Thereof and the Preparations Thereof

Field of the Invention

The present invention relates to the preparation of novel polymorphic forms of 4-[(4- methoxyphenylJmethyll-δ-^hfluoromethylJ-I H-pyrazole-S-yll^-deoxy^-fluoro-beta-D- glucopyranoside and hydrates thereof which are suitable for the treatment of certain diseases and conditions including, but not limited to, diabetes.

Background of the Invention

Published United States Patent Application US 2004 /0259819 discloses certain heterocyclic fluoroglycoside derivatives having an effect on SGLTs. More particularly, said published application discloses the use of 4-[(4-methoxyphenyl)methyl]-5- (thfluoromethyl)-i H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside (figure 1 , n = 0) for treating diabetes by affecting SGLT2.

Figure 1

The preparation of 4-[(4-methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H-pyrazole-3-yl]- 4-deoxy-4-fluoro-beta-D-glucopyranoside is disclosed in Published United States Patent Application US 2004 /0259819. However, the aforementioned patent application makes no mention as to the polymorphic form, hydration state or physical purity of the compound provided from the procedure. Furthermore, there is no reported physical chemical data reported for 4-[(4-methoxyphenyl)methyl]-5- (thfluoromethyl)-i H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside in said published application that suggests the physical form of the product obtained.

A primary concern for the manufacture of large-scale pharmaceutical compounds is that the active substance should have a stable crystalline form to ensure consistent processing parameters and pharmaceutical quality. If an unstable crystalline form is used, that crystalline form may change during manufacture and/or storage resulting in quality control problems, and formulation irregularities. Such a change may affect the reproducibility of the manufacturing process and thus lead to final formulations which do not meet the high quality and stringent requirements imposed on formulations of pharmaceutical compositions.

The large-scale manufacturing of a pharmaceutical composition poses many challenges to the chemist and chemical engineer. While many of these challenges relate to the handling of large quantities of reagents and control of large-scale reactions, the handling of the final product poses special challenges linked to the nature of the final active product itself. Not only must the product be prepared in high yield, stable, substantially free of impurities and capable of ready isolation, the product must possess properties that are suitable for the types of pharmaceutical preparations in which they are likely to be ultimately used. The stability of the active ingredient of the pharmaceutical preparation must be considered during each step of the manufacturing process, including the synthesis, isolation, bulk storage, pharmaceutical formulation and long-term formulation. Each of these steps may be impacted by various environmental conditions of temperature and humidity.

The pharmaceutically active substance used to prepare the pharmaceutical compositions should be as pure as possible and its chemical and physico-chemical stability on long-term storage must be assured under various environmental conditions. This is needed to prevent the appearance of unintended degradation products in pharmaceutical compositions. As such degradation products may be potentially toxic or result simply in reducing the potency of the composition.

The present invention comprises novel polymorphic forms of a drug substance, 4-[(4- methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D- glucopyranoside, and hydrates thereof. Although widespread, not all pharmaceutically active compounds form hydrates or solvates. The existence of hydrates, their crystal structure and properties are unpredictable and therefore not obvious.

Summary of the Invention

The present invention comprises process for the preparation of novel polymorphic 4- [(4-methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside, and hydrates thereof substantially free of residual organic solvent contaminants and impurities. Said compound can exist in at least 4 crystalline forms of varying degrees of hydration.

The present invention also comprises administering to a patient in need of treatment a therapeutically effective amount of a composition comprising at least one crystalline form selected from the group consisting of Form B, Form C and Form D.

