WO2017121379A1 - P-toluenesulfonate salt for regulating kinase compound, and crystals thereof - Google Patents

Abstract

The present application relates to a p-toluenesulfonate salt for regulating a kinase compound, and crystals thereof, and specifically, to an N-{3-[3-(9H-purine-6-group)pyridine-2-group amino]-4-chlorine-2-fluorophenyl}-3-fluoropropane-1-sulfonamide p-toluenesulfonate salt and crystals thereof. The salt and the crystals thereof provided in the present application have advantages in bioavailability, hygroscopicity, stability, solubility, purity, easy preparation, and the like.

Description

A p-toluenesulfonate which modulates a kinase compound and its crystallization

Cross-reference to related applications

The present application claims priority to and the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of

Technical field

The present application belongs to the field of medicine, and relates to a p-toluenesulfonate and a crystal thereof for regulating a kinase compound, in particular, to N-{3-[3-(9H-嘌呤-6-yl)pyridin-2-ylamino ]-4-Chloro-2-fluorophenyl}-3-fluoropropane-1-sulfonamide p-toluenesulfonate and its crystallization.

Background technique

Example 9 of WO2013071865A1 discloses a kinase-regulating compound having the chemical name N-{3-[3-(9H-indol-6-yl)pyridin-2-ylamino]-4-chloro-2 -Fluorophenyl}-3-fluoropropane-1-sulfonamide, the structure is as shown in Formula I:

N-{3-[3-(9H-嘌呤-6-yl)pyridin-2-ylamino]-4-chloro-2-fluorophenyl}-3-fluoropropane-1-sulfonamide disclosed in this patent document (Compound of Formula I) as a free form is a kinase-modulating compound useful in the treatment of diseases and conditions associated with modulation of kinase activity. In particular, the compounds of formula I have excellent anti-B-RAF enzyme activity in vitro and are useful in the treatment of diseases and conditions associated with modulation of B-RAF enzyme activity.

However, there is still a need to develop N-{3-[3-(9H-indol-6-yl)pyridin-2-ylamino]-4-chloro-2-fluorophenyl}-3-fluoropropane-1- Compared with the free form of the sulfonamide, it has more excellent properties in terms of physical properties and kinetics, and is a regulatory kinase compound having high applicability as a drug.

Summary of invention

In one aspect, the application provides a compound of formula II,

In another aspect, the application provides crystallization of a compound of formula II,

The compound of formula II is crystallized using an X-ray powder diffraction pattern of Cu Kα radiation, and the diffraction angle (2θ ± 0.2°) has diffraction peaks at about 4.59°, 7.99°, 8.37°, 9.18°, 18.52°, and 20.78°. .

In yet another aspect, the present application provides a crystalline composition comprising a crystal of a compound of formula II as described herein, wherein the compound of formula II comprises more than 50% by weight of the crystalline composition, 80 More than %, more than 90%, more than 95% or more than 99%.

In a further aspect, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula II as described herein or a crystalline form of said compound of formula II or a crystalline composition as described above, and one or A variety of pharmaceutically acceptable carriers.

In another aspect, the application provides a compound of formula II as described herein or a crystalline form of the compound of formula II or a crystalline composition as described above or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment of a protein kinase mediated disease or condition the use of.

The present application also provides a compound of Formula II described herein or a compound of Formula II described herein or a crystalline composition thereof or a pharmaceutical composition as described above for use in the treatment of a protein kinase mediated disease or condition.

The present application also provides a method of treating a protein kinase mediated disease or condition, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula II as described herein or a crystal of said compound of formula II or a combination of said crystals Or the above pharmaceutical composition.

In a further aspect, the present application provides a process for the preparation of a crystallization of a compound of formula II comprising crystallizing a compound of formula II in a C _1-4 alcohol solvent to provide a crystallization of the compound of formula II.

Detailed description of the invention

In one aspect, the application provides N-{3-[3-(9H-indol-6-yl)pyridin-2-ylamino]-4-chloro-2-fluorophenyl}-3 as shown in Formula II -Fluoropropane-1-sulfonamide p-toluenesulfonate (hereinafter referred to as a compound of formula II):

In the compound of formula II, N-{3-[3-(9H-indol-6-yl)pyridin-2-ylamino]-4-chloro-2-fluorophenyl}-3-fluoropropane-1-sulfonamide The molar ratio to p-toluenesulfonic acid is about 1:1.

