EA044230B1 - NEW CRYSTAL FORMS OF MCL-1 INHIBITOR, METHOD FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

Field of technology

The present invention relates to new crystalline forms of 2-{[5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2, 3-b]pyrimidin-4-yl]oxy}-3-(2-{[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}-phenyl)propanoic acid, which is referred to herein as compound A. In this specification disclosed crystalline forms of 2-{[5-{3-chloro-2-methyl-4[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-b ]pyrimidin-4-yl]oxy}-3-(2-{[2(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid, which are also called crystalline forms A and M. In addition, in this The description discloses two other crystalline forms of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno [2 ,3b]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid, which are called the crystalline forms MH and MHD.

The present invention further discloses a method for preparing said crystalline forms of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl) thieno[2,3b]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid.

The present invention further discloses pharmaceutical compositions containing said crystalline forms of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl} 6-(4-fluorophenyl )thieno[2,3-b]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)propanoic acid, and the use of said compositions for the treatment of cancer , diseases of the immune system and autoimmune diseases.

Prerequisites for creating the invention

2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3b]pyrimidin-4 -yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid, is an Mcl-1 inhibitor useful for the treatment of cancer, immune system diseases and autoimmune diseases diseases, the preparation, use and pharmaceutical compositions of which are previously described in WO 2015/097123, the contents of which are incorporated herein by reference. Its preparation is specifically disclosed in Example 30 of patent application WO 2015/097123.

In a specific embodiment, Compound A is (211)-2-{[(5S _a )-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl } -6-(4fluorophenyl)thieno[2,3-b]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)-pyrimidin-4yl]methoxy}phenyl)propanoic acid. In a further embodiment, Compound A used in the composition described herein is the free molecule (not a salt thereof).

Although Compound A is a very promising drug, it is difficult to prepare. In water, its solubility is below 0.001 mg/ml (at pH 7.5). Because a chemical can exhibit different physical properties when in one crystalline form or another, this polymorphism of the drug molecule can affect the shelf life, solubility, formulation properties, processing properties, and potency of the drug. Additionally, different polymorphs may have different absorption rates in the body, resulting in lower or higher

- 1 044230 higher biological activity than desired. In extreme cases, the unwanted polymorph may even exhibit toxicity. Thus, understanding and controlling polymorphism provides a distinct advantage in bringing new drugs to market that may be more active, more stable, or cheaper to produce. However, although polymorphism has been the subject of intense research, understanding and controlling this phenomenon poses a major scientific challenge. It is difficult to predict whether a given molecule will crystallize into one or more crystalline forms and to find the conditions that lead to such crystallization.

From an industrial perspective, it is critical to be able to synthesize a compound in superior purity, especially in a perfectly reproducible form, with valuable dissolution, filtration, drying characteristics, ease of preparation, and stability allowing for long-term storage without special requirements for temperature, light, humidity, or oxygen levels .

The present invention relates to new crystalline forms of Compound A with the above-mentioned advantages, and also describes methods for obtaining Compound A in a well-defined, perfectly reproducible crystalline form (in particular Form A or Form M) having very good stability, which is compatible with industrial limitations preparation, especially filtration and storage of pharmaceutical compositions.

Brief description of the figures

In fig. Figure 1 shows an X-ray powder diffraction (XRPD) pattern of compound A, crystal form M.

In fig. Figure 2 shows an enlarged image of the XRPD diffraction pattern of compound A, crystal form M.

In fig. Figure 3 shows the water sorption profile (WAP) of compound A, crystalline form M.

In fig. Figure 4 shows the solid-state ¹³ C NMR spectroscopy spectrum of compound A, crystal form M.

In fig. Figure 5 shows the mid-infrared (MIR) spectrum of compound A, crystal form M.

In fig. Figure 6 shows an enlarged view of the MIR spectrum of compound A, crystal form M.

In fig. Figure 7 shows the Raman spectrum of compound A, crystal form M.

In fig. Figure 8 shows an enlarged view of the Raman spectrum of compound A, crystal form M.

In fig. Figure 9 shows the ORTEP figure for compound A, crystal form M.

In fig. Figure 10 shows an XRPD diffraction pattern of compound A, crystalline form A.

In fig. Figure 11 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of compound A, crystal form M.

In fig. 12 shows an XRPD diffraction pattern of compound A, crystal form MH.

In fig. 13 shows an XRPD diffraction pattern of compound A, crystal form M _HD .

Detailed Description of the Invention

Compound A is 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4fluorophenyl)thieno[2,3-d] pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)propanoic acid, more preferably (2R)-2-{[(5S _a )-5 -{3-chloro-2-methyl-4-[2(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy }-3-(2-{[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid.

As used herein, the term containing means including and does not imply the exclusion of the presence of any additional component unless the context requires otherwise, for example, when the sum of the components together is 100%.

Cancer refers to a class of disease in which a group of cells exhibit uncontrolled growth. Types of cancer include hematologic cancers (lymphoma and leukemia) and solid tumors including carcinoma, sarcoma, or blastoma. Cancers include bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphoid leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphomas (eg, non-Hodgkin B-cell lymphoma or diffuse large B-cell lymphoma), melanomas, blood malignancies (eg myelodysplastic syndrome), myelomas (eg multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.

Free molecule and free base are used interchangeably herein and refer to Compound A unless it is in salt form.

Substantially pure, when used for the crystalline form of compound A, means having a purity of greater than 90% by weight, preferably greater than 95% by weight, more preferably greater than 97% by weight, even more preferably greater than 99% by weight, and also including purity which is equal to approximately 100% by weight of compound A, based on the weight of the compound.

ICH stands for International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use.

Embodiments of the Invention

- 2 044230

A number of embodiments of the invention are described below.

E1. Crystal Form M 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}6-(4-fluorophenyl)thieno[2,3-d ]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)propanoic acid (compound A).

E2. The crystalline form M of compound A according to E1 is in substantially pure form.

E3. Crystalline form M of compound A according to E1 or E2 is characterized in that it has a powder x-ray diffraction pattern showing at least the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 8.94 and 18 ,24.

E4. Crystal form M of compound A according to E1 or E2 is characterized in that it has a powder x-ray diffraction pattern showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 6.27; 8.94; 9.09; 12.16; 13.67; 14.75; 15.06; 16.97; 17.22; 17.44; 18.24; 19.16; 19.93; 20.91; 25.88.

E5. The crystalline form M of compound A according to E4 is characterized in that it has a powder x-ray diffraction pattern containing the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 8.94; 13.67; 14.75; 17.22; 18.24.

E6. The crystalline form M of compound A according to E4 is characterized in that it has a powder x-ray diffraction pattern containing the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 6.27; 8.94; 9.09; 12.16; 13.67; 14.75; 15.06; 16.97; 17.22; 17.44; 18.24; 19.16; 19.93; 20.91; 25.88.