Form B of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D- glucopyranoside dihydrate (Figure I wherein n is 2) is characterized by the following peaks as measured by XPRD: 5.20, 6.57, 9.01 , 10.41 , 11.39, 13.19, 15.43, 15.85, 17.95, 18.79, 19.91 , 20.32, 20.72, 21.26, 21.90, 22.39, 23.37, 23.87, 24.41 , 24.73, 25.08, 26.48, 28.52 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation. In particular Form B is characterized by representative peaks at 5.2, 6.57, 13.19, 19.91 , 21.26 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation. Further Form B is characterized by infrared: peaks found at 1513, 1504 and 1160 +/-1 cm ^"1 . Form C of 4-[(4-methoxyphenyl)nnethyl]-5-(trifluoronnethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside (Figure I wherein n is 0) is characterized by the following peaks as measured by XPRD: 4.30, 8.61 , 11.21 , 15.88, 17.29, 18.63, 19.61 , 20.45, 20.48, 21.14, 21.47, 22.65, 23.39, 25.43, 27.01 , 28.52, 30.34 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation. In particular Form C is characterized by representative peaks at 4.3, 8.61 , 15.88, 20.45, 22.65 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation. Further Form C is characterized by infrared: peaks found at 1508 (with a shoulder) and 1023 +/-1 cm ^"1 .

Form D of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside monohydrate (Figure I wherein n is 1 ) is characterized by the following peaks as measured by XPRD: 5.97, 7.57, 12.22, 14.55, 15.20, 18.39, 19.51 , 19.97, 20.51 , 22.52, 22.77, 24.08, 26.56, 27.37, 28.12 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation. In particular Form D is characterized by representative peaks at 7.57, 14.55, 19.97, 20.61 , 22.77 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation. Further Form D is characterized by infrared: peaks found at 1512, 1481 , 1460 and 1440 +/-1 cm ^"1 .

Detailed Description of the Drawings

Figure 1 is the structure of 4-[(4-methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside and hydrates thereof.

Figure 2 is the XPRD of Form B the dihydrate of 4-[(4-methoxyphenyl)methyl]-5- (thfluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside

Figure 3 is the Infrared Spectrum of Form B

Figure 4 is the Differential Scanning Calohmetry Trace of Form B

Figure 5 is the TGA of Form B

Figure 6 is the XPRD of Form C Figure 7 is the Infrared Spectrum of Form C

Figure 8 is the Raman Spectrum of Form C

Figure 9 is the Differential Scanning Calohmetry Trace of Form C

Figure 10 is the TGA of Form C Figure 11 is the XPRD of Form D

Figure 12 is the Infrared Spectrum of Form D

Figure 13 is the Raman Spectrum of Form D

Figure 14 is the Differential Scanning Calorimetry Trace of Form D

Figure 15 is the TGA of Form D Detailed Description of the Invention

The preparation of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside is disclosed in Published United States Patent Application US 2004 /0259819. However, the aforementioned patent application makes no mention as to the physical form or state of hydration of the compound provided from the procedure. Neither is any physical chemical data reported for 4-[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside in Application US 2004 /0259819 that would suggest the particular physical form of the product obtained. The present invention relates to novel physical forms of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4- fluoro-beta-D-glucopyranoside, each with its own unique physico-chemical properties. Form D is a monohydrate. Form C is an anhydrate and Form B is a dihydrate.

The procedures described herein provide novel and unexpected stable polymorphs and hydrates of this compound or a tautomer thereof. These experiments comprise thermodynamically controlled crystallizations of essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside hydrated forms by varying solvent and cooling rate and also by adding anti-solvents. The particular forms may also be produced through maturation procedures and/or dehydration of hydrates.

Form B may be produced from essentially pure 4-[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside monohydrate in a heterogeneous manner. For example, crystallization/recrystallization of essentially pure 4-[(4-methoxyphenyl)methyl]- 5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside from n-propanol/water mixture containing 1 .9 equivalents of KOAc/HOAc (pH about 6) at onset of 22 - 32°C initially produces a monohydrate. However, heating and digesting the above mixture at about 35°C, then slow cooling and aging at about 1 °C, gives Form B on isolation by filtration under vacuum. Temperature ramping rates, aging, temperature/times, the presence of additives and pH are important in controlling the form of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside that is isolated. Additives other than KOAc/HOAc, such as, for example, NaOAc, LiOAc, KCI, NaCI, LiCI, K ₃ PO ₄ , HK ₂ PO ₄ , H ₂ KPO ₄ , and their respective Na, Li, Mg, and Zn salts may also be used in the crystallization/recrystallization processes.

