HK40043661A - Crystalline forms of a quinazole compound and its hydrochloride salts - Google Patents

Description

Crystalline forms of quinazoline compounds and their hydrochlorides

Cross Reference to Related Applications

This application claims priority to U.S. provisional application No. 62/731,500, filed on 2018, 9, 14, the entire disclosure of which is incorporated herein by reference.

Technical Field

This patent document relates to crystalline forms of quinazoline compounds and their hydrochloride forms. More particularly, these crystalline forms are derived from 1- (4- (4- (3, 4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidin-1-yl) prop-2-en-1-one, and a pharmaceutical composition comprising the same.

Background

Compounds of the following chemical formula (1) having the general formula 1- (4- (4- (3, 4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidin-1-yl) prop-2-en-1-one are disclosed in korean patent No. 1,013,319 and U.S. patent No. 8,003,658, and these patents disclose that the above compounds have antiproliferative activity (e.g., anticancer activity) and can selectively and effectively treat drug resistance induced by tyrosine kinase mutation:

[ chemical formula (1) ]

However, the compounds of formula (1) prepared in the above-cited patents are generally prepared in the form of amorphous solids or incomplete crystals, which are not well suited for large-scale pharmaceutical processing, and there is no description about the preparation of specific crystalline forms.

The compound of formula (1) prepared by the above-cited patent has a disadvantage of very low solubility in water. Furthermore, since the compounds of formula (I) prepared by the cited patents are not available in a homogeneous crystalline form, meeting the physicochemical stability criteria required for pharmaceutical drugs may be distressing.

Accordingly, there is a need to prepare salts of the compounds of formula (1) in crystalline form that improve solubility in water while still adequately meeting the stringent requirements and specifications for pharmaceutical formulations.

The above information disclosed in this background section is only for enhancement of understanding of the background of the invention and therefore it is not meant in any way to constitute an admission that the information contained in the present invention constitutes prior art known to a person of ordinary skill in the art.

Disclosure of Invention

An object of the present patent document is to provide crystalline forms of the quinazoline compound of the above chemical formula (1) and crystalline hydrochloride forms thereof, and pharmaceutical compositions comprising the same.

In particular, the preferred crystalline form of the quinazoline compound of the formula (1) is

1) A crystalline hydrate form of a quinazoline compound of the formula (1), and

2) an anhydrous crystalline form of a quinazoline compound of the formula (1).

Furthermore, a preferred crystalline hydrochloride form of the quinazoline compound of the formula (1) is

1) A crystalline hydrochloride hydrate form of a quinazoline compound of the formula (1),

2) an anhydrous crystalline hydrochloride salt form of a quinazoline compound of the formula (1).

More preferred examples of crystalline forms are as follows:

crystalline dihydrate (2H) of the compound of formula (1) when irradiated with a Cu-Kalpha light source₂O) form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles (2 Θ ± 0.2 °) of 9.4 °, 13.0 ° and 18.5 °;

the anhydrous crystalline form I of the compound of formula (1) has an XRPD pattern comprising peaks at diffraction angles (2 Θ ± 0.2 °) of 6.0 °, 18.3 ° and 22.7 ° when illuminated with a Cu-ka light source;

the anhydrous crystalline form II of the compound of formula (1) has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2 Θ ± 0.2 °) of 4.9 °, 5.9 ° and 11.8 ° when irradiated with a Cu-K α light source;

when irradiated with a Cu-Ka light sourceCrystalline monohydrochloride monohydrate (1HCl · 1H) of a compound of formula (1)₂O) form has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2 Θ ± 0.2 °) of 8.9 °, 13.4 °, 21.1 ° and 23.5 °; and

an anhydrous crystalline monohydrochloride (1HCl) form of the compound of formula (1) has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2 Θ ± 0.2 °) of 9.5 °, 23.0 °, 23.2 °, and 23.5 ° when illuminated with a Cu-ka light source; and crystalline dihydrate (2H) of the compound of formula (1)₂O) forms having chemical shifts (ppm. + -. 0.5ppm) comprising 165.4ppm, 156.2ppm and 147.7ppm¹³C CP/MAS TOSS (total suppression of cross-polarized/magic angle spinning sidebands) solid-state nuclear magnetic resonance (ssNMR) spectroscopy;

anhydrous crystalline forms of the compound of formula (1) formula I having chemical shifts (ppm. + -. 0.5ppm) comprising 156.7ppm, 146.9ppm, 127.3ppm and 54.3ppm¹³C CP/MAS TOSS solid-state nuclear magnetic resonance spectroscopy;

anhydrous crystalline form II of the compound of formula (1) having chemical shifts (ppm. + -. 0.5ppm) comprising 165.2ppm, 156.7ppm, 153.1ppm and 129.2ppm¹³C CP/MAS TOSS ssNMR spectra;

crystalline monohydrochloride monohydrate (1HCl · 1H) of compound of formula (1)₂O) forms having chemical shifts (ppm. + -. 0.5ppm) comprising 164.5ppm, 157.8ppm and 145.8ppm¹³C CP/MAS TOSS solid-state nuclear magnetic resonance spectroscopy; and

anhydrous crystalline monohydrochloride (1HCl) form of the compound of formula (1) having chemical shifts (ppm. + -. 0.5ppm) comprising 163.0ppm, 158.7ppm and 146.9ppm¹³C CP/MAS TOSS solid-state nuclear magnetic resonance spectroscopy.

The crystalline form of the compound of formula (1) or its hydrochloride salt is "substantially pure", wherein the expression "substantially pure" denotes at least 95%, preferably 99%.

That is, a purity of 95% to 99% means that the specific crystalline form of the compound of formula (1) or its hydrochloride is 95% to 99% or more, and the other crystalline forms (amorphous or crystalline form of the compound of formula (1), except for the specific crystalline form) are 5% to 1% or less.

Furthermore, this patent document provides an amorphous monohydrochloride form of the quinazoline compound of the formula (1).

According to another object of the present invention, the present patent document provides a pharmaceutical composition comprising a crystalline form of the compound of formula (1) or a crystalline form of its hydrochloride salt, and at least one pharmaceutically acceptable carrier or diluent.

The pharmaceutical compositions have antiproliferative activity (e.g., anti-cancer activity) and are useful for selectively and effectively treating resistance induced by tyrosine kinase mutations.

The crystalline form of the compound of formula (1) according to the present patent document and the hydrochloride crystalline form thereof are excellent in various physical and chemical properties such as solubility in water, hygroscopicity and chemical stability, and thus can be easily used for producing a pharmaceutical composition containing the same as an active ingredient.

Also provided is a method of treating a tumor in a subject comprising administering to a subject in need thereof a novel crystalline form of a compound of formula (1), a pharmaceutical composition thereof, or a composition thereof with one or more other agents.

Another aspect of this patent document provides a method of preparing the crystalline form of the present invention.

Drawings

The above and other features of the crystalline forms will now be described in detail with reference to certain exemplary embodiments illustrated in the accompanying drawings, which are given by way of illustration only, and thus do not limit the invention, and wherein:

fig. 1A, 1B, 1C, 1D and 1E show X-ray powder diffraction (XRPD) spectra of a compound of formula (1) and its crystalline hydrochloride salt form according to an example: figure 1A shows the XRPD of the crystalline form prepared in example 1; figure 1B shows the XRPD of the crystalline form prepared in example 2; figure 1C shows the XRPD of the crystalline form prepared in example 3; figure 1D shows the XRPD of the crystalline form prepared in example 4; figure 1E shows the XRPD of the crystalline form prepared in example 5.

Fig. 1F and 1G show XRPD spectra of the compound of formula (1) and its amorphous hydrochloride salt form according to a comparative example; figure 1F shows the XRPD of the amorphous form prepared in example 6; fig. 1G shows XRPD of the compound of formula (1) prepared in the reference example.

