Novel salt of bcl-2 inhibitor, related crystalline form, method for preparing the same, and pharmaceutical compositions containing the same

Abstract

To provide a novel salt of a compound that is a Bcl-2 inhibitor.SOLUTION: The present invention provides a novel salt, which is a hydrogen sulfate salt, represented by the following structural formula; related crystalline forms, characterized by X-ray powder diffraction patterns; a method for preparing the same; and pharmaceutical compositions containing the same.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a novel salt of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (herein referred to as "Compound A"), or a polymorph or solvate thereof, a process for its preparation and a pharmaceutical composition thereof. In particular, the present invention relates to the hydrogen sulfate salt of Compound A (herein referred to as "Compound A, H 2 SO 4 "), and its crystalline form I. The present invention further discloses a method for preparing said crystalline form and a pharmaceutical composition comprising said crystalline form. The present invention also relates to the use of such a composition for the treatment of cancer, diseases of the immune system and autoimmune diseases. Finally, compounds A, H 2 SO 4 This invention discloses an anhydrous crystalline form of [Background technology]

[0002] The chemical structure of compound A is: [ka] It is.

[0003] Its preparation, its use as a Bcl-2 inhibitor for the treatment of cancer and its pharmaceutical formulation are described in WO 2015 / 011400 (Example 386), the contents of which are incorporated by reference. The preparation of Compound A in the form of hydrochloride ("Compound A.HCl") is specifically disclosed in this document. It is obtained as a lyophilizate.

[0004] Compound A is a very promising drug, but a difficult compound to formulate. In particular, it is only sparingly soluble in water (less than 0.01 mg / mL of the free base). Since a chemical substance may exhibit different physical properties in any of its salt forms or crystalline forms, this polymorphism of the drug molecule may affect the shelf life, solubility, formulation properties, processing properties, and drug action. Furthermore, different polymorphs may have different uptake rates in the body, leading to lower or higher biological activity than desired. In extreme cases, undesired polymorphs may even be toxic. Therefore, understanding and controlling polymorphism offers a crucial advantage in bringing new drugs to market that may be more active, more stable, or cheaper to produce. However, even though polymorphism has been the subject of intensive research, understanding and controlling this phenomenon represents a substantial scientific challenge. It is difficult to predict whether a given molecule will crystallize in one or several crystalline forms, and to find the conditions that lead to such crystallization.

[0005] From an industrial point of view, it is essential to be able to synthesize compounds with high purity and in a highly reproducible form, and in particular with the valuable features of solubility, filterability, dryness, ease of formulation and stability (which allows their long-term storage without special requirements as to temperature, light, humidity or oxygen concentration).

[0006] The present invention also provides compounds A, H, and HN in well-defined and completely reproducible crystalline forms (Type I) with exceptional stability that meets the industrial constraints of preparation (particularly filtration) and storage of pharmaceutical compositions. 2 SO 4 A method for obtaining the above will be described. [Brief description of the drawings]

[0007] [Figure 1] 1 shows the powder X-ray diffraction pattern (XPRD) of crystalline form I of compound A, H2SO4. [Diagram 2] 1 shows the powder X-ray diffraction pattern (XPRD) of the anhydrous crystalline form of Compound A, hydrogen sulfate salt. [Diagram 3]1 shows the powder X-ray diffraction pattern (XPRD) of crystalline Form I of Compound A, hydrochloride salt. [Figure 4] 1 shows the DSC and TGA profiles of crystalline Form I of Compound A, hydrogen sulfate salt. [Diagram 5] 1 shows DSC and TGA profiles of crystalline Form I of Compound A, hydrochloride salt. [Figure 6] 1 shows the solid-state C13 NMR spectrum of crystalline form I of compound A, H2SO4.

[0008] Detailed Description of the Invention As used herein, the term "comprise" means "contain" and is not intended to exclude the presence of any additional components (unless the context suggests otherwise, for example when the components add up to 100%).

[0009] The term "alcohol" refers to any C alkane, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol, 2-pentanol, 3-pentanol, isopentanol, hexanol, and the like. 1 -C 6 It means alcohol.