Form B may be isolated from crystallization of essentially pure 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside using 1 -PrOH/HOAc/water or 1 -PrOH/THF/water. Form B may also be isolated from isopropyl acetate/n-heptane solutions when the water content is between 3 and 10 equivalents after formation of a monohydrate. Under these conditions, but with water content greater than 10 equivalents, Form B may be obtained directly. Furthermore, Form B may be obtained by stirring suspensions of 4-[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside monohydrate at 20 ⁰ C in alcohol/water mixtures with a water activity of 0.7 or higher.

Form C is obtained by dissolving essentially pure 4-[(4-methoxyphenyl)methyl]- 5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside monohydrate in isopropyl acetate. The aforesaid solution is then heated to drive off water at high temperature prior to precipitation by addition of n-heptane. Form C may also be obtained from the melt of a hydrate.

Form D may be prepared by stirring suspensions of a hydrate or an anhydrate in alcohol/water systems at high temperature, such as, for example, above 60 ⁰ C. Form D may also be isolated by crystallization from a solution of essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside in aqueous ethanol or in aqueous isopropanol and isolating at high temperature, such as, for example, above 60°C

All X-ray powder diffraction experiments (XPRD) are performed with a STOE Stadi-P transmission diffractometer using Cu-Kαi radiation. For room temperature powder diffraction, linear position sensitive detectors are used. Dry samples are investigated in a flat preparation. The measured data is evaluated and plotted with the software WinXPOW v2.12.

All DSC measurements are performed with a METTLER DSC822e (module DSC822e/700/109/414935/0025). If not indicated differently, 4OpL Al-crucibles with sealed lid and hole are used. All measurements are carried out in a nitrogen gas flow of 50 mL/min and typical heating rates range from 1 to 50 ^o /min. The measured data is evaluated via the software provided with said instrument.

The thermogravimetric analyses are performed with a METTLER TGA85 1 e (module TGAISDTA85 1 elSF 1 1001042). Open 100p1 A1203 crucibles are used and the measurements are performed in a nitrogen gas flow of 50 mL/min. The measured data is evaluated via the software STARe V8.10.

Infra-red absorption spectra are recorded on a FT-IR Spectrometer (Nexus 470, NICOLET). The spectra are evaluated and plotted by the software Omnic V. 6.1 A.

Raman spectra are recorded with an FT-Raman spectrometer (RFS-1 OOIS, BRUKER) equipped with a 1 .5 W NIR-Laser (Nd:YAG; h=1064 nm) and a nitrogen-cooled D4 1 8-T NIR-Detector. The spectra are evaluated and plotted by the software OPUS V. 4.2.

If not stated differently, the crystallization experiments may be performed with essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside (for example, greater than 98% HPLC purity).

The following examples detailed below are provided to more specifically describe and to better teach how to make and practice the claimed compounds of the present invention and methods for their preparation. The examples are provided for illustrative purposes only and it is to be recognized that not all embodiments of the invention can be disclosed in this manner. Therefore, the examples are to be construed in this way and should not be interpreted as limiting the spirit and scope of the invention. Example 1a Preparation of Form B

Essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4- deoxy-4-fluoro-beta-D-glucopyranoside monohydrate (0.218 g) was allowed to maturate in 1.5 ml_ of water/ethanol (vol/vol 1 :1 ) at 20 ⁰ C for up to six weeks. The solids in the slurry were identified as Form B.

Example 1b Preparation of Form B

Essentially pure 4-[(4-methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H-pyrazole-3-yl]-4- deoxy-4-fluoro-beta-D-glucopyranoside monohydrate (5g) was allowed to maturate overnight in 125 ml_ of a 1 -propanol (25%)/water (75%) mixture at room temperature (20 ⁰ C). After filtration, solids were identified as Form B.

