CZ201629A3 - Crystalline modifications of the (3R)-3-cyclopentyl-3- [4-(7H-pyrrolo [2,3-d] pyrimidin-4yl) pyrazol-1yl] propanenitrile salts and the method of their preparation - Google Patents

Abstract

The present invention relates to crystalline modifications of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -pyrazol-1-yl] -propanenitrile salts of Formula I wherein HX represents at least one acid component, preferably hydrochloric acid, phosphoric acid, fumaric acid and L-tartaric acid. The invention further relates to a process for preparing such modifications and to the use of such modifications in pharmaceutically acceptable compositions. Also included is the use of said crystalline modifications of ruxolitinib and the salts produced to prepare (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile in free form or any pharmaceutically acceptable salt thereof.

Description

(57) Annotation:

The present invention relates to crystalline modifications of the salts of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile of formula I, wherein IIX represents at least one an acid component, preferably hydrochloric, phosphoric, fumaric and L-tartaric acid. The invention further relates to a process for the preparation of these modifications and to the use of these modifications in pharmaceutically acceptable compositions. The solution also includes the use of said crystalline modifications of ruxolitinib and the prepared salts for the preparation of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile in free 1 or in the form of any pharmaceutically acceptable salt thereof.

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Crystalline modifications of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salts and methods for their preparation

Field of technology

The present invention relates to crystalline modifications of the salts of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile of formula I,

Η — X (I) wherein HX represents at least one acid component, preferably hydrochloric, phosphoric, film-forming and L-tartaric acid. The present invention also relates to methods of preparing these modifications as well as to said use in pharmaceutically acceptable compositions. The invention also relates to the use of said crystalline modifications of ruxolitinib and the salts produced for the preparation of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile in in free form or in the form of any pharmaceutically acceptable salt thereof.

Prior art

(3R) -3-Cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile, also known as ruxolitinib (CAS No: 941678- 49-5) acts as a selective inhibitor of Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2) enzymes. It is a medicine indicated for the treatment of moderate or high-risk myelofibrosis, a type of bone marrow cancer.

The enzymes Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2) are non-receptor tyrosine kinases that mediate signal transduction along the JAK-STAT pathway. Cytokines • · play an important role in controlling cell growth and the immune response. More specifically, Janus kinases by phosphorylation activate cytokine receptors, which in turn activate transcription factors called STATs, which modulate gene transcription.

WO2007070514 describes protein kinase inhibitors with valuable pharmacological activity in the treatment of related diseases. One example of the disclosed compounds is (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile. The preparation of the base is also described.

(3R) -3-Cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salts prepared with maleic acid, sulfuric acid and phosphoric acid are described in WO2008157208. WO2010083283 describes a process for the preparation of ruxolitinib phosphate with good yield and optical purity.

Many solid pharmaceuticals can occur in a variety of crystalline modifications referred to as polymorphs and hydrates / solvates having different crystal structures and thus physicochemical properties, including melting point, solubility, dissolution rate, and finally bioavailability. Several solid phase analytical methods can be used to distinguish individual solid modifications of a single substance, eg X-ray powder diffraction, solid phase NMR and Raman spectroscopy, thermoanalytical methods.

The discovery of new solid forms (polymorphs, solvates and hydrates) of an active pharmaceutical substance offers the opportunity to find a suitable modification which will have the desired physicochemical properties and processability and will improve the properties of the pharmaceutical product. For this reason, there is a significant need for new solid forms (polymorphs, solvates, hydrates) of ruxolitinib and its salts, especially in crystalline form.

The essence of the invention

The object of the present invention is to form new crystalline salts containing (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile of formula I and at least one acid an ingredient (HX) suitable for oral administration that will meet pharmaceutical requirements,

N — N

H H-X (I) wherein HX represents at least one acid component, preferably hydrochloric acid, phosphoric acid, film-forming acid, L-tartaric acid.

In some embodiments of the invention, the solid modifications are characterized by various solid phase analytical data, including, for example, X-ray powder diffraction (XRPD) recording and differential scanning calorimetry (DSC) curves.

The present is a crystalline modification of 5 salts of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and hydrochloric acid of formula I, wherein X represents Cl, exhibiting X-ray powder diffraction (XRPD) characteristic peaks at about 3.7; 8.4; 14.3; 20.9 and 25.2 ± 0.2 ° 2-theta measured by CuKα radiation. In some embodiments, crystalline modification 5 is characterized by a differential scanning calorimetry curve characterized by a melting process with a peak temperature T _pea k = 90.9 ° C. In some embodiments, crystalline modification 5 is characterized by a thermogravimetric curve exhibiting an 8.95% weight loss in the range of 25 ° C to 80 ° C.

It is to be understood that the relative intensity may vary depending on several factors, including the preparation and location of the sample, the instrument and analytical procedure, and the settings used to obtain the spectrum.

The invention also relates to a process for the preparation of crystalline modification 5, in which the salt of ruxolitinib and hydrochloric acid is suspended in a methanol-water mixture, suitably in the range from 0 to 40% v / v. methanol in water and the suspension was stirred for about 72 hours. In some embodiments, the method of preparing crystalline modification 2 further comprises the steps of: a) suspending the salt of ruxolitinib and hydrochloric acid in water or a mixture of methanol and water, preferably in the range of 0 to 40% v / v. methanol in water, preferably at room temperature; b) stirring the suspension from step a / at room temperature for about 72 hours; c / isolation

I • · • ·

crystalline modification 5 of the ruxolitinib hydrochloric acid salt and d) optionally drying the product from step c) under laboratory conditions until a constant weight of product is reached.

Presented is a crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and phosphoric acid of formula I, wherein X represents phosphate, exhibiting X-ray powder diffraction (XRPD) characteristic peaks at about 3.9; 14.5; 15.9; 20.2 and 24.9 ± 0.2 ° 2-theta measured with CuKcc radiation. In some embodiments, the crystalline modification 1 is characterized by a differential scanning calorimetry curve characterized by a melting process with an onset temperature T _onS et ⁼ 141.3 ° C and a peak temperature T _onak = 191.5 ° C. In some embodiments, crystalline modification 1 is characterized by a thermogravimetric curve exhibiting a 0.6% weight loss in the range of 25 ° C to 190 ° C.

It is to be understood that the relative intensity may vary depending on several factors, including the preparation and location of the sample, the instrument and analytical procedure, and the settings used to obtain the spectrum.

Another object of the present invention is a process for preparing crystalline modification 1, wherein ruxolitinib free base is dissolved in a polar aprotic solvent and then phosphoric acid is added, the polar aprotic solvent preferably having a temperature of 50 ° C, followed by heating the system to 50 ° C. C, followed by the addition of a counterion, the temperature is maintained at 50 ° C for a further 1 hour and the mixture is finally cooled to 0-5 ° C. The polar aprotic solvent is selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, acetonitrile, acetone, methyl ethyl ketone or a mixture thereof, preferably the polar aprotic solvent is ethyl acetate, more preferably ethyl acetate at 50 ° C.

In some embodiments, the method of preparing crystalline modification 1 further comprises the steps of: a) dissolving ruxolitinib free base in a polar aprotic solvent selected from the group consisting of: methyl acetate, ethyl acetate, butyl acetate, acetonitrile, acetone, methyl ethyl ketone or a mixture thereof, more preferably in ethyl acetate at 50 ° C. ; b) dropwise addition of 85% aqueous phosphoric acid solution; c) stirring the solution from step b) at 50 ° C for another 1 hour; d) cooling the solution from step c) to a temperature of 0 to 5 ° C, whereby precipitation occurs; e) maintaining the suspension from step d / 16 hours at 0 to 5 ° C; f) isolating the salt of ruxolitinib and phosphoric acid in crystalline modification 1 and g) optionally drying the product of step f) under laboratory conditions until a constant weight of product is reached.

