POLYMORPHS TROGLITAZONE HYDROCHLORIDE AND THIER USE AS ANTIDIABETICS
PREPARATION Field of the Invention This invention relates to novel polymorphic/pseudopolymorphic forms of 5-[4-[2- (5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione and its stereoisomers hydrochloride having formula (I). The invention also relates to a pharmaceutical composition comprising the novel polymorphic forms or mixture thereof and a pharmaceutically acceptable carrier. The polymorphic forms of the present invention are more active, as an antidiabetic agent than the hitherto known 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl] thiazolidine-2,4-dione hydrochloride.
The present invention also relates to a process for the preparation of various polymorphic/pseudopolymorphic forms of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy] benzyl]thiazolidine-2,4-dione hydrochloride, having the formula (I) shown above.
The polymorphic forms of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl] thiazolidine- 2,4-dione hydrochloride, of formula (I) defined above of the present invention reduce blood glucose and has beneficial effect on coronary heart disease and atherosclerosis. Out of the many drugs available for the treatment of diabetic ailments, the thiazolidinedione derivatives are very prominent and are considered as much superior effective constituents compared to the sulphonyl ureas. 5-[4-[2-(5-ethyl-2-pyridyl) ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride, one such thiazolidinedione which exhibited euglycemic effect, was reported in the year 1988 by Takeda Chemical Industries (EP 0193256 Al) and created interest in the field, ever since.
The novel polymorphic forms of 5-[4-[2-(5-ethyl-2-ρyridyl)ethoxy]benzyl] thiazolidine-2,4-dione hydrochloride, of formula (I) defined above of the present invention is useful in reducing body weight and for the treatment and/or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. The novel polymorphic forms of 5-[4-[2-(5-ethyl-
2-pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride, of formula (I) of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy. The novel polymorphic forms of 5-[4-[2-(5-ethyl-2- pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride, of formula (I) are also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders. These novel polymorphic forms of 5-[4-[2-(5-ethyl-2-pyridyl) ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride of formula (I) may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia, treating diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy, pancreatitis, arteriosclerosis, retinopathy, xanthoma, inflammation and for the treatment of cancer. The novel polymorphic forms of 5-[4-[2-(5-ethyl-2- pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride, of formula (I) of the present invention are useful in the treatment and/or prophylaxis of the above said diseases in combmation/con-comittant with one or more HMG CoA reductase inhibitors, hypolipidemic/ hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, and probucol.
Background of the invention The latest trend that has, of late, crept into the pharmaceutical industry is the studies on polymorphism in drugs and the difference in the activity of different polymorphic forms of a given drug. By the term polymorphism we mean to include different physical forms, crystal forms, crystalline / liquid crystalline / non-crystalline (amorphous) forms. This has especially become very interesting after observing that many antibiotics, antibacterials, tranquilizers etc., exhibit polymorphism and some/one of the polymorphic forms of a given drug exhibit superior bio-availability and consequently show much higher activity compared to other polymorphs. Sertraline, Frentizole, Ranitidine, Sulfathiazole, Indomethacine etc. are some of the important examples of pharmaceuticals which exhibit polymorphism. Polymorphism in drugs is a topic of current interest and is evident from the host of patents being granted. To cite a few, U.S. 5,700,820 discloses six polymorphic forms of Troglitazone, U.S. 5,248,699 discusses
about five polymorphic forms of Sertraline hydrochloride while EP 014590 describes four polymorphic forms of Frentizole. EP 490648 and EP 022527 also deal with the subject of polymorphism in drugs.
Several references discloses the structure of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy] benzyl]thiazolidine-2,4-dione hydrochloride but no such reference touch upon the possibility/observation that 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4- dione hydrochloride exists in different polymoφhic forms. There is no published literature regarding such an observation till date. Polymorphism in drugs is a topic of current interest and is evident from the host of patents being granted to cite a few U.S. 5,248,699 discusses about five polymorphic forms of Sertraline hydrochloride while EP 014590, describes four polymorphic forms of Frentizole EP 490648 and EP 022527, six polymorphic forms of Troglitazone WO 97/27191 also deal with the subject of polymorphism in drugs. The fact that polymorphism in 5-[4-[2-(5-ethyl-2-pyridyl) ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride has not been studied earlier coupled with the current interest in the field of polymorphism in drugs prompted us to take-up this investigation our observations and results from the subject matter of the present invention.
