OA20227A - Novel salt of A BCL-2 inhibitor, related crystalline form, method for preparing the same and pharmaceutical compositions containing the same. - Google Patents

Novel salt of A BCL-2 inhibitor, related crystalline form, method for preparing the same and pharmaceutical compositions containing the same. Download PDF

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OA20227A
OA20227A OA1202100188 OA20227A OA 20227 A OA20227 A OA 20227A OA 1202100188 OA1202100188 OA 1202100188 OA 20227 A OA20227 A OA 20227A
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ppm
compound
crystalline form
hydrogen sulfate
sait
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OA1202100188
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Michael Lynch
Frédéric VILLARD
Patrick Mouchet
Pascal TAULELLE
Ludovic MASSON
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Les Laboratoires Servier
Vernalis (R&D) Limited
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Abstract

Novel salt and related crystalline forms of Compound A:

Description

NOVEL SALT OF A BCL-2 INHIBITOR, RELATED CRYSTALLINE FORM, METHOD FOR PREPARING THE SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
FIELD OFTHE INVENTION
The invention relates to a novel sait of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(lH)-yl]carbonyl} phenyl)-A/-(5-cyano-l,2-dimethyl-l/7-pyrrol-3-yl)-/V(4-hydroxyphenyl)-l,2-dimethyl-l/7-pyrrole-3-carboxamide, referred to herein as 'Compound A', or polymorphs or solvatés thereof, methods for preparing the same as well as pharmaceutical compositions thereof. In particular, the invention relates to the hydrogen sulfate sait of Compound A, referred to herein as 'Compound A, H2SO4', and the crystalline form I thereof. The présent invention further discloses a process for preparing said crystalline form and pharmaceutical compositions comprising said crystalline form. The invention also relates to the use of such compositions for the treatment of cancer, diseases ofthe immune System and auto-immune diseases. Last, an anhydrous crystalline form of Compound A, H2SO4 is disclosed.
BACKGROUND OF THE INVENTION
The Chemical structure of Compound A is:
Its préparation, its use as a Bcl-2 inhibitor for the treatment of cancer and pharmaceutical formulations thereof are described in WO 2015/011400 (Example 386), the content of which is incorporated by reference. The préparation of Compound A in the form of a hydrochloride sait ('Compound A.HCI') is specifically disclosed in this document. It is obtained as a lyophilisate.
Although Compound A is a very promising drug, it is a difficult compound to formulate. In particular, it is slightly soluble in water (< 0.01 mg/mL for the free base). As a Chemical substance can exhibit different physical properties being in one or another sait form or crystalline form thereof, this polymorphism of the drug molécule can affect the shelf life, solubility, formulation properties, processing properties, and the action of a drug. In addition, different polymorphs can hâve different rates of uptake in the body, leading to lower or higher biological activity than desired. In extreme cases, an undesired polymorph can even show toxicity. Understanding and controlling polymorphism, then, gives a decided advantage in bringing new drugs to the marketplace, which may be more active, more stable, or more cheaply manufactured. However, even though polymorphism has been a subject for intensive investigations, understanding and controlling this phenomenon represents a substantial scientific challenge. It is hard to predict whether a given molécule will crystallize in one or several crystal forms, and to find conditions leading to such crystallization.
From the industrial point of view, it is impérative to be able to synthesise the compound with excellent purity, and in particular in a highly reproducible form, having valuable characteristics of dissolution, filtration, drying, ease of formulation and stability enabling 20 the prolonged storage thereof without particular requirements for température, light, humidity or oxygen levels.
The présent invention also describes a process for obtaining Compound A, H2SO4 in a well-defined, perfectly reproducible crystalline form (Form I) having very good stability that is compatible with the industrial constraints of préparation, especially filtration, and 25 storage of pharmaceutical compositions.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the X-ray powder diffraction pattern (XPRD) of the crystalline form I of Compound A, H2SO4.
Figure 2 shows the X-ray powder diffraction pattern (XPRD) of the anhydrous crystalline form of Compound A, hydrogen sulfate sait.