• ·

AND

Presented is a crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and fumaric acid of formula I, wherein X represents fumarate exhibiting X-ray powder diffraction (XRPD) characteristic peaks at about 5.6;

13.1; 18.1; 22.6; 23.5 and 25.5 ± 0.2 ° 2-theta measured with CuKα radiation. In some embodiments, the crystalline modification 1 is characterized by a differential scanning calorimetry curve characterized by a melting process with a peak temperature T _pea k ⁼ 169.3 ° C. In some embodiments, crystalline modification 1 is characterized by a thermogravimetric curve exhibiting a 0.6% weight loss in the range of 25 ° C to 150 ° C.

It is to be understood that the relative intensity may vary depending on several factors, including the preparation and location of the sample, the instrument and analytical procedure, and the settings used to obtain the spectrum.

Another object of the present invention is a process for preparing crystalline modification 1, wherein ruxolitinib free base is dissolved in a polar protic solvent and then a solution of fumaric acid in a polar protic solvent is added, the polar protic solvent preferably having a temperature of 50 ° C, followed by heating. system to 50 ° C, followed by the addition of a counterion, maintaining the temperature at 50 ° C for an additional 1 hour, and finally cooling the mixture to 0-5 ° C. The polar protic solvent is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or a mixture thereof, preferably the polar protic solvent is ethanol, more preferably ethanol at 50 ° C.

In some embodiments, the method of preparing crystalline modification 1 further comprises the steps of: a / dissolving ruxolitinib free base in a polar protic solvent selected from the group consisting of: methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, or a mixture thereof; more preferably a suitable polar protic solvent is ethanol, more preferably ethanol at 50 ° C; b) dropwise addition of a fumaric acid solution; c) stirring the solution from step b) at 50 ° C for another 1 hour; d) cooling the solution from step c) to a temperature of 0 to 5 ° C, whereby precipitation occurs; e) maintaining the suspension from step d / 16 hours at 0 to 5 ° C; f) isolating the ruxolitinib salt and fumaric acid in crystalline modification 1 and g) optionally drying the product from step f) under laboratory conditions until a constant weight of product is reached.

A crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and L-tartaric acid of formula I is provided, wherein X represents L-tartrate, showing X-ray powder diffraction (XRPD) characteristic peaks at about

1 ..

4.1; 8.2; 16.2; 20.9 and 25.5 ± 0.2 ° 2-theta measured with CuKoc radiation. In some embodiments, the crystalline modification 1 is characterized by a differential scanning calorimetry curve characterized by a melting process with an onset temperature T _on set ⁼ 39.1 ° C and a peak temperature Tpeak® H6.4 ° C. In some embodiments, crystalline modification 1 is characterized by a thermogravimetric curve exhibiting a 1.64% weight loss in the range of 25 ° C to 110 ° C.

It is to be understood that the relative intensity may vary depending on several factors, including the preparation and location of the sample, the instrument and analytical procedure, and the settings used to obtain the spectrum.

Another object of the present invention is a process for preparing crystalline modification 1, wherein ruxolitinib free base is dissolved in a polar protic solvent and then a solution of L-tartaric acid in a polar protic solvent is added, the polar protic solvent preferably having a temperature of 50 ° C, and then preferably followed by heating the system to 50 ° C, followed by the addition of a counterion, maintaining the temperature at 50 ° C for an additional 1 hour, and finally cooling the mixture to 0-5 ° C. The polar protic solvent is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or a mixture thereof, preferably the polar protic solvent is ethanol, more preferably ethanol at 50 ° C.

In some embodiments, the method of preparing crystalline modification 1 further comprises the steps of: a / dissolving ruxolitinib free base in a polar protic solvent selected from the group consisting of: methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, or a mixture thereof; more preferably a suitable polar protic solvent is ethanol, more preferably ethanol at 50 ° C; b) dropwise addition of L-tartaric acid solution; c) stirring the solution from step b) at 50 ° C for another 1 hour; d) cooling the solution from step c) to a temperature of 0 to 5 ° C, whereby precipitation occurs; e) maintaining the suspension from step d / 16 hours at 0 to 5 ° C; f) isolating the salt of ruxolitinib and L-tartaric acid in crystalline modification 1 and g) optionally drying the product from step f) under laboratory conditions until a constant weight of product is reached.

Presented is a crystalline modification of 2 salts of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and L-tartaric acid of formula I, wherein X represents L-tartrate, exhibiting X-ray powder diffraction (XRPD) characteristic peaks at about 6.3; 9.1; 13.3; 16.3; 18.7; 19.4 and 22.8 ± 0.2 ° 2-theta measured with CuKα radiation. In some embodiments, the crystal modification 1 is characterized by a differential scanning curve i

··

t .. i:

Calorimetry characterized by a melting process with an onset temperature T _onse t = _53.1 ° C and a peak temperature T _P eak = 108.0 ° C. In some embodiments, crystalline modification 1 is characterized by a thermogravimetric curve exhibiting a 3.42% weight loss in the range of 25 ° C to 97 ° C.

It is to be understood that the relative intensity may vary depending on several factors, including the preparation and location of the sample, the instrument and analytical procedure, and the settings used to obtain the spectrum.

Another object of the present invention is a process for preparing crystalline modification 2, wherein ruxolitinib free base is dissolved in a polar aprotic solvent and then a L-tartaric acid solution is added, the polar aprotic solvent preferably having a temperature of 50 ° C, followed by heating the system to at 50 ° C, followed by the addition of a counterion, the temperature is maintained at 50 ° C for a further 1 hour and the mixture is finally cooled to 0-5 ° C. The polar aprotic solvent is selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, acetonitrile, acetone, methyl ethyl ketone or a mixture thereof, preferably the polar aprotic solvent is ethyl acetate, more preferably acetonitrile at 50 ° C.

In some embodiments, the method of preparing crystalline modification 2 further comprises the steps of: a) dissolving ruxolitinib free base in a polar aprotic solvent selected from the group consisting of: methyl acetate, ethyl acetate, butyl acetate, acetonitrile, acetone, methyl ethyl ketone or a mixture thereof, more preferably in acetonitrile and even more preferably in acetonitrile at 50 ° C; b) dropwise addition of L-tartaric acid solution; c) stirring the solution from step b) at 50 ° C for another 1 hour; d) cooling the solution from step c) to a temperature of 0 to 5 ° C, whereby precipitation occurs; e) maintaining the suspension from step d / 16 hours at 0 to 5 ° C; f) isolating the salt of ruxolitinib and tartaric acid in crystalline modification 1 and g) optionally drying the product from step f) under laboratory conditions until a constant weight of product is reached.

