JP2004505971A - Tartrate salt of thiazolidinedione derivative - Google Patents

Abstract

5- [4-2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione meso-tartrate or a solvate thereof, a novel pharmaceutical compound, and such a compound , A pharmaceutical composition comprising such a compound, and the use of such a compound in medicine.

Description

【００５２】
９０．５５ＭＨｚで操作するＢｒｕｋｅｒ ＡＭＸ３６０装置にて生成物の固体ＮＭＲスペクトルを記録した（図４）：Ｋｅｌ−Ｆキャップを装備した４ｍｍジルコニアＭＡＳローター中に固体を詰め、約１０ｋＨｚでローターを回転させた。Ｈａｒｔｍａｎｎ−Ｈａｈｎ適合プロトンからの交差分極（ＣＰ接触時間３分、反復時間１５秒）により^１３Ｃ ＭＡＳスペクトルを捕捉し、獲得の間、二パルス位相変調（ＴＰＰＭ）複合系列を使用してプロトンをデカップリングさせた。化学シフトは、ＴＭＳと比較して１７６．４ｐｐｍのグリシンのカルボキシレートシグナルを外部基準とし、
１８３．０、１７７．２、１７５．４、１７３．０、１６０．０、１５９．０、１５１．８、１４４．２、１３８．９、１３４．３、１３０．８、１２８．２、１２３．６、１１３．７、１１２．８、７７．４、７６．７、７４．５、５５．５、５３．５、５０．０、４２．４、３６．６、３３．８ｐｐｍで見られた。
【００５３】
メソ−酒石酸塩の特性
実施例１の生成物について記録したメソ−酒石酸塩の固体安定性
当該物質約１．０ｇをガラスビン中にて、ｉ）４０℃／相対湿度（ＲＨ）７５％で開放暴露して１ヶ月間、および、ｂ）５０℃で密閉して１ヶ月間、貯蔵することにより、当該薬物の固体安定性を決定した。両方のケースにおいて、最終含量および分解生成物について該物質をＨＰＬＣによりアッセイした。
ａ）４０℃／ＲＨ７５％：有意な分解は観察されなかった（ＨＰＬＣアッセイ９７％初期）。
ｂ）５０℃：有意な分解は観察されなかった（ＨＰＬＣアッセイ９８％初期）。
【００５４】
メソ−酒石酸塩の融点
Ｂｕｃｈｉ ５４５融点測定器を使用して、米国薬局方 ＵＳＰ ２３， １９９５， ＜７４１＞ “Ｍｅｌｔｉｎｇ ｒａｎｇｅ ｏｒ ｔｅｍｐｅｒａｔｕｒｅ， Ｐｒｏｃｅｄｕｒｅ ｆｏｒ Ｃｌａｓｓ Ｉａ”に記載された方法に従ってメソ−酒石酸塩の融点を決定した。
実施例１の生成物、融点：１４９℃
実施例２の生成物、融点：１５３℃
実施例３の生成物、融点：１５５℃
【００５５】
メソ−酒石酸塩のＴ_{ｏｎｓｅｔ}
Ｐｅｒｋｉｎ−Ｅｌｍｅｒ ＤＳＣ装置を使用して、示差走査熱量測定により薬物のＴ_{ｏｎｓｅｔ}を決定した。
実施例１の生成物、Ｔ_{ｏｎｓｅｔ}（１０℃／分、密閉パン）：１４６℃
実施例２の生成物、Ｔ_{ｏｎｓｅｔ}（１０℃／分、密閉パン）：１５３℃
実施例３の生成物、Ｔ_{ｏｎｓｅｔ}（１０℃／分、密閉パン）：１５４℃[0001]
The present invention relates to a novel drug, a method for producing the drug and the use of the drug in medicine.
[0002]
European Patent Application, Publication No. 0,306,228, relates to certain thiazolidinedione derivatives disclosed as having hypoglycemic and lipid-lowering activity. The compound of Example 30 of EP 0,306,228 was prepared as follows: 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione "Compound (I)").
[0003]
International patent application, publication number WO 94/05659, discloses certain salts of the compounds of EP 0,306,228, one of which is tartrate. The preferred salt of WO 94/05659 is the maleate salt.
[0004]
It has now been found that compound (I) forms a novel tartrate salt (hereinafter also referred to as “meso-tartrate salt”).
