Crystalline form of (1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-A]pyrazin-3-yl)cyclohexanecarboxamide

Abstract

A crystalline form of (1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide, pharmaceutical compositions containing it and its use in the prevention or treatment of cardiovascular diseases.

Claims

1. A crystalline form of (1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide: ##STR00008##

2. A crystalline form according to claim 1, characterised in that it has that has an X-ray powder diffraction pattern with at least one specific peak at 2 about =9.7, 10.6, 15.8, 16.7, 17.3, 18.7, 19.5, 21.3, 23.3 and/or 24.8 when measured using CuK radiation.

3. A crystalline form according to claim 1, characterised in that it has an X-ray powder diffraction pattern with at least one specific peak at 2 about =9.7, 15.8, 17.3, 19.5 and/or 24.8 when measured using CuK radiation.

4. A crystalline form according to claim 1, characterised in that it has an X-ray powder diffraction pattern with specific peaks at 2 about =9.7, 15.8, 17.3, 19.5 and 24.8 when measured using CuK radiation.

5. A crystalline form according to claim 1, characterised in that it has an X-ray powder diffraction pattern with specific peaks at 2 about =9.7, 10.6, 15.8, 16.7, 17.3, 18.7, 19.5, 21.3, 23.3 and 24.8 when measured using CuK radiation.

6. A crystalline form according to claim 1, characterised in that it has an X-ray powder diffraction pattern substantially as shown in FIG. 1, when measured using CuK radiation.

7. A pharmaceutical composition comprising a crystalline form as claimed in claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier.

8. A method of treating acute coronary syndrome comprising administering a crystalline form according to claim 1 to a patient in need thereof.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 shows an X-ray powder diffraction pattern of Example 1 (Form A).

(2) FIG. 2 shows DSC of Example 1 (Form A).

EXAMPLES

(3) The present invention will now be further explained by reference to the following illustrative examples in which, unless stated otherwise: (i) Temperatures are given in degrees Celsius ( C.); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25 C. (ii) In general, the course of reactions was followed by HPLC and reaction times are given for illustration only. (iii) Yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required. (iv) Chemical symbols have their usual meanings; SI units and symbols are used. (v) Solvent ratios are given in volume: volume (v/v) terms. (vi) Unless stated otherwise, starting materials were commercially available.
X-Ray Powder Diffraction Analysis

(4) A sample was mounted on single silicon crystal (SSC) wafer mount and powder X-ray diffraction was recorded with a Theta-Theta PANalytical XPert PRO (wavelength of X-rays 1.5418 nickel-filtered Cu radiation, Voltage 45 kV, filament emission 40 mA). Automatic variable divergence and anitscatter slits were used and the samples were rotated during measurement. Samples were scanned from 2-50 2Theta using a 0.013 step width and a 233 seconds step measurement time using a PIXCEL detector (active length 3.35 2Theta).

(5) It is known in the art that an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation. For example, persons skilled in the art of X-ray powder diffraction will realise that the relative intensities of peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used. The skilled person will also realise that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Hence a person skilled in the art will appreciate that the diffraction pattern data presented herein is not to be construed as absolute and any crystalline form that provides a power diffraction pattern substantially identical to those disclosed herein fall within the scope of the present disclosure (for further information see Jenkins. R & Snyder. R. L. Introduction to X-Ray Powder Diffractometry John Wiley & Sons. 1996).

(6) Generally, a measurement error of a diffraction angle in an X-ray powder diffractogram may be approximately plus or minus 0.1 2-theta, and such a degree of a measurement error should be taken into account when considering the X-ray powder diffraction data. Furthermore, it should be understood that intensities might fluctuate depending on experimental conditions and sample preparation (e.g. preferred orientation).). The following definitions have been used for the relative intensity (%): 81-100%, vs (very strong); 41-80%, str (strong); 21-40%, med (medium); 10-20%, w (weak); 1-9%, vw (very weak).

(7) TABLE-US-00001 TABLE 1 Peaks of Compound (I) Form A Position 2theta Intensity 6.4 vw 9.6 m 9.7 s 10.6 vw 12.8 vw 15.8 vs 16.2 w 16.7 m 17.3 s 18.2 vw 18.7 m 19.3 vw 19.5 s 20.0 m 20.5 vw 21.3 s 21.7 w 22.2 m 23.3 s 24.8 vs 25.3 m 25.9 m 26.5 w 27.8 w
General Methods

(8) The crystalline forms of the present application will now be further explained by reference to the following non limiting example.

(9) In the examples, high resolution mass spectra were recorded on a Micromass LCT mass spectrometer equipped with an electrospray interface (LC-HRMS). .sup.1H NMR measurements were performed on Varian UNITY plus 400, 500 and 600 spectrometers or Varian INOVA 400, 500 and 600 spectrometers or Bruker Avance 400, 500 and 600 spectrometers, operating at .sup.1H frequencies of 400, 500 and 600 MHz, respectively. The experiments were typically recorded at 25 C. Chemical shifts are given in ppm with the solvent as internal standard. Flash chromatography was performed using straight phase flash chromatography on a SP1 Purification system from Biotage using normal phase silica FLASH+ (40M, 25M or 12 M) or SNAP KP-Sil Cartridges (340, 100, 50 or 10) unless otherwise stated. In general, all solvents used were commercially available and of analytical grade. Anhydrous solvents were routinely used for reactions. Phase Separators used in the examples are ISOLUTE Phase Separator columns. The Intermediates and Examples named below were named using ACD/Name 12.01 from Advanced Chemistry Development, Inc. (ACD/Labs).

(10) Experimental. DSC: Thermal events were analysed by modulated differential scanning calorimetry on a TA DSC Q2000 instrument. 9.7 mg of material contained in a standard aluminium closed cup with a pinhole was measured over the temperature range 0 C. to 260 C. at a constant heating rate of 5 C. per minute, with a overlayed modulation of 0.53 C. at a modulation interval of 40 seconds. A purge gas using nitrogen was used (flow rate 50 mL per minute). The melting point onset temperatures presented are not to be taken as absolute values. It is known that the melting point onset temperature may be affected by several parameters such as impurity content and particle size.

Abbreviations

(11) The following abbreviations have been used:

(12) AcOH acetic acid

(13) Aq: aqueous

(14) MeCN: acetonitrile

(15) MeOH: methanol

(16) DCM: dichloromethane

(17) DMF: dimethylformamide

(18) Et.sub.2O: diethyl ether

(19) EtOAc: ethyl acetate

(20) MgSO.sub.4: magnesium sulphate

(21) NaHCO.sub.3: sodium hydrogen carbonate

(22) NH.sub.4Cl: ammonium chloride

(23) T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide

(24) TFA: trifluoroacetic acid

Example 1

(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide (Crystalline Form A)

(25) (1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide methanol solvate, prepared as Intermediate 8 below, (6.070 kg, 13.19 mol) in acetone (66 L) and water (7.3 L) was heated to 55 C. then cooled to 30 C. and the solution filtered. This was then distilled at atmospheric pressure to about 24 L. 2-Methyltetrahydrofuran (36.5 L) was charged and distilled at atmospheric pressure to about 24 L. Further 2-methyltetrahydrofuran (36.5 L) was charged and distilled at atmospheric pressure to about 24 L. Further 2-methyltetrahydrofuran (36.5 L) was charged and distilled at atmospheric pressure to about 24 L. The suspension was cooled to 20 C. and resulting solid filtered and washed with 2-methyltetrahydrofuran (6.1 L). The solid was dried under vacuum at 60 C. to give the title compound (crystalline Form A) (5.679 kg, 12.40 mol, 94% yield).