[0010] "Cancer" refers to a category of diseases in which a group of cells show uncontrolled growth. Types of cancer include blood cancers (lymphomas and leukemias) and solid cancers, including carcinomas, sarcomas, or blastomas. "Cancer" includes bladder, brain, breast, and uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal and liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphomas (e.g., non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma), melanoma, malignant haemopathies (e.g., myelodysplastic syndromes), myelomas (e.g., multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, and small cell lung cancer.

[0011] "Free molecule" and "free base" are used interchangeably herein and refer to Compound A when not in the form of a salt.

[0012] EMBODIMENTS OF THE PRESENT DISCLOSURE Described below are several embodiments of the present invention.

[0013] E1. Hydrogen sulfate salt of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (Compounds A, H 2 SO 4 ).

[0014] E2. Hydrogen sulfate salt of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide according to E1 (Compounds A, H 2 SO 4 ) having the following diffraction lines (represented by Bragg angles 2θ (degrees, ±0.2°): 5.55; 6.62 and 7.39 The crystalline form has a powder X-ray diffraction pattern showing:

[0015] E3. Hydrogen sulfate salt of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide according to E1 (Compounds A, H 2 SO 4 ) having the following diffraction lines (represented by Bragg angles 2θ (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 A crystalline form having an X-ray powder diffraction pattern exhibiting at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of the following:

[0016] E4. The following diffraction lines (represented by Bragg angles 2θ (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 Crystalline form I of the hydrogen sulfate salt of compound A according to E3, characterized in that it has an X-ray powder diffraction pattern having the following formula:

[0017] E5. The following powder X-ray diffraction pattern measured using a PANalytical X'Pert Pro MPD diffractometer equipped with an X'Celerator detector and expressed in terms of line positions (expressed in Bragg angles 2θ (degrees, ±0.2°)) and interplanar distances d (expressed in Å):

[0018] [Table 1] The crystalline form I of the hydrogen sulfate salt of compound A according to E4, characterized in that it has the following structure:

[0019] E6. 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. A solid having 13 The crystalline form I of the hydrogen sulfate salt of compound A according to any one of items E1 to E5, characterized by having a C CP / MAS NMR spectrum:

[0020] E7. A pharmaceutical composition comprising as an active ingredient the hydrogen sulfate salt of compound A according to E1 in combination with one or more pharma- ceutically acceptable excipients.

[0021] E8. A pharmaceutical composition comprising, as an active ingredient, crystalline Form I of the hydrogen sulfate salt of Compound A according to any one of E2 to E6, in combination with one or more pharma- ceutically acceptable excipients.

[0022] E9. The pharmaceutical composition of E7 or E8 for use in the treatment of cancer, autoimmune diseases and diseases of the immune system.

[0023] E10. The pharmaceutical composition according to E9, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer and uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal and liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma (e.g., non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma), melanoma, malignant hemopathy (e.g., myelodysplastic syndrome), myeloma (e.g., multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, and small cell lung cancer.

[0024] E11. The hydrogen sulfate salt of compound A according to E1 for use as a medicine.

[0025] E12. The hydrogen sulfate salt of compound A according to E1 for use in the treatment of cancer, autoimmune diseases and diseases of the immune system.

[0026] E13. The hydrogen sulfate salt of compound A according to E12, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer and uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal and liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma (e.g., non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma), melanoma, malignant hemopathy (e.g., myelodysplastic syndrome), myeloma (e.g., multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, and small cell lung cancer.

[0027] E14. Crystalline form I of the hydrogen sulfate salt of compound A according to any one of E2 to E6 for use as a medicament.

[0028] E15. Crystalline form I of the hydrogen sulfate salt of compound A according to any one of E2 to E6 for use in the treatment of cancer, autoimmune diseases and diseases of the immune system.

[0029] E16. The crystalline form I of the hydrogen sulfate salt of compound A according to E15, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer and uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal and liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma (e.g., non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma), melanoma, malignant hemopathy (e.g., myelodysplastic syndrome), myeloma (e.g., multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, and small cell lung cancer.

[0030] E17. A method for preparing crystalline form I of hydrogen sulfate of Compound A according to any one of E2 to E6, comprising crystallizing the hydrogen sulfate of Compound A in a polar medium.

[0031] E18. The method for preparing crystalline Form I of the hydrogen sulfate salt of Compound A according to E17, wherein the polar medium is composed of one or more solvents selected from water and alcohols.

