservatives and buffers are also dissolved in the vehicle. To improve stability, the composition can be frozen after filling the vial and the water removed under reduced pressure.

Parenteral suspensions are prepared in substantially the same manner except that the active compound is suspended in the vehicle instead of being dissolved and sterilized by exposure to ethylene oxide before suspension in the sterile vehicle. Is prepared in. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound. As in the general method, the composition will generally be accompanied by written or printed instructions for use in the relevant medical treatment. The term "pharmaceutically acceptable" as used herein includes compounds, compositions and ingredients for human and veterinary use: For example, the term "pharmaceutically acceptable salt" Wrap with veterinary acceptable salt. The present invention further provides a method for the treatment and / or prevention of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof in a human or non-human mammal, wherein the treatment and / or prevention is required. Provided is a method which comprises administering to a human or non-human mammal an effective, non-toxic amount of a hydrobromide salt or a hydrate thereof. Advantageously, the active ingredient can be administered as a pharmaceutical composition as described above, which forms a special aspect of the invention.

In a further aspect, the invention provides a hydrobromide salt or a solvate thereof in the manufacture of a medicament for the treatment and / or prevention of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof. Provide use. In the treatment and / or prevention of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof, hydrobromide or a solvate thereof may be administered at a suitable dose, eg EP 0,306,228, WO 94/05659. Or WO98 / 5512
It may be provided in an amount to give compound (I) in a dosage as described in 2. No adverse toxicological effects are shown in the above treatments with the compounds according to the invention. The following examples illustrate the invention but do not limit it in any way.

Example 1: 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide 5- [4 A mixture of-[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 cleared. Heated to reflux for 10 minutes until a different solution was observed. Hydrobromic acid (48% w / w aqueous solution, 0.31 ml) was then added dropwise and the reaction mixture was refluxed with stirring for 10 minutes and then cooled to 21 ° C. The product was collected by filtration, washed with propan-2-ol (10 ml), 5- [4-
[2- (N-Methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide (0.41 g) was obtained as a white crystalline solid.

Example 2: 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 (3.0 g) and acetone (100 m).
The mixture of l) was stirred and heated at reflux for 15 minutes until a clear solution was observed. Hydrobromic acid (48% w / w aqueous solution, 0.95 ml) was added and the reaction mixture was refluxed with stirring for 15 minutes and then cooled to 21 ° C. After standing for 120 hours, the mother liquor was decanted, the crystalline product was washed with acetone (10 ml), dried under reduced pressure for 3 hours and treated with 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 containing 0.5% wt / wt of acetone.
Consistent with-[2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide.

Example 3: 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 (15.0 g) and acetone (230
ml) was stirred and heated to reflux for 15 minutes until a clear solution was observed.
Hydrobromic acid (48% w / w aqueous solution, 4.75 ml) was 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,
Wash with acetone (100 ml) and wash with 5- [4- [2- (N-methyl-N- (2-
Pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide (17.7 g) was obtained as a white crystalline solid.

Characteristic Data for Hydrobromide Salt (1) Recording for Compound of Example 3 Solubility of Hydrobromide The solubility of the substance is 1 to 1000 in about 100 mg of drug substance until the powder is dissolved.
It was measured by adding ml of water in aliquots. The apparent solubility was confirmed by a saturated solution HPLC assay. Solubility: 6 mg / ml Solid Stability of Hydrobromide The solid stability of the drug substance, about 1.0 g substance in a glass bottle, i) 40 ° C
/ Relative Humidity (RH) 75% for about 1 month, open exposure, and b) storage at 50 ° C for about 1 month in closed storage. a) 40 ° C./75% RH: No significant degradation was observed (98% of initial in HPLC assay). b) 50 ° C .: no significant degradation was observed (98% initial by HPLC assay)
%).

Flow Properties of Hydrobromide The ratio between the bulk density and the tap bulk density of hydrobromide (Hausner ratio
Ratio)) as a standard method ("Pharmaceutics-Science of dosage form design" edited by M. Aulton, 1988
, Churchill Livingstone). Hausner ratio: 1.3

[0027] The _{T onset} of the drug substance using a Perkin-Elmer DSC7 apparatus was measured by differential scanning calorimetry. _Tonset : 182.5 ° C

[0028]   The melting point of the drug substance was determined visually by hot stage microscopy.   Melting point: 181 ° C

(2) Recording of the product of Example 2 An infrared absorption spectrum of a mineral oil dispersion of the product was obtained with a Nicolet 710 FT-IR spectrometer at a resolution of 2 cm ^-1 (Fig. 1). The data was digitized at 1 cm ⁻¹ intervals. Bands: 2923, 2854, 2749, 1745, 1698, 164
3, 1610, 1544, 1515, 1459, 1419, 1378, 1327
, 1313, 1287, 1256, 1240, 1228, 1203, 1185,
1151, 1071, 1054, 1032, 1014, 985, 906, 803
, 771, 738, 712, 524 cm ⁻¹ .