Figure 3 shows the X-ray powder diffraction pattern (XPRD) of the crystalline form I of Compound A, hydrochloride sait
Figure 4 shows the DSC and TGA profiles of the crystalline form I of Compound A, hydrogen sulfate sait
Figure 5 shows the DSC and TGA profiles of the crystalline form I of Compound A, 10 hydrochloride sait
Figure 6 shows the solid-state 13C NMR spectrum of the crystalline form I of Compound A, H2SO4.
DETAILED DESCRIPTION OFTHE INVENTION
As used herein, the term 'comprising' means 'including', and is not intended to exclude 15 the presence of any additional component, unless the context suggests otherwise, for example when the components together sum to 100%.
The term alcohols means Ci-Ce alcohols such as methanol, éthanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol, 2-pentanol, 3-pentanol, isopentanol, hexanol.
'Cancer' means a class of disease in which a group of cells display uncontrolled growth. Cancer types include haematological cancers (lymphoma and leukemia) and solid tumors including carcinoma, sarcoma, or blastoma. 'Cancer' includes cancer of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, for example non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant haemopathies, for example myelodysplastic syndrome, myelomas,
I for example multiple myeloma, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
'free molécule' and 'free base' are used interchangeably herein and refer to Compound A when not in sait form.
Embodiments of the invention
Described below are a number of embodiments of the invention.
El. The hydrogen sulfate sait of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(lH)-yl]carbonyl} phenyl)-/V-(5-cyano-l,2-dimethyl-l/-/-pyrrol-3-yl)-/V(4-hydroxyphenyl)-l,2-dimethyl-lH-pyrrole-3-carboxamide (Compound A, H2SO4).
E2. A crystalline form I of the hydrogen sulfate sait of 5-(5-chloro-2-{[(3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l/7)-yl]carbonyl} phenyl)-A/-(5-cyano-l,2dimethyl-lH-pyrrol-3-yl)-/\/-(4-hydroxyphenyl)-l,2-dimethyl-l/7-pyrrole-3-carboxamide (Compound A, H2SO4) according to El, wherein the crystalline form has an X-ray powder diffraction diagram showing the following diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.55 ; 6.62 and 7.39.
E3. A crystalline form I of the hydrogen sulfate sait of 5-(5-chloro-2-{[(3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl} phenyl)-/V-(5-cyano-l,2dimethyl-l/-/-pyrrol-3-yl)-A/-(4-hydroxyphenyl)-l,2-dimethyl-lH-pyrrole-3-carboxamide (Compound A, H2SO4) according to El, wherein the crystalline form has an X-ray powder diffraction diagram showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or ail of the following diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.55; 5.62; 6.62; 7.39; 10.17; 11.49; 11.83; 16.01; 16.54; 17.04; 18.98; 19.18; 21.90; 22.28; 24.89.
E4. The crystalline form I of the hydrogen sulfate sait of Compound A according to E3, characterized in that it has an X-ray powder diffraction diagram having the following !
diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.55; 5.62; 6.62; 7.39; 10.17; 11.49; 11.83; 16.01; 16.54; 17.04; 18.98; 19.18; 21.90; 22.28; 24.89.
E5. The crystalline form I of the hydrogen sulfate sait of Compound A according to E4, characterized in that it has the following X-ray powder diffraction diagram, measured 5 using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector and expressed in terms of line position (Bragg's angle 2 thêta, expressed in degrees ±0.2°) and interplanar distances d (expressed in Â):
Line no. Angle 2-theta (degrees) Interplanar distance (Â)
1 5.55 15.93
2 5.62 15.73
3 6.62 13.36
4 7.39 11.95
5 10.17 8.70
6 11.49 7.70
7 11.83 7.48
8 16.01 5.53
9 16.54 5.36
10 17.04 5.20
11 18.98 4.67
12 19.18 4.63
13 21.90 4.06
14 22.28 3.99
15 24.89 3.58
E6. The crystalline form I of the hydrogen sulfate sait of Compound A according to any one of El to E5, characterised in that it has a solid-state 13C CP/MAS NMR spectrum having the following peaks (expressed in ppm ± 0.2 ppm): 173.31 ppm, 155.32 ppm, 140.46 ppm, 139.19 ppm, 137.42 ppm, 134.68 ppm, 131.65 ppm, 131.14 ppm, 129.37 ppm, 126.32 ppm, 118.77 ppm, 117.36 ppm, 116.54 ppm, 113.61 ppm, 112.69 ppm,
110.74 ppm, 102.33 ppm, 101.45 ppm, 63.06 ppm, 57.19 ppm, 54.87 ppm, 52.06 ppm, 44.71 ppm, 43.94 ppm, 34.42 ppm, 32.89 ppm, 31.28 ppm, 30.66 ppm, 14.40 ppm, 13.34 ppm, 12.49 ppm and 10.50 ppm.