Brief description of the drawings

The figures in the drawings show the following spectra, records and curves of various solid forms prepared according to the invention

Figure 1 is an XRPD pattern of crystalline modification 5 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and hydrochloric acid salt;

Figure 2 is an FTIR spectrum of crystalline modification 5 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and hydrochloric acid salt;

i ·

Figure 3 is a Raman spectrum of crystalline modification 5 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and hydrochloric acid salt;

Figure 4 is a DSC curve of crystalline modification 5 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and hydrochloric acid salt;

Figure 5 is a TGA curve of crystalline modification 5 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and hydrochloric acid salt;

Figure 6 is an XRPD pattern of crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and phosphoric acid salt;

Figure 7 is an FTIR spectrum of crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and phosphoric acid salt;

Figure 8 is a Raman spectrum of crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and phosphoric acid salt;

Figure 9 is a DSC curve of crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and phosphoric acid salt;

Figure 10 is a TGA curve of crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and phosphoric acid salt;

Figure 11 is a 1 H-NMR spectrum of the salt of (3R) -1-cyclopentyl-3- [3- (7H-pyrrolo [4-d] pyrimidine-

2,3-yl) pyrazol-4-yl] propanenitrile and phosphoric acid prepared according to Example 2;

Figure 12 is an XRPD pattern of crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and cinnamic acid salt;

Figure 13 is an FTIR spectrum of crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and cinnamic acid salt;

Figure 14 is a Raman spectrum of crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and cinnamic acid salt;

Figure 15 is a DSC curve of crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and cinnamic acid salt;

Figure 16 is a TGA curve of crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and cinnamic acid salt;

Figure 17 is a ¹ H-NMR spectrum of the salt of (3R) -1-cyclopentyl-3- [3- (7H-pyrrolo [4-d] pyrimidine-

2,3-yl) pyrazol-4-yl] propanenitrile and fumaric acid prepared according to Example 4;

Figure 18 is an XRPD pattern of crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and L-tartaric acid;

Figure 19 is an FTIR spectrum of crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and L-tartaric acid salt;

Figure 20 is a Raman spectrum of crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and L-tartaric acid salt. ;

Figure 21 is a DSC curve of crystalline modification 2 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and L-tartaric acid salt;

Figure 22 is a TGA curve of crystalline modification 2 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and L-tartaric acid salt;

Figure 23 is a 1 H-NMR spectrum of the salt of (3R) -1-cyclopentyl-3- [3- (7H-pyrrolo [4-d] pyrimidine-

2,3-yl) pyrazol-4-yl] propanenitrile and L-tartaric acid prepared according to Example 5;

Figure 24 is an XRPD pattern of crystalline modification 2 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and L-tartaric acid salt;

Figure 25 is an FTIR spectrum of crystalline modification 2 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and L-tartaric acid salt;

Figure 26 is a Raman spectrum of crystalline modification 2 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and L-tartaric acid salt. ;

Figure 27 is a DSC curve of crystalline modification 2 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and L-tartaric acid salt;

Figure 28 is a TGA curve of crystalline modification 2 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and L-tartaric acid salt;

Figure 29 is the 1 H-NMR spectrum of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt of L-tartaric acid prepared according to Example 6

Detailed description of the invention

The purpose of the following description is to enable a person of ordinary skill in the art to develop and use various embodiments of the invention. The description of specific devices, methods and applications is given by way of example only. The various modifications of the examples described herein will be readily apparent to one of ordinary skill in the art, and the general principles used in this description may be applied to other examples and uses without departing from the spirit and scope of the various embodiments. That is, it is not intended to limit the individual embodiments to the examples described and presented in this specification, but these examples are intended to illustrate the essence of the invention set forth in the claims.

The aim of the present term is to present new crystalline modifications of the salts of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile of formula I,

(I) wherein HX represents at least one acid component, preferably hydrochloric acid, phosphoric acid, fumaric acid and L-tartaric acid, with advantageous physicochemical properties for pharmaceutical use, which can be produced in a reproducible manner on an industrial scale. The present invention also relates to methods of preparing these modifications as well as to said use in pharmaceutically acceptable compositions. The invention also relates to the use of said crystalline modifications of ruxolitinib and the salts produced for the preparation of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile in in free form or in the form of any pharmaceutically acceptable salt thereof.

Variations in the crystal structure of ruxolitinib may affect the solubility (which may affect bioavailability, etc.), processability (eg ease of handling, ability to consistently prepare doses of different strengths) and stability (eg thermal stability, storability, etc.) of the pharmaceutical drug. , especially when formed in a solid form for oral administration (e.g. in the form of a tablet). Therapeutic use and production of ruxolitinib involves the development of new salt forms of ruxolitinib that will have better bioavailability and stability.

The term "form" of ruxolitinib as used herein is synonymous with the terms "solid form", "solid variant" of ruxolitinib and includes crystalline modifications, hydrates and solvates of ruxolitinib.

The term "crystalline modification" of ruxolitinib as used herein is synonymous with the commonly used terms "polymorphic form" or "crystalline form" of ruxolitinib.

The use of the term "approximately" includes and describes the value of the parameter as such. E.g. "Approximately x" includes and describes "x" as such. In some embodiments, when the term "about" is used in conjunction with a numeric data or to modify a value, unit, constant, or range of values, it refers to deviations of +/- 20 percent, preferably +/- 10 percent, and more preferably +/- 5 percent.

The term "substantially" or "substantially pure" when used in conjunction with a particular solid form of a compound means that the polymorphic form contains about less than 30 percent, about less than 20 percent, about less than 15 percent, about less than 10 percent, about less than 5 percent or about less than 1 weight percent of impurities. In other embodiments, "substantially" or "substantially pure" refers to a substance that does not contain impurities. Impurities may include, for example, by-products or residual reagents from chemical reactions, contaminants, decomposition products, other polymorphic forms, water, and solvents.

It has now surprisingly been found that the above crystalline salts of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile with at least one acid component HX, where HX is preferably hydrochloric acid, phosphoric acid, fumaric acid and L-tartaric acid, can be prepared and have not yet been described in the literature and solid phase analytical data are not available for them (X-ray powder diffraction records, single crystal X-ray diffraction data, etc.). ), which would characterize the crystalline phases.

The crystalline modification 5 of the salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and hydrochloric acid according to the invention has the following characteristic XRPD pattern, shown in Fig. 1. XRPD record was taken on an X-ray powder diffractometer (X'PERT PRO MPD PANalytical). Crystalline modification of the salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and hydrochloric acid shows the following diffraction peaks in the XRPD record, see table 1 below:

Pos. [° 2Th.] d [A] Rel. int. [%] 3.68 23,979 th most common 100.0 7.50 11,782 th most common 26.2 8.38 10,543 th most common 82.0 8.93 9,894 th most common 23.1 9.81 9,005 th most common 35.0 10.21 8,659 th most common 12.3 14.33 6,178 th most common 42.5 14.68 6,029 th most common 18.7 15.15 5,843 th most common 32.0 16.65 5,321 th most common 20.3 16.95 5,226 th most common 22.9 17.33 5,113 th most common 10.4 17.77 4,988 th most common 17.6 18.77 4,723 th most common 30.8 19.48 4,554 th most common 19.0 20.93 4,242 th most common 53.8 21.80 4,078 th most common 6.5 22.22 3,998 th most common 8.1 22.81 3,896 th most common 22.2 23.38 3,802 th most common 23.4 23.71 3,749 th most common 31.5 24.04 3,700 th most common 16.7 24.47 3,635 th most common 12.1 25.19 3,533 th most common 59.8 25.63 3,472 th most common 24.4 26.10 3,412 th most common 40.2 26.80 3,324 th most common 25.7 28.12 3,171 th most common 16.3 29.04 3,072 th most common 18.9

Table 1

Crystalline modification of 5-salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and hydrochloric acid can be characterized by FTIR and Raman spectroscopy . Giant. 2 shows an FTIR spectrum (Nicolet Thermo 6700c) containing characteristic peaks at 3395, 3094, 2954, 2868, 2247, 1619, 1587, 1347, 816 and 742 cm ^-1 . Crystalline modification 5 of the salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and hydrochloric acid is characterized by a Raman spectrum (Bruker RFS 100 / S) comprising characteristic peaks at wave numbers 3115, 3068, 2964, 2951, 2872, 2247, 1624, 1549, 1315 and 593 cm ^-1, as shown in FIG. 3.