Fig. 2A, 2B, 2C, 2D, and 2E show solid state nuclear magnetic resonance (ssNMR) spectra of a compound of formula (1) and its crystalline hydrochloride salt form according to an embodiment; FIG. 2A shows ssNMR of the crystalline form prepared in example 1; FIG. 2B shows ssNMR of the crystalline form prepared in example 2; FIG. 2C shows ssNMR of the crystalline form prepared in example 3; FIG. 2D shows ssNMR of the crystalline form prepared in example 4; fig. 2E shows ssNMR of the crystalline form prepared in example 5.

Fig. 2F and 2G show ssNMR spectra of the compound of formula (1) and its amorphous hydrochloride salt form according to comparative examples; figure 2F shows an amorphous form of DVS prepared in example 6; fig. 2G shows ssNMR of the compound of formula (1) prepared in the reference example.

Fig. 3A, 3B, 3C, 3D, and 3E show Differential Scanning Calorimetry (DSC) profiles of a compound of formula (1) and its crystalline hydrochloride salt form according to an embodiment; FIG. 3A shows DSC of the crystalline form prepared in example 1; FIG. 3B shows DSC of the crystalline form prepared in example 2; figure 3C shows DSC of the crystalline form prepared in example 3; figure 3D shows DSC of the crystalline form prepared in example 4; figure 3E shows the DSC of the crystalline form prepared in example 5.

Fig. 4A, 4B, 4C, 4D, and 4E illustrate dynamic vapor adsorption (DVS) profiles of a compound of formula (1) and crystalline hydrochloride salt forms thereof, according to an embodiment; fig. 4A shows the crystalline form of DVS prepared in example 1; fig. 4B shows the crystalline form of DVS prepared in example 2; fig. 4C shows the DVS in crystalline form prepared in example 3; figure 4D shows the DVS in crystalline form prepared in example 4; fig. 4E shows the DVS in crystalline form prepared in example 5.

Fig. 4F and 4G show DVS plots of the compound of formula (1) and its amorphous hydrochloride salt form according to comparative examples; FIG. 4F shows ssNMR of the amorphous form prepared in example 6; and fig. 4G shows DVS of the compound of formula (1) prepared in the reference example.

Detailed Description

The present invention has been described in detail with reference to the preferred embodiments thereof. However, it would be appreciated by those skilled in the art that changes may be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the claims and their equivalents.

Definition of

Terms not specifically defined in the present specification have meanings that are understood by those skilled in the art from the technical and context. However, unless otherwise indicated, the following terms have the meanings indicated throughout the specification:

the term "about" as used herein means within 5%, preferably between 1% and 2% of a given value or range. For example, the expression "about 10%" means 9.5% to 10.5%, preferably 9.8% to 10.2%. As another example, the expression "about 100 ℃ C" means from 95 ℃ to 105 ℃, preferably from 98 ℃ to 102 ℃.

The term "chemical purity" as used herein refers to the weight% of a particular chemical entity, including a particular polymorphic form. For example, when the crystalline dihydrate (2H) of the compound of formula (1)₂O) is characterized by a chemical purity of greater than 95%, which means that greater than 95% by weight of the substance is the crystalline dihydrate (2H) of the compound of formula (1)₂O), less than 5% by weight of any other compound (including other amorphous and/or polymorphic forms). Similarly, when the specific monohydrochloride monohydrate crystalline form of the compound of formula (1) (1HCl 1H)₂O) is characterized by a chemical purity of greater than 95%, this particular crystalline form represents greater than 95% by weight of all forms of the compound of formula (1) in the same composition, including, for example, crystalline or amorphous forms, salt forms or non-salt forms, hydrates or anhydrous forms. In this context, the term "derived fromRaw "means that a desired crystalline form (e.g., anhydrous form, hydrate form, or pharmaceutically acceptable salt) of the compound of formula (1) is formed without changing the chemical structure of the compound. The term "pozitinib" as used in the present invention refers to any crystalline form of the compound of formula (1).

The peak in diffraction angle (2 θ) of the X-ray powder diffraction (XRPD) spectrum reported in this patent document is preferably within ± 0.5%, more preferably within ± 0.2% of the experimental error typically observed in the art.

Moreover, the chemical shifts in the solid-state nuclear magnetic resonance spectra reported in this patent document are to be preferably interpreted to within. + -. 0.5ppm, more preferably within. + -. 0.2%.

Crystalline forms of a quinazoline compound of formula (1) and crystalline hydrochloride forms thereof

This patent document provides compounds of the following formula (1), 1- (4- (4- (3, 4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidin-1-yl) prop-2-en-1-one and crystalline hydrochloride forms thereof:

[ chemical formula (1) ]

The compound of the above chemical formula (1) may be prepared according to the general procedure described in korean patent No. 1,013,319 and U.S. patent No. 8,003,658. All of these patent documents are incorporated by reference in their entirety.

The compound of formula (1) described in the above document is a poorly soluble compound which is amorphous and has a solubility in water of less than 1.0. mu.g/mL.

Generally, it is known that converting the free radical into a salt form helps to dissolve water-insoluble drug substances. However, these salts must have various physicochemical properties required pharmacologically, such as reproducibility for preparing a specific crystalline form, high crystallinity, stability of the crystalline form, chemical stability, non-hygroscopicity, and the like.

In order to select a suitable salt form of the compound of formula (1), different salts of the compound of formula (1) were prepared using different acids and solvents according to different conditions and processes, and their physicochemical properties were evaluated. Among the salts thus prepared, the different forms of the crystalline forms of the hydrochloride salt of the compound of formula (1) are the most excellent in terms of different physicochemical properties required pharmacologically, such as reproducibility in preparing a specific crystalline form, high crystallinity, stability of the crystalline form, chemical stability, non-hygroscopicity and the like.

Crystalline forms of a quinazoline compound of formula (1) and crystalline hydrochloride forms thereof

The salt of the compound of formula (1) may be prepared in a crystalline form, an amorphous form, or a mixture thereof, but preferably the salt is in a crystalline form. The crystalline hydrochloride form of the compound of formula (1) is preferred because of its excellent stability and physicochemical properties for ease of formulation.

According to the present invention, the compound of formula (1) may be in the form of various crystalline forms, for example, its crystalline dihydrate (2H)₂O) form and amorphous form.

According to the invention, the compound of formula (1) may also be in the form of various crystalline hydrochloride salts, for example, the crystalline monohydrochloride monohydrate (1HCl · 1H)₂O) form and its anhydrous crystalline monohydrochloride (1HCl) form.

Among the crystalline hydrochloride salts, as a result of the test of test example 1 described later, the solubility of the anhydrous crystalline monohydrochloride salt form in water is the most excellent, and as a result of the test of test example 2, it may be advantageous in terms of non-hygroscopicity and stability, and thus may be desirable as a useful active ingredient in a pharmaceutical composition.

Hereinafter, each of the crystalline forms according to the present patent document will be described in more detail.

As an example, this patent document provides a crystalline dihydrate (2H) of the compound of formula (1)₂O) form.

When in useCrystalline dihydrate (2H) of the compound of formula (1) when irradiated with a Cu-Kalpha light source₂O) has an XRPD spectrum comprising peaks at diffraction angles (2 θ ± 0.2 °) of 9.4 °, 11.4 °, 13.0 °, 16.1 °, 18.5 °, 19.3 °, 24.9 ° and 26.3 °. These peaks may be peaks having a relative intensity of about 10% to 20% or more.

The above crystalline forms may be in¹³The C CP/MASTOSS solid-state nuclear magnetic resonance (total suppression of cross-polarization/magic angle spin-sideband solid-state nuclear magnetic resonance, ssNMR) spectrum had chemical shifts of 147.7ppm, 156.2ppm, and 165.4ppm (ppm. + -. 0.5 ppm).

The crystalline form may have a moisture content of about 7.5% (theoretical moisture content of 6.83%), a condensation temperature of about 117 ℃ and 122 ℃ and a melting point of about 190 ℃ and 195 ℃.

The crystalline form described above may have an endothermic peak with a lowest point at about 111 ℃ when run from an onset of about 79 ℃ as measured by DSC (10 ℃/min).

The crystalline form has a hygroscopicity value of about 2% to 5% as measured by DVS in the relative humidity range of 0% to 90%.

As another example, this patent document provides anhydrous crystalline forms of the compound of formula (1) formula I.

The anhydrous crystalline form I of the compound of formula (1) has an XRPD spectrum comprising peaks at diffraction angles (2 Θ ± 0.2 °) of 6.0 °, 10.6 °, 10.9 °, 12.1 °, 16.0 °, 17.5 °, 18.3 °, 19.2 °, 20.3 °, 22.7 °, 23.7 ° and 26.3 ° when illuminated with a Cu-ka light source. These peaks may be peaks having a relative intensity of about 10% to 20% or more.

The above crystalline forms are described in¹³The C CP/MAS TOSS solid-state nuclear magnetic resonance (ssNMR) spectrum may have chemical shifts (ppm. + -. 0.5ppm) of 54.3ppm, 127.3ppm, 146.9ppm, and 156.7 ppm.

The crystalline form described above may have a moisture content of about 0.1% and a melting point of about 190 ℃ to 195 ℃.

The crystalline form described above may have an endothermic peak with a lowest point at about 191 ℃ when run from an onset of about 186 ℃, as measured by DSC (10 ℃/min).

The crystalline form described above has a hygroscopicity value of about 0.5% as measured by DVS in the range of 10% to 50% relative humidity and a hygroscopicity value of about 3% as measured in the range of 50% to 90% relative humidity.

As another example, this patent document provides anhydrous crystalline form II of the compound of formula (1).

The anhydrous crystalline form II of the compound of formula (1) may have an XRPD spectrum comprising peaks at diffraction angles (2 Θ ± 0.2 °) of 4.9 °, 5.9 °, 11.8 °, 18.8 ° and 19.9 ° when illuminated with a Cu-ka light source. These peaks may be peaks having a relative intensity of about 10% to 20% or more.

The above crystalline forms are described in¹³The C CP/MASTOSS solid state nuclear magnetic resonance (ssNMR) spectrum may have chemical shifts of 129.2ppm, 153.1ppm, 156.7ppm, and 165.2ppm (ppm. + -. 0.5 ppm).

The crystalline form may have a moisture content of about 0.3% and a melting point of about 183 ℃ to 185 ℃.

The crystalline form described above has a very low hygroscopicity, as measured by DVS, measured in the relative humidity range of 0% to 90%.

The crystalline form described above may have an endothermic peak with a lowest point at about 185 ℃ when run from an onset of about 181 ℃, as measured by DSC (10 ℃/min).

The crystalline form described above has a very low hygroscopicity, as measured by DVS, measured in the relative humidity range of 0% to 90%.

As another example, this patent document provides a crystalline monohydrochloride monohydrate (1 HCl.1H) of a compound of formula (1)₂O) form.

Crystalline monohydrochloride monohydrate (1HCl 1H) of a compound of formula (1) when irradiated with a Cu-K α light source₂O) form may have an XRPD spectrum comprising peaks at diffraction angles (2 θ ± 0.2 °) of 8.9 °, 13.4 °, 14.1 °, 16.0 °, 19.8 °, 21.1 °, 21.7 °, 23.5 °, 25.7 °, and 32.7 °. These peaks may be peaks having a relative intensity of about 10% to 20% or more.

The above crystalline forms are described in¹³The C CP/MASTOSS solid state nuclear magnetic resonance (ssNMR) spectrum may have chemical shifts of 145.8ppm, 157.8ppm, and 164.5ppm (ppm. + -. 0.5 ppm).

The crystalline form described above may have an endothermic peak with a lowest point at about 151 ℃ and an endothermic peak at about 178 ℃ when run from an onset of about 127 ℃, as measured by DSC (10 ℃/min).

The crystalline form may have a moisture content of about 3.2% (3.30% of theoretical moisture content) and a melting point of about 187-193 ℃.

The crystalline form described above has a very low hygroscopicity, as measured by DVS, measured in the relative humidity range of 10% to 90%.

As another example, this patent document provides an anhydrous crystalline monohydrochloride (1HCl) form of the compound of formula (1).

The anhydrous crystalline monohydrochloride (1HCl) form of the compound of formula (1) may have an XRPD spectrum comprising peaks at diffraction angles (2 θ ± 0.2 °) of 9.5 °, 12.3 °, 13.0 °, 13.5 °, 14.2 °, 21.4 °, 23.0 °, 23.2 °, 23.5 °, 27.2 ° and 27.5 ° when illuminated with a Cu-ka light source. These peaks may be peaks having a relative intensity of about 10% to 20% or more.

The above crystalline forms are described in¹³The C CP/MASTOSS solid state nuclear magnetic resonance (ssNMR) spectrum may have chemical shifts of 146.9ppm, 158.7ppm, and 163.0ppm (ppm. + -. 0.5 ppm).

The crystalline form described above may have an endothermic peak with a lowest point at about 230 ℃ when run from an onset of about 20 ℃, as measured by DSC (10 ℃/min).

The crystalline form may have a moisture content of about 0.1% and a melting point of about 238 ℃ to 243 ℃.

The crystalline form described above has a very low hygroscopicity, as measured by DVS, measured in the relative humidity range of 10% to 90%.

According to the present patent document a general process for the preparation of crystalline forms (hydrates or anhydrous) of the compound of formula (1) is provided. The method comprises the following steps:

(a) providing a solution of a compound of formula (1) in a solvent system (protic, aprotic, or mixed);

(b) cooling the solution to form a crystalline form (hydrate or anhydrous) of the compound of formula (1); and

(c) isolating a crystalline form (hydrate or anhydrous) of the compound of formula (1).

Also provided is a process for preparing a crystalline hydrochloride salt form (hydrate or anhydrous) of the compound of formula (1). The method comprises the following steps:

(a) providing a solution of a compound of formula (1) in a solvent system (protic, aprotic, or mixed);

(b) adding hydrochloric acid to the solution;

(c) cooling the solution to form a crystalline hydrochloride salt form (hydrate or anhydrous) of the compound of formula (1); and

(d) isolating the crystalline hydrochloride salt form (hydrate or anhydrous) of the compound of formula (1).

Non-limiting examples of solvent systems are as follows: acetone; acetonitrile; acetone/water; acetonitrile/water; ethanol; ethanol/water, DMSO; DMSO/water; DMF; DMF/water.

The process is highly reproducible and the crystalline product obtained has good filterability.

The crystalline form (hydrate or anhydrous) of the compound of formula (1) and the crystalline hydrochloride form (hydrate or anhydrous) thereof according to this patent document do not require specific storage conditions and can be stably maintained for a long time. Capable of satisfying physicochemical properties required for drugs, including excellent water solubility, they can be easily used for the manufacture of pharmaceutical compositions containing them as active ingredients.

The crystalline form (hydrate or anhydrous) of the compound of formula (1) according to this patent document has high chemical purity. In some embodiments, the chemical purity is greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 99%.

Pharmaceutical composition

As disclosed in korean patent No. 1,013,319 and U.S. patent No. 8,003,658, the entire contents of which are incorporated herein, it has been confirmed that the compound of formula (1) has antiproliferative activity, such as anticancer activity, and has activity of selectively and effectively inhibiting the growth and drug resistance of cancer cells induced by tyrosine kinase or mutation thereof.

In this regard, the crystalline form of the compound of formula (1) and the hydrochloride thereof may be used for the preparation of a pharmaceutical composition for the treatment or prevention of various solid cancers (such as cancer or tumor, particularly lung cancer, breast cancer, etc.) caused by tyrosine kinase or mutation thereof.

The dosage of the crystalline forms of the compound of formula (1) and the hydrochloride salts thereof may vary according to the subject to be treated, the severity of the disease or condition, the rate of administration and the judgment of the prescribing physician, but they will generally be administered as the active ingredient to a 70kg subject in an amount of 1-2000 mg/kg body weight (based on the free base of the compound of formula (1)), preferably 5-1000 mg, based on the compound of formula (1), by oral or parenteral route, in time or non-time, once to four times daily. In some cases, a dosage less than the above range may be more suitable, a dosage greater than the above range may also be used without causing harmful side effects, and in the case of higher doses, multiple administrations are given in divided doses per day.

The pharmaceutical compositions according to this patent document can be formulated according to conventional methods and can be prepared in various oral dosage forms (e.g., tablets, pills, powders, capsules, syrups, emulsions or microemulsions, etc.) or administered in parenteral dosage forms (e.g., intramuscular, intravenous or subcutaneous).

When the pharmaceutical composition according to the present patent document is prepared in the form of an oral formulation, examples of the carrier include cellulose, calcium silicate, corn starch, lactose, sucrose, glucose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents, diluents and the like. When the pharmaceutical composition according to the present patent document is prepared in the form of an injection, examples of the carrier include water, physiological saline, aqueous glucose solution, pseudosugar (pseudosugar) aqueous solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid ester, glyceride, surfactant, suspending agent, emulsifier, and the like.

In some embodiments, the pharmaceutical composition further comprises a non-metallic salt lubricant selected from the group consisting of glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl trimyristate, glyceryl tristearate, sucrose fatty acid ester, palmitic acid, palmitoyl alcohol, stearic acid, stearyl alcohol, fumaric acid, polyethylene glycol 4000, polyethylene glycol 6000, polytetrafluoroethylene, starch, talc, hydrogenated castor oil, mineral oil, hydrogenated vegetable oil, silicon dioxide, and any combination thereof.

In some embodiments, the pharmaceutical composition further comprises a metal salt lubricant. Non-limiting examples include magnesium stearate, magnesium silicate, stearic acid, and calcium stearate.

A related aspect of the invention includes a kit for treating cancer comprising a crystalline form of the invention or a pharmaceutical composition thereof. The kit or pharmaceutical composition may contain additional cytotoxic or molecular targeting agents. The crystalline form of the invention or pharmaceutical composition thereof and the additional cytotoxic agent may be administered sequentially or simultaneously, depending on the particular condition of the subject.

Cytotoxic agents refer to agents that have a cytotoxic effect on cells. Cytotoxic effects refer to the depletion, elimination and/or killing of target cells (i.e., tumor cells). The cytotoxic agent may be at least one selected from the group consisting of an antimetabolite, a mitotic inhibitor, an alkylating agent, a platinum-based antineoplastic agent, an mTOR inhibitor, a VEGF inhibitor, an aromatase inhibitor and a CDK4/6 inhibitor. The kit or pharmaceutical composition may comprise at least two cytotoxic agents. For example, the composition may comprise at least 2, at least 3 or at least 4 selected from the group consisting of antimetabolites, mitotic inhibitors, alkylating agents, platinum-based antineoplastic agents, mTOR inhibitors, VEGF inhibitors, aromatase inhibitors, CDK4/6 inhibitors, and all thereof.

An antimetabolite can be an agent that inhibits DNA synthesis in a cell by inhibiting the formation of purines or pyrimidines (which are nucleotide based). The antimetabolite may be selected from Capecitabine (Capecitabine), 5-fluorouracil, Gemcitabine (Gemcitabine), Pemetrexed (Pemetrexed), Methotrexate (Methotrexate), 6-mercaptopurine (mercaptopurine), Cladribine (Cladribine), arabinoside (Cytarabine), doxifluridine (doxifluorine), floxuridine, Fludarabine (Fludarabine), hydroxyurea (hydroxyarbamide), dacarbazine (decazine), hydroxyurea (hydroxyurea), and asparaginase.

The mitotic inhibitor may be a microtubule destabilizer, a microtubule stabilizer, or a combination thereof. The mitotic inhibitor can be a taxane (taxane), a vinca alkaloid (vinca alkaloid), an epothilone (epothilone), or a combination thereof.

The mitotic inhibitor is selected from BT-062, HMN-214, eribulin mesylate, vindesine, D-1069, EC-1456, EC-531, vintafolide, 2-methoxyestradiol, GTx-230, trastuzumab (trastuzumab emtansine), crolinin, D1302A-maytansinoid conjugate IMGN-529(D1302A-maytansinoid conjugates IMGN-529), moxin-lovastatin (loratuzumab mertansine), SAR-3419, SAR-566658, IMP-03138, topotecan/vincristine (vindesine) composition, BPH-8, CA4P, tromethamine (sbutyrin), vinorelbine (vincristine), vinorelbine (vinorelbine), vinorelbine (sodium phosphate), vinblastine (vinblastine), vinblastine acetate (sodium citrate), vinblastine (sodium citrate (sodium phosphate), vinblastine (sodium citrate (acetate), vinblastine (sodium citrate (acetate), vinblastine) (sodium citrate), vinblastine) (vinblastine) composition), vinblastine (sodium citrate (potassium citrate), vinblastine) (, Epothilone A, paclitaxel (patupilone), ixabepilone (ixabepilone), epothilone D, paclitaxel, docetaxel (docetaxel), DJ-927, discodermolide (discodermolide), eleutherobin (eleutherobin), and pharmaceutically acceptable salts or combinations thereof.

As used herein, an "alkylating agent" is one which is substituted with one or more alkyl groups (C)_nH_mWhere n and m are integers) to nucleic acids. In the present invention, the alkylating agent is selected from the group consisting of nitrogen mustards, nitrosoureas, alkyl sulfonates, triazines, ethyleneimines, and combinations thereof. Non-limiting example packages of nitrogen mustardsIncluding dichloromethyldiethanamine, chlorambucil, cyclophosphamide, bendamustine (bendamustine), ifosfamide, melphalan (melphalan), melphalan flufenamide, and pharmaceutically acceptable salts thereof. Non-limiting examples of nitrosoureas include streptozotocin (streptozocin), carmustine (carmustine), cyclohexylnitrosourea, and pharmaceutically acceptable salts thereof. Non-limiting examples of alkyl sulfonates include busulfan and pharmaceutically acceptable salts thereof. Non-limiting examples of triazines include dacarbazine, temozolomide (temozolomide), and pharmaceutically acceptable salts thereof. Non-limiting examples of ethyleneimine include thiotepa, altretamine, and pharmaceutically acceptable salts thereof. Other alkylating agents include ProLindac, Ac-225BC-8, ALF-2111, Triphosporamine, MDX-1203, thioureidobutyronitrile, dibromomannitol, dibromodulcitol, nimustine (nimustine), glufosfamide, a combination of HuMax-TAC and PBD ADC, BP-C1, busulfan (tresufan), nifurolimus (nifurtimox), improsulfan tosylate (improsulfan toilate), ranimustine (ranimustine), ND-01, HH-1, 22P1G cells and a combination of ifosfamide, estramustine phosphate (estramustine phosphate), prednimustine (prednimustine), lubeitidine (lurbinectin), pethidine (trabectedin), hexamethylmelamine (altretamine), SGN-CD33A, fotemustine (fotemustine), nedaplatin (nedaplatin), heptaplatin (heptaplatin), apastin (apazinone), apazirazinone (tluophone), tlu-58747 k, and pharmaceutically acceptable salts thereof.

The platinum-based antitumor agent may be, for example, Cisplatin (Cisplatin), carboplatin (carboplatin), Dicycloplatin (Dicycloplatin), Eptaplatin (Eptaplatin), Lobaplatin (Lobaplatin), Miriplatin (Miriplatin), nedaplatin, Oxaliplatin (oxaiplatin), Picoplatin (Picoplatin) or Satraplatin (Satraplatin).