With a view to prevent/cure the chronic complications of diabetes, research is being conducted throughout the world in recent times. 5-[4-[2-(5-ethyl-2-pyridyl) ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride is being considered today as one of the most effective anti-diabetic drugs which is as a multi-functional activity not only acting on diabetes itself but also on the reduction of the triglycerides and also on the complications mentioned above. Indeed the said 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy] benzyl]thiazolidine-2,4-dione hydrochloride is emerging as the second drug candidate of euglycemic class of antidiabetic agents.
With an objective to develop novel polymorphic forms for lowering cholesterol and reducing body weight with beneficial effects in the treatment and/or prophylaxis of diseases related to increased levels of lipids, atherosclerosis, coronary artery diseases, Syndrome-X, impaired glucose tolerance, insulin resistance, insulin resistance leading to type 2 diabetes and diabetes complications thereof, for the treatment of diseases wherein insulin resistance is the pathophysiological mechanism and for the treatment of hypertension, with better efficacy, potency and lower toxicity, we focussed our research
to develop new polymoφhic forms effective in the treatment of the above mentioned diseases. Effort in this direction has led to polymoφhic forms having the formula (I).
Another objective of the present invention is to provide polymoφhic forms of 5-
[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride, their stereoisomers, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures which may have agonist activity against
PPARα and/or PPARγ, and optionally inhibit HMG CoA reductase, in addition to having agonist activity against PPARα and/or PPARγ.
Another objective of the present invention is to provide novel polymoφhic forms of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride, their stereoisomers, pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activities, without toxic effect or with reduced toxic effect.
Yet another objective of the present invention to provide a process for the preparation of novel polymoφhic forms of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl] thiazolidine-2,4-dione hydrochloride, their stereoisomers, pharmaceutically acceptable solvates.
Still another objective of the present invention is to provide pharmaceutical compositions containing novel polymoφhic forms of 5-[4-[2-(5-ethyl-2-ρyridyl)ethoxy] benzyl]thiazolidine-2,4-dione hydrochloride, solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
The present invention relates to an observation that 5-[4-[2-(5-ethyl-2-pyridyl) ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride exhibits polymoφhism, which has not been reported till date. We now report here two polymoφhic forms of 5-[4-[2-(5- ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride, namely Form I and
Form II.
From powder X-ray diffraction studies Form I and Form II are found to be crystalline in nature. The polymoφhic forms were proved to be identical in solution as evident from
Nuclear Magnetic Resonance (NMR), Ultra Violet (UN) & Mass spectral data. On the other hand, solid state techniques like Differential Scanning Calorimetry (DSC), Powder
X-Ray Diffractometry (XRD) and Infra Red spectroscopy (IR) revealed the difference among these forms.
Brief Description of the Figures X-ray powder diffraction pattern has been obtained on a Rigaku D/Max 2200 model diffractometer equiped with horizontal gonimometer in Θ/2 Θ geometry. The copper K α ( λ=1.5418A) radiation was used and the sample was scanned between 3-45 degrees 2Θ.
Differential scanning calorimeter was performed on a Shimadzu DSC-50 equipped with a controller. The data was collected on to a Pentium PC using a Shimadzu TA-50 software. The samples weighed in aluminum cells were heated from room temperature to 220°C at a heating rate of 5°C /min. The empty aluminum cell was used as a reference. Dry nitrogen gas was purged through DSC cell continuously throughout the analysis at a flow of 30 ml/min.
FT-IR Spectrum was recorded in solid state as KBr dispersion using Perkin-Elmer 1650 FT-IR Spectrophotometer.