(26) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.10-1.55 (m, 4H), 1.74-1.82 (m, 2H), 1.95-2.08 (m, 2H), 2.28 (s, 3H), 2.99 (t, 1H), 3.70 (s, 2H), 3.82 (t, 1H), 4.21 (t, 2H), 6.58 (s, 1H), 7.82 (s, 1H), 7.90 (d, 2H), 8.01 (d, 2H), 8.33 (s, 1H), 9.15 (s, 1H), 12.76 (s, 1H)

Intermediate 1: 3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

(27) ##STR00002##

Step 13-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

(28) 3-Methyl-1H-pyrazole (2 mL, 24.8 mmol) was dissolved in 3,4-dihydro-2H-pyran (6.8 mL, 74.5 mmol). Trifluoroacetic acid (0.134 mL, 1.74 mmol) was added and the clear solution was warmed to 75 C. for 18 h. The reaction mixture was diluted with Et.sub.2O and the organic phase was washed with NaHCO.sub.3(sat, aq), water and brine, filtered using a phase separator and concentrated in vacuo. The residue was purified by flash chromatography (10%.fwdarw.20% of EtOAc in heptane) to give the subtitle compound. (2.4 g, 58%, 70% correct isomer)

(29) .sup.1H NMR (500 MHz, CDCl.sub.3) 7.44 (d, 1H), 7.40 (s, 0.3H), 6.04 (d, 1H), 6.00 (s, 0.3H), 5.21-5.28 (m), 3.94-4.09 (m), 3.57-3.68 (m), 2.47 (s, OH), 2.31 (s, 1H), 2.26 (s, 3H), 1.9-2.16 (m), 1.59-1.75 (m).

Step 23-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

(30) n-Butyllithium (6.1 mL, 15.2 mmol, 2.5M in THF) was added during 10 min to a solution of 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (2.4 g, 14.4 mmol) in THF (20 mL) at 78 C. During a period of 15 min tripropan-2-yl borate (3.7 mL, 15.9 mmol) was added dropwise at 78 C. and the reaction mixture was stirred for 15 min, where after it was allowed to reach ambient temperature. 2,3-Dimethylbutane-2,3-diol (1.88 g, 15.9 mmol) was added followed by AcOH (1.65 mL, 28.9 mmol) and the reaction mixture was stirred at rt over night. The reaction mixture was diluted with heptane and the organic phase was washed with NH.sub.4Cl (aq), NaHCO.sub.3 (aq) and brine, filtered using a phase separator and concentrated. The residue was diluted with heptane and concentrated to give the title compound (3.86, 91%). MS m/z 293.2 [M+H].sup.+

Intermediate 2: (1R,2R)-2-{4-[3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexanecarboxylic Acid

(31) ##STR00003##

(32) K.sub.2CO.sub.3 (4.02 g, 29.05 mmol) and Pd(dtbpf)Cl.sub.2 (0.28 g, 0.36 mmol) were added to a solution of (1R,2R)-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (2.26 g, 7.26 mmol) and 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 1, 3.18 g, 10.89 mmol) dissolved in 1,4-dioxane (40 mL) and water (20 mL). The mixture was evacuated and purged with nitrogen three times and then heated at 80 C. for 1 h. The mixture was cooled to rt and diluted with EtOAc. NaHCO.sub.3 (sat, aq) was added and the mixture was acidified with KHSO.sub.4 (1 M, aq). The phases were separated and the aqueous phase was extracted twice with EtOAc. The combined organic phase was dried using a phase separator and the solvent was removed under vacuum. The crude residue was purified by preparative HPLC on a Kromasil C8 column (10 m 25050 ID mm) using a gradient of 30%-90% MeCN in H.sub.2O/MeCN/AcOH (95/5/0.2) buffer system as mobile phase. The selected fractions were combined and concentrated under vacuum and the aqueous residue was extracted twice with DCM. The combined organic phase was dried using a phase separator and the solvent was removed under vacuum to give the title compound (2.79 g, 97%) as a light brown solid.