The term "mTOR inhibitor (mTOR inhibitor)" as used herein is a material used to inhibit the mTOR signaling pathway of conventional anticancer agents or immunosuppressants. The mTOR inhibitor may be rapamycin (rapamycin), temsirolimus (temsirolimus), everolimus (everolimus), ridaforolimus (ridaforolimus), MLN4924, XL388, GDC-0349, AZD2014, AZD8055, GSK105965, MLN0128 ridaforolimus, and the like.

A "VEGF inhibitor" as used herein is any substance that reduces VEGF-VEGFR pathway signaling. VEGF inhibitors can be small molecules, peptides, polypeptides, proteins, including more specific antibodies, including anti-VEGF antibodies, anti-VEGFR antibodies, intrabodies, macroantibodies (maxibodies), minibodies (minibodies), diabodies, Fc fusion proteins (e.g., peptibodies, receptors, soluble VEGF receptor proteins and fragments), and a variety of other antibodies, to name a few. Many VEGF inhibitors act by binding to VEGF or VEGF receptors. Other VEGF inhibitors act more indirectly by binding to VEGF or elements of VEGF receptors or other components of the VEGF signaling pathway. Still other VEGF inhibitors work by altering post-translational modifications that regulate the regulation of VEGF pathway signaling. VEGF inhibitors according to the invention may also act by a more indirect mechanism. Regardless of the mechanism involved, as used herein, a VEGF inhibitor reduces the effective activity of the VEGF signaling pathway in a given situation, over that which would be the case in the same situation in the absence of the inhibitor.

Non-limiting examples of VEGF inhibitors include: (a)4TBPPAPC or a closely related compound as described in US2003/0125339 or US patent No.6,995,162, which are incorporated herein by reference in their entirety, particularly disclosing the 4TBPPAPC and closely related VEGF inhibitor moieties; (b) AMG 706 or closely related substituted alkylamine derivatives as described in US2003/0125339 or US2003/0225106 or US patent No.6,995,162 or US patent No.6,878,714, each of which is incorporated herein by reference in its entirety, and in particular discloses AMG 706 and these closely related VEGF inhibitor moieties; (c) avastin^TMOr a closely related non-naturally occurring humanized monoclonal antibody that binds to VEGF is a VEGF inhibitor and is related in sequence to Avastin^TMAt least 90% identical; (d)or closely related substituted omega-carboxyaryl diphenylureas or derivatives thereof as described in WO00/42012, WO00/41698, US2005/0038080A1, US2003/0125359A1, US2002/0165394A1, US2001/003447A1, US2001/0016659A1 and US2002/013774A1, the entire contents of which are hereby incorporated by reference, especially disclosing parts of these VEGF inhibitors; (e) PTK/ZK or closely related anilinophthalazine (anilinophthhalazine) or derivatives thereof that bind to and inhibit the activity of a variety of receptor tyrosine kinases, including binding to protein kinase domains, and inhibition of VEGFR1 and VEGFR 2; (f)or (5- [ 5-fluoro-2-oxo-1, 2-indolin- (3Z) -ylidenemethyl) which is a VEGF inhibitor]-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid [ 2-diethylaminoethyl group]Amides); and (g) VEGF inhibitors as described in US2006/0241115, including those of formula IV therein.

Other examples of VEGF inhibitors are as follows: (a)4TBPPAPC as described in US2003/0125339 or U.S. patent No.6,995,162, the entire contents of which are incorporated herein by reference, particularly disclosing part of the 4 TBPPAPC; (b) AMG 706 as described in US2003/0125339 or US patent No.6,995,162 or US patent No.6,878,714, the entire contents of which are incorporated herein by reference, particularly to disclose portions of AMG 706; (c) avastin^TM(ii) a (d) Such as described in WO00/42012, WO00/41698, US2005/0038080A1, US2003/0125359A1, US2002/0165394A1, US2001/003447A1, US2001/0016659A1 and US2002/013774A1The entire contents of these patents are incorporated by reference into this application, specifically for disclosureA moiety of (a); (e) PTK/ZK; (f)and (g) a VEGF inhibitor of formula IV as described in US 2006/0241115.

In some embodiments, the VEGF inhibitor is pegaptanib (pegaptanib). In one embodiment, the VEGF inhibitor is bevacizumab (bevacizumab). In one embodiment, the VEGF inhibitor is ranibizumab (ranibizumab). In one embodiment, the VEGF inhibitor is lapatinib (lapatinib). In one embodiment, the VEGF inhibitor is sorafenib (sorafenib). In one embodiment, the VEGF inhibitor is sunitinib (sunitinib). In one embodiment, the VEGF inhibitor is axitinib. In one embodiment, the VEGF inhibitor is pazopanib (pazopanib). In one embodiment, the VEGF inhibitor is aflibercept.

"aromatase inhibitors" refers to non-steroidal and steroidal compounds that inhibit aromatase, thereby preventing the conversion of androgens to estrogens, preferably those that inhibit aromatase activity in vitro and have an IC50 value of less than 10-5M, and pharmaceutically acceptable salts thereof. Exemplary aromatase inhibitors for use in the methods of the present invention include, but are not limited to, anastrozole (anastrozole), letrozole (letrozole), exemestane (exemestane), vorozole (vorozole), formestane (formestane), fadrozole (fadrozole), aminoglutethimide (aminoglutethimide), testolactone, 4-hydroxyandrostenedione, l,4, 6-androstatriene-3, 17-dione, and 4-androstene-3, 6, 17-trione.

The terms "cyclin-dependent protein kinase 4/6 inhibitor" and "CDK 4/6 inhibitor" as used herein refer to a compound that selectively targets, reduces or inhibits at least one activity of CDK4 and/or CDK 6. Non-limiting examples of CDK4/6 inhibitors include Abbecilib (Abemaciclib) (LY2835219), palbociclib (palbociclib) (PD0332991), LEE-011 (ribociclib)), LY2835219 (Abbecilib), G1T28-1, SHR6390, or P276-00, or a derivative of any of palbociclib, LEE-011, G1T28-1, SHR6390, or P276-00. In certain embodiments, the CDK4/6 inhibitor may be derived from a pyridopyrimidine, pyrrolopyrimidine, or indolocarbazole compound.

As used herein, a "molecular targeting agent" is a functional substance that interferes with a single molecule or group of molecules when administered to a subject, preferably those involved in tumor growth and development. Non-limiting examples of molecular targeting agents of the present patent document include unidirectional signal transduction inhibitors, modulators of gene expression and other cellular functions, immune system modulators, antibody-drug conjugates (ADCs), and compositions thereof.

The molecular targeting agent can be selected from the group consisting of epidermal growth factor receptor family inhibitors (EGFRi), mammalian rapamycin target protein (mTor) inhibitors, immune checkpoint inhibitors, Anaplastic Lymphoma Kinase (ALK) inhibitors, B-cell lymphoma-2 (BCL-2) inhibitors, B-Raf inhibitors, cyclin-dependent protein kinase inhibitors (CDKi), ERK inhibitors, histone deacetylase inhibitors (HDACi), heat shock protein 90 inhibitors (HSP90i), Janus kinase inhibitors, mitogen-activated protein kinase (MAPK) inhibitors, MEK inhibitors, Poly ADP Ribose Polymerase (PARP) inhibitors, phosphoinositide 3-kinase inhibitors (PI3Ki), Ras inhibitors, and combinations thereof.