E7. The crystalline form M of compound A according to E6 is characterized in that it has the following X-ray powder diffraction pattern measured in spinner transmission mode using a PANalytical Empyrean diffractometer with a PIXCel 1D detector and expressed in terms of line positions (Bragg angle 2 theta, expressed in degrees ± 0.2°) and interplanar distance d (expressed in A):

Line no. Angle 2-theta (degrees) Interplanar distance (A) 1 6.27 14.10 2 8.94 9.89 3 9.09 9.73 4 12.16 7.28 5 13.67 6.48 6 14.75 6.00 7 15.06 5.88 8 16.97 5.22 9 17.22 5.15 10 17.44 5.08 eleven 18.24 4.86 12 19.16 4.63 13 19.93 4.45 14 20.91 4.25 15 25.88 3.44

E8. Crystalline form M of compound A, according to any one of E1 to E7, is characterized in that it has a ¹³ C CP/MAS NMR solid state spectroscopy spectrum containing the following peaks (expressed in ppm ± 0.2 ppm): 175.1, 153 .7, 134.8, 108.9, 71.4 and 35.1.

E9. Crystalline form M of compound A, according to any one of E1 to E7, is characterized in that it has a ¹³ C CP/MAS NMR solid state spectroscopy spectrum containing the following peaks (expressed in ppm ±0.2 ppm): 175.1, 168 ,5, 167.4, 164.6, 162.6, 157.5, 156.3, 153.7, 135.5, 134.8, 130.4, 129.9, 128.4, 126.8 , 120.9, 119.9, 118.5, 116.9, 112.5, 111.1, 108.9, 78.7, 71.4, 54.9, 42.1, 35.1 and 18 ,2.

E10. Crystalline form M of compound A, according to any one of E1 to E7, is characterized in that it has a Raman spectrum containing the following peaks (expressed in cm ^-1 ): 1516.0, 1220.0, 770.0, 752.0, 380.0.

E11. Crystalline form M of compound A, according to any one of E1 to E7, is characterized in that it has a Raman spectrum containing the following peaks (expressed in cm ^-1 ): 1602.0, 1544.0, 1518.0, 1478.0, 1376.0, 1286.0, 1220.0, 1164.0, 1130.0, 1048.0, 1034.0, 988.0, 812.0, 770.0, 752.0, 634, 0, 566.0, 508.0, 414.0, 380.0, 254.0.

E12. A pharmaceutical composition containing as an active ingredient a crystalline form M of compound A according to any one of E1 to E11 in combination with one or more pharmaceutically acceptable carriers, glidants, diluents, excipients or stabilizers.

E13. Pharmaceutical composition in accordance with E12 for use in the treatment of cancer, autoimmune diseases and diseases of the immune system.

E14. Pharmaceutical composition for use in accordance with E13, where cancer is selected from cancer

- 3 044230 bladder, brain cancer, breast cancer, uterine cancer, chronic lymphoid leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphomas (for example, non-Hodgkin B-cell lymphoma or diffuse large B-cell lymphoma), melanomas, blood malignancies (eg myelodysplastic syndrome), myelomas (eg multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.

E15. Crystalline form M of compound A according to any one of E1 to E11 for use as a drug.

E16. Crystalline form M of compound A according to any one of E1 to E11 for use in the treatment of cancer, autoimmune diseases and diseases of the immune system.

E17. Crystalline form M of compound A for use in accordance with E16, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphoid leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphomas (eg, non-Hodgkin B-cell lymphoma or diffuse large B-cell lymphoma), melanomas, blood malignancies (eg, myelodysplastic syndrome), myelomas (eg, multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.

E18. A method for preparing crystalline form M of compound A according to any one of E1E11, wherein compound A is crystallized in a solvent selected from toluene, 2-methyltetrahydrofuran (Me-THF) or a mixture of toluene and methyl tert-butyl ether (MTBE), more preferably toluene or mixtures of toluene and MTBE.

E19. A method for obtaining crystalline form M of compound A in accordance with E18, where the solvent is a mixture of toluene and MTBE, preferably 75/25 w/w. toluene/MTBE mixture.

E20. A method for obtaining crystalline form M of compound A in accordance with E18, where the concentration of Compound A in the solvent is from 5 to 15% w/w. preferably from 7 to 13% w/w. more preferably 10 to 12.5% w/w.

E21. A process for preparing crystalline form M of compound A according to any one of E18E20, wherein the suspension of compound A in a solvent obtained in the process is filtered and dried in vacuo at a temperature of from 20 to 80°C, preferably from 20 to 75°C, more preferably from 35 to 75°C.

E22. A method for obtaining crystalline form M of compound A in accordance with E19, wherein the suspension of compound A in a solvent obtained in the process is filtered and dried in two steps, comprising:

a first step in which the filtered solid is dried in vacuum at 20°C until the ICH residual solvent limit for MTBE is reached, and a second step in which the solid obtained in the first step is dried in vacuum at 70°C until the ICH residual solvent limit is reached solvent for toluene.

E23. A method for producing crystalline form M of compound A according to any one of E18E22, wherein crystallization is induced by seeding using a very small amount of crystalline form M of compound A, in particular crystallization is induced by seeding using 0.5-5% w/w. crystalline form M of compound A, preferably 0.5-3%.

E24. A method for obtaining crystalline form M of compound A according to E23, in which crystallization is induced by introducing a seed at a temperature of from 20 to 60°C.

E25. A method for obtaining crystalline form M of compound A according to E24, in which crystallization is induced by introducing a seed at a temperature of from 30 to 45°C.

E26. Crystal form A 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}6-(4-fluorophenyl)thieno[2,3-d ]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)propanoic acid (compound A).

E27. Crystalline Form A of Compound A according to E26 is in substantially pure form.

E28. Crystalline Form A of Compound A according to E26 or E27 is characterized in that it has a powder x-ray diffraction pattern showing at least the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 7.52 and 16 ,61.

E29. Crystalline Form A of Compound A according to E26 or E27 is characterized in that it has a powder x-ray diffraction pattern showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15. 16 or all of the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 7.52; 8.89; 9.58; 10.35; 11.25; 13.08; 14.44; 16.61; 17.07; 17.71; 19.10; 20.60; 20.80; 21.69; 22.14; 23.63; 27.36.

E30. Crystalline Form A of Compound A according to E29 is characterized in that it has a powder x-ray diffraction pattern showing the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 7.52; 8.89; 10.35; 16.61; 19.10.

E31. Crystalline Form A of Compound A according to E29 is characterized in that it has a powder x-ray diffraction pattern showing the following diffraction characteristics:

- 4 044230 lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 7.52; 8.89; 9.58; 10.35; 11.25; 13.08;

14.44; 16.61; 17.07; 17.71; 19.10; 20.60; 20.80; 21.69; 22.14; 23.63; 27.36.

E32. Crystalline Form A of Compound A according to E31 is characterized in that it has the following X-ray powder diffraction pattern measured in spinner transmission mode using a PANalytical Empyrean diffractometer with a PIXCel 1D detector and expressed in terms of line positions (Bragg angle 2 theta, expressed in degrees ± 0.2°) and interplanar distance d (expressed in A):

Line no. Angle 2-theta (degrees) Interplanar distance (A) 1 7.52 11.76 2 8.89 9.95 3 9.58 9.23 4 10.35 8.55 5 11.25 7.87 6 13.08 6.77 7 14.44 6.13 8 16.61 5.34 9 17.07 5.19 10 17.71 5.01 eleven 19.10 4.64 12 20.60 4.31 13 20.80 4.27 14 21.69 4.10 15 22.14 4.02 16 23.63 3.77 17 27.36 3.25

E33. A pharmaceutical composition containing as an active ingredient crystalline form M of compound A according to any of E26 to E32 in combination with one or more pharmaceutically acceptable carriers, glidants, diluents, excipients or stabilizers.

