RU2847971C2 - New crystalline forms of the mcl-1 inhibitor, method for obtaining them, and pharmaceutical compositions containing them - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to the crystalline form M of 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-4-yl]methoxy}phenyl)propanoic acid (Compound A), characterised 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 2θ 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. The invention relates to a pharmaceutical composition that inhibits Mcl-1, containing as an active ingredient the crystalline form M of Compound A of the invention in combination with one or more pharmaceutically acceptable carriers, glidants, diluents, fillers or stabilisers. The invention also relates to a method for obtaining the crystalline form M of Compound A according to the invention, in which Compound A is crystallised in a solvent selected from toluene, 2-methyltetrahydrofuran or a mixture of toluene and methyl tert-butyl ether.

EFFECT: stable 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-4-yl]methoxy}phenyl)propanoic acid.

19 cl, 13 dwg, 20 ex

Description

AREA OF TECHNOLOGY

The present invention relates to novel crystalline forms of 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-4-yl]methoxy}phenyl)propanoic acid, which is referred to herein as Compound A. Disclosed herein are crystalline forms of 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-4-yl]methoxy}phenyl)propanoic acid, which are also referred to as Crystal Forms A and M. Furthermore, two other crystalline forms of 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-4-yl]methoxy}phenyl)propanoic acid are disclosed herein, which are referred to as crystalline forms M _h and M _hd .

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[2,3-d]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-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]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 THE CREATION OF THE INVENTION

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-4-yl]methoxy}phenyl)propanoic acid,

is an Mcl-1 inhibitor useful for the treatment of cancer, immune system diseases and autoimmune diseases, the preparation, use and pharmaceutical compositions of which were 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

(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-(2-methoxyphenyl)-pyrimidin-4-yl]methoxy}phenyl)propanoic acid. In a further embodiment, Compound A used in the composition described herein is a free molecule (not a salt thereof).

Although Compound A is a very promising drug, it is difficult to prepare. Its solubility in water is less than 0.001 mg/mL (at pH 7.5). Because a chemical can exhibit different physical properties in one crystalline form or another, this polymorphism of the drug molecule can affect shelf life, solubility, formulation properties, processing properties, and drug performance. Furthermore, different polymorphs can have different absorption rates in the body, resulting in lower or higher biological activity than desired. In extreme cases, an undesirable polymorph can even exhibit toxicity. Therefore, understanding and controlling polymorphism offers a clear advantage in bringing new drugs to market, which may be more active, more stable, or less expensive to produce. However, despite the fact that polymorphism has been the subject of intensive research, understanding and controlling this phenomenon presents a significant scientific challenge. It is difficult to predict whether a given molecule will crystallize in one or more crystalline forms and to find the conditions that lead to such crystallization.

From an industrial perspective, it is of critical importance to be able to synthesize a compound with excellent purity, especially in a perfectly reproducible form, with valuable dissolution, filtration, drying properties, ease of preparation, and stability that allows 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 preparing Compound A in a well-defined, perfectly reproducible crystalline form (in particular, in Form A or Form M), having very good stability, which is compatible with industrial limitations of preparation, especially filtration and storage of pharmaceutical compositions.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the X-ray powder diffraction (XRPD) pattern of Compound A, crystalline Form M.

Figure 2 shows an enlarged image of the XRPD diffraction pattern of Compound A, crystalline Form M.

Figure 3 shows the water sorption profile (WSP) of Compound A, crystalline Form M.

Figure 4 shows the solid-state ^13C NMR spectrum of Compound A, crystalline Form M.

Figure 5 shows the mid-infrared (MIR) spectrum of Compound A, crystalline Form M.

Figure 6 shows an enlarged image of the MIR spectrum of Compound A, crystalline Form M.

Figure 7 shows the Raman spectrum of Compound A, crystalline Form M.

Figure 8 shows an enlarged image of the Raman spectrum of Compound A, crystalline Form M.

Figure 9 shows an ORTEP drawing of Compound A, crystal Form M.

Figure 10 shows the XRPD pattern of Compound A, crystalline Form A.

Figure 11 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of Compound A, crystalline Form M.