The compounds of formula II provided herein are superior to the compounds of formula I or other salts of the compounds of formula I in at least one aspect, such as bioavailability, hygroscopicity, stability, solubility, purity, ease of preparation, and the like.

In another aspect, the application provides crystallization of a compound of formula II,

Wherein the crystals of the compound of formula II are substantially free of water of crystallization and/or other solvents.

Crystallization of the compound of formula II In the X-ray powder diffraction pattern of Cu Kα radiation, diffraction angles (2θ ± 0.2°) have diffraction peaks at about 4.59°, 7.99°, 8.37°, 9.18°, 18.52°, and 20.78°.

Crystallization of the compound of formula II using an X-ray powder diffraction pattern of Cu Ka radiation, diffraction angles (2θ ± 0.2°) are about 4.59°, 7.99°, 8.37°, 9.18°, 18.52°, 20.78°, 21.60°, and 21.92. There is a diffraction peak at °.

Crystallization of the compound of formula II Using an X-ray powder diffraction pattern of Cu Ka radiation, the diffraction angle (2θ ± 0.2°) is about 4.59°, 7.99°, 8.37°, 9.18°, 18.52°, 20.78°, 21.60°, 21.92. There are diffraction peaks at ° and 25.36 °.

Crystallization of the compound of formula II Using an X-ray powder diffraction pattern of Cu Ka radiation, the diffraction angle (2θ ± 0.2°) is about 4.59°, 7.99°, 8.37°, 9.18°, 14.75°, 16.73°, 17.35°, 18.52. There are diffraction peaks at °, 20.78°, 21.60°, 21.92°, and 25.36°.

Crystallization of the compound of formula II using an X-ray powder diffraction pattern of Cu Ka radiation, diffraction angle (2θ ± 0.2°) About 4.59°, 7.99°, 8.37°, 9.18°, 14.75°, 16.73°, 17.35°, 18.52°, 18.98°, 20.09°, 20.78°, 21.60°, 21.92°, 23.11°, 25.36°, 26.08°, There are diffraction peaks at 26.62°, 27.41°, 27.85°, and 28.32°.

Crystallization of the compound of formula II Using an X-ray powder diffraction pattern of Cu Ka radiation, the diffraction angle (2θ ± 0.2°) is about 4.59°, 7.99°, 8.37°, 9.18°, 10.86°, 14.75°, 16.73°, 17.35. There are diffraction peaks at °, 18.52, 18.98, 20.09, 20.78, 21.60, 21.92, 23.11, 24.30, 25.36, 26.08, 26.62, 27.41, 27.85 and 28.32.

Crystallization of the compound of formula II Using an X-ray powder diffraction pattern of Cu Ka radiation, the diffraction angle (2θ ± 0.2°) is about 4.59°, 7.99°, 8.37°, 9.18°, 10.86°, 14.75°, 16.73°, 17.35. °, 18.52, 18.98, 20.09, 20.78, 21.60, 21.92, 23.11, 24.30, 25.36, 26.08, 26.62, 27.41, 27.85, 28.32, 29.41, 30.19, There are diffraction peaks at 30.90°, 31.97°, 33.47°, 34.06°, 37.82°, 39.38°, 40.00°, 42.33°, and 43.93°.

Without limitation, a typical example of crystallizing a compound of formula II of the present application using an X-ray powder diffraction (XRD) pattern of Cu Ka radiation has the following characteristics:

Without limitation, a typical example of a crystal of a compound of formula II of the present application has an X-ray powder diffraction (XRD) pattern substantially as shown in FIG.

Without limitation, a typical example of a crystal of a compound of formula II of the present application has an XRD pattern substantially as shown in FIG.

Without limitation, a differential scanning calorimetry (DSC) measurement chart of a typical example of the crystallization of the compound of Formula II of the present application has an onset temperature of about 260.5 ° C, specifically, a difference substantially as shown in FIG. A scanning calorimetry (DSC) measurement chart is shown.

