KR20070113328A - Novel polymorphic forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation - Google Patents

Abstract

This invention relates to novel polymorphic/pseudopolymorphic forms of 5-[4-[2[N-methyl-N-(2-pyridyl) amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate having formula (I). The invention also relates to a pharmaceutical composition comprising the novel polymorphic form or their mixture and a pharmaceutically acceptable carrier. The polymorphic forms of the present invention are more active, as antidiabetic agent, than the hitherto known 5-[4-[2-[N-(2-methyl-N-(2- pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate.

Description

Novel polymorphic form of 5- [4- [2- [ene-methyl-ene- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine 4-dione maleate and its preparation method {NOVEL POLYMORPHIC FORMS OF 5- [4- [2- [N-METHYL-N- (2-PYRIDYL) AMINO] ETHOXY] BENZYL] THIAZOLIDINE-2,4-DIONE MALEATE AND PROCESS FOR THEIR PREPARATION}

The present invention provides a novel polymorphic form of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine 4-dione maleate of formula (I). It relates to a pseudopolymorph and its stereoisomer.

The present invention also relates to pharmaceutical compositions comprising the novel polymorphic form or mixtures thereof and a pharmaceutically acceptable carrier. The polymorph of the present invention is more effective than the currently known antidiabetic agents 5- [4- [2- [N-methyl-N- (2pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione malate to be.

                               (Ⅰ)

The invention also relates to the various polymorphisms of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine 4-dione maleate of formula (I). A method for producing a pseudo polymorphic shape. The polymorphism produced by the production method of the present invention is more effective as a therapeutic agent for diabetes.

Polymorph of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate of formula (I) It is effective in reducing coronary artery disease and atherosclerosis.

Among many antidiabetic agents, thiazolidine dione derivatives are excellent and are known to be more effective ingredients than sulfonyl urea. 5- [4- [2- [N-inethyl-N- (2pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione malate is one of the thiazolidine diones with polymorphic effects. It was reported by Beecham group England (EP 0306228Al) and has since been of interest to date.

Novel of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate of the general formula (I) of the present invention Polymorphisms of are useful for the treatment of weight loss and for the treatment and prevention of hypertension, coronary artery disease, arteriosclerosis, stroke, peripheral vascular disease and other related diseases. Novel polymorphs of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate of general formula (I) The compounds of the present invention are useful for the treatment and prevention of glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephropathy. Novel polymorphs of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate of general formula (I) Is also useful for the treatment of abnormalities associated with X syndrome, such as insulin resistance (type 2 diabetes), leptin resistance, impaired glucose tolerance, hemostatics, and hypertension, obesity, insulin resistance, coronary artery disease and other cardiovascular abnormalities. . These compounds are also useful for improving cognitive function, diabetic complications, abnormalities associated with endothelial cell activity, psoriasis, polycystic ovary syndrome (PCOS), infectious bowel disease, atrophic myopathy, osteoporosis, pancreatitis, arteriosclerosis, and xenomas in dementia And aldose reductase inhibitors for the treatment of cancer. Novel polymorphs of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate of general formula (I) May also be used in combination with one or more HMG CoA reductase inhibitors and / or therapeutic agents for hyperlipidemia / hyperproteinosis, such as, for example, fibric acid derivatives, nicotinic acid, corestir-amine, cholestipol, or probucol It can be cured.

A recent trend in the pharmaceutical industry is to study the polymorphisms of drugs to study the differences in activity of a given drug's polymorphisms. By polymorphism is meant to include all other physical shapes, crystalline forms, crystal / liquid crystals, and non-crystalline (amorphous) forms. Examination of many antibiotics, bactericidal agents, and neurostabilizers shows that some / one of the polymorphs has better biocompatibility and significantly better activity than the other polymorphs. Sertraline, prentazole, ranitidine, sulfatiazole, indomethacin and the like are important examples of the polymorphism. Evidence that the topic of polymorphism in medicine is of recent interest can be obtained from registered patents. For example, US Pat. No. 5700820 describes six polymorphs of troglitazone, US Pat. No. 5248699 describes five polymorphs of sertraline hydrochloride, EP 014590 discloses four polymorphs of prentazole, EP 490648 and EP 022527 also deal with the polymorphism of the drug.

