Field of the Invention

The present invention provides mirabegron dimethyl sulphoxide, processes for its preparation, a pharmaceutical composition comprising it, and its use for the treatment of overactive bladder. The present invention also provides processes for the preparation of mirabegron using mirabegron dimethyl sulphoxide solvate.

Background of the Invention

Mirabegron is a beta-3 adrenergic agonist disclosed in U.S. Patent No. 6,346,532. It is chemically designated as 2-(2-aminothiazol-4-yl)-N-[4-[2-{[(2R)-2-hydroxy-2- phenylethyl]amino}ethyl)phenyl]acetamide, and has the structure depicted by Formula I.

Formula I

Mirabegron is marketed in the United States under the brand name Myrbetriq ^® for the treatment of overactive bladder with symptoms of urinary incontinence, urgency, and urinary frequency.

The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides new opportunities to improve the performance characteristics of a pharmaceutical product.

Polymorphs of mirabegron are disclosed in U.S. Patent No. 7,342, 117, PCT Publication No. WO 2012/156998, and IP.com disclosure No. IPCOM000228561D.

Solvates of mirabegron are not disclosed in the literature. The present invention provides mirabegron dimethyl sulphoxide solvate.

Summary of the Invention

The present invention provides mirabegron dimethyl sulphoxide solvate, processes for its preparation, a pharmaceutical composition comprising it, and its use for the treatment of overactive bladder. The mirabegron dimethyl sulphoxide solvate of the present invention is stable, easily reproducible, and is suitable for the preparation of pharmaceutical compositions. The present invention also provides processes for the preparation of mirabegron by desolvation of the mirabegron dimethyl sulphoxide solvate.

A first aspect of the present invention provides the mirabegron dimethyl sulphoxide solvate of Formula II:

Formula II

characterized by X-ray diffraction peaks at d-spacings of 5.14, 4.95, 4.45, 4.32, and 3.39

A.

A second aspect of the present invention provides a process for the preparation of the mirabegron dimethyl sulphoxide solvate of Formula II:

Formula II

comprising contacting mirabegron of Formula I with dimethyl sulphoxide in the presence of a solvent.

Formula I

A third aspect of the present invention provides a process for the preparation of mirabegron of Formula I:

Formula I

comprising desolvation of the mirabegron dimethyl sulphoxide solvate of Formula II.

Formula II

A fourth aspect of the present invention provides a pharmaceutical composition comprising the mirabegron dimethyl sulphoxide solvate of Formula II and one or more pharmaceutically acceptable carriers, diluents, or excipients.

A fifth aspect of the present invention provides the use of the mirabegron dimethyl sulphoxide solvate of Formula II for the treatment of overactive bladder with symptoms of urinary incontinence, urgency, and urinary frequency.

Other objects, features, advantages, and aspects of the present invention will become apparent to those skilled in the art from the description provided herein.

Brief Description of the Figures

Figure 1 : X-ray Powder Diffraction (XRPD) pattern of the mirabegron dimethyl sulphoxide solvate of Formula II.

Figure 2: Differential Scanning Calorimetry (DSC) thermogram of the mirabegron dimethyl sulphoxide solvate of Formula II.

Figure 3 : Thermogravimetric Analysis (TGA) of the mirabegron dimethyl sulphoxide solvate of Formula II.

Detailed Description of the Invention

Various embodiments and variants of the present invention are described hereinafter.

The term "contacting", as used herein, includes dissolving, slurrying, stirring, or combinations thereof.

The term "about", as used herein, refers to a variation of up to ±5% in the value of a parameter, such as temperature or stirring time.

Mirabegron dimethyl sulphoxide solvate of Formula II is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 17.25 (d-spacing at 5.14 A), 17.92 (4.95 A), 19.97 (4.45 A), 20.58 (4.32 A), and 26.28 (3.39 A) ± 0.2 degrees 2Θ. It may be further characterized by an XRPD pattern having peaks at 3.73 (23.71 A), 9.94 (8.90 A), 21.42 (4.15 A), 21.85 (4.07 A), and 22.94 (3.88 A) ± 0.2 degrees 2Θ. Table 1 summarizes the d-spacing values in A, and the corresponding 2Θ values in degrees 2Θ, of the mirabegron dimethyl sulphoxide solvate of Formula II.