E34. Pharmaceutical composition in accordance with E33 for use in the treatment of cancer, autoimmune diseases and diseases of the immune system.

E35. Pharmaceutical composition for use in accordance with E34, where the cancer is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphoid leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphomas (eg , non-Hodgkin B-cell lymphoma or diffuse large B-cell lymphoma), melanomas, blood malignancies (eg, myelodysplastic syndrome), myelomas (eg, multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, and small cell cancer lungs.

E36. A method for preparing crystalline form A of compound A according to any one of E26E32, compound A is crystallized in a solvent selected from dimethoxy-1,2-ethane (DME) or a mixture of dimethoxy-1,2-ethane and di-isopropyl ether (DIPE).

E37. A method for producing crystalline form M of compound A according to E18, wherein compound A is crystalline form A of compound A.

E38. Crystal form MH 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3- d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid (compound A).

E39. The crystalline form _MH of compound A according to E38 is in essentially pure form.

E40. The _MH crystalline form of compound A according to E38 or E39 is characterized in that it has a powder x-ray diffraction pattern showing at least the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 11.05 and 20.04.

E41. The _MH crystal form of compound A according to E38 or E39 is characterized in that it has a powder x-ray diffraction pattern showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14. 15, 16, 17 or all of the following diffraction lines (Bragg angle 2 theta expressed in degrees ± 0.2°): 6.29, 7.26, 7.92, 8.35, 10.11, 11.05 , 11.49, 12.74, 16.72, 17.36, 18.47, 20.04, 20.53, 21.07, 21.58, 22.22, 23.15, 24.41.

E42. The crystalline form M _H of compound A according to E41 is characterized in that it has a powder x-ray diffraction pattern having the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 7.26, 7.92, 11 .05, 12.74, 20.04, 20.53, 24.41.

E43. The crystalline form M _H of compound A according to E41 is characterized in that it has a powder x-ray diffraction pattern having the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 6.29, 7.26, 7 ,92, 8.35, 10.11, 11.05, 11.49, 12.74,

- 5 044230

16.72, 17.36, 18.47, 20.04, 20.53, 21.07, 21.58, 22.22, 23.15, 24.41.

E44. The MH crystal form of Compound A according to E43 is characterized in that it has the following powder X-ray diffraction pattern measured in spinner transmission mode using a PANalytical Empyrean diffractometer with a PIXCel 1D detector and expressed in terms of line positions (Bragg angle 2 theta, expressed in degrees ± 0.2°) and interplanar distance d (expressed in A):

Line no. Angle 2-theta (degrees) Interplanar distance (A) 1 6.29 14,056 2 7.26 12,181 3 7.92 11,170 4 8.35 10,594 5 10.11 8,751 6 11.05 8,008 7 11.49 7,699 8 12.74 6,949 9 16.72 5,304 10 17.36 5.109 eleven 18.47 4.805 12 20.04 4.431 13 20.53 4.326 14 21.07 4.216 15 21.58 4.118 16 22.22 4,001 17 23.15 3.841 18 24.41 3.647

E45. A pharmaceutical composition containing as an active ingredient the crystalline form MH of Compound A according to any of E38 to E44 in combination with one or more pharmaceutically acceptable carriers, glidants, diluents, excipients or stabilizers.

E46. Pharmaceutical composition in accordance with E45 for use in the treatment of cancer, autoimmune diseases and diseases of the immune system.

E47. Pharmaceutical composition for use in accordance with E46, where the cancer is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphoid leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphomas (eg , non-Hodgkin B-cell lymphoma or diffuse large B-cell lymphoma), melanomas, blood malignancies (eg, myelodysplastic syndrome), myelomas (eg, multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, and small cell cancer lungs.

E48. Crystal form of MHD 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3- d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid (compound A).

E49. The MHD crystalline form of Compound A according to E48 is in essentially pure form.

E50. The MHD crystalline form of compound A according to E48 or E49 is characterized in that it has a powder x-ray diffraction pattern showing at least the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 13.30 and 21 .00.

E51. The MHD crystalline form of compound A according to E48 or E49 is characterized in that it has a powder x-ray diffraction pattern showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or all of the following diffraction lines (Bragg angle 2 theta expressed in degrees ± 0.2°): 6.03, 8.45, 10.14, 10.42, 11.29, 11.82, 13 ,30, 15.85, 17.07, 17.77, 18.05, 18.84, 19.14, 20.05, 21.00, 21.92, 22.99, 27.27.

E52. The MHD crystal form of compound A according to E51 is characterized in that it has a powder X-ray diffraction pattern having the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 10.14, 13.30, 15, 85, 18.05, 18.84, 19.14, 21.00.

E53. The MHD crystalline form of compound A according to E51 is characterized in that it has a powder x-ray diffraction pattern having the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 6.03, 8.45, 10, 14, 10.42, 11.29, 11.82, 13.30, 15.85, 17.07, 17.77, 18.05, 18.84, 19.14, 20.05, 21.00, 21.92, 22.99, 27.27.

E54. The MHD crystalline form of Compound A according to E53 is characterized in that it has the following powder X-ray diffraction pattern measured in spinner transmission mode using a PANalytical Empyrean diffractometer with a PIXCel 1D detector and expressed in terms of line positions (Bragg angle 2 theta, expressed in degrees ± 0.2°) and

- 6 044230 interplanar distance d (expressed in A):

Line no. Angle 2-theta (degrees) Interplanar distance (A) 1 6.03 14,647 2 8.45 10,459 3 10.14 8,720 4 10.42 8,491 5 11.29 7.835 6 11.82 7,484 7 13.30 6,656 8 15.85 5,591 9 17.07 5,194 10 17.77 4,990 eleven 18.05 4.915 12 18.84 4,710 13 19.14 4.636 14 20.05 4,429 15 21.00 4.231 16 21.92 4,056 17 22.99 3,868 18 27.27 3,270

E55. A pharmaceutical composition containing as an active ingredient a crystalline form of MHD compound A according to any of E48 to E54 in combination with one or more pharmaceutically acceptable carriers, glidants, diluents, excipients or stabilizers.

E56. Pharmaceutical composition in accordance with E55 for use in the treatment of cancer, autoimmune diseases and diseases of the immune system.

E57. Pharmaceutical composition for use in accordance with E56, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphoid leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphomas (eg , non-Hodgkin B-cell lymphoma or diffuse large B-cell lymphoma), melanomas, blood malignancies (eg, myelodysplastic syndrome), myelomas (eg, multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, and small cell cancer lungs.

The preparation of crystalline forms of compound A, in particular crystalline form M or crystalline form A of compound A, has the advantage that it allows the preparation of pharmaceutical compositions having a constant and reproducible composition and having good stability characteristics. The preparation of crystalline forms of compound A, in particular crystalline form _MH or crystalline form _MHD of compound A, has the advantage that it allows the preparation of pharmaceutical compositions having a constant and reproducible composition and having good stability characteristics.