Figure 12 shows the XRPD pattern of Compound A, crystalline Form M _n .

Figure 13 shows the XRPD pattern of Compound A, crystalline 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-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]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-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid.

As used herein, the term "comprising" means "including" and does not imply the exclusion of the presence of any additional component unless the context otherwise requires, such as when the sum of the components together equals 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. "Cancer" includes bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphomas (eg, non-Hodgkin's B-cell lymphoma or diffuse large B-cell lymphoma), melanoma, malignant blood diseases (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 the form of a salt.

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

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

Embodiments of the invention

A number of embodiments of the invention are described below.

E1. Crystalline Form M of 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-4-yl]methoxy}phenyl)propanoic acid (Compound A).

E2. Crystalline Form M of Compound A according to E1 is essentially in pure form.

E3. Crystalline Form M of Compound A according to E1 or E2 is characterized in that it has an X-ray powder diffraction pattern showing at least the following diffraction lines (Bragg angle 2 theta, expressed in degrees ±0.2°): 8.94 and 18.24.

E4. Crystalline Form M of Compound A according to E1 or E2 is characterized in that it has an X-ray powder 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. Crystalline Form M of Compound A according to E4 is characterized in that it has an X-ray powder 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. Crystalline Form M of Compound A according to E4 is characterized in that it has an X-ray powder 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. 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 position (Bragg angle 2 theta, expressed in degrees ±0.2°) and interplanar spacing d (expressed in ):

E8. Crystalline Form M of Compound A, according to any one of E1 to E7, is characterized in that it has a solid-state ^13C CP/MAS NMR 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 solid-state ^13C CP/MAS NMR 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 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 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 comprising, as an active ingredient, crystalline Form M of Compound A according to any of E1 to E11 in combination with one or more pharmaceutically acceptable carriers, glidants, diluents, fillers or stabilizers.

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

E14. A pharmaceutical composition for use according to E13, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphomas (e.g. non-Hodgkin's B-cell lymphoma or diffuse large B-cell lymphoma), melanomas, malignant blood diseases (e.g. myelodysplastic syndrome), myelomas (e.g. 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 of E1 to E11 for use as a medicinal product.

E16. Crystalline Form M of Compound A according to any 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 according to 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 (e.g. non-Hodgkin's B-cell lymphoma or diffuse large B-cell lymphoma), melanomas, malignant blood diseases (e.g. myelodysplastic syndrome), myelomas (e.g. multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.

E18. A process for preparing crystalline Form M of Compound A according to any one of E1 to E11, 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 a mixture of toluene and MTBE.

E19. A process for preparing crystalline Form M of Compound A according to E18, wherein the solvent is a mixture of toluene and MTBE, preferably a 75/25 w/w toluene/MTBE mixture.

E20. The process for preparing crystalline Form M of Compound A according to E18, wherein the concentration of Compound A in the solvent is from 5 to 15% w/w, preferably from 7 to 13% w/w, more preferably from 10 to 12.5% w/w.

E21. The method for preparing crystalline Form M of Compound A according to any of E18 to E20, wherein the suspension of Compound A in a solvent obtained in the process is filtered and dried under vacuum at a temperature of from 20°C to 80°C, preferably from 20°C to 75°C, more preferably from 35°C to 75°C.

E22. A process for preparing crystalline Form M of Compound A according to 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 under vacuum at 20°C until the ICH limit of residual solvent for MTBE is reached, and

- the second stage, in which the solid obtained in the first stage is dried in vacuum at 70°C until the ICH limit of residual solvent for toluene is reached.

E23. A process for preparing crystalline Form M of Compound A according to any one of E18 to E22, wherein the crystallization is caused by seeding using a very small amount of crystalline Form M of Compound A, in particular the crystallization is caused by seeding using 0.5% to 5% w/w of crystalline Form M of Compound A, preferably 0.5% to 3%.

E24. A process for preparing crystalline Form M of Compound A according to E23, wherein crystallization is induced by introducing a seed at a temperature of from 20°C to 60°C.