[0005]
The novel meso-tartrate salts are stable, high melting crystalline and are therefore suitable for mass production and mass processing. Meso-tartrate salts are particularly susceptible to sterilization by large-scale pharmaceutical processing in manufacturing processes that require or generate heat, such as milling, fluid bed drying, spray drying, hot melt processing, and autoclaving. Meso-tartrate can also be produced by an efficient, economical and reproducible process, especially suitable for large-scale production.
The novel meso-tartrate salts also have useful pharmaceutical properties, in particular being useful in the treatment and / or prevention of diabetes mellitus, the symptoms associated with diabetes mellitus and certain complications thereof. Is shown.
[0006]
Accordingly, the present invention provides 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione meso-tartrate or a solvate thereof. provide.
[0007]
Suitably, the meso-tartrate is a monotartrate.
Monotartrate may also include another monovalent salt forming ion, such as an alkali metal or ammonium cation.
[0008]
In one preferred embodiment, the meso-tartrate provides an infrared spectrum substantially consistent with FIG.
In one preferred embodiment, the meso-tartrate provides a Raman spectrum substantially consistent with FIG.
In one preferred embodiment, the meso-tartrate provides an X-ray powder diffraction pattern (XRPD) substantially consistent with Table 1 or FIG.
In one preferred embodiment, the meso-tartrate provides a solid state ¹³ C NMR spectrum substantially consistent with FIG.
In one preferred embodiment, the meso-tartrate has a melting point in the range of 147 to 157C, for example, 148 to 155C, for example, 148C, 153C and 155C.
[0009]
In a preferred embodiment, the present invention provides
(I) an infrared spectrum substantially consistent with FIG. 1; and (ii) a Raman spectrum substantially consistent with FIG. 2; and (iii) an X-ray powder diffraction pattern substantially consistent with Table 1 or FIG. (XRPD); and (iv) 5- [4- [2- (N-methyl-N- (2-pyridyl) amino] characterized by providing a solid state ¹³ C NMR spectrum substantially consistent with FIG. ) Ethoxy] benzyl] thiazolidine-2,4-dione meso-tartrate.
[0010]
The present invention includes the meso-tartrate salt or its solvate when isolated in pure form or mixed with other substances. Thus, in one aspect, there is provided an isolated form of the meso-tartrate salt or a solvate thereof.
[0011]
In a further aspect, a purified form of the meso-tartrate salt or solvate thereof is provided.
In a further aspect, there is provided a meso-tartrate salt or a solvate thereof in crystalline form.
[0012]
The present invention also provides a meso-tartrate salt or a solvate thereof in solid pharmaceutically acceptable form, such as a solid dosage form, especially when suitable for oral administration.
Furthermore, the invention also relates to pharmaceutical treatments, especially in the course of production, which require or generate heat, such as milling; for example, heat drying, in particular fluidized-bed drying or spray-drying; Providing meso-tartrate or a solvate thereof in pharmaceutically acceptable form, in particular in bulk form, which can be heat-sterilized, for example by autoclaving.
[0013]
Furthermore, the present invention relates to pharmaceutically acceptable forms, in particular in bulk form, in particular those which have been processed in the course of a manufacturing process which requires or generates heat, for example in finely divided form; In particular, there is provided a meso-tartrate salt or solvate thereof in fluidized bed or spray dried form; for example, in a hot melt treated form; for example, in a heat sterilized form such as by autoclaving.
A suitable solvate is a hydrate.
[0014]
The present invention also preferably relates to 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4 dispersed or dissolved in a suitable solvent. Reacting a dione (compound (I)) or a salt thereof with a source of meso-tartrate ions, then, if necessary, producing a solvate of the resulting meso-tartrate salt; Alternatively, there is provided a method for producing the meso-tartrate salt or a solvate thereof, which comprises recovering the solvate thereof.
[0015]
Suitable reaction solvents are ketones, for example acetone, or ethers, for example tetrahydrofuran, alkanols such as propan-2-ol, hydrocarbons such as toluene, esters such as ethyl acetate, nitriles such as acetonitrile, or A halogenated hydrocarbon such as dichloromethane, or water, or an organic acid such as acetic acid; or a mixture thereof.