European Patent No. 0306338, International Publication No. 94/25026, and US Patent Application No. 5,646,169 describe the configuration of isomers as determined by x-ray crystallographic analysis, 5- [4- [2- [N- Ten crystals and the molecular structure of methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate are described. This report describes the possibility of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] thoxy] enzyl] thiazolidine-2,4-dione maleate in other polymorphic forms. It is not mentioned, and it has never been published in any literature. Patents relating to polymorphisms that are currently attracting interest in medicine include European Patent No. 014590, Troglitazone's six polymorphisms, which describe the four polymorphs of Prentizol, US Pat. European Patent Nos. 490648 and 022527, and WO 97/27191. 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate has not yet been studied for polymorphisms , The first attempted and studied in the present invention.

Recently, studies on the prevention and treatment of diabetes complications have been conducted. 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione malate is recognized today as the most effective treatment for diabetes and diabetes It is known to act not only on its own but also on the reduction of triglycerides and the above complications. 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate has emerged as a secondary medicinal candidate for diabetes.

An object of the present invention is to lower cholesterol, which is effective in the treatment and prevention of diseases associated with high lipid levels, atherosclerosis, coronary artery disease, X syndrome, impaired glucose tolerance, insulin resistance, insulin resistance causing form 2 diabetes and diabetes complications. And weight loss; Treatment of diseases in which insulin resistance is a pathophysiological mechanism; It is to provide a compound for making the treatment of hypertension, atherosclerosis, and coronary vascular disease more efficient and less toxic. Efforts for this purpose have led to the development of the polymorphic form of formula (I).

Another object of the present invention is a novel 5- [4- [2- [N-methyl-N- (2-pyridyl) which has a promoting activity against PPARα and / or PPARγ and optionally inhibits HMG CoA reductase. A pharmaceutical composition comprising a polymorph of amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate, stereoisomers thereof, pharmaceutically acceptable solvates thereof, and mixtures thereof or mixtures thereof To provide.

Another object of the present invention is a novel 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thia with improved activity and non-toxic or reduced toxicity. To provide a pharmaceutical composition comprising a polymorphic form of zolidine-2,4-dione maleate, stereoisomers thereof, pharmaceutically acceptable solvates thereof, and mixtures thereof or mixtures thereof.

It is another object of the present invention to provide a novel product of the novel 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate. To provide a shape, a stereoisomer thereof, and a pharmaceutically acceptable solvate thereof.

Another object of the invention is a polymorphic form of novel 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate Providing a pharmaceutical composition comprising a mixture of these stereoisomers, pharmaceutically acceptable solvates thereof, or mixtures thereof with a suitable carrier, solvent, diluent and other media generally used to prepare such compositions. It is.

5- [4- [2- [N-methyl-N- (2pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate exhibiting polymorphisms not reported to date It is about. Polymorphs I, II, III and IV are obtained from different solvents, ethanol, acetone, methanol and 1,4-dioxane, respectively.

Form I, II, III and IV were found to be crystals in nature from powder X-ray diffraction analysis.

DSC of Polymorph I shows an endotherm at 100.53 ° C. Form II shows an endotherm at 127.67 ° C. Form III shows an endotherm at 126.41 ° C. and Form IV shows an endotherm at 125.39 ° C.

All these polymorphisms have proven identical in solutions such as nuclear magnetic resonance (NMR), ultraviolet (UV) and mass spectral data, whereas differential scanning calorimetry (DSC), powder X-ray diffraction (XRD) and infrared spectroscopy Solid state analysis, such as an analyzer (IR), showed a difference.

The polymorphisms of formula (I) of the present invention can be used to treat and prevent diseases associated with high lipid levels, arteriosclerosis, coronary artery disease, X syndrome, impaired glucose tolerance, insulin resistance, insulin resistance causing type 2 diabetes, and diabetes complications. Cholesterol lowering and weight loss that are beneficial for Treatment of diseases in which insulin resistance is a pathophysiological mechanism; Treatment of hypertension, arteriosclerosis, and coronary vascular disease can be made more efficient and less toxic.

Novel of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate specified by the following data according to the invention Polymorph-I and its stereoisomers.

DSC endotherm at 100.53 ° C. (onset at 88.65 ° C.) (FIG. 1).

X-ray powder diffraction (2Θ): 10.90, 14.54, 15.96, 18.46, 18.60, 19.76, 20.72, 21.84, 22.36, 22.46, 23.90, 24.04, 24.72, 25.30, 25.98, 27.44, 29.70 (Figure 5).

IR (cm ^-1 ): 3435 (m), 2997 (w), 2773 (m), 1750 (m), 1701 (s), 1620 (m), 1510 (m), 1362 (m), 1332 (m ), 1237 (s), 1165 (m), 864 (s), 764 (s), 717 (m), 654 (m), 540 (w), (FIG. 10).

Novel of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate specified by the following data according to the invention Polymorph-II and its stereoisomers.