Without limitation, a differential scanning calorimetry (DSC) measurement chart of a typical example of the crystallization of a compound of Formula II of the present application has an onset temperature of about 258.8 °C, specifically, a difference substantially as shown in FIG. A scanning calorimetry (DSC) measurement chart is shown.

It should be noted that the crystallization of the compound of the formula II of the present application includes not only the diffraction angle of the peak in the X-ray powder diffraction completely coincides with the above diffraction angle or the crystal of ±0.2°, but also the diffraction angle having a uniform error of ±0.2°. crystallization.

In the crystal of the compound of formula II of the present application, N-{3-[3-(9H-indol-6-yl)pyridin-2-ylamino]-4-chloro-2-fluorophenyl}-3-fluoropropane- The molar ratio of 1-sulfonamide to p-toluenesulfonic acid is about 1:1.

In still another aspect, the present application provides a crystalline composition comprising the crystal of the compound of the above formula II, wherein the crystal of the compound of the formula II accounts for 50% or more, 80% or more, 90% or more by weight of the crystal composition. More than 95% or more than 99%.

In still another aspect, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula II or a compound of Formula II, or a crystalline composition thereof, and one or more pharmaceutically acceptable carriers . The pharmaceutical compositions of the present application can be prepared by crystallizing a compound of formula II or a compound of formula II or a combination of the above crystalline compositions with a suitable pharmaceutically acceptable carrier.

In a further aspect, the application provides the use of a compound of formula II or a compound of formula II above, or a crystalline composition as described above, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment of a protein kinase mediated disease or condition, preferably in preparation thereof Use in a medicament for treating a B-raf kinase mediated disease or condition, such as a cancer, mediated by a protein kinase (including B-raf kinase).

The present application also provides a compound of formula II, or a crystalline composition of the above formula II, or a crystalline composition thereof, or a pharmaceutical composition as described above, for use in the treatment of a disease or condition mediated by a protein kinase, including a B-raf kinase. . The disease or condition mediated by the protein kinase (including B-raf kinase) can be, for example, a cancer.

The present application also provides a method of treating a disease or condition mediated by a protein kinase, including B-raf kinase, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of Formula II described herein or a formula thereof. The compound II crystallizes or the above crystalline composition or the above pharmaceutical composition. The disease or condition mediated by the protein kinase (including B-raf kinase) can be, for example, a cancer.

The protein kinase (including B-raf kinase) mediated diseases or conditions described in the present application are selected from the group consisting of melanoma, colorectal cancer, colon cancer, gastric cancer, pelvic cancer, esophageal cancer, brain cancer, testicular cancer, bone cancer, lymph Cancer, lung cancer, breast cancer, pancreatic cancer, thyroid cancer, ovarian cancer, liver cancer, kidney cancer, glioma, sarcoma, medullary thyroid carcinoma, carcinoid, small cell lung cancer, leukemia, neurofibromatosis, myelodysplastic syndrome , tumor angiogenesis, neuropathic pain, inflammatory pain, acute and chronic pain, cancer-related pain, migraine, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis, multiple infarct dementia, head Injury, spinal cord injury, Parkinson's disease, Alzheimer's disease, psoriasis, arthritis, osteoarthritis, fibrosis, rheumatoid arthritis, inflammatory bowel disease, immunodeficiency disease, organ transplant rejection, graft Anti-host disease, diabetic nephropathy, polycystic kidney disease, renal cirrhosis, glomerulonephritis, benign prostatic hyperplasia, diabetes, obesity, Helicobacter pylori infection, hepatitis infection, flu Viral infection, fever, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, muscular dystrophy, motor neuron disease, neuromuscular junction disease, endocrine disorders, peripheral neuropathy, gland disease, body and muscle metabolic diseases .

The crystallization of the compound of formula II provided herein is at least one aspect superior to the compound of formula I or other salt of the compound of formula I in terms of bioavailability, hygroscopicity, stability, solubility, purity, ease of preparation, and the like.