[0016]
Conveniently, the source of meso-tartrate ions is meso-tartaric acid. The meso-tartaric acid is preferably added as a solid or in a solution, for example water or a lower alcohol such as methanol, ethanol or propan-2-ol, or a solvent mixture. Another source of meso-tartrate ions is provided by a suitably soluble basic salt of tartaric acid, for example, ammonium meso-tartrate, or a meso-tartrate salt of an amine, for example, ethylamine or diethylamine.
[0017]
The concentration of compound (I) is preferably in the range from 2 to 25% weight / volume, more preferably in the range from 5 to 20%. The concentration of the tartaric acid solution preferably ranges from 5 to 125% weight / volume.
[0018]
The reaction is usually carried out at ambient or elevated temperature, for example at the reflux temperature of the solvent, but any convenient temperature that will yield the desired product can be used.
Solvates, such as hydrates, of the meso-tartrate salt are prepared according to conventional techniques.
Recovery of the desired compound generally involves crystallization from a suitable solvent, or mixture of solvents, conveniently the reaction solvent, which is usually aided by cooling. For example, the meso-tartrate salt can be crystallized from a ketone such as acetone, or an ether such as tetrahydrofuran, or water or a mixture thereof. If desired, the salt yield is improved by evaporating some or all of the solvent in multiple steps or by crystallization at elevated temperatures followed by controlled cooling. Careful control of the precipitation temperature can improve the reproducibility of the product form.
[0019]
Crystallization can also be initiated by seeding crystals of the meso-tartrate or solvate thereof, but this is not essential.
[0020]
Where the monotartrate salt comprises another monovalent salt-forming ion, such as an alkali metal or ammonium cation, the ion is advantageously combined with the monotartrate salt and a selected monovalent salt-forming ion, for example, It is formed by reacting with a solution of metal or ammonium ions. Alternatively, compound (I) can be treated with a monotartrate salt containing a monovalent salt forming ion.
[0021]
Compound (I) is prepared according to known methods, such as those disclosed in EP 0,306,228 and WO 94/05659. The disclosures of EP 0,306,228 and WO 94/05659 are hereby incorporated by reference.
[0022]
Meso-tartaric acid is a commercially available compound.
As used herein, the term " _Tonset " is generally determined by differential scanning calorimetry and is described, for example, in Pharmaceutical Thermal Analysis, Technologies and Applications, "Ford and Timmins in the Former Group, 1989". It has the meaning commonly understood in the art as described as "temperature corresponding to the intersection with the extrapolated leading edge."
[0023]
As used herein with respect to certain compounds, the term "good flowability" suitably has a Hausner ratio of 1.5 or less, especially 1.25 or less. Characterized by the compound.
"Hausner ratio" is a technically accepted term.
[0024]
As used herein, the term "prevention of symptoms associated with diabetes mellitus" includes treatment of conditions such as insulin resistance, glucose intolerance, hyperinsulinemia and gestational diabetes.
Diabetes mellitus preferably refers to type II diabetes mellitus.
[0025]
Symptoms associated with diabetes include hyperglycemia and insulin resistance and obesity. Additional symptoms associated with diabetes include hypertension, cardiovascular disease, particularly with atherosclerosis, certain eating disorders, especially with undereating such as anorexia nervosa. Regulation of appetite and food intake in subjects suffering from certain disorders and disorders associated with overeating, such as obesity and neurological hunger. Additional symptoms associated with diabetes include polycystic ovary syndrome and steroid-induced insulin resistance.
[0026]
The complications of the symptoms associated with diabetes mellitus encompassed herein include renal disease, particularly diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephropathy, and end-stage renal disease Kidney diseases associated with the occurrence of type II diabetes, including diseases.
[0027]
As mentioned above, the compounds of the invention have useful therapeutic properties. The present invention therefore provides such meso-tartrate salts or solvates thereof for use as active therapeutic substances.
[0028]
More particularly, the present invention provides meso-tartrate or a solvate thereof for use in the treatment and / or prevention of diabetes mellitus, symptoms associated with diabetes mellitus and certain complications thereof.
[0029]
The meso-tartrate salt or solvate thereof may be administered per se, or preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. Suitable methods of formulating the meso-tartrate salt or a solvate thereof are generally those described for compound (I) in the above publication.
[0030]
Accordingly, the present invention also provides a pharmaceutical composition comprising a meso-tartrate salt or a solvate thereof and a pharmaceutically acceptable carrier.