The IR spectrum of the solid product was recorded with a universal ATR accessory.
Bands: 2929, 2859, 2749, 1745, 1694, 1641, 1
608, 1543, 1514, 1445, 1419, 1382, 1358, 13
26, 1311, 1287, 1255, 1240, 1202, 1184, 114
8, 1070, 1053, 1031, 1014, 985, 906, 862, 84
4, 802, 768, 737, 710, 657 cm ⁻¹ . The sample was put into an NMR tube, and it was excited by using a Nicolet 960 ESP FT-Raman spectrometer having a resolution of 4 cm ^{−1 and} an Nd: V04 laser (1064 nm) with an output of 400 mW, and the Raman spectrum of the product was recorded (FIG. 2). did. Bands are: 3067, 2997,
2926, 2884, 2860, 1747, 1611, 1588, 1545, 1
445, 1382, 1360, 1315, 1287, 1240, 1213, 11
85, 1070, 1016, 986, 917, 826, 769, 740, 712
, 659, 636, 620, 605, 506, 470, 405, 332, 303
, 134, 99 cm ⁻¹ .

The XRPD pattern of the product (FIG. 3) was recorded using the following collection conditions: tube anode: Cu, generator voltage: 40 kV, generator current: 40.
mA, start angle: 2.0 ° 2θ, final angle: 35.0 ° 2θ, step width: 0.
02 ° 2θ, step time: 2.5 seconds. Table 1 shows characteristic XRPD angles and relative intensities
To record.

[0032]   Table 1

[Table 1]

[Table 2]

[Brief description of drawings]

FIG. 1 shows the infrared spectrum of hydrobromide.

FIG. 2 shows a Raman spectrum of hydrobromide.

FIG. 3 shows an X-ray powder diffraction pattern of hydrobromide.

FIG. 4 shows a solid-state NMR spectrum of hydrobromide.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE, TR), OA (BF , BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, G M, KE, LS, MW, MZ, SD, SL, SZ, TZ , UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, B Z, CA, CH, CN, CO, CR, CU, CZ, DE , DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, I S, JP, KE, KG, KP, KR, KZ, LC, LK , LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, P T, RO, RU, SD, SE, SG, SI, SK, SL , TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Tim Ching Ting Ho             United Kingdom, Tien 11.9, Yen, Ken             To, Tonbridge, Near Lee, All             De Powder Mills, GlaxoSmithsk             line F-term (reference) 4C063 AA01 BB07 CC62 DD12 EE01                 4C086 AA01 AA03 AA04 BC82 GA08                       GA10 GA13 MA01 MA04 MA34                       NA02 NA03 ZC35

Claims (10)

[Claims] 1. A compound 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof. . 2. Two or more: (i) an infrared spectrum substantially according to FIG. I; (ii) a Raman spectrum substantially according to FIG. II; (iii) substantially in Table 1 or FIG. X-ray powder diffraction pattern (XRP
D); (iv) a solid state ¹³ C NMR spectrum substantially according to Figure IV; and (v) in the range 175 to 185 ° C, in particular 180 to 185 ° C, for example 181.
2. The compound according to claim 1, wherein the compound has a melting point of ° C. 3. A compound according to claim 1 or claim 2 in pure form. 4. A compound according to any one of claims 1 to 3 in solid dosage form. 5. A compound according to any one of claims 1 to 3 in a pharmaceutically acceptable form which can be milled. 6. A compound according to any one of claims 1 to 3 which is in a pharmaceutically acceptable form with good flow properties. 7. 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof. A process for the preparation, comprising reacting 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione or a salt thereof with a hydrobromic acid source. And then optionally preparing a solvate of the hydrobromide salt; recovering the hydrobromide salt or solvate. 8. 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof, and A pharmaceutical composition comprising a pharmaceutically acceptable carrier. 9. A compound 5- [4- [2-] for use as an active therapeutic substance.
(N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof. 10. 5- [4- [2] in the manufacture of a medicament for the treatment and / or prevention of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
Use of-(N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof.