Crystalline form of a JAK3 kinase inhibitor

Abstract

The invention relates to novel co-crystals of a drug substance and their use to treat respiratory diseases such as asthma and COPD.

Claims

1. A co-crystal of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridine-3-yl)-1H-imidazo[4,5-b]pyridine-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile.

2. A 1:1 co-crystal of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridine-3-yl)-1H-imidazo[4,5-b]pyridine-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile with maleic acid.

3. A co-crystal according to claim 2 having an X-ray powder diffraction pattern which shows the following diffraction angles (2Theta) using copper K radiation: at approximately 8.4; at approximately 8.8; at approximately 11.5; at approximately 16.2; at approximately 18.6; at approximately 21.6; at approximately 23.9; and at approximately 25.9.

4. A co-crystal according to claim 3 having a single endotherm with an onset temperature of 166.2 C. and a peak maximum of 181.4 C.

5. A 1:1 co-crystal of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridine-3-yl)-1H-imidazo[4,5-b]pyridine-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile with gentisic acid.

6. A co-crystal according to claim 4 having an X-ray powder diffraction pattern which shows the following diffraction angles (2Theta) using copper K radiation: at approximately 7.1; at approximately 8.9; at approximately 14.3; at approximately 16.3; at approximately 18.0; at approximately 21.7; at approximately 25.8; and at approximately 28.2.

7. A 2:1 co-crystal of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridine-3-yl)-1H-imidazo[4,5-b]pyridine-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile with adipic acid.

8. A co-crystal according to claim 6 having an X-ray powder diffraction pattern which shows the following diffraction angles (2Theta) using copper K radiation: at approximately 4.6; at approximately 9.3; at approximately 10.7; at approximately 14.3; at approximately 15.5; at approximately 17.2; at approximately 18.5; and at approximately 22.4.

9. A pharmaceutical composition comprising a co-crystal of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridine-3-yl)-1H-imidazo[4,5-b]pyridine-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile and a pharmaceutically acceptable carrier or excipient.

10. The composition according to claim 9 wherein the co-crystal is a 1:1 co-crystal with maleic acid.

11. A method of treating asthma or chronic obstructive pulmonary disease (COPD) comprising administering to a patient in need thereof a maleic acid co-crystal of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridine-3-yl)-1H-imidazo[4,5-b]pyridine-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile.

12. The method according to claim 11 in which the co-crystal is a 1:1 co-crystal with maleic acid.

13. The method according to claim 11 wherein treating the disease is an acute or prophylactic treatment.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the XRPD pattern of the 1:1 VR588 maleic acid co-crystal.

(2) FIG. 2. shows the differential scanning calorimetry (DSC) trace for the 1:1 VR588 maleic acid co-crystal.

(3) FIG. 3. shows the XRPD pattern of the 1:1 VR588 gentisic acid co-crystal.

(4) FIG. 4. shows the differential scanning calorimetry (DSC) trace for the 1:1 VR588 gentisic acid co-crystal.

(5) FIG. 5. shows the XRPD pattern of the 1:1 VR588 adipic acid co-crystal.

(6) FIG. 6. shows the differential scanning calorimetry (DSC) trace for the 1:1 VR588 adipic acid co-crystal.

EXAMPLES

(7) The following examples illustrate the invention.

(8) General Methodology

(9) X-Ray Powder Diffraction Characterisation:

(10) X-Ray Powder Diffraction patterns were collected on a PANalytical X'Pert PRO diffractometer using CuK radiation (45 kV, 40 mA), - goniometer, focusing mirror (Cu W/Si), divergence slit (), soller slits at both incident and diffracted beam (0.04 RAD), fixed mask (4 mm) and a PIXcel detector. The software used for data collection was X'Pert Data Collector, version 2.2f. The instrument was performance checked using a certified Standard Reference Material 640d, Silicon Powder (NIST). XRPD patterns were acquired under ambient conditions via a transmission foil sample stage (polyimideKapton, TF-475, 7.5 m thickness film). The specimen was examined as received with approximately 5 mg of the sample examined as dispensed onto the sample stage. The data collection range was 2.994-35.00562 with a step size of 0.0263 and a continuous scan speed of 0.202004s.sup.1.

(11) Thermal AnalysisDifferential Scanning Calorimetry (DSC):

(12) DSC data were collected on a PerkinElmer Pyris 4000 DSC equipped with a 45 position sample holder. The instrument was verified for energy and temperature calibration using certified indium. A predefined amount of the sample, 0.5-3.0 mg, was placed in a pin holed aluminium pan and heated at 20 C..Math.min.sup.1 from 30 to 350 C. A purge of dry nitrogen at 60 ml.Math.min.sup.1 was maintained over the sample. The instrument control, data acquisition and analysis were performed with Pyris Software v9.0.1.0203.

Example 1. 1:1 Maleic Acid Co-Crystal

(13) (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridine-3-yl)-1H-imidazo[4,5-b]pyridine-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile (100 mg) and maleic acid (28 mg) were weighed into a glass vial. Nitromethane (1.5 ml) was added to the vial, the vial was sealed and placed on a shaker for 24 hours. The product was filtered and dried in a vacuum oven (50 C.) overnight before being analysed by XRPD.

(14) Larger Scale Method

(15) (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridine-3-yl)-1H-imidazo[4,5-b]pyridine-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile (2.00 g) and maleic acid (0.56 g) were placed in a round bottom flask. Nitromethane (40 ml) was added and the slurry was stirred for 24 hour at room temperature. The product was filtered and dried in a vacuum oven (50 C.) overnight before being analysed by XRPD.

(16) 1.2 XRPD Characterisation of a 1:1 Maleic Acid Co-Crystal

(17) The experimental XRPD pattern of the 1:1 VR588 maleic acid co-crystal is shown in FIG. 1. Table 1 lists the angles, 20.22, and d-spacing of the peaks identified in the XRPD pattern of FIG. 1. The entire list of peaks, or a subset thereof, may be sufficient to characterise the co-crystal. For example, the co-crystal may be characterised by at least four peaks selected from the peaks at 8.4, 8.8, 11.5, 16.2, 18.6, 21.6, 23.9 and 25.920.22 as well as by a XRPD pattern substantially similar to FIG. 1.

(18) TABLE-US-00001 TABLE 1 Angle d value Intensity 2 0.2 2 Angstrom % 7.8 11.40 18.40 8.4 10.54 56.50 8.8 10.02 100.00 11.5 7.71 62.70 14.9 5.95 10.10 15.6 5.67 8.30 16.2 5.47 27.90 16.9 5.25 19.80 17.4 5.09 27.70 17.9 4.96 30.60 18.6 4.75 25.40 19.4 4.57 8.40 19.9 4.45 12.30 20.2 4.40 8.40 21.0 4.22 12.30 21.3 4.17 11.90 21.6 4.11 25.00 22.6 3.93 8.30 22.9 3.87 22.30 23.3 3.81 35.10 23.9 3.72 45.40 24.4 3.65 7.70 24.8 3.58 12.90 25.1 3.55 9.30 25.9 3.44 58.90 26.4 3.37 11.20 27.1 3.29 15.60 27.6 3.23 21.30 28.9 3.08 10.90 30.0 2.98 11.30 30.7 2.91 6.10 31.1 2.88 6.40

(19) 1.3 DSC of 1:1 Maleic Acid Co-Crystal

(20) The differential scanning calorimetry (DSC) trace, FIG. 2, shows a single endotherm with an onset temperature of 166.2 C. and a peak maximum of 181.4 C.

Example 2. 1:1 Gentisic Acid Co-Crystal

(21) (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridine-3-yl)-1H-imidazo[4,5-b]pyridine-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile (100 mg) and gentisic acid (37 mg) were weighed into a glass vial. Nitromethane (1.5 ml) was added to the vial, the vial was sealed and placed on a shaker for 24 hours. The product was filtered and dried in a vacuum oven (50 C.) overnight before being analysed by XRPD.

(22) Larger Scale Method

(23) (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridine-3-yl)-1H-imidazo[4,5-b]pyridine-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile (3.00 g) and gentisic acid (1.11 g) were placed in a round bottom flask. Nitromethane (45 ml) was added and the slurry was stirred for 24 hour at room temperature. The product was filtered and dried in a vacuum oven (50 C.) overnight before being analysed by XRPD.

(24) 2.2 XRPD Characterisation of a 1:1 Gentisic Acid Co-Crystal

(25) The experimental XRPD pattern of the 1:1 gentisic acid co-crystal is shown in FIG. 3. Table 2 lists the angles, 20.22, and d-spacing of the peaks identified in the XRPD pattern of FIG. 3. The entire list of peaks, or a subset thereof, may be sufficient to characterise the co-crystal. For example, the co-crystal may be characterised by at least four peaks selected from the peaks at 7.1, 8.9, 14.3, 16.3, 18.0, 21.7, 25.8 and 28.220.22 as well as by a XRPD pattern substantially similar to FIG. 3.

(26) TABLE-US-00002 TABLE 2 Angle d value Intensity 2 0.2 2 Angstrom % 7.1 12.5 23.3 8.9 9.9 100.0 13.6 6.5 18.4 14.3 6.2 43.3 16.3 5.4 32.3 17.6 5.0 14.1 18.0 4.9 27.7 18.7 4.8 7.3 19.8 4.5 14.4 20.3 4.4 7.4 20.6 4.3 8.2 20.9 4.2 8.6 21.5 4.1 12.8 21.7 4.1 29.5 22.2 4.0 21.5 22.9 3.9 6.6 24.5 3.6 6.5 24.7 3.6 10.5 25.8 3.4 38.1 26.6 3.4 17.6 27.1 3.3 7.4 28.2 3.2 58.2

(27) 2.3 DSC of 1:1 Gentisic Acid Co-Crystal

(28) The differential scanning calorimetry (DSC) trace, FIG. 4, shows a single endotherm with an onset temperature of 196.8 C. and a peak maximum of 224.4 C.

Example 3. 2:1 Adipic Acid Co-Crystal

(29) (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridine-3-yl)-1H-imidazo[4,5-b]pyridine-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile (100 mg) and adipic acid (18 mg) were weighed into a glass vial. Nitromethane (1.5 ml) was added to the vial, the vial was sealed and placed on a shaker for 24 hours. The product was filtered and dried in a vacuum oven (50 C.) overnight before being analysed by XRPD.

(30) Larger Scale Method

(31) (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridine-3-yl)-1H-imidazo[4,5-b]pyridine-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile (3.00 g) and adipic acid (0.53 g) were placed in a round bottom flask. Nitromethane (45 ml) was added and the slurry was stirred for 24 hour at room temperature. The product was filtered and dried in a vacuum oven (50 C.) overnight before being analysed by XRPD.

(32) 3.2 XRPD Characterisation of a 2:1 Adipic Acid Co-Crystal

(33) The experimental XRPD pattern of the 2:1 adipic acid co-crystal is shown in FIG. 5. Table 3 lists the angles, 20.22, and d-spacing of the peaks identified in the XRPD pattern of FIG. 5. The entire list of peaks, or a subset thereof, may be sufficient to characterise the co-crystal. For example, the co-crystal may be characterised by at least four peaks selected from the peaks at 4.6, 9.3, 10.7, 14.3, 15.5, 17.2, 18.5 and 22.420.22 as well as by a XRPD pattern substantially similar to FIG. 5.

(34) TABLE-US-00003 TABLE 3 Angle d value Intensity % 2-Theta Angstrom % 4.6 19.3 7.7 7.9 11.2 21.1 8.2 10.8 9.8 9.3 9.5 26.1 10.7 8.3 55.0 13.6 6.5 8.1 13.9 6.3 16.8 14.3 6.2 15.7 15.5 5.7 8.9 16.0 5.5 12.4 16.4 5.4 13.0 17.2 5.2 23.5 17.8 5.0 37.1 18.5 4.8 26.0 19.5 4.5 18.1 20.0 4.4 8.6 22.5 3.9 45.6 23.0 3.9 18.2 23.8 3.7 10.2 24.4 3.6 37.2 25.2 3.5 14.4 25.5 3.5 100.0 27.6 3.23 5.50 29.2 3.05 7.70 30.5 2.93 5.50 33.2 2.69 5.50

(35) 3.3 DSC of 2:1 Adipic Acid Co-Crystal

(36) The differential scanning calorimetry (DSC) trace, FIG. 6, shows a single endotherm with an onset temperature of 209.7 C. and a peak maximum of 224.9 C.

(37) 4. Fine Particle Fraction Data

(38) Co-crystals of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridine-3-yl)-1H-imidazo[4,5-b]pyridine-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile (Compound 1) were prepared according to the examples 1-3 above.

(39) The aerodynamic particle size distribution (APSD) of the formulations was evaluated with the Next Generation Impactor (NGI) tested at a flow rate of 80 Lmin.sup.1 in the GyroHaler device (Compound 1Gentisic Acid) and 60 Lmin.sup.1 in the F1 device (Compound 1, Compound 1Maleic Acid and Compound 1Adipic Acid). One dose was collected for each NGI measurement. Compound 1 deposition on the NGI components was measured by a gradient high performance liquid Chromatography (HPLC) method with UV detection.

(40) The co-crystals with adipic acid and maleic acid were tested in a Vectura unit dose device as disclosed in WO2010/086285, and the gentisic acid co-crystal was tested in a GyroHaler device. All three co-crystals exhibited good fine particle mass data and associated stability as shown in the table below, with the maleic acid co-crystal being particularly advantageous.

(41) TABLE-US-00004 Fine particle Mass (g < 5 m) - 1000 g dose load in 20 mg formulation Crystal T = 0 w T = 4 w T = 12 w Compound 1 418.2 450.7 415.3 Compound 1: 412.4 396.4 469.6 Maleic Acid Compound 1: 349.1 296.6 261.0 Adipic Acid Compound 1: 378.8 309.3 310.6 Gentisic Acid