E25. A process for preparing crystalline Form M of Compound A according to E24, wherein crystallization is induced by introducing a seed at a temperature of from 30°C to 45°C.

E26. Crystalline Form A of 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-4-yl]methoxy}phenyl)propanoic acid (Compound A).

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

E28. Crystalline Form A of Compound A according to E26 or E27 is characterized in that it has an X-ray powder 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 an X-ray powder 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 characterised in that it has an X-ray powder 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 an X-ray powder diffraction pattern showing 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.

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 the transmission spinner 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 spacing d (expressed in ):

E33. A pharmaceutical composition comprising, 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, fillers or stabilizers.

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

E35. A pharmaceutical composition for use according to E34, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphomas (e.g. non-Hodgkin's B-cell lymphoma or diffuse large B-cell lymphoma), melanomas, malignant blood diseases (e.g. myelodysplastic syndrome), myelomas (e.g. multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.

E36. A method for preparing crystalline Form A of Compound A according to any of E26 to E32, 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 process for preparing crystalline Form M of Compound A according to E18, wherein Compound A is crystalline Form A of Compound A.

E38. Crystalline Form M _n 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-4-yl]methoxy}phenyl)propanoic acid (Compound A).

E39. Crystalline Form M _of Compound A according to E38 is essentially in pure form.

E40. Crystalline Form M _n of Compound A according to E38 or E39, is characterised in that it has an X-ray powder diffraction pattern showing at least the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 11.05 and 20.04.

E41. Crystalline Form M _n of Compound A according to E38 or E39, is characterized in that it has an X-ray powder 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. Crystalline Form M _n of Compound A according to E41 is characterized in that it has an X-ray powder 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. Crystalline Form M _n of Compound A according to E41 is characterized in that it has an X-ray powder 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, 16.72, 17.36, 18.47, 20.04, 20.53, 21.07, 21.58, 22.22, 23.15, 24.41.

E44. Crystalline Form M _n of Compound A according to E43 is characterized in that it has the following X-ray powder diffraction pattern measured in the transmission spinner 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 spacing d (expressed in ):

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

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

E47. A pharmaceutical composition for use according to E46, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphomas (e.g. non-Hodgkin's B-cell lymphoma or diffuse large B-cell lymphoma), melanomas, malignant blood diseases (e.g. myelodysplastic syndrome), myelomas (e.g. multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.

E48. Crystalline Form M _hd 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-4-yl]methoxy}phenyl)propanoic acid (Compound A).

E49. Crystalline Form M _hd of Compound A according to E48 is essentially in pure form.

E50. Crystalline Form M _Hd of Compound A according to E48 or E49 is characterised in that it has an X-ray powder diffraction pattern showing at least the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 13.30 and 21.00.

E51. Crystalline Form M _hd of Compound A according to E48 or E49 is characterized in that it has an X-ray powder 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. Crystalline Form M _hd of Compound A according to E51 is characterised in that it has an X-ray powder 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. Crystalline Form M _hd of Compound A according to E51 is characterized in that it has an X-ray powder 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. Crystalline Form M _hd of Compound A according to E53 is characterized in that it has the following X-ray powder diffraction pattern measured in the transmission spinner 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 spacing d (expressed in ):

E55. A pharmaceutical composition containing, as an active ingredient, crystalline Form M _hd of Compound A according to any of E48 to E54 in combination with one or more pharmaceutically acceptable carriers, glidants, diluents, fillers or stabilizers.

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

E57. A pharmaceutical composition for use according to E56, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, acute myeloid leukemia, lymphomas (e.g. non-Hodgkin's B-cell lymphoma or diffuse large B-cell lymphoma), melanomas, malignant blood diseases (e.g. myelodysplastic syndrome), myelomas (e.g. multiple myeloma), ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and small cell lung cancer.

The production of crystalline forms of Compound A, in particular crystalline Form M or crystalline Form A of Compound A, has the advantage of enabling the production of pharmaceutical compositions having a constant and reproducible composition and exhibiting good stability characteristics. The production of crystalline forms of Compound A, in particular crystalline Form M _n or crystalline Form M _hd of Compound A, has the advantage of enabling the production of pharmaceutical compositions having a constant and reproducible composition and exhibiting good stability characteristics.

Another aspect of the present invention is a pharmaceutical composition comprising 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 comprising novel crystalline forms of Compound A, in particular crystalline Form M _h or crystalline Form M _hd 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 comprising 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 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 comprising novel crystalline forms of Compound A, in particular crystalline Form M _h or crystalline Form M _hd of Compound A, which can be formulated in accordance with standard pharmaceutical practice for use in a therapeutic combination for 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 comprising 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, fillers, or stabilizers. Suitable carriers, diluents, glidants, fillers, 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 comprising crystalline forms of Compound A, in particular crystalline Form M _n or crystalline Form M _hd of Compound A, in combination with one or more pharmaceutically acceptable carriers, glidants, diluents, fillers, or stabilizers. Suitable carriers, diluents, glidants, fillers, 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).

The pharmaceutical compositions according to the present invention will be dosed and administered in a manner—that is, in amounts, concentrations, regimens, courses, carriers, and routes of administration—that are consistent with good medical practice. Factors to 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 practicing physicians.

Furthermore, 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 their storage for an extended period without special conditions for temperature, light, humidity, or oxygen levels. In particular, 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, crystalline Form M of Compound A remains stable after a 12-month storage period under conditions of 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 process according to the invention, Compound A (free base) as the starting material can be obtained by any method. For example, Compound A can be synthesized according to WO 2015/097123.

EXAMPLE 1: Method for preparing crystalline Form M of Compound A At room temperature, Compound A was added to toluene to achieve a 7% w/w (weight ratio) concentration. The mixture was stirred at room temperature for approximately 8 hours. The resulting suspension was then filtered and dried at a temperature of 20°C to 70°C under vacuum to obtain crystalline Form M of Compound A. The solid was characterized using an X-ray powder diffraction pattern as shown in Example 7.

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

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

EXAMPLE 2: Method for preparing 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. The mixture was cooled, and when the temperature reached approximately 30°C, the solution was seeded with the undried slurry of Compound A obtained in Example 1 (4.4% by weight of the starting material). The mixture was further stirred for 25 h at 5°C. The slurry was then filtered, washed with water, and dried at 70°C under vacuum. After drying, crystalline Form M of Compound A was obtained in approximately 87% yield and 99.37% purity. The solid was characterized by an X-ray powder diffraction pattern as shown in Example 7.

EXAMPLE 3: Alternative method for preparing crystalline Form M of Compound A

Compound A (10 g; free base) was taken up in toluene at room temperature to a concentration of 10.4 mL/g or 10% w/w. The 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. The mixture was cooled to 43 °C and seeded with the undried slurry of Compound A obtained in Example 1 (4% by weight of starting material). MTBE was added to give a 75/25 w/w toluene/MTBE solution. The final concentration of Compound A was 12% w/w. The mixture was cooled and stirred for 15 h at 20 °C. The suspension was then filtered, washed with MTBE and dried at 70 °C under vacuum. After drying, crystalline Form M of Compound A was obtained in approximately 89% yield and 99.6% purity. The solid was characterized by powder X-ray diffraction pattern as shown in Example 7.