[0032] E19. The method for preparing crystalline form I of the hydrogen sulfate salt of Compound A according to E18, wherein the alcohol is ethanol.

[0033] E20. The method for preparing crystalline Form I of the hydrogen sulfate salt of Compound A according to E18, wherein said polar medium is an ethanol / water mixture.

[0034] E21. A method for preparing crystalline form I of the hydrogen sulfate salt of Compound A according to any one of E17 to E20, wherein the crystallization is seeded with a small amount of crystalline form I of the hydrogen sulfate salt of Compound A.

[0035] E22. Hydrogen sulfate salt of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide according to E1 (Compounds A, H 2 SO 4) having the following diffraction lines (represented by Bragg angles 2θ (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 A crystalline form having an X-ray powder diffraction pattern exhibiting at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all of the following:

[0036] E23. The following powder X-ray diffraction pattern measured using a PANalytical X'Pert Pro MPD diffractometer equipped with an X'Celerator detector and expressed in terms of line positions (expressed in Bragg angles 2θ (degrees, ±0.2°)) and interplanar distances d (expressed in Å):

[0037] [Table 2] The anhydrous crystalline form according to E22, characterized in that it has

[0038] Obtaining crystalline form I of the hydrogen sulfate of compound A has the advantage of having good stability characteristics. More specifically, only one crystalline form was observed in the solvent and temperature range used in screening, indicating that the polymorphism of the hydrogen sulfate is limited under the conditions tested. Moreover, the crystalline form I of the hydrogen sulfate of compound A obtained thereby is sufficiently stable and can be stored for a long period of time without any specific conditions of temperature, light, humidity or oxygen concentration.

[0039] The following examples herein illustrate the invention but do not limit it in any way.

[0040] Example 1: Method for obtaining crystalline form I of the hydrogen sulfate salt of compound A 25 g of compound A (free base) was placed in 239.5 g of ethanol at ambient temperature. The mixture was then heated at 65° C. An aqueous solution of sulfuric acid (H 2 SO4 4.27g + water 59.87g) was added slowly. The mixture was stirred for 1 hour and then cooled to 10°C. When crystallization was complete, the suspension was filtered, washed with ethanol / water mixture at 10°C, filtered and dried under reduced pressure. After drying, crystalline form I of the hydrogen sulfate salt of Compound A was obtained in about 70% yield and more than 99.8% purity. The solid was characterized by X-ray powder as described in Example 3. In the crystallization method according to the present invention, Compound A (free base) is obtained by any method that may be used.

[0041] Example 2: Method for obtaining crystalline form I of the hydrogen sulfate salt of Compound A (seeding) 25 g of compound A (free base) was placed in 239.5 g of ethanol at ambient temperature. The mixture was then heated at 65° C. An aqueous solution of sulfuric acid (H 2 SO 4 4.27g + water 59.87g) was added slowly. The mixture was stirred for 30 minutes. The mixture was then cooled slightly and seeded with crystalline form I of the hydrogen sulfate salt of compound A (2% by weight of starting material). The mixture was stirred for 30 minutes and cooled to 10°C. When crystallization was complete, the suspension was filtered, washed with ethanol / water mixture at 10°C, filtered and dried under reduced pressure. After drying, crystalline form I of the hydrogen sulfate salt of compound A was obtained in about 70% yield and more than 99.8% purity. The solid was characterized by powder X-ray as described in Example 3. In the crystallization method according to the present invention, Compound A (free base) is obtained by any method that may be used.

[0042] Example 3: Crystalline Form I of the hydrogen sulfate salt of Compound A (X-ray powder diffraction diagram) Data were recorded in transmission mode using a PANalytical X'Pert Pro MPD diffractometer equipped with an X'Celerator detector under the following conditions: - Voltage 45kV, current 40mA, - Mount: θ / θ method, - Anode: copper, - Kα-1 wavelength: 1.54060 Å, - Kα-2 wavelength: 1.54443 Å, - ratio of Kα-2 / Kα-1: 0.5, - Measurement mode: Continuous measurement from 3° to 55° (Bragg angle 2θ) in 0.017° increments, - Measurement time per step: 35.5301 seconds.