Table 1: XRPD peaks of mirabegron dimethyl sulphoxide solvate

d-spacing [A] Pos. [°2Θ] Rel. Int. [%]

23.71 3.73 35.47

11.90 7.43 4.20

8.90 9.94 34.36

8.56 10.33 9.93

7.41 11.94 12.56

6.88 12.87 5.92

6.17 14.35 3.51

5.70 15.54 17.39

5.51 16.10 7.16

5.14 17.25 79.04

5.05 17.57 34.61

4.95 17.92 80.93

4.77 18.59 30.41

4.70 18.88 38.11

4.58 19.36 20.56

4.45 19.97 100

4.32 20.58 78.31

4.15 21.42 26.62

4.07 21.85 47.93

3.97 22.40 56.35

3.88 22.94 54.84

3.77 23.64 27.43

3.71 23.97 16.60

3.66 24.33 36.13

3.59 24.77 19.29

3.54 25.16 22.72

3.50 25.42 28.39

3.47 25.68 11.29

3.39 26.28 69.78

3.27 27.30 27.39

3.18 27.70 23.27

3.10 28.01 11.60

3.22 28.83 10.01

3.06 29.22 28.56

2.99 29.88 18.13

2.90 30.87 10.65

2.86 31.32 17.42

2.83 31.63 21.78

2.78 32.20 9.63 2.71 33.03 10.45

2.65 33.84 13.26

2.61 34.39 14.20

2.56 35.01 11.40

2.52 35.57 6.29

2.48 36.25 7.74

2.41 37.32 7.00

2.35 38.30 8.44

2.27 39.73 10.62

The mirabegron dimethyl sulphoxide solvate of Formula II may also be characterized by a DSC thermogram having endotherms at about 91.50°C and about 93.68°C.

The mirabegron dimethyl sulphoxide solvate of Formula II may also be characterized by an XRPD pattern, a DSC thermogram, and a TGA as depicted in Figures 1-3, respectively.

Mirabegron used for the preparation of the mirabegron dimethyl sulphoxide solvate of Formula II may be obtained by the methods known in the literature, such as those described in U.S. Patent No. 7,342,117 and PCT Publication No. WO 2012/156998 which are incorporated herein by reference.

The preparation of the mirabegron dimethyl sulphoxide solvate of Formula II is carried out by contacting mirabegron of Formula I with dimethyl sulphoxide at a temperature of about 20°C to the reflux temperature of the solvent. The preparation of the mirabegron dimethyl sulphoxide solvate of Formula II may also be carried out using a solvent selected from the group comprising of aromatic hydrocarbons, alkyl acetates, and mixtures thereof. Examples of aromatic hydrocarbons include toluene and xylene.

Examples of alkyl acetates include ethyl acetate, propyl acetate, isopropyl acetate, and t- butyl acetate.

The preparation of the mirabegron dimethyl sulphoxide solvate of Formula II may also be carried out by stirring the reaction mixture at a temperature of about 20°C to about 40°C for about 15 minutes to about 4 hours.

Isolation of the mirabegron dimethyl sulphoxide solvate of Formula II may be accomplished by crystallization, concentration, precipitation, cooling, filtration, centrifugation, or a combination thereof, followed by drying. Any suitable method of drying may be employed such as drying under reduced pressure, vacuum tray drying, air drying, or a combination thereof. Drying is carried out at a temperature of about 20°C to about 40°C for about 30 minutes to about 20 hours.

In an embodiment of the present invention, the mirabegron dimethyl sulphoxide solvate of Formula II is prepared by dissolving mirabegron in a mixture of dimethyl sulphoxide and an aromatic hydrocarbon solvent, stirring the reaction mixture for about 15 minutes to about 2 hours at a temperature of about 20°C to about 40°C, followed by isolation.

In another embodiment of the present invention, the mirabegron dimethyl sulphoxide solvate of Formula II is prepared by dissolving mirabegron in a mixture of dimethyl sulphoxide and an alkyl acetate solvent, stirring the reaction mixture for about 15 minutes to about 2 hours at a temperature of about 20°C to about 40°C, followed by isolation.

In the preferred embodiments of the present invention, the mirabegron dimethyl sulphoxide solvate of Formula II is prepared by using a mixture of dimethyl sulphoxide with toluene, or a mixture of dimethyl sulphoxide with i-butyl acetate as a solvent.

The desolvation of the mirabegron dimethyl sulphoxide solvate is carried out by stirring a reaction mixture containing the mirabegron dimethyl sulphoxide solvate in a solvent selected from the group comprising of water, chlorinated hydrocarbons, alcohols, ketones, and mixtures thereof at a temperature of about 0°C to about 50°C. Examples of chlorinated hydrocarbons include dichloromethane and chloroform. Examples of alcohols include methanol, ethanol, iso-propanol, and butanol. Examples of ketones include acetone, dimethyl ketone, ethyl methyl ketone, and methyl iso-butyl ketone.