Fig 1 is a characteristic differential scanning calorimetric thermogram of Form I Fig 2 is a characteristic differential scanning calorimetric thermogram of Form II Fig 3 is a characteristic X-ray diffraction pattern of Form I Fig 4 is a characteristic X-ray diffraction pattern of Form II Fig 5 is a characteristic infrared absoφtion spectrum of Form I in potassium bromide.
Fig 6 is a characteristic infrared absoφtion spectrum of Form II in potassium bromide.
Summary of the invention According to a feature of the present invention, there is provided a novel polymoφhic Form-I of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride, and its stereoisomers having the formula I which is characterized by the following data:
DSC: 184.91°C(endotherm), 157.90°C (onset temperature) (Fig.l). X Ray powder diffraction (2Θ): 8.64, 12.70, 18.72, 19.68, 20.00, 20.66, 22.12,
22.70, 26.08, 27.36, 28.22, 31.12, 31.96 (Fig.3).
IR ^m"1): 2928, 2742, 2616, 1743, 1692, 1510, 1461, 1333, 1314, 1243, 1152, 1037, 849, 712 (Fig.5).
According to another feature of the present invention, there is provided a novel polymoφhic Form-II of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride, and its stereoisomers having the formula I which is characterized by the following data: DSC: 180.64°C(endotherm), 178.42°C (onset temperature) (Fig.2)
X Ray powder diffraction (2Θ): 6.16, 9.12, 10.38, 12.38, 15.16, 16.44, 18.60,
21.3, 23.92, 24.92, 25.68, 28.10, 31.00 (Fig.4)
IR (cm"1): 2965, 2583, 1705, 1610, 1515, 1331, 1253, 1180, 1159, 1040, 823, 721.
(Fig.6) According to another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form-I of 5-[4-[2-(5-ethyl-2-pyridyl) ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride, of the formula I, having the characteristics described earlier, which comprises:
(i) synthesizing 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4- dione hydrochloride, employing known methods and dissolving in hot methanol, ethanol, isopropyl alcohol or t-butyl alcohol,
(ii) filtering the hot solution to remove any undissolved matter, (iii) cooling the solution to room temperature for 24 h and (iv) filtering the crystals of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl] thiazolidine-2,4-dione hydrochloride formed.
According to another feature of the present invention, there is provided a process for the preparation of novel polymoφhic Form-II of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy] benzyl]thiazolidine-2,4-dione hydrochloride, of the formula I, having the characteristics described earlier, which comprises: (i) synthesizing 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4- dione hydrochloride, employing known methods and dissolving in hot diethyl ketone, (ii) filtering the hot solution to remove any undissolved matter, (iii) cooling the solution to room temperature for 24 h and (iv) filtering the crystals of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl] thiazolidine-2,4-dione hydrochloride formed.
The crude 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride of formula (I) is prepared by a process described in European Patent No.
EP 0506273 and International Publication No. 93/13095, which is shown in scheme 1 below:
(I) Scheme 1
The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). Conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or
chromatography and the stereoisomers of compound of formula (I) may be prepared by hydrolyzing the pure diastereomeric amide.
The present invention also envisages a pharmaceutical composition comprising a polymoφhic Forms I and II of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4- dione hydrochloride, of the formula (I) and a pharmaceutically acceptable carrier .
The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavourants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. Such compositions typically contain from 1 to 25 %, preferably 1 to 15 % by weight of active ingredient, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
The polymoφhic forms of the formula (I) as defined above are clinically administered to mammals, including man, via either oral, nasal, pulmonary, transdermal or parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication, or absoφtion following oral administration is impaired, as by disease or other abnormality, it is essential that the drag be administered parenterally. By either route, the dosage is in the range of about 0.01 to about 100 mg / kg body weight of the subject per day or preferably about 0.01 to about 30 mg / kg body weight per day administered singly or as a divided dose. However, the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage.
Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active ingredient will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the polymoφhic form can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavourants, sweeteners, excipients
and the like. For parenteral administration, the polymoφhic form can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds. Aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil may also be used for injectable solutions. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans. For nasal administration, the preparation may contain the polymoφhic forms of the present invention dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, such as propylene glycol, surfactants, absoφtion enhancers such as lecithin (phosphatidylcholine) or cyclodextrin or preservatives such as parabenes. Tablets, dragees or capsules having talc and / or a carbohydrate carried binder or the like are particularly suitable for any oral application. Preferably, carriers for tablets, dragees or capsules include lactose, corn starch and / or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed. A typical tablet production method is exemplified below: Tablet Production Example : a) 1) Active ingredient 30 g
2) Lactose 95 g
3) Corn starch 30 g
4) Carboxymethyl cellulose 44 g
5) Magnesium stearate i g
200 g for 1000 tablets The ingredients 1 to 3 are uniformly blended with water and granulated after drying under reduced pressure. The ingredient 4 and 5 are mixed well with the granules and compressed by a tab letting machine to prepare 1000 tablets each containing 30 mg of active ingredient.
b) 1) Active ingredient 30 g
2) Calcium phosphate 90 g
3) Lactose 40 g
4) Corn starch 35 g
5) Polyvinyl pyrrolidone 3.5 g
6) Magnesium stearate 1.5 g
200 g for 1000 tablets The ingredients 1-4 are uniformly moistened with an aqueous solution of 5 and granulated after drying under reduced pressure. Ingredient 6 is added and granules are compressed by a tabletting machine to prepare 1000 tablets containing 30 mg of ingredient 1.
The present invention is described in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
EXAMPLES Example 1 In a 20 L round bottom flask 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl] thiazolidine-2,4-dione (1165 g), methanol (5.8 ml) and concentrated hydrochloric acid (583 ml) are placed and heated to 45-50°C. The undissolved material is filtered out. The filtrate is diluted with ethyl acetate (11.65 L) and cooled to 0-5 °C and stirred for 1 h. The precipitated material filtered and washed with ethyl acetate (1L), dried and collected as first crop (787 g). The mother liquor is concentrated to half of its volume and cooled. The precipitated solid is filtered and dried to get second crop (259 g). The combined yield of both the crops of 90%.
Example 2 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride (500 mg, 1.27 mnioles) obtained in Example 1 is dissolved in hot methanol (15 ml). The solution is filtered in hot condition to remove any undissolved particles. The filtrate is kept for recrystallization at ambient temperature for 24 h. The white crystals obtained are filtered and dried to yield Form I of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl] thiazolidine-2,4-dione hydrochloride (100 mg).
Example 3 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride (500 mg, 1.27 mmoles) obtained in Example 1 is dissolved in hot ethyl alcohol (15 ml). The solution is filtered in hot condition to remove any undissolved particles. The filtrate is kept for recrystallization at ambient temperature for 24 h. The white crystals obtained are filtered and dried to yield Form I of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl] thiazolidine-2,4-dione hydrochloride (100 mg).
Example 4 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione hydrocl loride (50 mg, 0.127 mmoles) obtained in Example 1 is dissolved in hot t-butyl alcohol (20 ml). The solution is filtered in hot condition to remove any undissolved particles. The filtrate is kept for recrystallization at ambient temperature for 24 h. The white crystals obtained are filtered and dried to yield Form I of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl] thiazolidine-2,4-dione hydrochloride (10 mg). Example 5
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride (100 mg, 0.254 mmoles) obtained in Example 1 is dissolved in hot isopropyl alcohol (20 ml). The solution is filtered in hot condition to remove any undissolved particles. The filtrate is kept for recrystallization at ambient temperature for 24 h. The white crystals obtained are filtered and dried to yield Form I of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy] benzyl]thiazolidine-2,4-dione hydrochloride (50 mg).
Example 6 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione hydrochloride (50 mg, 0.127 mmoles) is dissolved in hot diethyl ketone (10 ml). The solution is filtered in hot condition to remove any undissolved particles. The filtrate is kept for recrystallization at ambient temperature for 24 h. The white crystals obtained are filtered and dried to yield Form π of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]thiazolidine-2,4- dione hydrochloride (10 mg).