[0043] The powder X-ray diffraction pattern of Form I of the hydrogen sulfate salt of Compound A obtained according to the method of Example 1 or 2 is represented by line positions (expressed in Bragg angles 2θ (degrees, ±0.2°)) and interplanar distances d (expressed in Å). Significant lines are collated in the following table:

[0044] [Table 3]

[0045] Example 4: Stability Study For all storage conditions and periods, 20 mg of the crystalline form of the salt of Compound A was placed in a 30 mL vial for HPLC analysis after storage. The content of drug substance was determined by LC (%m / m).

[0046] [Table 4]

[0047] The appearance (white color) and chemical stability of the powder remained unchanged under all conditions tested: 25°C / 60% relative humidity, 30°C / 65% relative humidity, 40°C / 75% relative humidity for more than 3 months, and 50°C / 75% relative humidity for 6 weeks. Furthermore, the results of X-ray diffraction show that T 0 The crystal form remains unchanged after analysis at 25°C / 90% relative humidity and after storage for 6 weeks in an open glass bottle. In conclusion, the drug substance can be considered to be physically and chemically stable throughout the study period.

[0048] Example 5: Method for obtaining anhydrous crystalline form of the hydrogen sulfate salt of Compound A (seeding) 5.83 Kg of compound A (free base) was placed in 55.85 Kg of ethanol at ambient temperature. The mixture was then heated at 65° C. An aqueous solution of sulfuric acid (H 2 SO 4 1Kg+13.96Kg water) was added slowly. The mixture was stirred for 30 minutes. The mixture was then cooled slightly and seeded with crystalline form I of the hydrogen sulfate salt of compound A (2% by weight of starting material). The mixture was stirred for 30 minutes and cooled to 10°C. When crystallization was complete, the suspension was filtered, washed with ethanol / water mixture at 10°C, filtered and dried under reduced pressure. The dried product was then stored under an inert atmosphere (nitrogen). The anhydrous crystalline form of the hydrogen sulfate salt of compound A was obtained in about 78±5% yield, with a purity of more than 99.9% and a water content of about 0.43%. The solid was characterized by powder X-ray as described in Example 6. In the crystallization method according to the present invention, Compound A (free base) is obtained by any method that may be used.

[0049] Example 6: Anhydrous crystalline form of the hydrogen sulfate salt of Compound A (X-ray powder diffraction pattern) The data was recorded under the following conditions: Approximately 30-50 mg of the sample to be analyzed is placed between two polymer films (Kapton®) fixed on a sample holder disk. X-ray diffraction patterns of the test samples are recorded for 15 min using an X-ray diffractometer operating in transmission mode with CuKα radiation (=1.5418 Å) at 40 kV and 30 mA, with a step width ranging from 3° 2θ to at least 40° 2θ, ranging from 0.01 to 0.02° 2θ. These settings may vary depending on the diffractometer used.

[0050] The powder X-ray diffraction pattern of the anhydrous form of the hydrogen sulfate salt of Compound A, obtained according to the method of Example 5, is represented by line positions (expressed as Bragg angles 2θ (degrees, ±0.2°)) and interplanar distances d (expressed as Å) ( FIG. 2 ). Significant lines are listed in the table below.

[0051] [Table 5]

[0052] Example 7: Method for Obtaining Crystalline Form I of the Hydrogen Sulfate Salt of Compound A (Seeding, Kilogram Batch Size) 5.83 Kg of compound A (free base) was placed in 55.85 Kg of ethanol at ambient temperature. The mixture was then heated at 65° C. An aqueous solution of sulfuric acid (H 2 SO 4 1 Kg + 13.96 Kg water) was added slowly. The mixture was stirred for 30 minutes. The mixture was then cooled slightly and seeded with crystalline form I of the hydrogen sulfate salt of compound A (2% by weight of starting material). The mixture was stirred for 30 minutes and then cooled to 10°C. When crystallization was complete, the suspension was filtered, washed with ethanol / water mixture at 10°C, filtered and dried under reduced pressure. The product was then rehydrated at 40°C under an atmosphere of 50% relative humidity (RH). The product obtained was stored under an inert atmosphere (nitrogen). Crystalline form I of the hydrogen sulfate salt of compound A was obtained in a yield of about 78±5%, with a purity of more than 99.9% and a water content of about 6.5±1%. The solid was characterized by powder X-ray as described in Example 3. In the crystallization method according to the present invention, Compound A (free base) is obtained by any method that may be used.