E7. Pharmaceutical composition comprising as active ingrédient the hydrogen sulfate 5 sait of Compound A according to El in association with one or more pharmaceutically acceptable excipients.
E8. Pharmaceutical composition comprising as active ingrédient the crystalline form I of the hydrogen sulfate sait of Compound A according to any one of E2 to E6 in association with one or more pharmaceutically acceptable excipients.
E9. Pharmaceutical composition according to E7 or E8 for use in the treatment of cancers, auto-immune diseases and diseases of the immune system.
E10. Pharmaceutical composition according to E9, wherein the cancer is selected from the bladder, brain, breast and utérus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid 15 leukaemia, lymphomas, for example non-Hodgkin's B-cell lymphoma and diffuse large Bcell lymphoma, melanomas, malignant haemopathies, for example myelodysplastic syndrome, myelomas, for example multiple myeloma, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
Eli. The hydrogen sulfate sait of Compound A according to El for use as a 20 médicament.
E12. The hydrogen sulfate sait of Compound A according to El for use in the treatment of cancers, auto-immune diseases and diseases of the immune system.
E13. The hydrogen sulfate sait of Compound A according to E12 wherein the cancer is selected from the bladder, brain, breast and utérus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, for example non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant haemopathies, for example myelodysplastic syndrome, myelomas, for example multiple myeloma, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
E14. The crystalline form I of the hydrogen sulfate sait of Compound A according to any one of E2 to E6 for use as a médicament.
E15. The crystalline form I of the hydrogen sulfate sait of Compound A according to any one of E2 to E6 for use in the treatment of cancers, auto-immune diseases and diseases of the immune System.
E16. The crystalline form 1 of the hydrogen sulfate sait of Compound A according to E15 wherein the cancer is selected from the bladder, brain, breast and utérus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, for example nonHodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant haemopathies, for example myelodysplastic syndrome, myelomas, for example multiple myeloma, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
E17. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to any one of E2 to E6, wherein the hydrogen sulfate sait of Compound A is crystallised in a polar medium.
E18. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to E17, wherein the polar medium is composed of one or more solvents selected from water and alcohols.
E19. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of 5 Compound A according to E18, wherein the alcohol is éthanol.
E20. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to E18, wherein the polar medium is an ethanol/water mixture.
E21. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to any one of E17 to E20, in which process the crystallisation is 10 seeded using a very small amount of the crystalline form I of the hydrogen sulfate sait of
Compound A.
E22. Anhydrous crystalline form of the hydrogen sulfate sait of 5-(5-chloro-2-{[(3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl} phenyl)-A/-(5-cyano-l,2dimethyl-lE/-pyrrol-3-yl)-A/-(4-hydroxyphenyl)-l,2-dimethyl-lH-pyrrole-3-carboxamide 15 (Compound A, H2SO4) according to El, wherein the crystalline form has an X-ray powder diffraction diagram showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or ail of the following diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.19; 5.64; 6.74; 7.14; 8.04; 8.33; 9.17; 9.40; 10.68; 11.03; 11.35; 12.18; 12.59; 13.64; 14.78; 15.09.
E23. The anhydrous crystalline form according to E22, characterized in that it has the 20 following X-ray powder diffraction diagram, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector and expressed in terms of line position (Bragg's angle 2 thêta, expressed in degrees ±0.2°) and interplanar distances d (expressed in Â):
Line no. Angle 2-theta (degrees) Interplanar distance (Â)
1 5.19 17.03
2 5.64 15.66
3 6.74 13.12
4 7.14 12.39
5 8.04 10.99
6 8.33 10.61
7 9.17 9.64
8 9.40 9.41
9 10.68 8.29
10 11.03 8.02
11 11.35 7.79
12 12.18 7.26
13 12.59 7.03
14 13.64 6.49
15 14.78 5.99
16 15.09 5.87
Obtaining the crystalline form I of the hydrogen sulfate sait of Compound A has the advantage of having good characteristics of stability. More especially, only one crystalline form was observed in the range of solvents and températures used for the screening, showing a limited polymorphism of the hydrogen sulfate sait in the tested conditions.
Furthermore, the crystalline form I of the hydrogen sulfate sait of Compound A thereby obtained is sufficiently stable to allow its storage for an extended period without particular conditions for température, light, humidity or oxygen levels.
The Examples herein below illustrate the invention but do not limit it in any way.
Example 1: Process for obtaining crystalline form I of the hydrogen sulfate sait of
Compound A g of Compound A (free base) was placed in 239.5 g of éthanol at ambient température.
The mixture was then heated at 65°C. A solution of sulphuric acid in water (4.27 g of H2SO4 + 59.87 g of water) was then added gradually. The mixture was stirred for 1 h
-10before being cooled to 10°C. When the crystallisation was complété, the suspension was filtered, washed with an ethanol/water mixture à 10°C, filtered and dried under reduced pressure. After drying, crystalline form I of the hydrogen sulfate sait of Compound A was obtained in a yield of about 70% and with a purity greater than 99.8%. The solid was 5 characterised by the X-ray powder as set out in Example 3.
In the crystallisation process according to the invention, Compound A (free base) is obtained by any process which may be used.
Example 2: Process for obtaining crystalline form I of the hydrogen sulfate sait of Compound A (seeding)
25 g of Compound A (free base) was placed in 239.5 g of éthanol at ambient température.
The mixture was then heated at 65°C. A solution of sulphuric acid in water (4.27 g of H2SO4 + 59.87 g of water) was then added gradually. The mixture was stirred for 30 minutes. The mixture was then cooled slightly before being seeded with the crystalline form I of the hydrogen sulfate sait of Compound A (2% by weight of starting material).
The mixture was stirred for 30 minutes before being cooled to 10°C. When the crystallisation was complété, the suspension was filtered, washed with an ethanol/water mixture à 10°C, filtered and dried under reduced pressure. After drying, crystalline form I of the hydrogen sulfate sait of Compound A was obtained in a yield of about 70% and with a purity greater than 99.8%. The solid was characterised by the X-ray powder as set out in Example 3.
In the crystallisation process according to the invention, Compound A (free base) is obtained by any process which may be used.
Example 3: Crystalline form I of the hydrogen sulfate sait of Compound A (X-ray powder diffraction diagram)
Recording of the data was carried out in the transmission mode using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector under the following conditions:
Voltage 45 kV, current 40 mA,
Mounting: theta/theta,
-11Anode: copper,
K alpha-1 wavelength: 1.54060 Â,
K alpha-2 wavelength: 1.54443 Â,
K alpha-2/K alpha-1 ratio: 0.5,
- Measurement mode: continuous from 3° to 55° (Bragg's angle 2 thêta) in incréments of 0.017°,
Measurement time per step: 35.5301 s.
The X-ray powder diffraction diagram of the form I of the hydrogen sulfate sait of Compound A obtained according to the process of Example 1 or 2 is expressed in terms of line position (Bragg's angle 2 thêta, expressed in degrees ±0.2°) and interplanar distances (expressed in Â) (Figure 1). The significant lines hâve been collated in the following table:
Line no. Angle 2-theta (degrees) Interplanar distance (Â)
1 5.55 15.93
2 5.62 15.73
3 6.62 13.36
4 7.39 11.95
5 10.17 8.70
6 11.49 7.70
7 11.83 7.48
8 16.01 5.53
9 16.54 5.36
10 17.04 5.20
11 18.98 4.67
12 19.18 4.63
13 21.90 4.06
14 22.28 3.99
15 24.89 3.58
Example 4: Stability Studies
For ail storage conditions and storage periods, 20 mg of crystalline form of the sait of
Compound A were introduced in a 30-mL vial for post-storage HPLC analysis.
-12The drug substance content was determined by LC (% m/m).