(33) .sup.1H NMR (500 MHz, CDCl.sub.3) 1.21-1.64 (m, 6H), 1.71-1.94 (m, 4H), 2.02-2.12 (m, 2H), 2.23-2.31 (m, 1H), 2.34 (s, 3H), 2.52-2.64 (m, 1H), 2.93-3.02 (m, 1H), 3.53-3.66 (m, 2H), 4.11-4.19 (m, 1H), 5.13 (dd, 1H), 6.18 (s, 1H), 7.56-7.63 (m, 2H), 8.01-8.07 (m, 2H) MS m/z 395.3 [MH].sup.

Intermediate 3: Methyl 4-[(tert-butoxycarbonyl)amino]-1H-pyrazole-5-carboxylate

(34) ##STR00004##

(35) Di-tert-Butyl dicarbonate (159 mL, 0.68 mol) was added to methyl 4-amino-1H-pyrazole-3-carboxylate (87.6 g, 0.62 mol) and pyridine (100 mL, 1.24 mol) in MeOH (1 L) at 10 C. over a period of 15 min. The reaction mixture was stirred at rt for 5 h. The solvent was removed under vacuum. The crude product was purified by crystallization from MeOH (700 mL) to give the title compound (80 g, 53%) as a purple solid.

(36) MS m/z 228 [M+H].sup.+

(37) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.47 (s, 9H), 3.83 (s, 3H), 7.70-8.20 (m, 2H), 13.45 (s, 1H)

Intermediate 4: Methyl 1-(2-bromoethyl)-4-[(tert-butoxycarbonyl)amino]-1H-pyrazole-5-carboxylate

(38) ##STR00005##

(39) 1,2-dibromoethane (1.97 mL, 22.8 mmol) was added to a solution of methyl 4-[(tert-butoxycarbonyl)amino]-1H-pyrazole-5-carboxylate (Intermediate 3, 5.0 g, 20.7 mmol) and K.sub.2CO.sub.3 (4.3 g, 31.1 mmol) in DMF (50 mL) at 0 C. over a period of 10 min and the reaction mixture was stirred at rt for 5 h. Water was added to the reaction mixture and the aqueous phase was extracted with EtOAc. The organic layer was dried over MgSO.sub.4, filtered and evaporated and the crude product was purified by flash chromatography (5%.fwdarw.20% 2-methylpentane in EtOAc). Pure fractions were evaporated to dryness to give the title compound (2.5 g, 35%) as a colorless oil.

(40) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.47 (s, 9H), 3.80 (t, 2H), 3.87 (s, 3H), 4.79 (t, 2H), 7.86 (s, 1H), 8.24 (s, 1H)

(41) MS m/z 348 [M+H].sup.+

Intermediate 5: tert-Butyl (4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate

(42) ##STR00006##

(43) Ammonia hydrate (10 g, 287.2 mmol) was added to a solution of methyl 1-(2-bromoethyl)-4-[(tert-butoxycarbonyl)amino]-1H-pyrazole-5-carboxylate (Intermediate 4, 10.0 g, 28.7 mmol) in MeCN (100 mL) and the reaction vessel was sealed and heated at 90 C. for 20 h. The solvent was removed under vacuum and the crude product was purified by flash chromatography, elution gradient (1%.fwdarw.10% DCM in MeOH). Pure fractions were evaporated to dryness to give the title compound (6.0 g, 83%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.47 (s, 9H), 3.60 (t, 2H), 4.22 (t, 2H), 7.76 (s, 1H), 7.95 (s, 1H), 8.30 (s, 1H)

(44) MS m/z 253 [M+H].sup.+

Intermediate 6: 3-Amino-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one hydrochloride

(45) ##STR00007##

(46) HCl (g) was added to a solution of tert-butyl (4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)carbamate (Intermediate 5, 9 g, 35.68 mmol) in MeOH (50 mL) and the reaction mixture was stirred at rt for 2 h. The precipitate was collected by filtration, washed with EtOAc and dried under vacuum to give the title compound (6.00 g, 89%) as a white solid.