[0053] Example 8: Method for obtaining crystalline form I of the hydrochloride salt of compound A and its characterizing powder X-ray diffraction diagram 1510 mg of the amorphous hydrochloride salt of Compound A (Example 386 of WO 2015 / 011400) was converted to its crystalline ethanol solvate by slurrying in 15 mL of ethanol for 48 h. The remaining solid was filtered, washed twice with 1 mL of ethanol, and then suspended in 10 mL of water for 5 min. After difficult filtration, the remaining solid was dried overnight at 30 °C / 10 mbar and analyzed by X-ray diffraction (3-30 ° 2θ / 10 min). The preparation method of the HCl salt first results in an ethanol solvate, which is then resuspended in water and then dissolved in H2 This is complicated by the fact that HCl is substituted with 0 to give a hydrated form. The resulting hydrated HCl salt formed fine needles that were very difficult to filter.

[0054] The powder X-ray diffraction pattern of Form I of the hydrochloride salt of Compound A obtained according to the method described above is represented by the line positions (expressed as Bragg angles 2θ (degrees, ±0.2°)) and relative intensities (expressed as %) (Figure 3). Significant lines are listed in the table below.

[0055] [Table 6]

[0056] Example 9: DSC and TGA profiles of crystalline form I of the hydrochloride and hydrogen sulfate salts of Compound A H 2 SO 4 salt Differential scanning calorimetry (DSC) profiles of samples (approximately 4 mg) of the hydrogen sulfate salt Form I were recorded in a TA Instruments Q1000 (or Q2000) differential scanning calorimeter under a positive flow of nitrogen in an aluminum pan with a pinhole at 10° C. / min from 0° C. to 250° C. (FIG. 4). Thermogravimetric analysis (TGA) profiles of samples (approximately 10 mg) of the hydrogen sulfate salt Form I were recorded on a TA Instruments Q5000 thermogravimetric analyzer at 10°C / min in an open aluminum pan under positive nitrogen flow between 25°C and 250°C (Figure 4).

[0057] Hydrochloride DSC profiles of samples (approximately 4 mg) of the hydrochloride salt Form I were recorded on a TA Instruments Q1000 (or Q2000) differential scanning calorimeter from 0° C. to 250° C. at 10° C. / min in pinhole-pierced aluminum pans under positive nitrogen flow (FIG. 5).

[0058] The TGA profile of a sample (approximately 6 mg) of the hydrochloride salt form I was recorded on a TA Instruments Q5000 thermogravimetric analyzer in an open aluminum pan under positive nitrogen flow at 10° C. / min between 25° C. and 250° C. (FIG. 5).

[0059] H 2 SO 4 The DSC profile of the salt is less complex than that of the HCl salt. 2 SO 4 The TGA profile of the salt shows a loss of water between 25 and 100 °C. A melting / decomposition endotherm is seen in the DSC profile towards 224 °C. The melting temperature and enthalpy of the HCl salt are 2 SO 4 This is lower than that of salt. 2 SO 4 This may suggest that the HCl salt has a lower degree of crystallinity after dehydration compared to the HCl salt.

[0060] Example 10: Compounds A and H 2 SO 4 Crystal form I of (Solid-state NMR spectrum) Compound A, H 2 SO 4 The crystalline form I of Compound A was also characterized by solid-state nuclear magnetic resonance spectroscopy (Figure 6). 2 SO 4 Solid 13 C NMR spectra were recorded at ambient temperature using a Bruker SB Avance III HD 500 spectrometer equipped with a 4 mm CP / MAS SB VTN type probe under the following conditions: - Frequency: 125.76MHz, - Spectral width: 37kHz, - Magic angle rotation speed: 10kHz, - Pulse programs: SPINAL64 cross-polarization with decoupling, - Recycle delay 10 seconds, - Data acquisition time: 46 ms, - Contact time: 4ms, - Number of scans: 4096.

[0061] Prior to Fourier transformation, a line-broadening of 5 Hz was applied. The spectra obtained were referenced against a sample of adamantane (the high frequency peak of adamantane was set at 38.5 ppm).