The molecular targeting agent may be selected from ado-trastuzumab, alemtuzumab (alemtuzumab), cetuximab (cetuximab), tiprimumab (ipilimumab), ofatumumab (ofatumumab), panitumumab (panitumumab), pertuzumab (pertuzumab), rituximab (rituximab), tositumomab (tositumomab), 131I-tositumomab, trastuzumab, bentuximab (brentuximab vedotin), dinil (denileukin diftitox), ibritumomab (ibritumomab tiuxetan), axitinib (axitinib), bortezomib (bortezomib), bosutinib (bosutinib), cabozatinib (cabozatinib), bortezomib (bortezomib), bosutinib (bortetinib), bosutinib (bortezomib), cabozoiib (cabozolinib), erlotinib (bortezomib), erlotinib (erlotinib), erlotinib (bortezomib (nifediib), erlotinib (bortezomib), erlotinib (bortebuclizib), erlotinib (bortebuclizib), gefitinib (bortebuclizib), erlotinib (gefitinib (bortebuclizib), gefitinib (ge, Ruxolitinib (ruxolitinib), sorafenib, sunitinib, tofacitinib (tofacitinib), vandetanib (vandetanib), vemurafenib (vemurafenib), alitretinoin (alitentin), bexarotene (bexarotene), everolimus, romidepsin (romidepsin), temsirolimus, tretinoin (tretinoin), vorinostat (vorinostat), and pharmaceutically acceptable salts or compositions thereof. The molecular targeting agent may comprise an antibody or antibody moiety.

EGFRi may be selected from erlotinib, gefitinib, lapatinib, canertinib (canetinib), pelitinib (pelitinib), neratinib (neratinib), (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) but-2-enoyl) azepin-3-yl) -1H-benzo [ d ] imidazol-2-yl) -2-methylisonicotinamide, trastuzumab, Margetuximab, panitumumab, matuzumab (matuzumab), rituximab (Necitumumab), pertuzumab, nimotuzumab (nimotuzumab), lutumab, cetuximab, erlotinib (icotinib), afatinib (afatinib), and pharmaceutically acceptable salts thereof. The molecular targeting agent may be an anti-EGFR family antibody or a complex comprising an anti-EGFR family antibody. The anti-EGFR family antibody may be an anti-HER 1 antibody, an anti-HER 2 antibody, or an anti-HER 4 antibody.

Methods of treating cancer

Another aspect of the inventionThere is provided a method of treating a tumour in a subject comprising administering to a subject in need thereof the novel crystalline form of the present invention, pharmaceutical compositions thereof (in combination with one or more pharmaceutical agents) or a kit comprising the novel crystalline form.

Non-limiting examples of tumors that can be treated according to this patent document include lung cancer, breast cancer, gastric cancer, colon cancer, pancreatic cancer, prostate cancer, myeloma, head and neck cancer, ovarian cancer, esophageal cancer, or metastatic cell cancer, including non-small cell lung cancer. In some embodiments, the tumor associated with overexpression or amplification of at least one gene of HER1, HER2, and HER4 or mutants thereof may be abnormal growth of a tissue, which is commonly referred to as an amplified tumor having overexpression of at least one of HER1, HER2, HER4, and mutants thereof, or encoded by at least one gene of HER1, HER2, and HER4 or mutants thereof, if the tissue forms a tumor. The mutant may be HER1 having an exon 19 deletion, a T790M substitution, a L828R substitution, or a combination thereof. "overexpression" as used in the present invention indicates that the protein is expressed at a higher level than in normal cells. Expression levels can be measured using immunohistochemistry, Fluorescence In Situ Hybridization (FISH), or Chromogenic In Situ Hybridization (CISH).

The term "wild-type" as used herein is understood in the art to refer to a polypeptide or polynucleotide sequence that occurs in the natural population without genetic modification. As understood in the art, a "mutant" includes a polypeptide or polynucleotide sequence having at least one modification to an amino acid or nucleic acid as compared to the corresponding amino acid or nucleic acid found in a wild-type polypeptide or polynucleotide, respectively. Included within the term mutant are Single Nucleotide Polymorphisms (SNPs) in which there is a single base pair difference in the sequence of a single stranded nucleic acid as compared to the most commonly found (wild-type) strand nucleic acid.

Tumors comprising wild type, or HER1, HER2 or HER4 mutants, or cancers with amplification of the HER1, HER2 or HER4 genes, or with overexpression of the HER1, HER2 or HER4 proteins can be identified by known methods.

For example, wild-type or mutant HER1, HER2, and HER4 tumor cells can be identified by DNA amplification and sequencing techniques, DNA and RNA detection techniques (including but not limited to Northern and Southern blot hybridization), and/or various biochip and array techniques or in situ hybridization, respectively. Wild-type and mutant polypeptides can be detected by a variety of techniques, including but not limited to immunodiagnostic techniques such as ELISA, Western blot hybridization, or immunocytochemistry.

The cancer to be treated may be associated with EGFR and/or HER2 exon 20 mutations (e.g., exon 20 insertion mutations). For example, the novel crystalline forms of the compounds of this patent document or their compositions with one or more agents may be used to treat NSCLC patients suffering from EGFR exon 20 mutation.

In some aspects, the cancers treated with the novel crystalline forms of the compounds of this patent document or their combination with one or more agents are oral cancer, oropharyngeal cancer, nasopharyngeal cancer, respiratory cancer, genitourinary cancer, gastrointestinal cancer, cancer of the central or peripheral nervous system tissue, endocrine or neuroendocrine cancer or hematopoietic cancer, glioma, sarcoma, carcinoma of the malignant epithelium (carcinoma), lymphoma, melanoma, fibroma, meningioma, brain cancer, oropharyngeal cancer, nasopharyngeal cancer, renal cancer, cholangiocarcinoma, pheochromocytoma, islet cell carcinoma, Li-Fraumeni tumor, thyroid cancer, parathyroid cancer, pituitary tumor, adrenal tumor, osteosarcoma tumor, neuroendocrine tumors of types I and II, breast cancer, lung cancer, head and neck cancer, prostate cancer, esophageal cancer, tracheal cancer, liver cancer, bladder cancer, stomach cancer, pancreatic cancer, cervical cancer, and combinations thereof, Ovarian cancer, uterine cancer, cervical cancer, testicular cancer, colon cancer, rectal cancer, or skin cancer. In a particular aspect, the cancer is non-small cell lung cancer.

The term "treatment" and derivatives thereof as used herein refers to therapeutic treatment. For specific diseases, treatment refers to: (1) ameliorating or preventing a symptom of one or more physiological manifestations of the disease, (2) interfering with (a) one or more points in a biological cascade leading to or responsible for the disease, or (b) one or more physiological manifestations of the disease, (3) alleviating one or more symptoms, effects, or side effects associated with the disease or treatment thereof, or (4) slowing the progression of the disease or one or more physiological manifestations of the disease. Prophylactic treatment is therefore also contemplated. The skilled person will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to mean the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition or its physiological manifestations, or to delay the onset or physiological manifestations of such a disease. Prophylactic treatment is appropriate, for example, when the subject is considered to be at high risk of developing cancer, such as when the subject has a strong family history of cancer or when the subject is exposed to a carcinogen.

Administration of therapeutically effective amounts of novel crystalline forms of the compound of formula (1) or its combination with other agents is superior to many other conventional therapies, including: i) a stronger anti-cancer effect than the most active single agent, ii) a synergistic or highly synergistic anti-cancer activity, iii) a dosing regimen that provides enhanced anti-cancer activity and reduced side effects, iv) reduced toxicity effects, v) increased therapeutic window, vi) increased bioavailability of one or both component compounds, or vii) increased apoptosis of a single component compound.