[0031]
The meso-tartrate salt or solvate thereof is usually administered in a unit dosage form.
[0032]
The active compound may be administered by any route, but is usually administered by the oral or parenteral route. For such use, the compounds are usually used in the form of a pharmaceutical composition, together with a pharmaceutical carrier, diluent and / or excipient, but the precise form of the composition will, of course, vary depending on the mode of administration. Dependent.
[0033]
The composition is prepared by mixing and is suitably suitable for oral, parenteral or topical administration, such as tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles, reconstituted Powders, injection and infusion solutions or suspensions, suppositories and transdermal devices. Compositions for oral administration are preferred because they are convenient for general use, and shaped oral compositions are particularly preferred.
[0034]
Tablets and capsules for oral administration are usually presented in unit dosage and are prepared using conventional agents such as binders, fillers, diluents, tableting agents, lubricants, disintegrants, colorants, flavors, and wetting agents. Containing excipients. Tablets may be coated according to methods well known in the art.
[0035]
Suitable fillers to 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 wetting agents include sodium lauryl sulfate.
[0036]
Solid oral compositions are prepared by conventional methods, such as blending, filling, or tableting. An iterative blending operation can be used to distribute the active agent throughout these compositions with large amounts of filler. Such operations are, of course, conventional in the art.
[0037]
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or for reconstitution with water or other suitable vehicle before use. It may be provided as a dry drug. Such liquid preparations may contain suspending agents, such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hardened edible fat, emulsifiers such as lecithin, sorbitan monooleate, or acacia; Aqueous vehicles (including edible oils) such as tonsil oil, fractionated coconut oil, oily esters such as glycerin, propylene glycol, or ethyl alcohol; preservatives such as methyl or p-hydroxy p-hydroxybenzoate It may contain conventional additives such as propyl benzoate or sorbic acid and, if desired, conventional flavors or colorants.
[0038]
For parenteral administration, fluid unit dosage forms are prepared containing a compound of the present invention and a sterile vehicle. The compound can either be suspended or dissolved, depending on the vehicle and concentration. Parenteral solutions are usually prepared by dissolving the active compound in a vehicle, filter sterilizing and then filling suitable vials or ampoules and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance stability, the composition can be frozen after filling into vials and the water removed under vacuum.
[0039]
Parenteral suspensions are prepared in substantially the same manner, except that the active compound is suspended in the vehicle, rather than dissolved, and sterilized by exposure to ethylene oxide before suspension in a sterile vehicle. . Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound.
[0040]
As is common practice, the compositions will usually be accompanied by instructions for use in the relevant medical procedure.
As used herein, the term "pharmaceutically acceptable" includes compounds, compositions and components for human and veterinary use. For example, “pharmaceutically acceptable salts” includes veterinarily acceptable salts.
[0041]
The present invention is further directed to a method of treating and / or preventing diabetes mellitus, symptoms associated with diabetes mellitus and certain complications thereof in a human or non-human mammal, comprising a human or non-human in need thereof. A method comprising administering to a human mammal an effective non-toxic amount of meso-tartrate or a solvate thereof.
[0042]
Advantageously, the active ingredient can be administered as a pharmaceutical composition as defined above, which forms a particular aspect of the invention.
In a further aspect, the present invention relates to the use of meso-tartrate or a solvate thereof for the manufacture of a medicament for the treatment and / or prevention of diabetes mellitus, symptoms associated with diabetes mellitus and certain complications thereof. I will provide a.
[0043]
In the treatment and / or prevention of diabetes mellitus, the symptoms associated with diabetes mellitus and certain complications thereof, meso-tartrate or a solvate thereof is disclosed in EP 0,306,228, WO 94/05659 or WO 98/55122 are administered in an amount to provide a suitable dose of Compound (I).
No detrimental toxicological effects are shown in the treatments described above for the compounds of the invention.
The following examples illustrate the invention and do not limit it in any way.
[0044]
EXAMPLES Example 1 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione meso-tartrate 5- [4- [2 A mixture of-(N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (8.0 g) and tetrahydrofuran (160 ml) was stirred and heated to 50C. A solution of meso-tartaric acid (3.84 g) in water (20 ml) was added, the mixture was stirred at 50 ° C. for 15 minutes, filtered and the clear filtrate was cooled to 21 ° C. The solvent was evaporated at 40 ° C. under reduced pressure, acetone (40 ml) was added and the mixture was stirred at 21 ° C. to give a white suspension. The product is collected by filtration, washed with acetone, dried in vacuo, and 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine as a white crystalline solid. -2,4-dione meso-tartrate (10.6 g) was obtained.