Another aspect of the present invention is a pharmaceutical composition containing novel crystalline forms of Compound A, in particular crystalline Form M or crystalline Form A of Compound A, which can be formulated in accordance with standard pharmaceutical practice for use in the therapeutic treatment (including prophylactic treatment) of cancer, autoimmune diseases and diseases of the immune system in mammals, including humans. Another aspect of the present invention is a pharmaceutical composition containing novel crystalline forms of Compound A, in particular the _MH crystalline form or the _MHD crystalline form of Compound A, which can be formulated in accordance with standard pharmaceutical practice for use in therapeutic treatment (including prophylactic treatment) cancer, autoimmune diseases and diseases of the immune system in mammals, including humans.

Another aspect of the present invention is a pharmaceutical composition containing novel crystalline forms of compound A, in particular crystalline form M or crystalline form A of compound A, which can be formulated in accordance with standard pharmaceutical practice for use in a therapeutic combination for therapeutic treatment (including prophylactic treatment ) cancer, autoimmune diseases and diseases of the immune system in mammals, including humans. Another aspect of the present invention is a pharmaceutical composition containing novel crystalline forms of Compound A, in particular the _MH crystalline form or the _MHD crystalline form of Compound A, which can be formulated in accordance with standard pharmaceutical practice for use in a therapeutic combination for therapeutic treatment (including preventive treatment) of cancer, autoimmune diseases and diseases of the immune system in mammals, including humans.

Another aspect of the present invention is a pharmaceutical composition containing

- 7 044230 presenting crystalline forms of compound A, in particular crystalline form M or crystalline form A of compound A, in combination with one or more pharmaceutically acceptable carriers, glidants, diluents, excipients or stabilizers. Suitable carriers, diluents, glidants, excipients or stabilizers are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like (Remington's Pharmaceutical Sciences (1995), 18th edition, Mack Publ. Co., Easton, PA). Another aspect of the present invention is a pharmaceutical composition containing crystalline forms of Compound A, in particular crystalline form MH or crystalline form M _HD of compound A, in combination with one or more pharmaceutically acceptable carriers, glidants, diluents, excipients or stabilizers. Suitable carriers, diluents, glidants, excipients or stabilizers are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like (Remington's Pharmaceutical Sciences (1995), 18th edition, Mack Publ. Co., Easton, PA).

Pharmaceutical compositions in accordance with the present invention will be dosed and administered in a manner, that is, in amounts, concentrations, modes, courses, vehicles and routes of administration that are consistent with good medical practice. Factors that should be considered in this context include the specific disease being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the route of administration, the schedule of administration and other factors known to medical practitioners.

In addition, the crystalline forms of compound A thus obtained, in particular crystalline form M or crystalline form A of compound A, are stable enough to allow storage for a long period without special conditions for levels of temperature, light, humidity or oxygen. In particular, the crystalline form M of compound A was found to be very stable with respect to temperature and humidity after a 6-month storage period under various conditions. More specifically, the crystalline form M of compound A remains stable after a 12-month storage period at 25°C/60% RH or 30°C/65% RH.

The following examples illustrate the invention but do not limit it in any way. In the crystallization method according to the invention, compound A (free base) as a starting material can be obtained by any method. For example, compound A can be synthesized according to WO 2015/097123.

Example 1. Method for obtaining crystalline form M of compound A

At room temperature, Compound A was added to toluene to achieve 7% w/w. (mass ratio) concentration. This mixture was stirred at room temperature for approximately 8 hours. The resulting slurry was then filtered and dried at 20 to 70° C. in vacuo to obtain crystalline Form M of Compound A. The solid was characterized by X-ray powder diffraction diffraction, as shown in example 7.

Melting point: 148.7°C (determined by DSC at 10°C/minute under nitrogen using TA Instruments Q1000 DSC)

Alternatively, the resulting slurry before filtration can be directly used as a seed in the crystallization process, as shown in Examples 2-5 herein below.

Example 2. Method for obtaining crystalline form M of compound A (with seed).

Compound A (9 g; free base) was added to toluene at room temperature at a concentration of 6.5 ml/g or 15% w/w. This mixture was then heated to 70°C to dissolve Compound A. This mixture was cooled and, when the temperature reached approximately 30°C, the solution was seeded - the undried slurry of Compound A obtained in Example 1 (4.4% by weight of starting material) . This mixture was further stirred for 25 hours at 5°C. This suspension was then filtered, washed with water and dried at 70°C in vacuum. After drying, crystalline form M of compound A was obtained in approximately 87% yield and 99.37% purity. The solid was characterized using a powder X-ray diffraction pattern as shown in Example 7.

Example 3. Alternative method for obtaining crystalline form M of compound A.

Compound A (10 g; free base) was taken up in toluene at room temperature at a concentration of 10.4 ml/g or 10% w/w. This mixture was then heated at 70°C and concentrated in vacuo at 60°C to achieve a concentration of 6.5 ml/g or 15% w/w. This mixture was cooled to 43°C and a seed was introduced into it - an undried suspension of compound A obtained in example 1 (4% by weight of the starting material). MTBE was added to obtain 75/25 w/w. toluene/MTBE solution. The final concentration of Compound A was 12% w/w. This mixture was cooled and stirred for 15 hours at 20°C. This suspension was then filtered, washed with MTBE and dried at 70°C in vacuum. After drying, crystalline form M of compound A was obtained in approximately 89% yield and 99.6% purity. The solid was characterized using dia.

- 8,044,230 grams of powder X-ray diffraction as shown in example 7.

Example 4. Alternative method for obtaining crystalline form M of compound A.

Compound A (275 g; free base) was placed in a toluene/acetone binary mixture with a mass ratio of 75/25 toluene/acetone at room temperature at a concentration of 16.5% w/w. Acetone was removed from toluene by distillation in vacuo at approximately 50°C. After adding toluene to achieve a concentration of 16.5% w/w, the mixture was heated to 40°C and then seeded with the undried slurry of Compound A obtained in Example 1 (1-2% by weight of starting material). After stirring at 40°C, MTBE was slowly added to obtain 75/25 w/w. toluene/MTBE solution. The final concentration of Compound A was 12% w/w. The said mixture was stirred for 30 minutes at 40°C and cooled at 20°C for 2 hours. Then the said suspension was filtered, washed with 75/25 wt./wt. toluene/MTBE solution and dried first at 20°C in vacuum until the ICH residual solvent limit for MTBE was reached, then dried a second time at 70°C in vacuum until the ICH residual solvent limit for toluene was reached. After drying, crystalline form M of compound A was obtained in approximately 93% yield and with a purity greater than 99%. The solid was characterized using a powder X-ray diffraction pattern as shown in Example 7.

Example 5. Alternative method for obtaining crystalline Form M.

Connections A.

Compound A (free base) was placed at room temperature in a 2-methyltetrahydrofuran (Me-THF)/water binary mixture with a ratio of approximately 10% water w/w. with a concentration of approximately 12% w/w. This mixture was heated at 40°C under vacuum to replace water (solvent exchange) with Me-THF. Me-THF was added until there was less than 1% water in the condensate and until the final volume of the mixture was reached at a ratio of 12% w/w. At 40°C, this mixture was seeded (1% by weight of the starting material) with a suspension of compound A (obtained in Example 1) in Me-THF at a concentration of approximately 7% w/w. After stirring for 1 hour, this suspension was cooled to 10°C and stirred for a further 2 hours. This suspension was then filtered, washed with Me-THF and dried at 40°C in vacuo. After drying, crystalline form M of compound A was obtained in approximately 62% yield and 99.6% purity. The solid was characterized using a powder X-ray diffraction pattern as shown in Example 7.