EXAMPLE 4: Alternative method for preparing crystalline Form M of Compound A

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

EXAMPLE 5: Alternative method for preparing crystalline Form M of Compound A

Compound A (free base) was placed at room temperature in a binary mixture of 2-methyltetrahydrofuran (Me-THF)/water at 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 exchange water (solvent exchange) with Me-THF. Me-THF was added until less than 1% water was in the condensate and until the final volume of the mixture was 12% w/w. At 40°C, this mixture was seeded (1% by weight of the starting material) with a slurry of Compound A (prepared 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 an additional 2 hours. This suspension was then filtered, washed with Me-THF, and dried at 40°C under vacuum. After drying, crystalline Form M of Compound A was obtained in approximately 62% yield and 99.6% purity. The solid was characterized by powder X-ray diffraction 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 under vacuum (temperature approximately 50°C) at constant volume until the density of toluene was reached in the condensate trap. When the density of toluene was reached, the volume was adjusted with toluene to a concentration of 16.5% of the product weight and the temperature was maintained at 50°C. After cooling to 40°C, crystallization was induced by seeding with a suspension of Compound A in toluene (a slurry with a concentration of 7% of the product weight, prepared according to 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 to reach 20°C. After completion of the reaction, this suspension was then filtered, washed with MTBE (3.8 kg), purged with nitrogen to reach 10% residual solvent, and dried first at 20°C under vacuum to reach the ICH limit of residual solvent for MTBE, then dried a second time at 70°C under vacuum to reach the ICH limit of residual solvent for toluene. After drying, crystalline Form M of Compound A was obtained in approximately 93% yield and approximately 99.8% purity. The solid was characterized by X-ray powder diffraction pattern as shown in Example 7. EXAMPLE 7: XRPD Pattern of Crystalline Form M of Compound A Data were recorded in spinner transmission mode on 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

K alpha-2 wavelength: 1.54443

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

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

Measurement time per stage: 34.9250 s.

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

EXAMPLE 8: Hygroscopicity

The hygroscopicity of crystalline Form M of Compound A, prepared according to any of the methods of Examples 1-6, was assessed using the dynamic vapor sorption (DVS) method. From 5 to 10 mg of the drug sample to be tested were accurately weighed into a DVS sample pan operated at 25°C under controlled humidity. The mass of the sample was recorded at a relative humidity of 50% until a stable value was reached. Thereafter, the mass change was recorded between 50% RH and 90% RH at a rate of 10% per hour. Mass changes were also recorded between 90% RH and 0% RH and back from 0% to 50% RH. The relative humidity was maintained constant upon reaching 0 or 90% RH until the mass change was less than 0.002% per minute over a period of 15 hours.

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

The sample mass decrease was approximately 0.5% and was recorded from 90% to 0% relative humidity, while the sample mass increase of approximately 0.1% was recorded between 0% and 50% relative humidity.

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

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 crystalline Form M of Compound A, prepared according to any of the methods of Examples 1-6, was determined by coulometric titration using a Metrohm coulometer consisting of a 774 sample processor with oven, a 774 SC controller, an 831 KF coulometer, and an 846 dosing interface with Tiamo 1.2 software. About 10 mg of accurately weighed micronized drug substance was introduced into vials heated for 10 minutes 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 periods, 20 mg of crystalline Form M of Compound A, prepared according to any of the processes of Examples 1-6, was placed in a 30 ml vial for HPLC analysis after storage (packaging: PVO = open glass container; VRAC PA = double polyethylene bag). The following results were obtained:

Crystalline Form M of Compound A remains stable with respect to temperature and humidity after a 6-month storage period under various conditions. More specifically, crystalline Form M of Compound A remains stable after a 12-month storage period under conditions of 25°C/60% RH or 30°C/65% RH.

EXAMPLE 11: Solid-state ^13C NMR 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 ^13C nuclear magnetic resonance spectroscopy (Figure 4). The solid-state ^13C NMR spectrum of crystalline Form M of Compound A was 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 seconds

Exposure time: 46 milliseconds

Contact time: 4 milliseconds

Number of scans: 2048

Before Fourier transformation, a 5 Hz line broadening was applied. The resulting spectrum was compared with an adamantane sample (the high-frequency peak of adamantane was found 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):

The column labeled "A5 ppm" indicates the relative chemical shifts in ppm of all peaks relative to the lowest peak in ppm identified in the ^13C Form M spectrum.

More specifically, the characteristic peaks (expressed in ppm ± 0.2 ppm) are 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 16, was also characterized using a mid-infrared spectroscopy method, the data of which were recorded in ATR mode using a Bruker Vertex MIR spectrometer under the following conditions:

Number of scans: 32

Resolution: 2 cm ^-1

The MIR spectrum of crystalline Form M of Compound A is shown in Figures 5 and 6.

The characteristic peaks (expressed in cm ^-1 ) are 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 16, was also characterized using Raman spectroscopy, the data of which were recorded using a Perkin-Elmer RS400 Raman spectrometer under the following conditions:

Number of scans: 10

Exposure time: 0.5 seconds.