[0045]
Example 2 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione meso-tartrate 5- [4- [2- ( Reflux while stirring a mixture of N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (3.0 g, 8.4 mmol), acetone (40 ml) and tetrahydrofuran (5 ml). Heated under for 2.5 hours. To this was added a solution of meso-tartaric acid monohydrate (1.41 g, 8.4 mmol) in water (2 ml). The reaction mixture was heated under reflux for 2.5 hours with stirring, then cooled to 21 ° C. and stirred at 21 ° C. for 16 hours. The white solid was collected by filtration, washed with acetone (40 ml), and dried under reduced pressure at 21 ° C. for 2.5 hours to give 5- [4- [2- (N-methyl-N-) as a white crystalline solid. (2-Pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione meso-tartrate (3.25 g) was obtained.
[0046]
Example 3 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione meso-tartrate 5- [4- [2- ( A mixture of N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (10.0 g, 28 mmol), acetone (120 ml) and tetrahydrofuran (15 ml) is stirred under reflux. And heated for 50 minutes. To this was added a solution of meso-tartaric acid monohydrate (4.7 g, 28 mmol) in water (6.0 ml). The reaction mixture was heated under reflux for 1 hour with stirring, then cooled to 21 ° C. and stirred at 21 ° C. for 16 hours. The white solid was collected by filtration, washed with acetone (50 ml), C. for 3 hours under reduced pressure to give 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione meso as a white crystalline solid. -Tartrate (11.7 g) was obtained.
[0047]
Characterization data recorded for the product of Example 1 An infrared absorption spectrum of the mineral oil dispersion of the product was obtained using a Nicolet 710 FT-IR spectrophotometer with 2 cm ^-1 resolution (Figure 1). Data was digitized at 1 cm ^-1 intervals.
3405, 1738, 1694, 1629, 1556, 1537, 1505, 1459, 1436, 1418, 1330, 1268, 1249, 1223, 1182, 1167, 1143, 1104, 1074, 1057, 1033, 1000, 949, 916, 887, Bands were observed at 853, 818, 771, 717, 668, 619, 568, 528, and 515 cm ^{- 1} .
[0048]
The infrared spectrum of the solid product was recorded using a Perkin-Elmer Spectrum One FT-IR spectrophotometer equipped with a universal ATR accessory.
3407, 2937, 2750, 1739, 1693, 1628, 1555, 1535, 1504, 1476, 1459, 1412, 1388, 1358, 1330, 1261, 1248, 1222, 1182, 1167, 1143, 1101, 1074, 1056, 1033, Bands were observed at 999, 948, 916, 887, 853, 818, 771, 744, 717, and 667 cm ^{- 1} .
[0049]
Nicolet 960 with 4 cm ^{- 1} resolution using excitation from a 400 mW Nd: V04 laser (1064 nm). S. P. The Raman spectrum of the product was recorded for the sample in the NMR tube using an FT-Raman spectrophotometer (FIG. 2).
3101, 3059, 2952, 2922, 2877, 1739, 1604, 1544, 1458, 1438, 1394, 1331, 1270, 1222, 1203, 979, 887, 827, 739, 668, 638, 605, 472, 344 cm ^{- 1} . A band was seen.
[0050]
An X-ray powder diffraction pattern of the product was recorded using the following acquisition conditions (FIG. 3): tube anode: Cu, generator voltage: 40 kV, generator current: 40 mA, starting angle: 2.0 ° 2θ, Final angle: 35.0 ° 2θ, step size: 0.02 ° 2θ, time per step: 2.5 seconds. Table 1 shows characteristic XRPD angles and relative intensities.