Example 6: Alternative method for preparing crystalline form M of compound A.

Compound A (1 kg), toluene (4.2 kg) and acetone (1.4 kg) were introduced into the reactor at 20°C for dissolution. Acetone was replaced by toluene by distillation in vacuum (temperature approximately 50°C) at constant volume until the density of toluene in the condensate trap was reached. When the density of the toluene was reached, the volume was adjusted to 16.5% by weight of the product with toluene and the temperature was maintained at 50°C. After cooling to 40° C., crystallization was induced by seeding a suspension of compound A in toluene (a slurry with a concentration of 7% by weight of the product obtained in accordance with the method of Example 1). After 2 hours at 40°C, MTBE (1.8 kg) was added at 40°C for at least one hour and then the reaction mixture was cooled until it reached 20°C. After completion of the reaction, this suspension was then filtered, washed with MTBE (3.8 kg), purged with nitrogen to achieve 10% residual solvent and dried first at 20°C in vacuum until the ICH limit of residual solvent for MTBE was reached, then dried a second time at 70°C in vacuum until the ICH residual solvent limit for toluene is reached. After drying, crystalline form M of compound A was obtained in approximately 93% yield and approximately 99.8% purity. The solid was characterized using a powder X-ray diffraction pattern as shown in Example 7.

Example 7: XRPD diagram of crystal form M of compound A

Data recording in the spinner transmission mode was carried out on an Empyrean diffractometer from PANalytical with a PIXCel 1D detector under the following conditions:

voltage: 45 kV;

current: 40 mA;

setting: theta/theta;

anode: copper;

K alpha-1 wavelength: 1.54060 A;

K alpha 2 wavelength: 1.54443 A;

K alpha-2/K alpha-1 ratio: 0.5;

measurement mode: continuous from 3.5° to 55° (Bragg angle 2 theta) in steps of 0.017°;

measurement time per stage: 34.9250 s.

The X-ray powder diffraction pattern of Form M of compound A obtained in accordance with any of the methods of Examples 1-6 is expressed in terms of line positions (Bragg angle 2 theta, expressed in degrees ± 0.2°) and interplanar spacing (expressed in A) (Fig. 1 and 2). Representative lines are collected in the following table:

- 9 044230

Line no. Angle 2-theta (degrees) Interplanar distance (A) 1 6.27 14.10 2 8.94 9.89 3 9.09 9.73 4 12.16 7.28 5 13.67 6.48 6 14.75 6.00 7 15.06 5.88 8 16.97 5.22 9 17.22 5.15 10 17.44 5.08 eleven 18.24 4.86 12 19.16 4.63 13 19.93 4.45 14 20.91 4.25 15 25.88 3.44

Example 8. Hygroscopicity.

The hygroscopicity of crystalline form M of compound A, obtained in accordance with any of the methods of examples 1-6, was assessed using the method of dynamic vapor sorption (DSP). 5 to 10 mg of the test drug sample was accurately weighed into a chipboard sample cuvette operated at 25°C under controlled humidity. The sample weight was recorded at 50% relative humidity until a stable value was reached. Thereafter, the change in mass was recorded between 50% RH and 90% RH at a rate of 10% per hour. Changes in mass between 90% RH and 0% RH and back from 0% to 50% RH were also recorded. The relative humidity was kept constant at 0 or 90% relative humidity until the mass change was less than 0.002% per minute over a period of 15 h.

An increase in sample mass of approximately 0.4% was recorded using DSP analysis when the sample was exposed to 50 to 90% relative humidity at 25°C.

A decrease in sample weight of approximately 0.5% was recorded between 90 and 0% RH, while an increase in sample weight of approximately 0.1% was recorded between 0% and 50% RH.

The DSP profile (Fig. 3) shows that the sorption and desorption of water are practically reversible without changing the crystalline form M observed in the powder X-ray diffraction pattern after the sorption/desorption/sorption cycle of water.

The crystalline form M of compound A can be considered slightly hygroscopic according to the European Pharmacopoeia (Ph. Eur.).

Example 9: Coulometric Titration

The water content of the crystalline form M of compound A, obtained in accordance with any of the methods of examples 1-6, was determined by coulometric titration using a Metrohm coulometer consisting of a 774 sample processor with furnace, a 774 SC controller, an 831 KF coulometer and an 846 dosing interface with software providing Tiamo 1.2. About 10 mg of precisely weighed micronized drug was added to vials heated for 10 min at 140°C.

The water content in the studied samples reached 0.1% by weight.

Example 10 Stability studies of crystalline form M of compound A.

For all storage conditions and storage periods, 20 mg of crystalline form M of compound A, obtained according to any of the processes of examples 1-6, was placed in a 30 ml vial for analysis by HPLC after storage (packaging: PVO = open glass container; VRAC PA = Double plastic bag). We got the following results:

^''-storage conditions Periods ⁴ ^^ storage 25 °C 60% RH VRAC RA 25 °C 90% OM OBM 30°C 65% RH VRAC RA 40°C 75% RH VRAC RA 50°C 75% RH PVO (i) Polymorphic form and (th) chemical stability (% w/w)* 6 weeks (i) Form M (th) 100.0% (i) Form M (th) 100.2% 3 months (i) not studied 100.0% (i) Form M (th) 99.7% (i) not researched (th) 99.6% (i) Form M (th) 99.9% (i) Form M (th) 100.1% 6 months (i) not studied 99.7% (i) not researched (th) 100.0% (i) Form M (th) 100.0% 12 months (i) Form M (th) 98.9% (i) Form M (th) 98.8%

*drug content determined by LC (% w/w) The crystalline form M of compound A remains stable with respect to temperature and humidity after 6 months

- 10044230 storage period under various conditions. More specifically, the crystalline form M of compound A remains stable after a 12-month storage period at 25°C/60% RH or 30°C/65% RH.

Example 11. Solid-state ¹³ C NMR spectroscopy spectrum of crystalline form M of compound A.

Crystalline Form M of Compound A prepared according to any of the methods of Examples 1-6 was also characterized by solid-state ¹³ C nuclear magnetic resonance spectroscopy (FIG. 4). Solid-state ¹³ C NMR spectrum Compounds of crystalline form M were recorded at room temperature using a Bruker SB Avance III 500 spectrometer with a 4 mm CP/MAS SB VTN probe under the following conditions:

frequency: 125.7 MHz;

spectral width: 37.5 kHz;

magic angle rotation speed: 13 kHz;

pulse program: cross-polarization with SPINAL64 decoupling;

recovery timeout: 10 s;

exposure time: 46 ms;

contact time: 4 ms;

number of scans: 2048.