Laser power: 100%

The Raman spectrum of crystalline Form M of Compound A is shown in Figures 7 and 8.

The characteristic peaks (expressed in cm ^-1 ) are 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 Form M of Compound A was selected and mounted on a PROXIMA II diffractometer with a synchrotron radiation beamline (SOLEIL, Saclay, France). The crystal was maintained at 100 K during data collection. Using Olex2 (Dolomanov et al., J. Appl. Cryst. 2009, 42, 339–3411), the structure was solved with the ShelXT structure solver using internal phasing (Sheldrick, Acta Cryst. 2015, A71, 3–8) and refined with the ShelXL structure refinement package using least-squares minimization (Sheldrick, Acta Cryst. 2015, C71, 3–8). Positions and atomic substitution parameters were refined by least-squares fitting in the full-matrix F2 approximation. The hydrogen atoms were placed using the "rider" model. The absolute structure was determined and corresponds to the pure enantiomeric phase of Compound A.

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

Space group P212121 (No. 19)

a = 10.610

b = 17,400

c = 23,720

V = 4379.0 ³

Z = 4

T = 100 K

Figure 9 shows a thermal ellipsoid image (obtained using the ORTEP program) of compound A, crystalline Form M.

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

Space group P2 ₁ 2 ₁ 2 ₁ (No. 19)

a = 10.6401

b = 17.3643

c = 24.0494

V = 4443.3 ³

Z = 4

T = 293 K

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

List of selected peaks with peak intensity 25 times higher than the noise intensity level (I/σI≥25)

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, crystalline Form M.

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 vacuo at 50°C and 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 an X-ray powder diffraction pattern as described below.

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

A variant 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. One-quarter of the solvent was removed by distillation, and DME was added again to achieve a concentration of 11 ml/g. The mixture was then heated at 35°C and seeded with Form A of Compound A (2% by weight of starting material). The 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 vacuo 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 an X-ray powder 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

K alpha-2 wavelength: 1.54443

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

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

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 ) (Figure 10). Representative lines are collected in the following table:

EXAMPLE 16: Method of preparing crystalline Form M of Compound A from crystalline Form A of Compound A

At room temperature, crystalline Form A of Compound A, obtained in Example 14, was added to toluene to achieve a concentration of 7% w/w. The mixture was stirred at room temperature for 8 hours to complete the polymorphic transformation. The resulting suspension was then filtered and dried at a temperature of 20°C to 70°C under vacuum 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 crystalline Form A of Compound A

For all storage conditions and periods, 1.2 mg of crystalline Form A of Compound A, prepared according to the method of Example 15, was placed in a special container for HPLC analysis after storage. The following results were obtained:

Crystalline Form A of Compound A remains stable after 24 months of storage at 25°C/60% RH. Crystalline Form A of Compound A remains stable relative to temperature and humidity after several months of storage under more stringent conditions.

EXAMPLE 18: DSC and TGA profiles of Compound A, crystalline Form M

The DSC profile of a sample of Compound A, crystalline Form M (prepared according to any of the methods of Examples 1-6), weighing approximately 3 mg, was recorded at 10°C/min from 25°C to 220°C in aluminum pinhole crucibles with a nitrogen pressurized flow in a TA Instruments Q2000 differential scanning calorimeter.

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/min from 25°C to 220°C in an open aluminum crucible with a nitrogen flow in a TA Instruments Q5000 thermogravimetric analyzer.

The DSC and TGA profiles (Figure 11) show that crystalline Form M of Compound A is anhydrous and melts at approximately 148°C.

EXAMPLE 19: Method for preparing crystalline Form M _n of Compound A and its X-ray powder diffraction pattern

The hydrated form of Compound A (referred to as Form M _H ) was obtained by storing Form M in water at 25°C. Approximately 100 mL of purified water was added to 1 g of Compound A placed in a 100-mL glass vial. The suspension was maintained for 4 days at 30°C with stirring at 500 rpm. After 4 days, the suspension was filtered under low vacuum, and the filtrate was dried under vacuum for an additional 30 minutes. A white paste was obtained, which slowly converted to a white powder upon trituration. The resulting powder was analyzed by XRPD. Subsequent X-ray powder diffraction analysis, combined with water content analysis, revealed that the white powder was hydrated Form M _H .