In some embodiments, kits or compositions of the novel crystalline forms of the compound of formula (1) of this patent document may comprise bosutinib and an anti-EGFR family antibody. The anti-EGFR family antibody can be trastuzumab, cetuximab, Margetuximab, matuzumab, panitumumab, cetuximab, or pertuzumab. One example of a composition may be bosutinib and trastuzumab; or bosutinib and cetuximab. The brigatinib may be a hydrochloride salt. The composition may further comprise a cytotoxic agent. The cytotoxic agent may be a mitotic inhibitor. The mitotic inhibitor can be a taxane, a vinca alkaloid, an epothilone, or a combination thereof. The vinca alkaloid can be at least one drug selected from vinblastine, vincristine, vindesine and vinorelbine. One example of a composition may comprise bosutinib; and trastuzumab and vinorelbine. Vinorelbine may be in the form of an injection. The taxane may be paclitaxel or docetaxel. Examples of the composition may comprise bosutinib; and cetuximab and paclitaxel. Paclitaxel may be in the form of an injection.

The novel crystalline form of the compound of formula (1) of this patent document can be administered in an amount of 0.1mg to 50 mg. Trastuzumab can be administered in an amount of 0.5 mg-10 mg/kg body weight. Cetuximab may be present at 100mg/m²To 500mg/m²The amount of body surface area is administered.

The vinorelbine can be in the range of 0.5mg/m²To 50mg/m²The amount of body surface area is administered. Furthermore, paclitaxel may be present at 100mg/m²To 300mg/m²The amount of body surface area is administered.

Trastuzumab (Herceptin therein under the trade name Herceptin)^TMSold) is a monoclonal antibody used to treat breast cancer. In particular, it is for breast cancer that is HER2 receptor positive. Trastuzumab is administered by slow injection into the vein as well as subcutaneous injection.

Cetuximab is an Epidermal Growth Factor Receptor (EGFR) inhibitor useful for the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and head and neck cancer. Cetuximab is a chimeric (mouse/human) monoclonal antibody administered by intravenous infusion, distributed by the Bristol-Myers Squibb pharmaceutical company in the united states and canada, and by the merck kgaa pharmaceutical company outside the united states and canada, under the trade name Erbitux. MerckkKGaA, Bristol-Myers Squibb and Eli Lilly are distributed together in Japan.

Paclitaxel (PTX), which is sold under the trade name Taxol, is a chemotherapeutic drug used to treat various types of cancer. This includes ovarian cancer, breast cancer, lung cancer, Kaposi's sarcoma (Kaposi sarcoma), cervical cancer, and pancreatic cancer. It is administered by injection into a vein.

In one embodiment, the kit/composition may comprise a novel crystalline form of the compound of formula (1) of this patent document and a mitotic inhibitor. The mitotic inhibitor is selected from BT-062, HMN-214, eribulin mesylate, vindesine, EC-1069, EC-1456, EC-531, vintafolide, 2-methoxyestradiol, GTx-230, trastuzumab, crolibulin, D1302A-maytansinoid conjugate, IMGN-529, Moxing-lovoruzumab, SAR-3419, SAR-566658, IMP-03138, topotecan/vincristine combination, BPH-8, CA4P tromethamine salt, estramustine sodium phosphate, vincristine, vinflunine, vinorelbine, RX-21101, cabazitaxel, STA-9584, vinblastine, epothilone A, paclitaxel, ixabepilone, epothilone D, paclitaxel, docetaxel, DJ-927, discodermolide, eleutherobin, and pharmaceutically acceptable salts or combinations thereof. An example of a composition may comprise bosutinib and a taxane, a vinca alkaloid, or a combination thereof. The vinca alkaloid may be at least one drug selected from vinblastine, vincristine, vindesine and vinorelbine. The taxane may be paclitaxel or docetaxel. One example of a composition may comprise bosutinib and paclitaxel (paclitaxel); or bosutinib and vinorelbine. The tumor may be breast cancer, wherein Her2 is overexpressed.

Boletinib may be administered in an amount of 0.1 mg-50 mg. Furthermore, vinorelbine may be present at 0.5mg/m²To 50mg/m²The amount of body surface area is administered. Similarly, paclitaxel may be present at 100mg/m²To 300mg/m²The amount of body surface area is administered.

Vinorelbine (NVB), which is sold under the trade name Navelbine, is a chemotherapeutic drug used to treat various types of cancer. This includes breast cancer and non-small cell lung cancer. It is administered by intravenous injection or orally. Vinorelbine belongs to the family of alkaloids of the vinca. It is thought to act by disrupting the normal function of microtubules, thereby preventing cell division.

In one embodiment, the composition may comprise a novel crystalline form of the compound of formula (1) of this patent document and an mTOR inhibitor. The mTOR inhibitor may be selected from Azotarolimus (zotarolimus), umirolimus, temsirolimus, sirolimus NanoCrvstal, sirolimus TransDerm, sirolimus-PNP, everolimus, biolimus A9, ridaforolimus, rapamycin, TCD-10023, DE-109, MS-R001, MS-R002, MS-R003, Perceiva, XL-765, quinacrine, PKI-587, PF-04691502, GDC-0980, dacolisib, CC-223, PWT-33597, P-7170, LY-3023414, INK-128, GDC-0084, DS-7423, DS-3078, CC-115, CBLC-137, CBD-2014, X-480, X-55414, EC-71, PQQR-5584, PQR-309, PQR-31, PQR-311, PQR-Na-33, PQR-3, PQR-311, PQVR-D-3, PQVR-, npT-MTOR, BC-210, WAY-600, WYE-354, WYE-687, LOR-220, HMPL-518, GNE-317, EC-0565, CC-214, ABTL-0812, and pharmaceutically acceptable salts thereof or compositions thereof. One example of a composition may comprise bosutinib and rapamycin. Rapamycin may be in the form of an injection. Rapamycin (Rapamycin), also known as sirolimus (sirolimus), is a compound produced by the bacterium Streptomyces hygroscopicus.

The novel crystalline form of the compound of formula (1) of this patent document may be administered in an amount of 0.1mg to 50 mg. Rapamycin may also be present at 0.5mg/m²To 10mg/m²The amount of body surface area is administered.

In one embodiment, the kit/composition may comprise the novel crystalline form of the compound of formula (1) of this patent document and an antimetabolite. The antimetabolite may be selected from the group consisting of capecitabine, 5-fluorouracil, gemcitabine, pemetrexed, methotrexate, 6-mercaptopurine, cladribine, arabinoside, doxifluridine, floxuridine, fludarabine, hydroxyurea, dacarbazine, hydroxyurea, and asparaginase. One example of a composition may comprise bosutinib and 5-fluorouracil. The 5-fluorouracil may be in the form of an injection.

The novel crystalline form of the compound of formula (1) of this patent document can be administered in an amount of 0.1mg to 50mg, and 5-fluorouracil can be administered at 100mg/m²To 3000mg/m²The amount of body surface area is administered.

Fluorouracil (5-FU), especially sold under the trade name Adrucil, is a drug used in the treatment of cancer. By injection into veins, it is used for colon, esophageal, gastric, pancreatic, breast and cervical cancers. [2] As a cream, it is used to treat basal cell carcinoma. Fluorouracil belongs to the family of antimetabolites and pyrimidine analogue drugs. How it functions is not completely clear, but is thought to involve blocking the action of thymidylate synthase and thus stopping DNA production.

In one embodiment, the kit/composition may comprise a novel crystalline form of the compound of formula (1) of this patent document and a platinum-based anti-tumor drug. The platinum-based antineoplastic agent may be selected from cisplatin, carboplatin, dicycloplatin, eptaplatin, lobaplatin, miboplatin, nedaplatin, oxaliplatin, picoplatin, and satraplatin. One example of a composition may comprise bosutinib and cisplatin. Cisplatin may be in the form of an injection.

The bovatinib may be administered in an amount of 0.1mg to 50 mg. Cisplatin can be used at 1mg/m²To 100mg/m²The amount of body surface area is administered.

Cisplatin is a chemotherapeutic drug used to treat a variety of cancers. This includes testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, brain tumors, and neuroblastoma. It is used by injection into a vein. Cisplatin belongs to the platinum-based antineoplastic drug family. Some of which act by binding to and inhibiting DNA replication.