Température Packaging Hydrogen sulfate sait, crystalline form 1
To >99.9
25°C/60%RH Double polyethylene bag placed in a plastic drum 100.7 after 3 months of storage
30°C/65%RH Double polyethylene bag placed in a plastic drum 100.6 after 3 months of storage
40°C/75%RH Double polyethylene bag placed in a plastic drum 100.0 after 3 months of storage
50°C/75%RH Open glass bottle 101.0 after 6 weeks of storage
The appearance of the powder (white) and Chemical stability remains unchanged under ail conditions tested: over 3 months at 25°C/60%RH, 30°C/65%RH, 4O°C/75°/oRH, and for 6 weeks at 50°C/75%RH.
Furthermore, the X-ray diffraction results show that the form does not change after analysis at To and after 6 weeks storage in open glass bottles at 25°C/90%RH.
In conclusion, the drug substance can be considered physically and chemically stable over the periods tested.
Example 5: Process for obtaining the anhydrous crystalline form of the hydrogen sulfate sait of Compound A (seeding)
5.83 kg of Compound A (free base) was placed in 55.85 kg of éthanol at ambient température. The mixture was then heated at 65°C. A solution of sulphuric acid in water (1 kg of H2SO4 + 13,96 kg of water) was then added gradually. The mixture was stirred for 30 minutes. The mixture was then cooled slightly before being seeded with the crystalline form I of the hydrogen sulfate sait of Compound A (2% by weight of starting material). The mixture was stirred for 30 minutes before being cooled to 10°C. When the
-13crystallisation was complété, the suspension was filtered, washed with an ethanol/water mixture à 10°C, filtered and dried under reduced pressure. Then, the dried product is stored under an inert atmosphère (nitrogen). The anhydrous crystalline form of the hydrogen sulfate sait of Compound A was obtained in a yield of about 78 ± 5% and with a purity greater than 99.9% and a water content of about 0.43%. The solid was characterised by the X-ray powder as set out in Example 6.
In the crystallisation process according to the invention, Compound A (free base) is obtained by any process which may be used.
Example 6: Anhydrous crystalline form of the hydrogen sulfate sait of Compound A (Xray powder diffraction diagram)
Recording of the data was carried out in the following conditions:
Approximately 30-50 mg of the sample to be analysed is placed between two polymeric films (Kapton®) fixed in a sample holder dise. The X-ray diffraction pattern of the test sample is recorded from 3° 2theta to at least 40° 2-theta in 15 min using an X-ray diffractometer operating in the transmission mode with CuKa radiation (λ = 1.5418 Â) at 40kV and 30mA and with a step size ranging from 0.01 to 0.02° 2-theta. These settings may vary according to the diffractometer used.
The X-ray powder diffraction diagram of the anhydrous form of the hydrogen sulfate sait 20 of Compound A obtained according to the process of Example 5 is expressed in terms of line position (Bragg's angle 2 thêta, expressed in degrees ±0.2°) and interplanar distances (expressed in Â) (Figure 2). The significant lines hâve been collated in the following table:
Line no. Angle 2-theta (degrees) Interplanar distance (Â)
1 5.19 17.03
2 5.64 15.66
3 6.74 13.12
4 7.14 12.39
5 8.04 10.99
6 8.33 10.61
-14-
7 9.17 9.64
8 9.40 9.41
9 10.68 8.29
10 11.03 8.02
11 11.35 7.79
12 12.18 7.26
13 12.59 7.03
14 13.64 6.49
15 14.78 5.99
16 15.09 5.87
Example 7: Process for obtaining crystalline form I of the hydrogen sulfate sait of Compound A (seeding, batch size of the order of the kilogram)
5.83 kg of Compound A (free base) was placed in 55.85 kg of éthanol at ambient température. The mixture was then heated at 65°C. A solution of sulphuric acid in water (1 kg of H2SO4 + 13.96 kg of water) was then added gradually. The mixture was stirred for 30 minutes. The mixture was then cooled slightly before being seeded with the crystalline form I of the hydrogen sulfate sait of Compound A (2% by weight of starting material). The mixture was stirred for 30 minutes before being cooled to 10°C. When the crystallisation was complété, the suspension was filtered, washed with an ethanol/water mixture at 10°C, filtered and dried under reduced pressure. The product was rehydrated thereafter at 40°C under an atmosphère with 50% of relative humidity (RH). The resulting product was stored under an inert atmosphère (nitrogen). The crystalline form I of the hydrogen sulfate sait of Compound A was obtained in a yield of about 78 ± 5% and with a purity greater than 99.9% and a water content of about 6.5 ± 1%. The solid was characterised by the X-ray powder as set out in Example 3.