[0051]
[Table 1]

[0052]
Solid NMR spectra of the product were recorded on a Bruker AMX360 instrument operating at 90.55 MHz (FIG. 4): The solid was packed into a 4 mm zirconia MAS rotor equipped with a Kel-F cap and the rotor was spun at about 10 kHz. . ¹³ C MAS spectra were captured by cross-polarization (3 min CP contact time, 15 sec repetition time) from Hartmann-Hahn matched protons and during acquisition decoupled protons using a two-pulse phase modulation (TPPM) composite series. I let it ring. The chemical shift is based on the carboxylate signal of glycine at 176.4 ppm compared to TMS as an external reference,
183.0, 177.2, 175.4, 173.0, 160.0, 159.0, 151.8, 144.2, 138.9, 134.3, 130.8, 128.2, 123. 6, 113.7, 112.8, 77.4, 76.7, 74.5, 55.5, 53.5, 50.0, 42.4, 36.6, and 33.8 ppm.
[0053]
Meso-Tartrate Properties Solid Stability of Meso-Tartrate Recorded for the Product of Example 1 Approximately 1.0 g of the substance was opened in a glass bottle at i) 40 ° C./75% relative humidity (RH). The solid stability of the drug was determined by storage for one month at b. In both cases, the substances were assayed by HPLC for final content and degradation products.
a) 40 ° C./75% RH: No significant degradation was observed (HPLC assay 97% early).
b) 50 ° C .: No significant degradation was observed (98% early in HPLC assay).
[0054]
Melting Point of Meso-Tartrate Melting point of meso-tartrate using a Buchi 545 melting point meter according to the method described in United States Pharmacopoeia USP 23, 1995, <741> “Melting range or temperature, Procedure for Class Ia”. It was determined.
Product of Example 1, melting point: 149 ° C
Product of Example 2, melting point: 153 ° C.
Example 3 product, melting point: 155 ° C.
[0055]
Meso - _{T onset} of tartrate
Use Perkin-Elmer DSC apparatus was determined _{T onset} of the drug by differential scanning calorimetry.
Product of Example 1, _Tonset (10 ° C / min, closed pan): 146 ° C
Product of Example 2, _Tonset (10 ° C / min, closed pan): 153 ° C
Product of Example 3, _Tonset (10 ° C / min, closed pan): 154 ° C

Claims (12)

Compound 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione.meso-tartrate or a solvate thereof. (I) an infrared spectrum substantially consistent with FIG. 1;
(Ii) a Raman spectrum substantially consistent with FIG. 2;
(Iii) providing an X-ray powder diffraction pattern (XRPD) substantially consistent with Table 1 or FIG. 3; or (iv) providing a solid state ¹³ C NMR spectrum substantially consistent with FIG. 2. The compound according to 1. (I) an infrared spectrum substantially consistent with FIG. 1; and (ii) a Raman spectrum substantially consistent with FIG. 2; and (iii) an X-ray powder diffraction pattern substantially consistent with Table 1 or FIG. (XRPD); and (iv) The compound of claim 1, which provides two or more solid state ¹³ C NMR spectra substantially consistent with FIG. The compound according to any one of claims 1 to 3, which is in a purified form. The compound according to any one of claims 1 to 3, which is in a solid dosage form. Pharmaceutical treatments in the manufacturing process that require or generate heat, such as milling; for example, heat drying, especially fluid bed drying or spray drying; hot melt treatment; heat sterilization, such as autoclaving. The compound according to any one of claims 1 to 3, which is in a form that can be carried out. Processed in a manufacturing process that requires or generates heat, for example, pulverized form; for example, heat-dried form, especially fluidized-bed or spray-dried form; for example, hot-melted form; The compound according to any one of claims 1 to 3, which is in a form sterilized by heat, such as by autoclaving. The compound according to any one of claims 1 to 3, which is in a pharmaceutically acceptable form having good flowability. Supplying 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (compound (I)) or a salt thereof with meso-tartrate ion Reacting with a source, and then, if necessary, producing a solvate of the obtained meso-tartrate salt; recovering the meso-tartrate salt or a solvate thereof. A method for producing Japanese products. 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione meso-tartrate or a solvate thereof and a pharmaceutically acceptable carrier A pharmaceutical composition comprising: Compound 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione meso-tartrate or a salt thereof for use as an active therapeutic substance Solvate. 5- [4- [2- (N-methyl-N- (2-pyridyl) for the manufacture of a medicament for the treatment and / or prevention of diabetes mellitus, symptoms associated with diabetes mellitus and certain complications thereof. ) Amino) ethoxy] benzyl] thiazolidine-2,4-dione meso-tartrate or a solvate thereof.

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