[0062] Compound A, H 2 SO 4 Crystalline form I of can be defined by the presence of a series of peaks whose chemical shifts are given in the following table (expressed in ppm ± 0.2 ppm):

[0063] [Table 7]

Claims

1. Hydrogen sulfate of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (Compound A, H ２ SO ４ ).

2. The hydrogen sulfate salt of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide according to claim 1 (Compound A, H ２ SO ４ ) having the following diffraction lines (represented by Bragg angles 2θ (degrees, ±0.2°)): 5.55; 6.62 and 7.39 The crystalline form has a powder X-ray diffraction pattern of:

3. The hydrogen sulfate salt of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide according to claim 1 (Compound A, H ２ SO ４ ) having the following diffraction lines (represented by Bragg angles 2θ (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 A crystalline form having an X-ray powder diffraction pattern exhibiting at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of the following:

4. The following diffraction lines (represented by Bragg angles 2θ (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 salt of compound A according to claim 3, characterized in that it has an X-ray powder diffraction pattern of:

5. The following powder X-ray diffraction pattern measured using a PANalytical X'Pert Pro MPD diffractometer equipped with an X'Celerator detector and expressed in terms of line positions (expressed in Bragg angles 2θ (degrees, ±0.2°)) and interplanar distances d (expressed in Å): 【Table 8】 5. The crystalline form I of the hydrogen sulfate salt of compound A according to claim 4, characterized in that it has the following formula:

6. 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 A solid having 13 The crystalline form I of the hydrogen sulfate salt of compound A according to any one of claims 1 to 5, characterized by having a C CP / MAS NMR spectrum:

7. 10. A pharmaceutical composition comprising as an active ingredient the hydrogen sulfate salt of compound A according to claim 1 in combination with one or more pharma- ceutically acceptable excipients.

8. A pharmaceutical composition comprising as an active ingredient the crystalline form I of the hydrogen sulfate salt of Compound A according to any one of claims 2 to 6 in combination with one or more pharma- ceutically acceptable excipients.

9. 9. A pharmaceutical composition according to claim 7 or 8 for use in the treatment of cancer, autoimmune diseases and diseases of the immune system.

10. The pharmaceutical composition of claim 9, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer and uterine cancer, chronic lymphocytic leukemia, colon cancer, esophageal and liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphoma (e.g., non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma), melanoma, malignant hemopathy (e.g., myelodysplastic syndrome), myeloma (e.g., multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, and small cell lung cancer.

11. 2. The hydrogen sulfate salt of compound A according to claim 1 for use as a medicament.

12. The crystalline form I of the hydrogen sulfate salt of compound A according to any one of claims 2 to 6 for use as a medicament.

13. A process for preparing the crystalline form I of the hydrogen sulfate salt of Compound A according to any one of claims 2 to 6, comprising crystallizing the hydrogen sulfate salt of Compound A in a polar medium.

14. 14. The method for preparing crystalline Form I of the hydrogen sulfate salt of Compound A according to claim 13, wherein the polar medium is comprised of one or more solvents selected from water and alcohols.

15. 15. The method for preparing crystalline Form I of the hydrogen sulfate salt of Compound A according to claim 14, wherein the alcohol is ethanol.

16. 15. The method for preparing crystalline Form I of the hydrogen sulfate salt of Compound A according to claim 14, wherein the polar medium is an ethanol / water mixture.

17. A method for preparing crystalline Form I of the hydrogen sulfate salt of Compound A according to any one of claims 13 to 16, wherein the crystallization is seeded with a small amount of crystalline Form I of the hydrogen sulfate salt of Compound A.

18. The hydrogen sulfate salt of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide according to claim 1 (Compound A, H ２ SO ４ ) having the following diffraction lines (represented by Bragg angles 2θ (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 A crystalline form having an X-ray powder diffraction pattern exhibiting at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all of the following:

19. The following powder X-ray diffraction pattern measured using a PANalytical X'Pert Pro MPD diffractometer equipped with an X'Celerator detector and expressed in terms of line positions (expressed in Bragg angles 2θ (degrees, ±0.2°)) and interplanar distances d (expressed in Å): 【Table 9】 19. The anhydrous crystalline form of the hydrogen sulfate salt of compound A according to claim 18, characterized in that it has the following structure:

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