Line broadening of 5 Hz was applied before the Fourier transform. The spectrum thus obtained was compared with a sample of adamantane (the high-frequency peak of adamantane was set at 38.5 ppm). Compound A, crystalline form M can be identified by the presence of the following peaks in the NMR spectrum (expressed in ppm ± 0.2 ppm):

Peak no. Chemical shift (ppm) Δδ ppm (-18.2 ppm) Peak no. Chemical shift (ppm) Δδ ppm (- 18.2 ppm) 1 175.1 156.9 15 120.9 102.7 2 168.5 150.3 16 119.9 101.7 3 167.4 149.2 17 118.5 100.3 4 164.6 146.4 18 116.9 98.7 5 162.6 144.4 19 112.5 94.3 6 157.5 139.3 20 111.1 92.9 7 156.3 138.1 21 108.9 90.7 8 153.7 135.5 22 78.7 60.5 9 135.5 117.3 23 71.4 53.2 10 134.8 116.6 24 54.9 36.7 eleven 130.4 112.2 25 42.1 23.9 12 129.9 111.7 26 35.1 16.9 13 128.4 110.2 27 18.2 0 14 126.8 108.6

The column labeled Δδ ppm indicates the relative chemical shifts in ppm of all peaks relative to the lowest ppm peak identified in the ¹³ C spectrum of Form M.

More specifically, the characteristic peaks (expressed in ppm ± 0.2 ppm) are found at: 175.1, 153.7, 134.8, 108.9, 71.4 and 35.1.

Example 12 MIR spectrum of crystalline form M of compound A.

Crystalline Form M of Compound A prepared according to any of the methods of Examples 1-6 was also characterized by mid-infrared spectroscopy, which was recorded in ATR mode using a Bruker Vertex MIR spectrometer under the following conditions:

number of scans: 32;

„ „ -, -1 resolution: 2 cm.

The MIR spectrum of crystalline form M of compound A is shown in FIG. 5 and 6.

Characteristic peaks (expressed in cm ^-1 ) are found at: 1603.7, 1569.0, 1556.5, 1544.9 1517.9, 1498.6, 1475.5, 1457.1, 1434.0, 1401.2 , 1374.2, 1364.6, 1278.7, 1239.2, 1226.7, 1187.1, 1163.0, 1118.7, 1072.4, 1031.9, 995.2, 884.3, 848 ,6, 811.0, 795.6, 770.5, 745.5, 690.5, 670.2.

More preferably, the characteristic peaks (expressed in cm ^-1 ) are at: 1475.5, 1457.1, 1434.0, 1278.7, 1226.7, 848.6, 770.5, 745.5.

Example 13: Raman spectrum of crystalline Form M of Compound A.

Crystalline Form M of Compound A prepared according to any of the methods of Examples 1-6 was also characterized by Raman spectroscopy, which was recorded using a Perkin-Elmer RS400 Raman spectrometer under the following conditions:

number of scans: 10;

exposure time: 0.5 s;

laser power: 100%.

The Raman spectrum of crystal form M of compound A is shown in FIG. 7 and 8.

- 11 044230

Characteristic peaks (expressed in ^cm'1 ) are found at: 1602.0, 1544.0, 1518.0, 1478.0, 1376.0,

1286.0, 1220.0, 1164.0, 1130.0, 1048.0, 1034.0, 988.0, 812.0, 770.0, 752.0, 634.0, 566.0, 508, 0, 414.0, 380.0,

254.0.

More preferably, the characteristic peaks (expressed in ^cm'1 ) are at: 1516.0, 1220.0, 770.0, 752.0, 380.0.

Example 14 Purity of crystalline form M of compound A determined by synchronous radiation (Soleil Synchrotron, Saclay, France).

A suitable crystal of crystal form M of compound A was selected and installed on a PROXIMA II diffractometer with a synchrotron radiation channel (SOLEIL, Saclay, France). During data collection, the crystal was kept at 100 K. Using O1ex2 (Dolomanov et al., J. Appl. Cryst. 2009, 42, 339-3411), the structure was solved using the ShelXT structure solver using internal phasing (Sheldrick, Acta Cryst. 2015, A71, 3-8) and modified by the ShelXL structure refinement package using the least squares method by minimization (Sheldrick, Acta Cryst. 2015, C71, 3-8). The positions and parameters of atomic substitution were refined by the least squares method in the full matrix approximation using F2. The placement of hydrogen atoms is done using the rider model. The absolute structure has been determined and corresponds to the pure enantiomeric phase of compound A.

1. Synchrotron data recorded at 100 K, along with an image of the thermal ellipsoid of an asymmetric element (1 molecule of compound A):

space group Ρ2ι2ι2ι (No. 19) a= 10.610 A

b = 17.400 A c = 23.720 A

V = 4379.0 A ³

Z=4

T= 100K

In fig. Figure 9 shows a thermal ellipsoid image (obtained using the ORTEP program) of compound A, crystal form M.

2. Crystal lattice parameters obtained from the powder X-ray diffraction pattern of compound A (form M) at room temperature:

Space group Ρ2ι2ι2ι (No. 19) a = 10.6401 A

b = 17.3643 A c = 24.0494 A

V = 4443.3 A ³

Z=4

T = 293 K

3. Peak positions and interplanar distances (ISD), calculated from data obtained for a single crystal (at 100 K).

List of selected peaks with peak intensity 25 times the noise intensity level (Ι/σΙ > 25)

100 k 2 theta (°) Interplanar distance (A) 6.29 14.03 9.02 9.80 9.12 9.68 12.29 7.20 13.67 6.47 14.86 5.96 15.13 5.85 17.12 5.18 17.29 5.12 18.30 4.84 19.38 4.58 19.94 4.45 21.12 4.20 22.47 3.95 24.71 3.60 26.12 3.41

The set of peaks obtained from the single crystal data closely matches those measured experimentally (see Example 7 for comparison). Therefore, these results confirm the high purity of compound A, crystal form M.

- 12044230

Example 15: Method for preparing crystalline Form A of Compound A and its X-ray powder diffraction pattern.

Compound A was dissolved in 2-methyltetrahydrofuran at room temperature at a concentration of 8 ml/g and dimethoxy-1,2-ethane (DME) was added to achieve a concentration of 11 ml/g. The mixture was then stirred at 35°C for 2 hours and 3 hours at 20°C. After crystallization, the solid was filtered, washed with acetone and dried in vacuum at 50°C, then at 70°C. After drying, crystalline Form A of Compound A was obtained in approximately 81% yield and 99.5% purity. The solid was characterized using a powder X-ray diffraction pattern as described below.

Melting point: 125.4°C (determined by DSC at 10°C/minute under nitrogen using a TA Instruments Q1000 DSC).

A variant of the method for obtaining Form A of Compound A (seed) is as follows:

compound A was dissolved in 2-methyltetrahydrofuran at room temperature at a concentration of approximately 11 ml/g and DME was added to achieve a concentration of 11 ml/g. A quarter of the solvent was removed by distillation and DME was added again to achieve a concentration of 11 ml/g. This mixture was then heated at 35°C and seeded with Form A of Compound A (2% by weight of starting material). This mixture was stirred at 35°C for 2 hours and 19 hours at 20°C. After crystallization, the solid was filtered, washed with acetone and dried in vacuum at 50°C, then at 70°C. After drying, crystalline form A of compound A was obtained in approximately 93% yield and with a purity greater than 99.0%. The solid was characterized using a powder X-ray diffraction pattern as described below.