The crystalline modification of the salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and hydrochloric acid can be further described by thermoanalytical methods. Giant. 4 shows a DSC (Mettler-Toledo 822e DSC) and FIG. 5 shows a TGA (NETZSCH TG 209 thermographic analyzer) curve measured in the range of 25 ° C to 350 ° C and 25 ° C to 350 ° C, respectively. Crystalline modification 5 of the salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and hydrochloric acid shows an 8.95% weight loss in the range of 25 ° C to 80 ° C. DSC measurements show a melting process with a peak temperature T _pca k = 90.9 ° C.

One object of the present invention is a process for preparing crystalline modification 5. In this process, the salt of ruxolitinib and hydrochloric acid is dissolved in a suitable organic solvent at room temperature. A suitable organic solvent is preferably a polar protic solvent or a mixture of this organic solvent with water, more preferably the polar protic solvent is selected from the group consisting of: methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or a mixture of any of these organic solvents with water, more preferably a mixture of methanol with water, even more preferably mixtures of methanol and water in the range of 0 to 40% v / v. water in methanol at room temperature.

Crystalline modification of the salt of ruxolitinib and hydrochloric acid can be prepared by a process comprising the following steps:

and / suspending the salt of ruxolitinib and hydrochloric acid in water or a mixture of methanol and water, preferably in the range of 0 to 40% v / v. methanol in water at room temperature;

b) stirring the suspension from step a / at room temperature for 72 hours;

c) isolating crystalline modification 5 of ruxolitinib salt and hydrochloric acid;

d) optionally drying the product from step c) under laboratory conditions until a constant weight of product is reached.

• ·

A suitable organic solvent is preferably a polar protic solvent, more preferably the polar protic solvent or a mixture thereof with water is selected from the group consisting of: methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or a mixture thereof, more preferably a mixture of methanol with water, even more preferably mixtures of methanol and water in the range of 0 to 40% v / v. water in methanol at room temperature.

The crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and phosphoric acid according to the invention has the following characteristic XRPD pattern, shown in Fig. 6. The XRPD record was taken on a retngen powder diffractometer (X'PERT PRO MPD PANalytical). Crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and phosphoric acid shows the following diffraction peaks in the XRPD record, see table 2 below:

Pos. [° 2Th.] d (A] Rel. int. [%] 3.95 22,370 th most common 100.0 4.79 18,430 th most common 36.8 7.52 11,751 th most common 1.6 7.90 11,120 th most common 1.1 8.27 10,682 th most common 1.9 9.69 9,122 th most common 1.9 12.05 7,338 th most common 1.4 12.46 7,099 th most common 1.5 12.92 6,849 th most common 4.9 13.81 6,410 th most common 2.8 14.09 6,281 th most common 2.5 14.49 6,110 th most common 13.7 14.75 6,002 th most common 5.1 15.89 5,575 th most common 17.0 16.46 5,381 th most common 2.5 16.68 5,312 th most common 3.5 17.33 5,113 th most common 4.9

• ·

17.64 5,024 th most common 3.8 18.70 4,743 th most common 8.7 19.63 4,519 th most common 11.3 20.16 4,402 th most common 13.9 20.80 4,268 th most common 8.1 21.68 4,097 th most common 11.0 22.71 3,912 th most common 4.5 23.13 3,843 th most common 5.6 23.74 3,745 th most common 4.9 24.86 3,578 th most common 12.4 25.21 3,529 th most common 10.7 26.29 3,387 th most common 9.9

Table 2

Crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and phosphoric acid can be characterized by FTIR and Raman spectroscopy . Giant. 7 shows an FTIR spectrum (Nicolet Thermo 6700c) containing characteristic peaks at wavelengths 3111, 2949, 2871, 2251, 1621, 1599, 1435, 1078, 815 and 732 cm ^-1 . Crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and phosphoric acid is characterized by a Raman spectrum (Bruker RFS 100 / S) comprising characteristic peaks at wave numbers 3146, 3126, 2967, 2931, 2873, 2252, 1624, 1496, 1306 and 818 cm ^-1, as shown in FIG. 8.

The crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and phosphoric acid can be further described by thermoanalytical methods. Giant. 9 shows a DSC (Mettler-Toledo 822e DSC) and FIG. 10 shows a TGA (NETZSCH TG 209 thermographic analyzer) curve measured in the range of 25 ° C to 350 ° C and 25 ° C to 350 ° C, respectively. Crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and phosphoric acid shows a 0.6% weight loss in range of 25 ° C to 190 ° C. DSC measurements show a melting process with an onset temperature T _O nset ⁼ 141.3 ° C and a peak temperature Τ _{ρε &} ^ 191.5 ° C.

One object of the present invention is a process for preparing crystalline modification 1. According to this process, ruxolitinib free base is dissolved in a suitable organic solvent.

by heating the system to 50 ° C. Phosphoric acid is added to the solution. A suitable organic solvent is preferably a polar aprotic solvent, more preferably a polar aprotic solvent selected from the group consisting of: methyl acetate, ethyl acetate, butyl acetate, acetonitrile, acetone, methyl ethyl ketone or a mixture thereof, preferably the polar aprotic solvent is ethyl acetate, more preferably ethyl acetate at 50 ° C.

The process for the preparation of crystalline modification 1 of the salt of ruxolitinib and phosphoric acid thus comprises the following steps:

a / dissolving ruxolitinib free base in a suitable organic solvent;

b / dropwise addition of an 85% aqueous solution of phosphoric acid accompanied by precipitation;

c) stirring the suspension from step b) at 50 ° C for another 1 hour;

d) cooling the suspension from step c) to a temperature of 0 to 5 ° C;

e) maintaining the suspension from step d / 16 hours at 0 to 5 ° C;

f) isolating the salt of ruxolitinib and phosphoric acid in crystalline modification 1;

g) optionally drying the product from step f) under laboratory conditions until a constant weight of product is reached.

A suitable organic solvent is preferably a polar aprotic solvent, more preferably a polar aprotic solvent selected from the group consisting of: methyl acetate, ethyl acetate, butyl acetate, acetonitrile, acetone, methyl ethyl ketone or a mixture thereof, preferably the polar aprotic solvent is ethyl acetate, more preferably ethyl acetate at 50 ° C.

Another method for preparing crystalline modification 1 of ruxolitinib salt and phosphoric acid comprises the following steps:

a / suspending the ruxolitinib salt and phosphoric acid in ethyl acetate at room temperature;

b) stirring the suspension from step a / at room temperature for 72 hours;

c) isolating crystalline modification 1 of ruxolitinib salt and phosphoric acid;

d) optionally drying the product from step c) under laboratory conditions until a constant weight of product is reached.

The crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and fumaric acid according to the invention has the following characteristic XRPD pattern, shown in Fig. 12. XRPD recording was performed on an X-ray powder diffractometer (XTERT PRO MPD PANalytical). Crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1116 salt] of propane nitrile and fumaric acid shows in the XRPD record the following diffraction peaks, see Table 3 below:

Pos. [° 2Th.J d (A] Rel. int. [%] 5.63 15,677 th most common 100.0 6.48 13,631 th most common 82.6 10.23 8,643 th most common 11.3 10.48 8,437 th most common 15.0 13.05 6,781 th most common 24.7 14.88 5,949 th most common 16.5 15.23 5,815 th most common 12.1 15.49 5,714 th most common 22.2 16.26 5,448 th most common 26.1 16.65 5,320 th most common 9.8 17.88 4,958 th most common 29.0 18.11 4,894 th most common 48.2 19.35 4,584 th most common 19.5 19.89 4,461 th most common 32.6 20.40 4,350 th most common 6.3 21.00 4,227 th most common 5.9 22.07 4,025 th most common 27.3 22.66 3,921 th most common 46.3 23.10 3,848 th most common 14.5 23.55 3,775 th most common 45.7 23.87 3,725 th most common 14.2 24.30 3,660 th most common 17.0 24.57 3,620 th most common 11.3 24.87 3,577 th most common 8.3 25.54 3,484 th most common 46.6 26.16 3,404 th most common 9.4 26.52 3,358 th most common 18.5 28.54 3,125 th most common 23.5

Table 3

Crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and fumaric acid can be characterized by FTIR and Raman spectroscopy . Giant. 13 shows an FTIR spectrum (Nicolet Thermo 6700c) containing characteristic peaks at 3201, 3132, 2957, 2266, 1696, 1592, 1346, 831, 737 and 608 cm ^-1 . The crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and fumaric acid is characterized by a Raman spectrum (Bruker RFS 100 / S) comprising characteristic peaks at wavelengths 3150,3131,3074,2940, 2876, 2266,1702,1594, 1350 and 829 cm ^-1, as shown in FIG. 14.

The crystalline modification of 1 (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and fumaric acid can be further described by thermoanalytical methods. Giant. 15 shows a DSC (Mettler-Toledo 822e DSC) and FIG. 16 shows a TGA (NETZSCH TG 209 thermographic analyzer) curve measured in the range of 25 ° C to 350 ° C and 25 ° C to 350 ° C, respectively. Crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and fumaric acid shows a 0.6% weight loss in range of 25 ° C to 150 ° C. DSC measurements show a melting process with a peak temperature T _pea k ⁼ 169.3 ° C.

One object of the present invention is a process for the preparation of crystalline modification 1. According to this process, ruxolitinib free base is dissolved in a suitable organic solvent by heating the system to 50 ° C. Fumaric acid is added to the solution. A suitable organic solvent is preferably a polar protic solvent selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or a mixture thereof, more preferably ethanol, even more preferably ethanol at 50 ° C.

The process for preparing the crystalline modification of ruxolitinib and fumaric acid salts thus comprises the following steps:

a / dissolving ruxolitinib free base in a suitable organic solvent;

b) dropwise addition of a solution of fumaric acid in a suitable organic solvent accompanied by precipitation;

c) stirring the suspension from step b) at 50 ° C for another 1 hour;

d) cooling the suspension from step c) to a temperature of 0 to 5 ° C;

e) maintaining the suspension from step d / 16 hours at 0 to 5 ° C;

f) isolating the salt of ruxolitinib and fumaric acid in crystalline modification 1;

g) optionally drying the product from step f) under laboratory conditions until a constant weight of product is reached.

• ·

A suitable organic solvent is preferably a polar protic solvent selected from the group consisting of: methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or a mixture thereof, more preferably ethanol, even more preferably ethanol at 50 ° C.

Another method for preparing crystalline modification 1 of ruxolitinib salt and fumaric acid comprises the following steps:

a / suspending the salt of ruxolitinib and fumaric acid in ethanol at room temperature; b) stirring the suspension from step a / at room temperature for 1 week;

c) isolating crystalline modification 1 of ruxolitinib salt and fumaric acid;

d) optionally drying the product from step c) under laboratory conditions until a constant weight of product is reached.

The crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and L-tartaric acid according to the invention has the following characteristic XRPD the record shown in Fig. 18. The XRPD record was taken on an X-ray powder diffractometer (XTERT PRO MPD PANalytical). Crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and L-tartaric acid shows the following diffraction peaks in the XRPD record, see table 4 below:

Pos. [° 2Th.] d [A] Rel. int. [% 1 4,099 th most common 21.5389 100 8,147 th most common 10.84423 20.31 11,329 th most common 7.80446 3.17 11,715 th most common 7.54802 2.44 14,096 th most common 6.27776 12.68 16,214 th most common 5.46214 20.01 17.28 5.1276 7.74 17.64 5.02318 5.91 18,712 th most common 4.73824 14.9 19,352 th most common 4,58294 11.51 20,873 th most common 4.25234 14.23 21,672 th most common 4.09746 6.26 22,705 th most common 3.91321 9.18

• ·

23.53 3.77794 6.29 24,687 th most common 3.6033 11.87 25,521 th most common 3.48748 12.22 26.13 3.40762 10.46 27,585 th most common 3.23108 8.05

Table 4

Crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and L-tartaric acid can be characterized by FTIR and Raman spectroscopy. Giant. 19 shows an FTIR spectrum (Nicolet Thermo 6700c) containing characteristic peaks at 3390, 3178, 3124, 2951, 2867, 2257, 1625, 1339, 1074 and 763 cm ^-1 . The crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and L-tartaric acid is characterized by a Raman spectrum (Bruker RFS 100 / S) comprising characteristic peaks at wave numbers 3122, 2961, 2926, 2872, 2259, 1628, 1356, 1241, 776 and 591 cm ^-1, as shown in FIG. 20.

The crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and L-tartaric acid can be further described by thermoanalytical methods. methods. Giant. 21 shows a DSC (Mettler-Toledo 822e DSC) and FIG. 22 shows a TGA (NETZSCH TG 209 thermographic analyzer) curve measured in the range of 25 ° C to 350 ° C and 25 ° C to 350 ° C, respectively. Crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and tartaric acid shows a 1.64% weight loss in range of 25 ° C to 110 ° C. DSC measurements show a melting process with an onset temperature T _onset = _39.1 ° C and a peak temperature Tpeak ^ 16.4 ° C.

One object of the present invention is a process for the preparation of crystalline modification 1. According to this process, ruxolitinib free base is dissolved in a suitable organic solvent by heating the system to 50 ° C. L-tartaric acid is added to the solution. A suitable organic solvent is preferably a polar protic solvent, more preferably the polar protic solvent is selected from the group consisting of: methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or a mixture thereof, even more preferably a suitable organic solvent is ethanol and even more preferably ethanol is a suitable organic solvent at 50 ° C.

• · · · · ·· ·· · ···· • · · ·· • · · · ·· · • · · · * ········ · · ···

Crystalline modification 1 of ruxolitinib salt and L-tartaric acid can be prepared by a process that includes the following steps:

a / dissolving ruxolitinib free base in a suitable organic solvent;

b) dropwise addition of a solution of L-tartaric acid in a suitable organic solvent;

c) stirring the solution from step b) at 50 ° C for another 1 hour;

d) cooling the solution from step c) to room temperature;

e) maintaining the solution from step d / 16 at room temperature for precipitation;

f) isolating the salt of ruxolitinib and L-tartaric acid in crystalline modification 1;

g) optionally drying the product from step f) under laboratory conditions until a constant weight of product is reached.

A suitable organic solvent is preferably a polar protic solvent, more preferably the polar protic solvent is selected from the group consisting of: methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or a mixture thereof, even more preferably a suitable organic solvent is ethanol and even more preferably, a suitable organic solvent is ethanol at 50 ° C.