DSC: endotherm at 127.67 ° C. (onset at 123.17 ° C.) (FIG. 2).

XRD (2Θ): 8.90, 15.40, 18.06, 19.20, 22.30, 23.40, 23.62, 24.80, 25.10, 25.84, 26.72, 27.18, 29.30, 29.54, 29.84, 33.26 (Figure 6).

IR: 3424 (w), 3040 (w), 2947 (m), 2720 (m), 1751 (m), 1702 (s), 1641 (m), 1618 (m), 1574 (w), 1541 (w ), 1412 (w), 1382 (w), 1359 (m), 1326 (m), 1265 (w), 1242 (s), 1213 (w), 1162 (s), 1067 (w), 1031 (w ), 865 (s), 773 (s), 713 (s), 667 (m), 576 (w), 539 (m) (FIG. 11)

Novel of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate specified by the following data according to the invention Polymorph-III and its stereoisomers.

DSC: endotherm at 126.41 ° C. (onset at 122.06) (FIG. 3).

XRD (2Θ): 4.60, 8.46, 9.24, 14.98, 15.86, 17.02, 18.60, 21.92, 23.50, 25.00, 25.44, 26.00, 26.38, 28.34, 33.90 (FIG. 7).

IR: 3429 (m), 2949 (m), 2738 (m), 1747 (w), 1704 (s), 1641 (m), 1617 (m), 1513 (s), 1464 (m), 1352 (m ), 1244 (s), 1178 (s), 1069 (m), 862 (w), 777 (s), 717 (m), 657 (m), 589 (w) (FIG. 12).

Novel of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate specified by the following data according to the invention Polymorph-IV and its stereoisomers.

DSC: endotherm at 125.39 ° C. (onset at 121.03) (FIG. 4).

XRD (2Θ): 7.4, 8.8, 9.54, 14.98, 15.32, 15.82, 16.90, 17.70, 18.40, 18.54, 19.08, 19.72, 20.22, 20.48, 21.36, 21.66, 22.18, 22.58, 23.32, 23.96, 24.52, 25.38, 26.48 , 27.00, 27.58, 27.94, 28.34, 28.54, 28.84, 29.10, 29.86, 30.02, 30.40, 30.52, 30.84, 31.40, 31.94 (FIG. 8).

IR: 3433 (m), 2930 (m), 1753 (w), 1705 (s), 1642 (w), 1617 (m), 1512 (s), 1467 (w), 1351 (m), 1244 (m ), 1162 (m), 1061 (w), 864 (s), 765 (s), 714 (w), 658 (m), 526 (w) (FIG. 13).

According to the invention, 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thia of the formula (I) having the above characteristics, which consists of the following steps: A novel process for preparing polymorph-I of zolidine-2,4-dione maleate is provided:

(i) 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate was prepared by a known method, followed by ethanol. Dissolved in,

(ii) the solution is heated in a steam bath to completely dissolve the solids,

(iii) the clear solution was filtered and cooled at room temperature for at least 18 hours

(iv) 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate of Form I formed is isolated.

 According to the invention, 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thia of formula (I) having the above characteristics, consisting of the following steps: A novel process for the preparation of novel polymorph-II of zolidine-2,4-dione maleate is provided:

(i) 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate was prepared by known methods, followed by acetone. Dissolved in,

(ii) the solution is heated in a steam bath to completely dissolve the solids,

(iii) the clear solution was filtered and cooled at room temperature for at least 18 hours

(iv) 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate of Form I formed is isolated.

According to the invention, 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thia of the formula (I) having the above characteristics, which consists of the following steps: A novel process for preparing polymorph-III of zolidine-2,4-dione maleate is provided:

(i) preparing 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate by known methods, followed by methanol Dissolved in,

(ii) the solution is heated in a steam bath to completely dissolve the solids,

(iii) the clear solution was filtered and cooled at room temperature for at least 18 hours

(iv) 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate of Form I formed is isolated.

According to the invention, 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thia of formula (I) having the above characteristics, consisting of the following steps: A novel process for the preparation of novel Polymorph-IV of zolidine-2,4-dione maleate is provided:

(i) preparing 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate by known method 1 In 4-dioxane,

(ii) the solution is heated in a steam bath to completely dissolve the solids,

(iii) the clear solution was filtered and cooled at room temperature for at least 18 hours

(iv) 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate of Form I formed is isolated.