In the crystallisation process according to the invention, Compound A (free base) is obtained by any process which may be used.
Example 8: Process for obtaining the crystalline form I of the hydrochloride sait of Compound A and the X-ray powder diffraction diagram characterising it
1510 mg of the amorphous hydrochloride sait of Compound A (Example 386 of WO 2015/011400) was converted into its crystalline éthanol solvaté by slurrying in 15 mL of 5 éthanol for 48h hours. The residual solid was filtered, washed twice with 1 mL of éthanol and then suspended in 10 mL of water for 5 min. After a difficult filtration, the residual solid was dried overnight at 30°C/10 mbar and analysed by X-ray diffraction (3-30° 2 theta/10 min).
The mode of préparation for the HCl sait is complicated by the fact that it initiaHy results 10 in an éthanol solvaté which is replaced by H2O after resuspension in water to give the hydrated form. The resulting hydrated HCl sait formed fine needles which were quite difficult to filter.
The X-ray powder diffraction diagram of the form I of the hydrochloride sait of Compound A obtained according to the process described previously is expressed in terms of line 15 position (Bragg's angle 2 thêta, expressed in degrees ±0.2°) and relative intensity (expressed in %) (Figure 3). The significant lines hâve been collated in the following table:
Line no. Angle 2-theta (degrees) Relative lntensity(%)
1 5.53 100.00
2 7.37 65.92
3 9.96 92.98
4 11.26 31.90
5 11.62 30.11
6 12.29 67.53
7 12.76 25.47
8 15.34 29.27
9 17.04 32.91
10 18.82 25.98
11 19.07 27.10
12 19.48 27.89
13 20.41 25.05
-16-
14 21.99 28.88
15 23.14 29.52
16 24.69 23.99
17 25.66 29.09
18 27.28 25.49
Example 9: DSC and TGA profiles of the crystalline forms I of the hydrochloride and hydrogen sulfate salts of Compound A
H2SO4 sait
The Differential Scanning Calorimetry (DSC) profile of a sample of the hydrogensulfate 5 sait, form I weighing approximately 4 mg was recorded between 0°C and 250°C at 10°C/min in pin-hole pierced aluminium pans under a positive flow of nitrogen on a TA Instruments Q1000 (or Q2000) Differential Scanning Calorimeter (Figure 4).
The Thermal Gravimétrie Analysis (TGA) profile of a sample of the hydrogensulfate sait, form I weighing approximately 10 mg was recorded between 25°C and 250°C at 10°C/min 10 in an open aluminium pan under a positive flow of nitrogen on a TA Instruments Q5000
Thermogravimetric Analyser (Figure 4).
HCI sait
The DSC profile of a sample of the hydrochloride sait, form I weighing approximately 4 mg 15 was recorded between 0°C and 250°C at 10°C/min in pin-hole pierced aluminium pans under a positive flow of nitrogen on a TA Instruments Q1000 (or Q2000) Differential Scanning Calorimeter (Figure 5).
The TGA profile of a sample of the hydrochloride sait, form I weighing approximately 6 mg was recorded between 25°C and 250°C at 10°C/min in an open aluminium pan under a 20 positive flow of nitrogen on a TA Instruments Q5000 Thermogravimetric Analyser (Figure 5).
The DSC profile of the H2SO4 sait is less complicated compared to that of the HCl sait.
Water loss is visible in the TGA profile of the H2SO4 sait between 25 and 100°C. A 25 melting/degradation endotherm is visible in the DSC profile towards 224°C. The melting temperature and enthalpy of the HCl sait is lower than that of the H2SO4 sait. This may suggest that the HCl has a lower degree of crystallinity following déhydration compared to the H2SO4 sait.