Crystalline modification 2 of the salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and L-tartaric acid according to the invention has a characteristic XRPD pattern shown in Fig. 24. XRPD record was taken on an X-ray powder diffractometer (X'PERT PRO MPD PANalytical). Crystalline modification of 2-salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and Lvinic acid shows the following diffraction peaks in the XRPD pattern, see Table 5 below:

Pos. [° 2Th.J d [A] Rel. int. [% 1 6.34 13,940 th most common 100.0 8.12 10,879 th most common 8.1 9.06 9,749 th most common 34.9 9.64 9,168 th most common 5.2 10.89 8,118 th most common 12.0 11.70 7,560 th most common 4.0 13.27 6,665 th most common 52.3 14.18 6,239 th most common 6.3

14.52 6,096 th most common 8.9 15.78 5,613 th most common 6.9 16.28 5,440 th most common 34.0 16.76 5,284 th most common 11.8 16.95 5,227 th most common 10.4 17.86 4,963 th most common 27.6 18.20 4,872 th most common 26.6 18.70 4,741 th most common 26.4 19.00 4,667 th most common 16.5 19.39 4,573 th most common 30.9 19.82 4,476 th most common 13.7 21.32 4,164 th most common 4.5 21.92 4,052 th most common 6.2 22.76 3,904 th most common 13.2 23.27 3,820 th most common 6.7 23.89 3,722 th most common 8.6 24.60 3,615 th most common 8.6 25.06 3,550 th most common 11.8 25.33 3,513 th most common 14.3 25.72 3,461 th most common 14.9 26.53 3,357 th most common 9.4 27.16 3,281 th most common 7.2 28.75 3,103 th most common 6.9 29.47 3,028 th most common 5.0 30.11 2,966 th most common 4.5

Table 5

The crystalline modification of 2 salts of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and L-tartaric acid can be characterized by FTIR and Raman spectroscopy. Giant. 25 shows an FTIR spectrum (Nicolet Thermo 6700c) containing characteristic peaks at wavelengths 3192, 3116, 2948, 2864, 2252, 1721, 1596, 1346, 1266 and 816 cm ^-1 . The crystalline modification of 2 salts of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and L-tartaric acid is characterized by a Raman spectrum (Bruker RFS 100 / S) containing characteristic

peaks at wavelengths 3148, 2956, 2933, 2869, 2253, 1619, 1582, 1350, 1144 and 819 cm ¹ shown in Fig. 26.

The crystalline modification of 2 salts of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and L-tartaric acid can be further described by thermoanalytical methods. methods. Giant. 27 is a DSC (Mettler-Toledo 822e DSC), and FIG. 28 is a TGA (NETZSCH TG 209 thermographic analyzer) curve measured in the range of 25 ° C to 350 ° C and 25 ° C to 350 ° C, respectively. Crystalline modification 2 of the salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and tartaric acid shows a 3.42% weight loss in range of 25 ° C to 97 ° C. DSC measurements show a melting process with an onset temperature T _on set ⁼ 53.1 ° C and a peak temperature T _peak = 108.0 ° C.

One object of the present invention is a process for preparing crystalline modification 2. According to this process, ruxolitinib free base is suspended in a suitable organic solvent by heating the system to 50 ° C. L-tartaric acid is added to the solution. A suitable organic solvent is preferably a polar aprotic solvent, more preferably a polar aprotic solvent selected from the group consisting of: acetone, acetonitrile, methyl ethyl ketone, ethyl acetate, butyl acetate, tetrahydrofuran or a mixture thereof, preferably acetonitrile is a suitable organic solvent. temperature of 50 ° C.

Crystalline modification 2 of ruxolitinib salt and L-tartaric acid can be prepared by a process that includes the following steps:

a / suspending ruxolitinib free base in a suitable organic solvent; b) dropwise addition of a solution of L-tartaric acid in a suitable organic solvent;

c) stirring the solution from step b) at 50 ° C for another 1 hour accompanied by precipitation;

d) cooling the suspension from step c) to room temperature;

e / maintaining the suspension from step d / 16 at room temperature;

f) isolating the salt of ruxolitinib and L-tartaric acid in crystalline modification 2;

g) optionally drying the product from step f) under laboratory conditions until a constant weight of product is reached.

A suitable organic solvent is preferably a polar aprotic solvent, more preferably a polar aprotic solvent selected from the group consisting of: acetone, acetonitrile, methyl ethyl ketone, ethyl acetate, butyl acetate, tetrahydrofuran or a mixture thereof, preferably acetonitrile is a suitable organic solvent. temperature of 50 ° C.

• ·

The term "room temperature" is defined for the purposes of this document as a temperature of 15 ° C to 29 ° C; preferably it is in the range of 20 to 23 ° C.

The term "drying under laboratory conditions" as used in this patent application means drying at room temperature and 20-60% relative humidity.

Analysis - XRPD (X-ray powder diffractometry)

Diffractograms were obtained using an X'PERT PRO MPD PANalytical diffractometer, using CuKα radiation (λ = 1.542 Å).

Generator settings:

excitation voltage 45 kV

- anode current 40 mA

Scanning description:

- scanning type - gonio

- measuring range 2 - 40 ° 20

- step size 0.01 ⁰ 20

- step duration: 0.5 s

Samples were measured as received on a Si plate (zero background holder).

Incident beam optics: programmable divergence screens (irradiated length 10 mm). 10 mm mask. 1/4 ° anti-scatter fixed orifice, 0.02 rad Soller orifice.

Distributed light optics: XOelerator detector, scanning mode, active length 2.122 °. 0.02 rad Soller diaphragm, 5.0 mm anti-scatter diaphragm, Ni filter.

Analysis - FTIR spectroscopy (infrared spectroscopy with Fourier transform)

FTIR spectra were measured using a Nicolet Thermo 6700 spectrometer

General settings:

Number of sample shots: 45

Number of background images: 45

Resolution: 4,000

Sample gain: 4.0

Optical speed: 0.6329

Aperture: 100.00

Analysis - Raman spectroscopy • · ·· ·· * • · · · · ··· · · · · · · · · · · · • · · · · ······· «·· ···

FTIR spectra were recorded using a FT-Raman Bruker RFS 100 / S spectrometer. General settings:

Excitation source: Laser Nd-YAG (1064 nm)

Applied spectral domain: 4000-200 cm ^-1

Used laser power: 250 mW

Detector: Li-diode detector cooled by liquid nitrogen (D418-T)

Resolution: 4 cm ' ¹

Number of accumulations: 128

Scattering geometry: 180 ° (rear scattering)

Aperture: 3.5 mm

Analysis - DSC (differential scanning calorimetry)

DSC measurements were performed using a Mettler-Toledo 822e DSC instrument.

The samples were placed in standard aluminum dishes (40 μΐ) closed with a perforated lid. The sample cell was heated under a nitrogen atmosphere at a rate of 10 ° C / min from 25 ° C to a final temperature of 300 ° C at a nitrogen level of 50 ml / min. The temperatures determined in the DSC analyzes are the peak temperature (T _pea k) and the onset temperature (T _onS et) of the peaks of the crystalline form. Enthalpy is given in J / g.

The weight of the sample was approx. 2.5-3 mg.

Analysis - TGA (Thermogravimetric Analysis)

TGA analyzes were performed using a NETZSCH TG 209 thermogravimetric analyzer (NETZSCH-Geratebau GmbH, Germany).

Each sample was placed in an aluminum sample dish and placed in a TG oven. The furnace was heated under a nitrogen atmosphere at a rate of 10 ° C / min from 25 ° C to a final temperature of 300 ° C.

The weight of the sample was approx. 5-15 mg.

Exemplary embodiments

The following examples are intended to further illustrate the present invention without limiting its scope.