Stereoisomers of the compounds that make up part of the present invention can be prepared using reactants in the form of a single colon. It is prepared by reacting in the form of a single coliform in the presence of reagents or toxins or by separating the stereoisomeric mixtures by known methods. The method is microbiological separation, maleic acid, camphorsulfonic acid, tartaric acid. Lactic acid and the like include a method for forming and separating a salt with a chiral acid, or a chiral base such as brucin, kinko alkaloids and derivatives thereof. Commonly used methods are described in Jaques, "Enantiomers, Racernates and Resolution" (Wiley Interscience, 19 8 1). Converting the acid to an amide using normal reaction conditions; The isomers can be separated by fractional crystallization or chromatography and the pure isomer amides can be hydrolyzed to produce stereoisomers of formula (I).

The present invention also provides novel novel 5- (4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate of formula (I). Provided is a pharmaceutical composition comprising one of the polymorphs I to IV of the present invention and a pharmaceutically acceptable carrier.

The invention also relates to 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate of formula (I). Provided is a pharmaceutical composition comprising at least one mixture selected from novel polymorphs I to IV and a pharmaceutically acceptable carrier.

 Pharmaceutical compositions may have formulations such as tablets, capsules, powders, syrups, solutions, suspensions, and the like, and may include flavorings, sweeteners, etc., injectable solutions or containing suitable solid or liquid carriers or diluents or suitable sterile media Suspensions can be prepared. Such pharmaceutical compositions consist of 1 to 25% by weight, preferably 1 to 15% by weight of active ingredient and the rest of the pharmaceutically acceptable carrier, seat or solvent.

Polymorphic compounds of formula (I) may be administered orally or by injection to mammals, including humans. Oral administration is more preferable because it can avoid pain caused by injection. However, if the patient is unable to swallow due to disease or other abnormal conditions, injection administration is essential. Whichever route is used, it is 0.01 to 100 mg / kg body weight per day, preferably 0.01 to 30 mg / kg body weight, and can be administered at one time or dividedly. However, the optimal dosage depends on the condition of the patient to be treated and may initially be administered in small amounts and then gradually increased.

Pharmaceutically acceptable carriers can include solid fillers or diluents, sterile aqueous solutions or organic solutions. The active compound is present in the above dosage ranges in a pharmaceutical composition. Thus, for oral administration, the compounds can be prepared in capsules, tablets, powders, syrups, solutions, suspensions, and the like, in combination with suitable solid or liquid carriers or diluents. If necessary, flavors, sweeteners, excipients and the like may be added. For injection administration, the compounds can be prepared in injectable solutions or suspensions in combination with sterile aqueous or organic media. For example, sesame oil or soybean oil solution, aqueous propylene glycol, and the like may be used, and a pharmaceutically acceptable acid addition salt or salt with a base of the compound may be used. An aqueous solution in which the active ingredient is dissolved in castor oil having a large number of hydroxyl groups may be prepared as an injection solution. Injection solutions prepared in this way can be injected intravenously, subcutaneously, intramuscularly, and the like, and for humans, intramuscular injection is preferred.

For nasal administration, the preparations can be prepared as aerosols by dissolving the polymorphs of the invention in liquid carriers, especially aqueous carriers. Carriers may include solubilizers such as propylene glycol, surfactants, adsorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrins, and preservatives such as parabens.

Tablets, dragees or capsules with talc and / or carbohydrate supported binders and the like are particularly suitable for oral use. Preferably, carriers for tablets, dragees or capsules include lactose, corn starch and / or potato starch. Syrups or chemicals may be used in containers in which sweetened excipients may be used.

A general method for preparing tablets is listed below.

refine Production Example :

a) 1) 30 g of active ingredient

   2) 95g lactose

   3) corn starch 30g

   4) carboxymethyl cellulose 44 g

   5) 1 g magnesium stearate

                             200 g for 1000 tablets

Ingredients 1-3 were mixed homogeneously with water and granulated after drying under reduced pressure. Ingredients 4 and 5 were added and compressed into tablet makers to prepare 1000 tablets each containing 30 mg of active ingredient.

b) 1) 30 g of active ingredient

   2) Calcium Phosphate 90g

   3) Lactose 40g

   4) 35g corn starch

   5) 3.5 g polyvinyl pyrrolidone

   6) 1g magnesium stearate

                             200 g for 1000 tablets

Components 1 to 4 were uniformly mixed with an aqueous solution of 5 and dried and dried under reduced pressure to granulate. Component 6 was added and the granules were compressed with a tablet maker to prepare 1000 tablets, each containing 30 mg of active ingredient.

The present invention is explained in more detail in the following examples. This embodiment is only for illustrating the present invention, and does not limit the present invention.

Example :

Example-1

5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione (69 g, 0.1 M) and maleic acid (22.8 g, 0.1 M) The mixture was heated to reflux in isopropanol (1.0 L) to give a clear solution (1-2 hours). The reaction was left at room temperature with stirring for 15-20 hours. The white crystalline compound was filtered off, washed with isopropanol (3 x 100 ml) and petroleum ether (2 x 100 ml) to give a white product (84.5 g; yield: 92%).