The crystal of the compound of the formula II provided by the present application has excellent solubility parameters suitable for the preparation of the drug; has high stability, for example, has higher stability than other salts of the compound of the formula I (such as potassium salt); is not easily deliquescent, for example, the compound of the formula I, hydrochloric acid Salts and sulfates are easily deliquescent; their impurity content is easily controlled, for example, in the preparation, under the experimental conditions of conventional stability investigation.

The compound of formula II of the present application can be prepared by the following method: a compound of formula I and p-toluenesulfonic acid are salted in a solvent to provide a compound of formula II.

The crystallization of the compound of the formula II of the present application can be obtained by the following method: a compound of the formula I and p-toluenesulfonic acid are salted in a solvent to obtain a compound of the formula II; the compound of the formula II is crystallized in a C _1-4 alcohol solvent to give a compound of the formula II. crystallization.

For example, a compound of formula I is added to p-toluenesulfonic acid in a solvent, stirred at room temperature or under heating to remove the solvent to give a compound of formula II; a compound of formula II in a C _1-4 alcoholic solvent at room temperature or under heating, for example, under reflux conditions The solution is formed under the following conditions, and the compound of the formula II is crystallized by cooling to about 0 ° C to room temperature, and dried by filtration to obtain a crystal of the compound of the formula II. It is optional during the crystallization to mix the solution while slowly cooling, which may be shaking or stirring.

The solvent used for salt formation is one or more polar protic solvents including, but not limited to, acetonitrile, tetrahydrofuran, ethyl acetate, methyl acetate, methyl formate, acetone or methyl ethyl ketone. . In some embodiments of the present application, the solvent used to form the salt is tetrahydrofuran. In the salt formation reaction, the molar ratio of the compound of the formula I to p-toluenesulfonic acid is from 1:1-5, preferably from 1:1 to 2.

The C _1-4 alcohol solvent is one or more selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol or tert-butanol, preferably methanol or ethanol. Or one or more of isopropanol, most preferably one or both of methanol or ethanol.

Unless otherwise stated, the following terms used in the specification and claims shall have the following meanings for the purposes of the present application.

"Patient" means a mammal, preferably a human.

"Pharmaceutically acceptable" is those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without undue Toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.

"Treatment" means administration of a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) preventing a disease or disease state from occurring in a mammal, particularly when such a mammal is susceptible to the disease state but has not been diagnosed as having the disease state;

(ii) inhibiting the disease or disease state, ie, curbing its development;

(iii) alleviating the disease or condition, even if the disease or condition resolves.

The XRD pattern of the crystal of the compound of formula II of the present application is tested as follows:

1. Instrument: PANalytical Company of the Netherlands (formerly Philips Analytical Instruments), X’Pert PRO MPD X-ray diffractometer

2. Measurement conditions: Cu Kα radiation, 0.15418 nm; tube pressure: 40 kV; tube flow: 40 mA; Ni filter; super-array probe (X'Celerator);

Incident light path: divergence slit 1°, anti-scatter slit 2°;

Reflected light path: anti-scatter slit 6.6 °;

Scanning situation: 0.033°/step; 20s/step

The test method for the DSC pattern of the crystal of the above formula II of the present application is as follows:

1. Instrument: Perkin Elmer Thermal Analysis.

2. Measurement conditions: starting temperature 50 ° C, termination temperature 300 ° C, heating rate: 10 ° C / min.

It should be noted that in the X-ray powder diffraction spectrum, the diffraction spectrum obtained from the crystalline compound is often characteristic for a specific crystal form, wherein the relative intensity of the band (especially at a low angle) may be due to the crystal. The dominant orientation effect due to the difference in conditions, particle size, and other measurement conditions varies. Therefore, the relative intensities of the diffraction peaks are not characteristic for the crystal form to be targeted. When judging whether they are the same as the known crystal forms, more attention should be paid to the relative positions of the peaks rather than their relative intensities. Furthermore, there may be slight errors in the position of the peak for any given crystal form, which is also well known in the field of crystallography. For example, the position of the peak can be shifted due to changes in temperature during sample analysis, sample movement, or calibration of the instrument, etc., and the measurement error of the 2θ value is sometimes about ±0.2°. Therefore, this error should be taken into account when determining each crystal structure. In the XRD pattern, the peak position is usually expressed by the 2θ angle or the crystal plane distance d, and there is a simple conversion relationship between them: d=λ/2sinθ, where d represents the crystal plane distance, λ represents the wavelength of the incident X-ray, and θ is Diffraction angle. For the same crystal form of the same compound, the peak positions of the XRD spectrum have similarities as a whole, and the relative intensity error may be large. It should also be noted that in the identification of the mixture, some of the diffraction lines are missing due to factors such as a decrease in content. At this time, it is not necessary to rely on all the bands observed in the high-purity sample, and even one band may be given. The crystals are characteristic.

DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or crystal melting. For the same crystal form of the same compound, in continuous analysis, the thermal transition temperature and melting point error is typically within about 5 ° C, usually within about 3 ° C, when we say a compound has a given DSC At the peak or melting point, this means the DSC peak or melting point ± 5 °C. DSC provides an auxiliary method for identifying different crystal forms. Different crystal morphology can be identified based on their different transition temperature characteristics. It should be noted that for the mixture, the DSC peak or melting point may vary over a larger range. In addition, the melting temperature is related to the rate of temperature increase due to decomposition during the melting of the substance.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an X-ray powder diffraction pattern of the crystal of the compound of formula II prepared in Example 3.

2 is an X-ray powder diffraction pattern of the crystal of the compound of Formula II prepared in Example 4.

3 is a differential scanning calorimetry (DSC) measurement chart of the crystal of the compound of Formula II prepared in Example 3.

4 is a differential scanning calorimetry (DSC) measurement chart of the crystal of the compound of Formula II prepared in Example 4.

detailed description

Example 1 N-{3-[3-(9H-Indol-6-yl)pyridin-2-ylamino]-4-chloro-2-fluorophenyl}-3-fluoropropane-1-sulfonamide (Formula I Preparation of compound)

The compound of formula I is prepared according to the method disclosed in Example 9 of WO2013071865A1.

Example 2 N-{3-[3-(9H-indol-6-yl)pyridin-2-ylamino]-4-chloro-2-fluorophenyl}-3-fluoropropane-1-sulfonamide p-toluene Preparation of acid salt (compound of formula II)

To a solution of the compound of the formula I (10.00 g, 0.021 mol) in tetrahydrofuran (200 mL), EtOAc (EtOAc) Stirring was continued for 2 hours after addition to give the compound of formula II (12.70 g, 94%).

Preparation of the crystal of the compound of the formula II of Example 3

To a one-necked flask containing the compound of the formula II (1.00 g) obtained in Example 2, anhydrous ethanol (200 mL) was added, and the mixture was stirred under reflux for 2 hours. After hot filtration, the filtrate was slowly dissolved and allowed to cool to room temperature, and stirring was continued overnight. Filtration, washing with ethanol, and drying under vacuum at 40 ° C gave crystals of the compound of formula II (0.65 g).

Preparation of the crystal of the compound of the formula II of Example 4

Methanol (60 mL) was added to a one-necked flask containing the compound of formula II (1.00 g) obtained in Example 2, and stirred under reflux for 2 hours. After hot filtration, the filtrate was slowly dissolved and allowed to cool to room temperature, and stirring was continued overnight. Filtration, washing with methanol, and drying in vacuo at 40 ° C afforded crystals (0.52 g).

Example 5 stability test (method refer to the Chinese Pharmacopoeia 2010 edition two appendix)

The compound of the formula II prepared in Example 3 was crystallized for a strong light irradiation test (4500 LX), a high temperature test (60 ° C) and a high humidity test (92.5%). The investigation time was 10 days, and the purity was sampled on the 0th day and the 10th day respectively. The test results are shown in Table 1.

Table 1 stability test results

time	Measurement item	HPLC normalized purity /%
0 days		99.92
10 days	Light 4500LX	99.91
10 days	High temperature 60 ° C	99.91
10 days	High humidity 92.5%	99.91

Example 6 wettability test

The crystallization of the compound of the formula II prepared in Example 3 was subjected to a wettability test. Test conditions: 25 ° C ± 1 ° C, RH80% ± 2% constant temperature and humidity box for more than 24h.