Data recording in the spinner transmission mode was carried out on an Empyrean diffractometer from PANalytical with a PIXCel 1D detector under the following conditions:

voltage: 45 kV;

current: 40 mA;

setting: theta/theta;

anode: copper;

K alpha-1 wavelength: 1.54060 A;

K alpha 2 wavelength: 1.54443 A;

K alpha-2/K alpha-1 ratio: 0.5;

measurement mode: continuous from 3.5° to 55° (Bragg angle 2 theta) in steps of 0.017°;

measurement time per stage: 34.9250 s.

The X-ray powder diffraction pattern of Form A of Compound A is expressed in terms of line positions (Bragg angle 2 theta, expressed in degrees ± 0.2°) and interplanar spacing (expressed in A) (FIG. 10). Representative lines are collected in the following table:

Line no. Angle 2-theta Interplanar (degrees) distance (A) 1 7.52 11.76 2 8.89 9.95 3 9.58 9.23 4 10.35 8.55 5 11.25 7.87 6 13.08 6.77 7 14.44 6.13 8 16.61 5.34 9 17.07 5.19 10 17.71 5.01 eleven 19.10 4.64 12 20.60 4.31 13 20.80 4.27 14 21.69 4.10 15 22.14 4.02 16 23.63 3.77 17 27.36 3.25

Example 16: Method for preparing crystalline form M of compound A from crystalline form A of compound A.

At room temperature, crystalline Form A of Compound A prepared in Example 14 was added to toluene to achieve a concentration of 7% w/w. This mixture was stirred at room temperature for 8 hours to complete the polymorphic transformation. The resulting suspension (slurry) was then filtered and dried at 20 to 70° C. in vacuo to obtain crystalline Form M of Compound A. The solid was characterized using an X-ray powder diffraction pattern as shown in Example 7.

Example 17 Stability studies of crystal form A of compound A.

For all storage conditions and storage periods, 1.2 mg of crystalline form A of compound A,

- 13 044230 obtained in accordance with the method of example 15, was placed in a special package for analysis by HPLC after storage. We got the following results:

Storage conditions Package (i) Polymorphic form (ii) Chemical stability (% w/w)* 25 °C/ 60% RH Plastic bag filled with sealed four-layer laminated foil pouch (i) Form A (th) 98.8% after 24 months of storage 30 °C/ 75% RH Plastic bag filled with sealed four-layer (i) Form A (th) 99.3% after 1 month laminated foil pouch storage 40°C / 75% RH Plastic bag filled with sealed four-layer laminated foil pouch (i) Form A (th) 99.5% after 6 months of storage 50 °C/ 75% RH Plastic bag filled with sealed four-layer laminated foil pouch (i) Form A (th) 99.3% after 1 month of storage

* drug substance content determined by LC (% w/w)

Crystalline Form A of Compound A remains stable after a 24-month storage period at 25°C/60% RH. The crystalline form A of compound A is still stable with respect to temperature and humidity after several months of storage under more severe conditions.

Example 18 DSC and TGA profiles of compound A, crystal form M.

The DSC profile of a sample of compound A, crystal form M (prepared according to any of the methods of Examples 1-6), weighing approximately 3 mg, was recorded at 10°C/minute from 25 to 220°C in aluminum crucibles with needle holes with forced flow nitrogen in a differential scanning calorimeter TA Instruments Q2000.

The TGA profile of a sample of compound A, crystalline form M (prepared according to any of the methods of Examples 1-6), weighing approximately 7.5 mg, was recorded at 10°C/minute from 25 to 220°C in an open aluminum crucible with forced flow nitrogen in a thermogravimetric analyzer TA Instruments Q5000.

The DSC and TGA profiles (FIG. 11) show that the crystalline form M of compound A is anhydrous and melts at approximately 148°C.

Example 19. Method for preparing the crystalline form _MH of compound A and its X-ray powder diffraction pattern

A hydrated form of compound A (referred to as _MH form) was prepared by keeping Form M in water at 25°C. Approximately 100 ml of purified water is added to 1 g of compound A placed in a 100 ml glass vessel. The suspension is kept for 4 days at 30°C and stirring at a speed of 500 rpm. After 4 days, the suspension is filtered under low vacuum and the filtrate is dried under vacuum for another 30 minutes. A white paste is obtained, which, when ground, slowly turns into a white powder. The resulting powder was analyzed by XRPD. Subsequent X-ray powder analysis combined with water content analysis showed that the white powder was a hydrated form of MH.

Data recording was carried out in transmission mode using a PANalytical Empyrean diffractometer with a PIXCel ID detector under the following conditions:

voltage: 45 kV;

current: 40 mA;

setting: theta/theta;

anode: copper;

K alpha-1 wavelength: 1.54060 A;

K alpha 2 wavelength: 1.54443 A;

K alpha-2/K alpha-1 ratio: 0.5;

measurement mode: continuous from 3.5° to 55° (Bragg angle 2 theta) in steps of 0.017°;

measurement time per stage: 35.5301 s.

The X-ray powder diffraction pattern of the M _H form of compound A is expressed in terms of line positions (Bragg angle 2 theta, expressed in degrees ± 0.2°) and relative intensity (expressed as a percentage relative to the most intense line) (Fig. 12). Representative lines are collected in the following table:

- 14 044230

Line no. Angle 2-theta (degrees) Interplanar distance (A) 1 6.29 14,056 2 7.26 12,181 3 7.92 11,170 4 8.35 10,594 5 10.11 8,751 6 11.05 8,008 7 11.49 7,699 8 12.74 6,949 9 16.72 5,304 10 17.36 5.109 eleven 18.47 4.805 12 20.04 4.431 13 20.53 4.326 14 21.07 4.216 15 21.58 4.118 16 22.22 4,001 17 23.15 3.841 18 24.41 3.647

The water content of the powder was also determined by coulometric method. The result showed that the new crystalline solid form of MH contains a significant amount of water (29.3%).

Example 20: Method for preparing the MHD crystalline form of Compound A and its X-ray powder diffraction pattern.

A new diffraction profile was recorded when the hydrated form of MH was heated at 1°C/min from 25 to 100°C. The powder obtained from the heat treatment was analyzed using XRPD. This new diffraction profile was assigned to the MHD form (i.e., the dehydrated form of the hydrated M form).

Data recording was carried out in transmission mode using a PANalytical Empyrean diffractometer with a PIXCel 1D detector under the following conditions:

voltage: 45 kV;

current: 40 mA;

setting: theta/theta;

anode: copper;

K alpha-1 wavelength: 1.54060 A;

K alpha 2 wavelength: 1.54443 A;

K alpha-2/K alpha-1 ratio: 0.5;

measurement mode: continuous from 3.5° to 55° (Bragg angle 2 theta) in steps of 0.017°;

measurement time per stage: 35.5301 s.