Example 10: Crystalline form I of Compound A, H2SO4(solid NMR Spectrum)
Crystalline form I of Compound A, H2SO4 was also characterized by solid-state Nuclear Magnetic Résonance spectroscopy (Figure 6). Solid-state 13C NMR spectra of Compound A, H2SO4 were recorded at ambient température using a Bruker SB Avance III HD 500 spectrometer with a 4 mm CP/MAS SB VTN type probe under the following conditions:
- Frequency: 125.76 MHz,
Spectral width: 37 kHz,
Magic angle spinning rate: 10 kHz,
Puise program: Cross Polarization with SPINAL64 decoupling
Recycle delay: 10 s,
- Acquisition time: 46 ms,
Contact time: 4 ms, Number of scans: 4096.
A 5 Hz line-broadening was applied prior to Fourier Transformation.
The spectrum thereby obtained was referenced relative to a sample of adamantane (the high frequency peak of adamantane was set to 38.5 ppm).
Crystalline form I of Compound A, H2SO4 can be defined by the presence of a set of peaks whose Chemical shifts are given in the table below (expressed in ppm ± 0.2 ppm):
No. (PPm)
1 173.31
2 155.32
3 140.46
4 139.19
5 137.42
6 134.68
7 131.65
8 131.14
9 129.37
10 126.32
11 118.77
12 117.36
13 116.54
14 113.61
15 112.69
16 110.74
17 102.33
18 101.45
19 63.06
20 57.19
21 54.87
22 52.06
23 44.71
24 43.94
25 34.42
26 32.89
27 31.28
28 30.66
29 14.40
30 13.34
31 12.49
32 10.50

Claims (19)

1. The hydrogen sulfate sait of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(l/7)-yl]carbonyl] phenyl)-/V-(5-cyano-l,2-dimethyl-l/-/-pyrrol-3-yl)-/\/(4-hydroxyphenyl)-l,2-dimethyl-lA/-pyrrole-3-carboxamide (Compound A, H2SO4).
2. A crystalline form I of the hydrogen sulfate sait of 5-(5-chloro-2-{[(35)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l/-/)-yl]carbonyl}phenyl)-A/-(5-cyano-l,2dimethyl-l/-/-pyrrol-3-yl)-/V-(4-hydroxyphenyl)-l,2-dimethyl-l/-/-pyrrole-3-carboxamide (Compound A, H2SO4) according to claim 1, wherein the crystalline form has an X-ray powder diffraction diagram showing the following diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.55 ; 6.62 and 7.39.
3. A crystalline form I of the hydrogen sulfate sait of 5-(5-chloro-2-{[(35)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l/7)-yl]carbonyl) phenyl)-/V-(5-cyano-l,2dimethyl-l/-/-pyrrol-3-yl)-/V-(4-hydroxyphenyl)-l,2-dimethyl-lH-pyrrole-3-carboxamide (Compound A, H2SO4) according to claim 1, wherein the crystalline form has an X-ray powder diffraction diagram showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or ail of the following diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.55; 5.62; 6.62; 7.39; 10.17; 11.49; 11.83; 16.01; 16.54; 17.04; 18.98; 19.18; 21.90; 22.28; 24.89.
4. The crystalline form I of the hydrogen sulfate sait of Compound A according to claim 3, characterized in that it has an X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.55; 5.62; 6.62; 7.39; 10.17; 11.49; 11.83; 16.01; 16.54; 17.04; 18.98; 19.18; 21.90; 22.28; 24.89.