The implementation steps are as follows:

1. Glass bottle preparation

A dry stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm) was taken and placed in a suitable 25 ° C ± 1 ° C constant temperature dryer on the day before the test, and the weight (m ₁ ) was accurately weighed.

2. Test sample

Take the appropriate amount of the test sample and tiling it in the above weighing bottle. The thickness of the test sample is generally about 1 mm, and the weight is accurately weighed (m ₂ ).

3. Operation

The weighing bottle was opened and placed under the above constant temperature and humidity conditions for 24 hours with the cap, and the weighing cap was covered, and the weight (m ₃ ) was accurately weighed.

Calculation formula:

4. The results are as follows:

Table 2 results of wettability test

m 1	m 2	m 3	% gain
50.5435	53.3926	53.3996	0.246

Claims (12)

1. a compound of formula II,

   
2. Crystallization of the compound of formula II,

   

   The compound of formula II is crystallized using an X-ray powder diffraction pattern of Cu Kα radiation, and the diffraction angle (2θ ± 0.2°) has diffraction peaks at about 4.59°, 7.99°, 8.37°, 9.18°, 18.52°, and 20.78°. .
3. The crystal of the compound of formula II according to claim 2, wherein the diffraction angle (2θ ± 0.2°) is about 4.59°, 7.99°, 8.37°, 9.18°, 14.75° in an X-ray powder diffraction pattern using Cu Kα radiation. There are diffraction peaks at 16.73, 17.35, 18.52, 18.98, 20.09, 20.78, 21.60, 21.92, 23.11, 25.36, 26.08, 26.62, 27.41, 27.85 and 28.32.
4. The crystal of the compound of formula II according to claim 2, wherein the diffraction angle (2θ ± 0.2°) is about 4.59°, 7.99°, 8.37°, 9.18°, 10.86° in an X-ray powder diffraction pattern using Cu Kα radiation. , 14.75°, 16.73°, 17.35°, 18.52°, 18.98°, 20.09°, 20.78°, 21.60°, 21.92°, 23.11°, 24.30°, 25.36°, 26.08°, 26.62°, 27.41°, 27.85°, 28.32 There are diffraction peaks at °, 29.41, 30.19, 30.90, 31.97, 33.47, 34.06, 37.82, 39.38, 40.00, 42.33 and 43.93.
5. Crystallization of a compound of formula II as claimed in claim 2 having an X-ray powder diffraction pattern substantially as shown in FIG.
6. Crystallization of a compound of formula II as claimed in claim 2, wherein the differential scanning calorimetry chart has an onset temperature of about 260.5 °C.
7. A crystalline composition comprising the compound of formula II according to any one of claims 2-6, Wherein the crystal of the compound of the formula II accounts for 50% or more, 80% or more, 90% or more, 95% or more or 99% or more by weight of the crystalline composition.
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula II according to claim 1 or a crystal of a compound of formula II according to any one of claims 2 to 6 or a crystal according to claim 7 A composition, and one or more pharmaceutically acceptable carriers.
9. The compound of the formula II according to claim 1 or the crystal of the compound of the formula II according to any one of claims 2 to 6 or the crystalline composition of claim 7 or the pharmaceutical composition according to claim 8 is prepared for use in the preparation of Use in a medicament for treating a protein kinase mediated disease or condition.
10. A compound of formula II according to claim 1 or a compound of formula II according to any one of claims 2 to 6 or a crystalline composition or claim as claimed in claim 7 for use in the treatment of a protein kinase mediated disease or condition The pharmaceutical composition of claim 8.
11. A method of treating a protein kinase mediated disease or condition, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula II according to claim 1 or a compound of formula II according to any one of claims 2-6 Crystallizing the crystalline composition of claim 7 or the pharmaceutical composition of claim 8.
12. A process for the preparation of a crystal of a compound of formula II according to any one of claims 2 to 6 which comprises crystallizing a compound of formula II in a C _1-4 alcohol solvent to give a crystal of the compound of formula II.

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