Example-2

10 g of 1 g of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate obtained in Example 1 It was added to EtOH and heated in a steam bath until the solid was completely dissolved. The clear solution was left at room temperature for at least 18 hours to yield 80% of> 99% pure polymorph I of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] Thiazolidine-2,4-dione 1 0 malate was obtained.

Example-3

50 ml of 1 g of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione malate obtained in Example 1 Placed in acetone and heated until the solids completely dissolved in the steam bath. The clear solution was left at room temperature for at least 18 hours to yield 60% of> 99% pure polymorph II 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl ] Thiazolidine-2,4-dione maleate was obtained.

Example-4

10 g of 1 g of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate obtained in Example 1 Methanol was added and heated in a steam bath until the solid was completely dissolved. The clear solution was left at room temperature for 18 hours or more to yield 75% of> 99% pure polymorph III 5- [4- [2- [N-methyl-N- (2-pyridyl) ainino] ethoxy] benzyl] Thiazolidine-2,4-dione maleate was obtained.

Example-5

10 g of 1 g of 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate obtained in Example 1 It was placed in 1,4-dioxanol and heated in a steam bath until the solid was completely dissolved. The clear solution was left at room temperature for at least 18 hours to yield 70%> 99% pure polymorphic IV [5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] Thiazolidine-2,4-dione maleate was obtained.

The polymorph of the present invention is more effective than the currently known antidiabetic agents 5- [4- [2- [N-methyl-N- (2pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione malate to be.

Powder X-ray diffraction (XRD) spectra were measured with a Rigaku D / Max 2200 model diffractometer equipped with a horizontal goniometer under the Θ / 2Θ geometry. Copper Kα (X = 1.5418A) spinning was used and samples were scanned at 3-45 degrees 2Θ.

Differential scanning calorimeter used a Shimadzu DSC-50 equipped with a controller. Data was collected on a Pentium PC using Shimadzu TA-50 software. The sample was weighed in an aluminum cell and heated at room temperature to 220 ° C. at 5 ° C./min. Empty aluminum cells were used as a control. Dry nitrogen gas was continuously purged through the DSC cell at a flow rate of 30 ml / min during the analysis.

1 is a temperature distribution diagram of a specific differential scanning calorimeter of Form I

2 is a temperature distribution diagram of a specific differential scanning calorimeter of Form II.

3 is a temperature distribution diagram of a particular differential scanning calorimeter of Form III.

4 is a temperature distribution diagram of a particular differential scanning calorimeter of Form IV.

      5 is a specific X-ray powder diffraction spectrum of Form I

6 is a specific X-ray powder diffraction spectrum of Form II

7 is a specific X-ray powder diffraction spectrum of Form III

8 is a specific X-ray powder diffraction spectrum of Form IV

9 is a multiplot of X-ray powder diffraction spectra of shapes I, II, III and IV.

10 is a specific infrared absorption spectrum of Form I in KB

11 is a specific infrared absorption spectrum of Form II in KB

12 is a specific infrared absorption spectrum of Form III in KB

FIG. 13 shows a specific infrared absorption spectrum of Form IV in KB.

Claims (6)

5- [4 of the following equation with an X-ray powder diffraction pattern at 2θ angles of 8.90, 15.40, 18.06, 19.20, 22.30, 23.40, 23.62, 24.80, 25.10, 25.84, 26.72, 27.18, 29.30, 29.54, 29.84 and 33.26 degrees -[2- [N-Methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2, polymorph of 4-dione maleate-II:

The polymorph-II of claim 1 having DSC (Differential Scanning Calorimetry) data endotherm at 127.67 ° C. and onset at 123.17 ° C. 7. 3424, 3040, 2947, 2720, 1751, 1702, 1641, 1618, 1574, 1541, 1412, 1382, 1359, 1326, 1265, 1242, 1213, 1162, 1067, 1031, 865, 773, Polymorph-II with an infrared absorption spectrum comprising peaks at 713, 667, 576 and 539 cm ⁻¹ . (i) 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione maleate is mixed with acetone (ii) heating the mixture to form a solution (iii) the acetone solution was cooled to form 5- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione of Form II. Recovering the maleate crystals Method for producing polymorph II of claim 1 consisting of. A therapeutic agent for diabetes comprising the polymorph of claim 1. A pharmaceutical composition for treating diabetes, comprising the polymorph of claim 1 and one or more pharmaceutical excipients.

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