The powder X-ray diffraction pattern of the MHD form of compound A is expressed in terms of line positions (Bragg angle 2 theta, expressed in degrees ± 0.2°) and relative intensity (expressed as a percentage of the most intense line) (Fig. 13). Representative lines are collected in the following table:

Line no. Angle 2-theta pos. [°2Θ] Interplanar distance (A) 1 6.03 14,647 2 8.45 10,459 3 10.14 8.72 4 10.42 8,491 5 11.29 7.835 6 11.82 7,484 7 13.30 6,656 8 15.85 5,591 9 17.07 5,194 10 17.77 4,990 eleven 18.05 4.915 12 18.84 4,710 13 19.14 4.636 14 20.05 4,429 15 21.00 4.231 16 21.92 4,056 17 22.99 3,868 18 27.27 3,270

-

Claims (27)

CLAIM 1. Crystalline form M 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6(4-fluorophenyl)thieno[2,3 -d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)propanoic acid (compound A), characterized in that it has a powder X-ray diagram diffraction showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction lines (2 theta Bragg angle expressed in degrees ± 0.2°): 6 ,27; 8.94; 9.09; 12.16; 13.67; 14.75; 15.06; 16.97; 17.22; 17.44; 18.24; 19.16; 19.93; 20.91; 25.88. 2. Crystalline form M of compound A according to claim 1, having a purity of more than 90 wt.%. 3. Crystalline form M of compound A according to claim 1 or claim 2, characterized in that it has a powder x-ray diffraction pattern having the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 8.94 ; 13.67; 14.75; 17.22; 18.24. 4. Crystalline form M of compound A according to claim 1 or claim 2, characterized in that it has a powder x-ray diffraction pattern having the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 6, 27; 8.94; 9.09; 12.16; 13.67; 14.75; 15.06; 16.97; 17.22; 17.44; 18.24; 19.16; 19.93; 20.91; 25.88. 5. Crystalline form M of compound A according to claim 4, characterized in that it has the following powder X-ray diffraction pattern, measured in spinner transmission mode using a PANalytical Empyrean diffractometer with a PIXCel 1D detector and expressed using line positions (Bragg angle 2 theta, expressed in degrees ± 0.2°) and interplanar distance d (expressed in A): Line no. Angle 2-theta (degrees) Interplanar distance (A) 1 6.27 14.10 2 8.94 9.89 3 9.09 9.73 4 12.16 7.28 5 13.67 6.48 6 14.75 6.00 7 15.06 5.88 8 16.97 5.22 9 17.22 5.15 10 17.44 5.08 eleven 18.24 4.86 12 19.16 4.63 13 19.93 4.45 14 20.91 4.25 15 25.88 3.44 6. Crystalline form M of compound A according to any one of claims 1 to 5, characterized in that it has a solid-state ¹³ C CP/MAS NMR spectroscopy spectrum containing the following peaks (expressed in ppm ± 0.2 ppm): 175.1, 153.7, 134.8, 108.9, 71.4 and 35.1. 7. Crystalline form M of compound A according to any one of claims 1 to 5, characterized in that it has a solid-state ¹³ C CP/MAS NMR spectroscopy spectrum containing the following peaks (expressed in ppm ± 0.2 ppm): 175.1, 168.5, 167.4, 164.6, 162.6, 157.5, 156.3, 153.7, 135.5, 134.8, 130.4, 129.9, 128.4, 126, 8, 120.9, 119.9, 118.5, 116.9, 112.5, 111.1, 108.9, 78.7, 71.4, 54.9, 42.1, 35.1 and 18.2. 8. A pharmaceutical composition containing as an active ingredient crystalline form M of compound A according to any one of claims 1 to 7 in combination with one or more pharmaceutically acceptable carriers, glidants, diluents, fillers or stabilizers. 9. Use of the pharmaceutical composition according to claim 8 for the treatment of cancer, autoimmune diseases and diseases of the immune system. 10. Use of a pharmaceutical composition according to claim 9, where the cancer is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphoid leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphomas, melanomas, malignant blood diseases, myelomas, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer. 11. Use of crystalline form M of compound A according to any one of paragraphs. 1-7 as a medicine. 12. Use of crystalline form M of compound A according to any one of claims 1 to 7 for the treatment of cancer, diseases of the immune system and autoimmune diseases. 13. Use of crystalline form M of compound A according to claim 12, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphoid leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia , lymphomas, melanomas, malignant blood diseases, myelomas, ovarian cancer, non-small cell cancer - 16 044230 lung, prostate and small cell lung cancer. 14. A method for obtaining crystalline form M of compound A according to any one of claims 1 to 7, in which compound A is crystallized in a solvent selected from toluene, 2-methyltetrahydrofuran or a mixture of toluene and methyl tert-butyl ether. 15. A method for producing crystalline form M of compound A according to claim 14, wherein compound A is crystalline form A of compound A. 16. A method for obtaining crystalline form M of compound A according to claim 14 or claim 15, in which the concentration of compound A in the solvent is from 5 to 15% w/w. 17. A method for obtaining crystalline form M of compound A according to any one of claims 14 to 16, in which the suspension obtained in the process is dried at a temperature of from 20 to 80°C. 18. A method for preparing crystalline form M of compound A according to any one of claims 14 to 16, wherein crystallization is induced by seeding using a very small amount of crystalline form M of compound A. 19. A method for obtaining crystalline form M of compound A according to claim 18, wherein crystallization is induced by introducing a seed at a temperature of from 20 to 60°C. 20. Crystal form A 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6(4-fluorophenyl)thieno[2,3 -d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)propanoic acid (compound A), characterized in that it has a powder X-ray diagram diffraction showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all of the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2 °): 7.52; 8.89; 9.58; 10.35; 11.25; 13.08; 14.44; 16.61; 17.07; 17.71; 19.10; 20.60; 20.80; 21.69; 22.14; 23.63; 27.36. 21. Crystalline Form A of compound A according to claim 20, characterized in that it has a powder x-ray diffraction pattern having the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 7.52; 8.89; 10.35; 16.61; 19.10. 22. Crystalline Form A of compound A according to claim 20, characterized in that it has a powder x-ray diffraction pattern having the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 7.52; 8.89; 9.58; 10.35; 11.25; 13.08; 14.44; 16.61; 17.07; 17.71; 19.10; 20.60; 20.80; 21.69; 22.14; 23.63; 27.36. 23. Crystal form A of compound A according to claim 22, characterized in that it has the following X-ray powder diffraction pattern measured in spinner transmission mode using a PANalytical Empyrean diffractometer with a PIXCel 1D detector and expressed in terms of line positions (Bragg angle 2 theta , expressed in degrees ± 0.2°) and interplanar distance d (expressed in A): Line no. Angle 2-theta (degrees) Interplanar distance (A) 1 7.52 11.76 2 8.89 9.95 3 9.58 9.23 4 10.35 8.55 5 11.25 7.87 6 13.08 6.77 7 14.44 6.13 8 16.61 5.34 9 17.07 5.19 10 17.71 5.01 eleven 19.10 4.64 12 20.60 4.31 13 20.80 4.27 14 21.69 4.10 15 22.14 4.02 16 23.63 3.77 17 27.36 3.25 24. A pharmaceutical composition containing as an active ingredient crystalline form A of compound A according to any one of claims 20 to 23 in combination with one or more pharmaceutically acceptable carriers, glidants, diluents, fillers or stabilizers. 25. Use of the pharmaceutical composition according to claim 24 for the treatment of cancer, autoimmune diseases and diseases of the immune system. 26. Use of a pharmaceutical composition according to claim 25, where the cancer is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphoid leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphomas, melanomas, malignant blood diseases, myelomas, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer. 27. A method for obtaining crystalline form A of compound A according to any one of claims 20 to 23, in which compound A is crystallized in a solvent selected from dimethoxy-1,2-ethane or a mixture of dimethoxy-1,2-ethane -