5. The crystalline form I of the hydrogen sulfate sait of Compound A according to claim 4, characterized in that it has the following X-ray powder diffraction diagram, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector
-20and expressed in terms of line position (Bragg's angle 2 thêta, expressed in degrees ±0.2°) and interplanar distances d (expressed in Â):
Line no. Angle 2-theta (degrees) Interplanar distance (Â)
1 5.55 15.93
2 5.62 15.73
3 6.62 13.36
4 7.39 11.95
5 10.17 8.70
6 11.49 7.70
7 11.83 7.48
8 16.01 5.53
9 16.54 5.36
10 17.04 5.20
11 18.98 4.67
12 19.18 4.63
13 21.90 4.06
14 22.28 3.99
15 24.89 3.58
6. The crystalline form I ofthe hydrogen sulfate sait of Compound A according to any one of claims 2 to 5, characterised in that it has a solid-state 13C CP/MAS NMR spectrum having the following peaks (expressed in ppm ± 0.2 ppm): 173.31 ppm, 155.32 ppm, 140.46 ppm, 139.19 ppm, 137.42 ppm, 134.68 ppm, 131.65 ppm, 131.14 ppm, 129.37 ppm, 126.32 ppm, 118.77 ppm, 117.36 ppm, 116.54 ppm, 113.61 ppm, 112.69 ppm, 110.74 ppm, 102.33 ppm, 101.45 ppm, 63.06 ppm, 57.19 ppm, 54.87 ppm, 52.06 ppm, 44.71 ppm, 43.94 ppm, 34.42 ppm, 32.89 ppm, 31.28 ppm, 30.66 ppm, 14.40 ppm, 13.34 ppm, 12.49 ppm and 10.50 ppm.
7. Pharmaceutical composition comprising as active ingrédient the hydrogen sulfate sait of Compound A according to claim 1 in association with one or more pharmaceutically acceptable excipients.
8. Pharmaceutical composition comprising as active ingrédient the crystalline form I of the hydrogen sulfate sait of Compound A according to any one of daims 2 to 6 in association with one or more pharmaceutically acceptable excipients.
9. Pharmaceutical composition according to claim 7 or 8 for use in the treatment of cancers, auto-immune diseases and diseases of the immune System.
10. Pharmaceutical composition according to claim 9, wherein the cancer is selected from the bladder, brain, breast and utérus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, including non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant haemopathies, including myelodysplastic syndrome, myelomas, including multiple myeloma, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
11. The hydrogen sulfate sait of Compound A according to claim 1 for use as a médicament for treating cancers, auto-immune diseases and diseases of the immune System.
12. The crystalline form I of the hydrogen sulfate sait of Compound A according to any one of daims 2 to 6 for use as a médicament for treating cancers, auto-immune diseases and diseases of the immune System.
13. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to any one of daims 2 to 6, wherein the hydrogen sulfate sait of Compound A is crystallised in a polar medium.
14. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to claim 13, wherein the polar medium is composed of one or more solvents selected from water and alcohols.
15. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to claim 14, wherein the alcohol is éthanol.
16. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to claim 14, wherein the polar medium is an ethanol/water mixture.
17. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to any one of claim 13 to 16, in which process the crystallisation is seeded using a very small amount of the crystalline form I of the hydrogen sulfate sait of Compound A.
18. Anhydrous crystalline form of the hydrogen sulfate sait of 5-(5-chloro-2-{[(3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l/7)-yl]carbonyl) phenyl)-/V-(5-cyano-l,2dimethyl-l/-/-pyrrol-3-yl)-/V-(4-hydroxyphenyl)-l,2-dimethyl-l/-/-pyrrole-3-carboxamide (Compound A, H2SO4) according to claim 1, wherein the crystalline form has an X-ray powder diffraction diagram showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or ail of the following diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.19; 5.64; 6.74; 7.14; 8.04; 8.33; 9.17; 9.40; 10.68; 11.03; 11.35; 12.18; 12.59; 13.64; 14.78; 15.09.
19. The anhydrous crystalline form of the hydrogen sulfate sait of Compound A according to claim 18, characterized in that it has the following X-ray powder diffraction diagram, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator
-23detector and expressed in terms of line position (Bragg's angle 2 thêta, expressed in degrees ±0.2°) and interplanar distances d (expressed in Â):
Line no. Angle 2-theta (degrees) Interplanar distance (Â)
1 5.19 17.03
2 5.64 15.66
3 6.74 13.12
4 7.14 12.39
5 8.04 10.99
6 8.33 10.61
7 9.17 9.64
8 9.40 9.41
9 10.68 8.29
10 11.03 8.02
11 11.35 7.79
12 12.18 7.26
13 12.59 7.03
14 13.64 6.49
15 14.78 5.99
16 15.09 5.87
OA1202100188 2018-10-31 2019-10-30 Novel salt of A BCL-2 inhibitor, related crystalline form, method for preparing the same and pharmaceutical compositions containing the same. OA20227A (en)

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