(47) MS m/z 153 [M+H].sup.+

Intermediate 7: (1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide HCl

(48) To (1R,2R)-2-{4-[3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzoyl}cyclohexanecarboxylic acid (Intermediate 2, 1.2 kg, 2.8 mol)) and 3-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one hydrochloride (Intermediate 6, 0.6 kg, 3 mol)) in ethyl acetate (7.8 L) was charged pyridine (1.5 kg, 19 mol). The mixture was cooled to 0-5 C. and then T3P (50% in ethyl acetate, 4.6 kg, 7.6 mmol) over 30 minutes maintaining the temperature below 5 C. The mixture was heated to 20 C. for 22 h then cooled to 10 C. Additonal ethyl acetate (5.6 L) was charged then water (5.6 L) maintaining the temperature below 15 C. The aqueous layer was removed and the organic phase washed with citric acid (0.28 kg, 1.5 mol) in water (5.3 L), citric acid (0.28 kg, 1.5 mol) in water (5.3 L), sodium hydrogen carbonate (0.28 kg, 3.3 mol) in water (5.3 L) and finally sodium chloride (1.5 kg, 25 mol) in water (4.2 L). The organic phase was distilled under vacuum, removing 7.8 L of distillate. 2-Methyltetrahydrofuran (6.4 L) was charged and the mixture distilled under vacuum, removing 6.1 L of distillate. Further 2-methyltetrahydrofuran (5.0 L) was charged followed by a solution of 37% hydrochloric acid (0.42 L) in water (2.1 L). The resulting precipitate was collected by filtration and washed with 3 L of the mother liquors, then 2-methyltetrahydrofuran (2.2 L), then further 2-methyltetrahydrofuran (2.2 L). The resulting solid was dried under vacuum at 40 C. to yield (1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide HCl (1.012 kg, 1.970 mol, 70% yield).

(49) 1H NMR (500 MHz, DMSO, 27 C.) 1.18 (1H, dd), 1.33-1.58 (3H, m), 1.71-1.84 (2H, m), 1.96 (1H, dd), 2.05 (1H, dd), 2.28-2.37 (3H, m), 2.98 (1H, ddd), 3.60 (2H, ddd), 3.69-3.78 (1H, m), 4.22 (2H, dd), 6.73 (1H, d), 7.84 (1H, s), 7.94-7.99 (2H, m), 8.02-8.07 (2H, m), 8.35 (1H, d), 9.16 (1H, s).

(50) Assigned Hs: 25.

Intermediate 8: (1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide, Methanol Solvate

(51) To a suspension of (1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide HCl (Intermediate 7, 2.25 kg, 4.43 mol) in methanol (11.3 L) and water (8.6 L) was added concentrated aqueous ammonia (0.54 L) over approximately 1 h. Further concentrated aqueous ammonia (2.2 L) was added over approximately 90 minutes. The mixture was stirred for 21 h at 20 C. and then filtered. The collected solid was washed with water (2.25 L2). The damp solid was returned to the vessel and methanol (9 L) and water (9 L) charged. To the mixture was added concentrated aqueous ammonia (0.54 L) and the mixture stirred at 20 C. for 2.5 h and the resulting solid was collected by filtration. The collected solid was washed with water (2.25 L2) then dried under vacuum at 60 C. to yield the title compound, Intermediate 8 (1.939 kg, 4.256 mol, 96% yield). DSC as shown in FIG. 2, DSC endotherm onset temperature 239.4 C. and peak at 242.6 C.

(52) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.10-1.55 (m, 4H), 1.74-1.82 (m, 2H), 1.95-2.08 (m, 2H), 2.28 (s, 3H), 2.99 (t, 1H), 3.70 (s, 2H), 3.82 (t, 1H), 4.21 (t, 2H), 6.58 (s, 1H), 7.82 (s, 1H), 7.90 (d, 2H), 8.01 (d, 2H), 8.33 (s, 1H), 9.15 (s, 1H), 12.76 (s, 1H)