Example 1 ·· ·· ·· · .ΐ. ** •: ·:::

. ·. · ·::: · ::

• 1 ·· ···· · »··· ··· ··

Preparation of crystalline modification 5 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and hydrochloric acid salt 5

200 mg (0.516 mm) of the ruxolitinib and hydrochloric acid salt was suspended in 0.2 ml of a 9010 v / v methanol-water mixture at room temperature.

The suspension was kept in a closed vessel at room temperature with constant stirring for 72 hours.

The solid obtained was collected by filtration and dried by vacuum suction under laboratory conditions.

The XRPD pattern was measured (Fig. 1) and showed that the substance was in a crystalline state, which was designated as a crystalline modification of the 5 salt of ruxolitinib and hydrochloric acid.

Example 2

Preparation of crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and phosphoric acid g (6.528 mmol) free base ruxolitinib was suspended in 10 mL of ethyl acetate by warming to ° C with stirring.

0.4 ml of phosphoric acid (6.528 mmol; 85% aqueous solution) was added dropwise to the ruxolitinib suspension at 50 ° C with constant stirring.

The suspension was stirred at this temperature for 1 hour and then placed on ice to cool. The solid obtained was filtered off and dried under laboratory conditions.

Product: 2.506 g (6.19 mmol) of an off-white crystalline solid

Yield: 95%

HPLC: 99.8%

The XRPD pattern was measured (Fig. 6) and the substance was shown to be in a crystalline state, which was designated as crystalline modification 1 of the ruxolitinib salt and phosphoric acid salt.

The 1 H-NMR spectrum (Fig. 11) was measured, which confirmed that the substance showed a 1: 1 API: phosphoric acid stoichiometry structure.

Example 3

Preparation of crystalline modification 1 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and phosphoric acid salt

200 mg (0.495 mmol) of the ruxolitinib and phosphoric acid salt was suspended in 0.5 ml of ethyl acetate at room temperature.

The suspension was kept in a closed vessel at room temperature with constant stirring for 1 week.

The solid obtained was collected by filtration and dried by vacuum suction under laboratory conditions.

The XRPD pattern was measured (Fig. 6) and the substance was shown to be in a crystalline state, which was designated as crystalline modification 1 of the ruxolitinib and phosphoric acid salt.

Example 4

Preparation of crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and cinnamic acid g (6.528 mmol) free base ruxolitinib was dissolved in 5 ml of ethanol at 50 ° C with stirring.

With stirring, a solution of 0.8 g of fumaric acid dissolved in 2 ml of ethanol at 50 ° C was added dropwise to the ruxolitinib solution. Precipitation occurred.

The suspension was further stirred at 50 ° C for another 1 hour and then cooled back to room temperature. The suspension was further stirred under laboratory conditions overnight.

The precipitated solid was collected by filtration and dried under laboratory conditions.

Product: 1.96 g (5.378 mmol) of an off-white crystalline solid

Yield: 89%

HPLC: 97.7%

The XRPD pattern was measured (Fig. 12) and the substance was shown to be in a crystalline state, which was designated as crystalline modification 1 of the ruxolitinib salt and fumaric acid salt.

The 1 H-NMR spectrum was measured (Fig. 17), which confirmed that the substance showed a 2: 1 API: cinnamic acid stoichiometry structure.

Example 5

Preparation of crystalline modification of 1 salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile and L-tartaric acid g (6.528 mmol) ruxolitinib was dissolved in 8 ml of ethanol at 50 ° C with stirring. With stirring, a solution of 1.0 g of L-tartaric acid (6.666 mmol) dissolved in 2 ml of ethanol at 50 ° C was added dropwise to the ruxolitinib solution.

The solution was further stirred at 50 ° C for another 1 hour, whereupon precipitation occurred.

The resulting suspension was cooled back to room temperature and stirred at this temperature overnight.

The precipitated solid was collected by filtration and dried under laboratory conditions

Product: 2.14 g (4.7 mmol) of an off-white crystalline solid

Yield: 72%

HPLC: 99.1%

The XRPD pattern was measured (Fig. 18) and the substance was shown to be in a crystalline state, which was designated as crystalline modification 1 of the ruxolitinib and L-tartaric acid salt.

The 1 H-NMR spectrum was measured (Fig. 23), which confirmed that the substance showed the structure of API: L-tartaric acid stoichiometry 1: 1

Example 6

Preparation of crystalline modification 2 of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile salt and L-tartaric acid g (3.264 mmol) ruxolitinib was suspended in 8 ml of acetonitrile at 50 ° C with stirring.

While stirring, a solution of 0.54 g of L-tartaric acid (3.6 mmol) in 2 mL of ethyl acetate at 50 ° C was added dropwise to the suspension of ruxolitinib with stirring to give a clear solution. The solution was further stirred at 50 ° C for another 1 hour, whereupon precipitation occurred.

The resulting suspension was cooled back to room temperature and stirred at this temperature overnight.

The precipitated solid was collected by filtration and dried under laboratory conditions

Product: 1.18 g (2.587 mmol) of an off-white crystalline solid

Yield: 79%

HPLC: 99.4%

The XRPD pattern was measured (Fig. 24) and showed that the substance was in a crystalline state, which was designated as a crystalline modification of the 5 salt of ruxolitinib and L-tartaric acid.

The 1 H-NMR spectrum was measured (Fig. 29), which confirmed that the substance showed the structure of API: L-tartaric acid stoichiometry 1: 1.5

Claims (43)