Example 1c Preparation of Form B

Essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside (5Og) was added to a reactor along with 150 ml_ of 1 -PrOH, 150 ml_ water, 20.6g of KOAc and 6.3ml_ of HOAc. The resultant mixture was stirred to dissolve and filtered into a 3L jacketed reactor. The filter was washed with 10OmL of 1 -PrOH/water (1 :1 ) and the washes added to the reactor. The solution was warmed to 45°C with stirring at which point an additional 55OmL of water were added over 4 minutes. The solution was reheated to 45°C and then cooled to 29°C over 23 minutes followed by cooling to 22°C at 4.5°C/hour. The thick suspension obtained was heated to 36°C, held for 80 minutes and then cooled at 3°C/hour to 1 ⁰ C and left to age overnight. A sample removed at this point was confirmed to be dihydrate Form B. The slurry was filtered, washed with water and dried yielding Form B. Example 1d Preparation of Form B

A 40 ml_ vial was charged with 15ml_ of a basic aqueous solution (6.36 wt% of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside). A sodium salt of the pyrazole functionality, or other suitable salt of the pyrazole could be used to prepare the solution, lsopropyl acetate (15 ml_) and glacial acetic acid (0.28ml_) were added. The resultant biphasic mixture was stirred vigorously for 60 minutes. After phase separation the organic phase was charged into a clean 4OmL vial and the water content was determined to be 25 equivalents by KF titration. A 9ml_ aliquot of this solution was removed, heated to 67°C and held at this temperature for 1 hour. n-Heptane (13.5 ml_) was added in two portions (9ml_ and 4.5ml_) and the solution was cooled to 25°C. A sample was taken and the contents were identified as Form B. After continuing to stir overnight at 25°C, the sample remained Form B.

Example 2a Preparation of Form C

Keeping a melt of a hydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside at 130 C for 6 hours provides Form C.

Example 2b Preparation of Form C

4-[(4-Methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4- fluoro-beta-D-glucopyranoside (2Og) was dissolved in 250 ml_ of isopropyl acetate at 30 ⁰ C. The resultant solution was concentrated to remove water and additional isopropyl acetate was added so that the volume reached 133 ml_. This solution was heated to 72°C, 133 ml_ of n-heptane were added and the mixture was held at 72°C until precipitation occurred. The slurry was cooled to room temperature, solids isolated by vacuum filtration and dried in a vacuum oven at 50 ⁰ C, yielding form C.

Example 3a Preparation of Form D

4-[(4-Methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4- fluoro-beta-D-glucopyranoside (0.51 g) was added to a 30 mL jacketed tube followed by 5 mL of 16.7% 1 -PrOH in water. The slurry was stirred and heated to 65°C to ensure dissolution. Water (5ml_) was added to precipitate out solids (temperature of slurry was 59.7°C). The slurry was filtered hot yielding Form D.

Referring now to the drawings,

Figure 1 is the structure of 4-[(4-methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside and hydrates thereof.

Figure 2 is the XPRD of Form B the dihydrate of 4-[(4-methoxyphenyl)methyl]-5- (thfluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside

Figure 3 is the Infrared Spectrum of Form B

Figure 4 is the Differential Scanning Calohmetry Trace Thermogram of Form B

Figure 5 is the TGA of Form B

Figure 6 is the XPRD of Form C

Figure 7 is the Infrared Spectrum of Form C

Figure 8 is the Raman Spectrum of Form C

Figure 9 is the Differential Scanning Calohmetry Trace of Form C Figure 10 is the TGA of Form C

Figure 11 is the XPRD of Form D

Figure 12 is the Infrared Spectrum of Form D

Figure 13 is the Raman Spectrum of Form D Figure 14 is the Differential Scanning Calorimetry Trace of Form D Figure 15 is the TGA of Form D