Data were recorded 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

K alpha-2 wavelength: 1.54443

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

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

Measurement time per stage: 35.5301 s

The X-ray powder diffraction pattern of Form M _n 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) (Figure 12). Representative lines are collected in the following table:

The water content of the powder was also determined coulometrically. The results showed that the new crystalline solid Form M _n contains a significant amount of water (29.3%).

EXAMPLE 20: Method for preparing crystalline Form M _HD of Compound A and its X-ray powder diffraction pattern

A new diffraction profile was recorded when hydrated Form M _n was heated at 1°C/min from 25°C to 100°C. The resulting powder was analyzed by XRPD. This new diffraction profile was assigned to Form M _hd (i.e., the dehydrated form of hydrated Form M).

Data were recorded 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

K alpha-2 wavelength: 1.54443

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

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

Measurement time per stage: 35.5301 s

The X-ray powder diffraction pattern of Form M _hd 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) (Figure 13). Representative lines are collected in the following table:

Claims (20)

1. Crystalline Form M of 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-4-yl]methoxy}phenyl)propanoic acid (Compound A), characterized in that it has an X-ray powder 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. 2. Crystalline Form M of Compound A according to claim 1, characterized in that it has an X-ray powder diffraction pattern having the following diffraction lines (Bragg angle 2 theta, expressed in degrees ± 0.2°): 8.94 and 18.24. 3. Crystalline Form M of Compound A according to claim 1, characterized in that it has an X-ray powder 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, characterized in that it has an X-ray powder 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 X-ray powder diffraction pattern measured in the transmission spinner mode using a PANalytical Empyrean diffractometer with a PIXCel 1D detector and expressed using the line position (Bragg angle 2 theta, expressed in degrees ± 0.2°) and the interplanar distance d (expressed in ): 6. Crystalline Form M of Compound A according to any one of claims 1 to 5, characterized in that it has a solid-state ^13C 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 1-5, characterized in that it has a solid-state ^13C 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 that inhibits Mcl-1, comprising 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. The pharmaceutical composition according to claim 8 for use in the treatment of cancer, autoimmune diseases and diseases of the immune system. 10. A pharmaceutical composition for use according to claim 9, 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 lung cancer, prostate cancer and small cell lung cancer. 11. Crystalline Form M of Compound A according to any one of claims 1 to 7 for use as a medicinal product inhibiting Mcl-1. 12. Crystalline Form M of Compound A according to any one of claims 1 to 7 for use in the treatment of diseases treatable by inhibiting Mcl-1, selected from cancer, diseases of the immune system and autoimmune diseases. 13. Crystalline Form M of Compound A for use 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 lung cancer, prostate cancer and small cell lung cancer. 14. A method for preparing crystalline Form M of Compound A according to any one of claims 1 to 7, wherein Compound A is crystallized in a solvent selected from toluene, 2-methyltetrahydrofuran, or a mixture of toluene and methyl tert-butyl ether. 15. The method of preparing crystalline Form M of Compound A according to claim 14, wherein Compound A is crystalline Form A of Compound A characterized in that it has an X-ray powder 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. 16. A method for producing crystalline Form M of Compound A according to claim 14 or 15, wherein the concentration of Compound A in the solvent is from 5 to 15% w/w. 17. A method for producing crystalline Form M of Compound A according to any one of paragraphs 14-16, wherein the suspension obtained in the process is dried at a temperature from 20°C to 80°C. 18. A method for producing crystalline Form M of Compound A according to any one of claims 14-16, wherein crystallization is induced by introducing a seed using 1%, 2%, 4% or 7% by weight of the starting material of crystalline Form M of Compound A. 19. A method for producing crystalline Form M of Compound A according to claim 18, wherein crystallization is induced by introducing a seed at a temperature from 20°C to 60°C.