PATENT CLAIMS ............ ?and/ A salt comprising (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile of formula I and at least one acid component (HX), wherein the acid addition salt is in crystalline form. H H-X (I) The crystalline salt according to claim 1, wherein the acid component (HX) is hydrochloric acid, phosphoric acid, fumaric acid or L-tartaric acid. The crystalline salt of claims 1 and 2 in the form of crystalline modification 5, wherein the acid component (HX) is hydrochloric acid, exhibiting X-ray powder diffraction (XRPD) characteristic peaks at about 3.7; 8.4; 14.3; 20.9 and 25.2 ± 0.2 ° 2-theta measured using CuKα radiation. Process for the preparation of the crystalline modification 5 characterized in claim 3, characterized in that the salt of ruxolitinib and hydrochloric acid is suspended in a polar protic solvent. Process according to claim 4, characterized in that the polar protic solvent is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or a mixture thereof in the form of a mixture of organic solvent and water. Process according to Claim 5, characterized in that the polar protic solvent is a mixture of methanol and water, preferably a mixture of methanol and water in the range from 0 to 40% v / v. methanol in water at room temperature. Method according to claims 4 to 6, characterized in that it comprises the following steps: a) suspending the salt of ruxolitinib and hydrochloric acid in a polar protic solvent, preferably in a polar protic solvent or a mixture thereof in the form of a mixture of an organic solvent and water, selected from the group consisting of: methanol, ethanol, 1-propanol, 2-propanol, 1- butanol, 2-butanol or a mixture thereof, more preferably a mixture of methanol with water, even more preferably mixtures of methanol and water in the range of 0 to 40% v / v. methanol in water at room temperature; b) stirring the suspension from step a / at room temperature for 72 hours; c) isolating crystalline modification 5 of the ruxolitinib salt and hydrochloric acid. The method of claim 7, optionally comprising drying the product of step c) under laboratory conditions until a constant weight of product is reached. The crystalline salt of claims 1 and 2 in the form of crystalline modification 1, wherein the acid component (HX) is phosphoric acid, exhibiting X-ray powder diffraction (XRPD) characteristic peaks at about 3.9; 14.5; 15.9; 20.2 and 24.9 ± 0.2 ° 2-theta measured using CuKα radiation. Process for the preparation of crystalline modification 1 according to claim 9, characterized in that ruxolitinib free base is dissolved in a polar aprotic solvent and then phosphoric acid is added. The method of claim 10, wherein the polar aprotic solvent is selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, acetonitrile, acetone, methyl ethyl ketone, or a mixture thereof. Process according to Claim 11, characterized in that the polar aprotic solvent is ethyl acetate at a temperature of 50 ° C. The method of claims 10 to 12, comprising the steps of: and / dissolving ruxolitinib free base in a polar aprotic solvent, wherein the polar aprotic solvent is selected from the group consisting of: methyl acetate, ethyl acetate, butyl acetate, acetonitrile, acetone, methyl ethyl ketone or a mixture thereof, preferably the polar aprotic solvent is ethyl acetate, more preferably ethyl acetate at 50 ° C; b / dropwise addition of an 85% aqueous solution of phosphoric acid accompanied by precipitation; c) stirring the suspension from step b) at 50 ° C for another 1 hour; d) cooling the suspension from step c) to a temperature of 0 to 5 ° C; e) maintaining the suspension from step d) for 16 hours at a temperature of 0 to 5 ° C; f) isolating crystalline modification 1 of ruxolitinib salt and phosphoric acid. The method of claim 13, optionally comprising the step of drying the product from step f) under laboratory conditions until a constant weight of product is reached, The crystalline salt of claims 1 and 2 in the form of crystalline modification 1, wherein the acid component (HX) is fumaric acid, exhibiting X-ray powder diffraction (XRPD) characteristic peaks at about 5.6; 13.1; 18.1; 22.6, 23.5 and 25.5 ± 0.2 ° 2theta measured using CuKα radiation. Process for the preparation of crystalline modification 1 according to claim 15, characterized in that ruxolitinib free base is dissolved in a polar protic solvent and then fumaric acid is added. The method of claim 16, wherein the polar protic solvent is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, or a mixture thereof. Process according to Claim 17, characterized in that the polar protic solvent is ethanol, preferably ethanol at 50 ° C. The method of claims 15 to 17, comprising the steps of: and / dissolving ruxolitinib free base in a polar protic solvent preferably selected from the group consisting of: methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or a mixture thereof, more preferably ethanol, even more preferably ethanol at 50 ° C; b) dropwise addition of a solution of fumaric acid in a suitable organic solvent accompanied by precipitation; c) stirring the suspension from step b) at 50 ° C for another 1 hour; d) cooling the suspension from step c) to a temperature of 0 to 5 ° C; e) maintaining the suspension from step d / 16 hours at 0 to 5 ° C; f) isolating crystalline modification 1 of ruxolitinib salt and fumaric acid. The method of claim 19, optionally comprising the step of drying the product from step f) under laboratory conditions until a constant weight of product is reached. The crystalline salt of claims 1 and 2 in the form of crystalline modification 1, wherein the acid component (HX) is L-tartaric acid, exhibiting X-ray powder diffraction (XRPD) characteristic peaks at about 4.1; 8.2; 16.2; 20.9 and 25.5 ± 0.2 ° 2-theta measured using CuKα radiation. Process for the preparation of crystalline modification 1 according to claim 21, characterized in that ruxolitinib free base is dissolved in a polar protic solvent and then fumaric acid is added. 23. The method of claim 22, wherein the polar protic solvent is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, or a mixture thereof. Process according to claim 23, characterized in that the polar protic solvent is ethanol, preferably ethanol at 50 ° C. The method of claims 22 to 24, comprising the steps of: a) dissolving ruxolitinib free base preferably in a polar protic solvent selected from the group consisting of: methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or a mixture thereof, even more preferably a suitable organic solvent is ethanol and even more preferably a suitable organic solvent is ethanol at 50 ° C; b) dropwise addition of a solution of L-tartaric acid in a suitable organic solvent; c) stirring the solution from step b) at 50 ° C for another 1 hour; d) cooling the solution from step c) to room temperature; e) maintaining the solution from step d / 16 at room temperature during which time precipitation occurs; f) isolating crystalline modification 1 of ruxolitinib salt and L-tartaric acid. The method of claim 25, optionally comprising the step of drying the product from step f) under laboratory conditions until a constant weight of product is reached. The crystalline salt of claims 1 and 2 in the form of crystalline modification 2, wherein the acid component (HX) is L-tartaric acid, exhibiting X-ray powder diffraction (XRPD) characteristics of peaks at about 6.3; 9.1; 13.3; 16.3; 18.7; 19.4 and 22.8 ± 0.2 ° 2-theta measured using CuKα radiation. Process for the preparation of crystalline modification 2 according to claim 27, characterized in that ruxolitinib free base is dissolved in a polar aprotic solvent and then L-tartaric acid is added. 29. The method of claim 28, wherein the polar aprotic solvent is selected from the group consisting of acetone, acetonitrile, methyl ethyl ketone, ethyl acetate, butyl acetate, tetrahydrofuran, or a mixture thereof. Process according to claim 29, characterized in that the polar protic solvent is acetonitrile, preferably acetonitrile at a temperature of 50 ° C. The method of claims 28 to 30, comprising the steps of: and / suspending ruxolitinib free base in a polar aprotic solvent, preferably the polar aprotic solvent is selected from the group consisting of: acetone, acetonitrile, methyl ethyl ketone, ethyl acetate, butyl acetate, tetrahydrofuran or a mixture thereof, preferably acetonitrile is a suitable organic solvent, more preferably acetonitrile is a suitable organic solvent. at 50 ° C; b) dropwise addition of a solution of L-tartaric acid in a suitable organic solvent; c) stirring the solution from step b) at 50 ° C for another 1 hour accompanied by precipitation; d) cooling the suspension from step c) to room temperature; e / maintaining the suspension from step d / 16 at room temperature; f) isolating crystalline modification 2 of ruxolitinib salt and L-tartaric acid. The method of claim 31, optionally comprising the step of drying the product from step f) under laboratory conditions until a constant weight of product is reached. A pharmaceutical composition comprising the salt of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile of formula I with at least one acid component (HX) , characterized in that the acid addition salt is in crystalline form. (AND) Pharmaceutical composition according to Claim 33, characterized in that the acid component (HX) is hydrochloric acid, phosphoric acid, fumaric acid or L-tartaric acid. • · The pharmaceutical composition of claims 33 and 34, further comprising one or more pharmaceutically acceptable carriers or excipients. A pharmaceutical composition according to claims 33 to 35, characterized in that it is in a pharmaceutical form suitable for oral administration. The pharmaceutical composition according to claims 33 to 36, characterized in that the composition is in the form of a tablet. A crystalline salt according to any one of claims 1 to 3, 9, 15, 21 and 27 for use in treating a disease in a patient, wherein said disease is associated with JAK activity. A crystalline salt according to any one of claims 1 to 3, 9, 15, 21 and 27 for use in the treatment of cancer. 40. The crystalline salt of claim 39, wherein the cancer is a hematological cancer. A crystalline salt according to any one of claims 1 to 3, 9, 15, 21 and 27 for use in treating chronic myelogenous leukemia (CML) in a patient, comprising administering to the patient a therapeutically effective amount of said crystalline salt. A crystalline salt according to any one of claims 1 to 3, 9, 15, 21 and 27 for use in treating acute lymphoblastic leukemia (ALL) in a patient, comprising administering to the patient a therapeutically effective amount of said crystalline salt. A crystalline salt according to any one of claims 1 to 3, 9, 15, 21 and 27 for use in treating chronic myelomonocytic leukemia (CMML) in a patient, comprising administering to the patient a therapeutically effective amount of said crystalline salt.