In one embodiment of the present invention, the desolvation of the mirabegron dimethyl sulphoxide solvate of Formula II is carried out by contacting the mirabegron dimethyl sulphoxide solvate of Formula II with water at a temperature of about 25 °C to about 35°C. The reaction mixture is stirred for about 30 minutes to about 2 hours, filtered, and the solid obtained is dried at a temperature of about 40°C to about 50°C under vacuum.

In another embodiment of the present invention, the desolvation of the mirabegron dimethyl sulphoxide solvate of Formula II is carried out by contacting the mirabegron dimethyl sulphoxide solvate of Formula II with acetone at a temperature of about 0°C to about 10°C. The reaction mixture is stirred for about 30 minutes to about 2 hours, filtered, and the solid obtained is dried at a temperature of about 20°C to about 40°C under vacuum.

Polymorphs and pseudomorphs of the mirabegron dimethyl sulphoxide solvate of Formula II are also included within the scope of the present invention.

Mirabegron dimethyl sulphoxide solvate of Formula II may be administered as part of a pharmaceutical composition for the treatment of overactive bladder. Accordingly, in a further aspect, there is provided a pharmaceutical composition comprising mirabegron dimethyl sulphoxide solvate of Formula II, one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally other therapeutic ingredients.

Pharmaceutical compositions comprising mirabegron dimethyl sulphoxide solvate of Formula II may be administered orally, topically, parenterally, by inhalation or spray, rectally, or in the form of injectables. The injectable compositions may include intravenous, intramuscular, subcutaneous, and parenteral injections, as well as use of infusion techniques.

In the foregoing section, embodiments are described by way of examples to illustrate the processes of invention. However, these are not intended in any way to limit the scope of the present invention. Variants of the examples that would be evident to persons ordinarily skilled in the art are within the scope of the present invention.

EXAMPLES

Method

The X-ray powder diffraction (XRPD) pattern was recorded using a PANalytical ^® X'pert PRO with X'celerator ^® as the detector.

The DSC was recorded using a Mettler-Toledo ^® 82 le. Data collection parameters: Scanning rate: 10°C/minute; Temperature: 30°C to 300°C.

The TGA was recorded using a TA Instruments ^® Q500.

The NMR spectrum was recorded using a Bruker ^® Avance III 400 MHz NMR spectrometer. Example 1 : Preparation of mirabegron dimethyl sulphoxide solvate

Method A:

Mirabegron (1.5 g) was suspended in a mixture of dimethyl sulphoxide (1.0 mL) and toluene (2 mL). The reaction mixture was stirred for about 30 minutes at a temperature of about 25°C to about 35°C. The reaction mixture was diluted with toluene (5 mL). The solid obtained was filtered, washed with toluene (40 mL), and dried in a vacuum tray dryer at a temperature of about 25°C to about 35°C for about 16 hours to obtain the mirabegron dimethyl sulphoxide solvate.

Yield: 1.79 g

i-NMR (DMSO- e, 400 MHz) δ (in ppm): 1.80 (1H, s), 2.53 (6H, s), 2.59-2.67 (4H, m), 2.69-2.79 (2H, m), 3.44 (2H, s), 4.58-4.61 (1H, m), 5.23 (1H, s), 6.29 (1H, s), 6.89 (2H, s), 7.10-7.12 (2H, d), 7.18-7.23 (1H, m), 7.27-7.33 (4H, m), 7.48-7.50 (2H), 10.00 (1H, s).

Method B:

Mirabegron (4.5 g) was suspended in a mixture of dimethyl sulphoxide (3 mL) and /-butyl acetate (45 mL). The reaction mixture was stirred at a temperature of about 25 °C to about 35°C for about 3 hours. The solid obtained was filtered, washed with i-butyl acetate (30 mL), and dried in a vacuum tray dryer at a temperature of about 25 °C to about 35°C for about 3 hours to obtain the mirabegron dimethyl sulphoxide solvate.

Yield: 5.18 g

Example 2: Preparation of mirabegron by desolvation of the mirabegron dimethyl sulphoxide solvate

Method A:

Water (15 mL) was added to mirabegron dimethyl sulphoxide solvate (500 mg) at about 25°C to about 35°C. The reaction mixture was stirred for about 1 hour. The solid obtained was filtered and dried under vacuum at about 45 °C for about 3 hours to obtain mirabegron.

Yield: 0.37 g

Method B:

Acetone (10 mL) was added to mirabegron dimethyl sulphoxide solvate (500 mg). The reaction mixture was stirred for about 1 hour at about 0°C to about 5°C. The solid obtained was filtered and dried under vacuum at about 25 °C to about 35°C for about 2 hours to obtain mirabegron.

Yield: 0.31 g.