The pharmaceutical preparations or medicaments in the kits may be presented in unit dosage form containing a predetermined amount of active ingredient per unit dose. As is well known to those skilled in the art, the amount of active ingredient per dose will depend on the disease being treated, the route of administration, and the age, weight and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of the active ingredient. Furthermore, such pharmaceutical preparations may be prepared by any method known in the art of pharmacy

The novel crystalline forms or compositions of the present invention are incorporated into convenient dosage forms such as capsules, tablets or intravenous injections. Solid or liquid pharmaceutical carriers are used. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline and water. Similarly, the carrier may include an extended release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely, but suitably may be from about 25mg to about 1g per dosage unit. When a liquid carrier is used, the preparation will suitably be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g., ampule), or aqueous or non-aqueous liquid suspension.

For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water, etc.). Powders are prepared by comminuting the compound to a suitable fine particle size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate (e.g. starch or mannitol). Flavoring, preservative, dispersing and coloring agents may also be included.

It is to be understood that, in addition to the above ingredients, the formulations may contain other agents conventional in the art having regard to the type of formulation, for example those suitable for oral administration may contain flavoring agents.

Hereinafter, this patent document will be described by referring to specific examples. However, the following embodiments are merely illustrative of the present invention, and the scope of the present patent document is not limited thereto.

Analytical instrument and measurement method

X-ray powder diffraction (XRPD)

The samples were tested for X-ray powder diffraction (XRPD) spectra from 3 ° 2 θ to 40 ° 2 θ on a D8 Advance (Bruker ASX, germany) analyzer. When the amount of sample is < 100mg, about 5-10 mg of sample is gently pressed onto the slide and mounted on the sample holder. When the amount of sample is >100mg, about 100mg of sample is gently pressed onto the plastic sample holder so that the sample surface is smooth and just above the level of the sample holder.

The following measurements were performed:

anode material (K α): cu Ka (1.54056A)

Scanning range: 3-40 degree

The generator is set up: 100mA, 40.0kV

Scanning speed: 1 second/step

Divergent slit size (divergent slit): 0.3 degree

Anti-scattering slit: 0.3 degree

Temperature: 20 deg.C

Step length: 0.022 degree of theta

Rotating: use of

Radius of goniometer: 435mm

2. Differential Scanning Calorimetry (DSC)

Differential Scanning Calorimetry (DSC) analysis was performed at 30-350 ℃ on a STA-1000(Scinco, Korea) analyzer. Samples from 5mg to 10mg were weighed in an aluminum DSC pan and non-hermetically sealed with a perforated aluminum lid and then monitored by heating the sample from 30 ℃ to 350 ℃ at a scan rate of 10 ℃/min, resulting in a heat flow reaction (DSC).

3. Dynamic vapor adsorption (DVS)

Dynamic Vapor Sorption (DVS) analysis was performed on a DVS advantage analyzer at 25 ℃ and 0% to 90% relative humidity.

10mg of sample was placed in a wire mesh vapor sorption equilibrium tray and connected to the DVS-advantaged dynamic vapor sorption equilibrium by a surface measurement system. The sample was applied to a gradual curve of Relative Humidity (RH) of 10% -90% (in 10% increments) while maintaining the sample at each step until a stable weight was reached (99.5% step complete). After the adsorption cycle is complete, the sample is dried using the same procedure, during which the relative humidity is returned to below 0% relative humidity. The change in weight during the adsorption/desorption cycle (repeated 3 times) was recorded to determine the hygroscopicity of the sample.

4. Solid state nuclear magnetic resonance (ssNMR)

To compare the crystalline polymorph in the solid state using nuclear magnetic resonance spectroscopy, solid state nuclear magnetic resonance (ssNMR) analysis was performed using a Bruker Avance II 500MHz solid state NMR system (Bruker, germany) analyzer at room temperature after placing 100mg of the sample in a 4mm sample tube.¹³C NMR spectrum (C: (C NMR)¹³C CP/MAS TOSS ssNMR) was as follows.

Frequency: 125.76MHz

Spectrum width: 20kHz

Sample rotation speed under magic angle: 5kHz

Pulse sequence: with decoupled CP (Cross-polarized) SPINAL64

(80kHz decoupling Power)

Repetition delay: 5 seconds

Contact time: 2ms

The scanning times are as follows: 4096

External marking: adamantane

5. High Performance Liquid Chromatography (HPLC)

High Performance Liquid Chromatography (HPLC) was performed on an agilient 1100/1200 series HPLC system (AGilent, usa) analyzer for purity and content analysis including stability testing, etc. The analytical conditions for HPLC are as follows.

Purity and content analysis conditions: thienopyrimidine compounds of formula (1)

Column: hydrosphere C18(YMC), 5 μm (150 mm. times.4.6 mm)

Column temperature: 30 deg.C

A detector: ultraviolet absorption meter

Detection wavelength: 254nm

Flow rate: 1.0mL/min

Analysis time: 35 minutes

Eluent: NaC1O₄-NaH₂PO₄Phosphate buffer (pH 2.5. + -. 0.1)/CH₃CN＝40/60(v/v％)

6. Ion Chromatography (IC)

Ion Chromatography (IC) analysis was performed on a Thermo Fisher Scientific ICS-2500 series IC system (U.S. A.) analyzer for analysis of hydrochloric acid content in hydrochloride salts. The analysis conditions for IC were as follows.

Conditions for content analysis: thienopyrimidine compounds of formula (1)

Column: IonPacAS19(Dionex), (250 mm. times.4 mm), guard (50 mm. times.4 mm)

Column temperature: 30 deg.C

A detector: conductivity Detector (CD)

A suppressor: ASRS 4mm, current 40mA

Flow rate: 1.0mL/min

Analysis time: 30 minutes

Eluent: 10mM potassium hydroxide solution

7. Moisture measurement

Moisture measurements were performed using a 795KFT Titrino (Metrohm, Switzerland) Karl-Fischer moisture analyzer.

8. Melting point measurement

Melting point measurements were performed using an IA9200(Electrothermal, uk) melting point apparatus.

Reference example: preparation of the Compound of formula (1)

100g of the compound of formula (1) prepared according to the method of korean patent registration No. 1,013,319 and U.S. patent No. 8,003,658 or the like, which are cited in the present specification, is dissolved in a mixed solution of 300mL of dichloromethane and 300mL of methanol, stirred at 40 ℃ for 30 minutes, and the insoluble solid is filtered using filter paper. 93g (yield 93%) of the title compound were distilled off under reduced pressure.

Moisture content: 2.1 percent of

Feature analysis

The analysis results of XRPD, ssNMR, DSC, and DVS of the compound of formula (1) prepared in the reference example are shown in fig. 1G, fig. 2G, and fig. 4G, respectively.

The compound of formula (1) prepared in the reference example did not show any specific diffraction value in the XRPD spectrum showing a typical spectrum of an amorphous substance.

Further, the compound of the reference example showed a broad peak in the spectrum by ssNMR, which is a typical peak pattern of an amorphous structure.

In addition, the compound of the reference example did not show any specific endothermic exothermic curve as measured by DSC (10 ℃/min).

In addition, the compounds of the reference examples showed a tendency to continuously absorb 1% to 3% of water in a relative humidity range of 10% to 90%, as measured by DVS.

Further, the moisture content of the amorphous form was 2.1% as measured by a Karl-Fischer moisture analyzer, and no characteristic melting point was observed.

Example (b): preparation of crystalline polymorphs of the compound of formula (I) and its hydrochloride salt

Example 1 crystalline dihydrate (2H) of the compound of formula (1)₂Preparation of form O)

To 10.0g of the compound of formula (1) of the reference example, 80mL of acetone and 20mL of water were added, followed by completely dissolving the compound of formula (1) by heating under reflux, followed by cooling to 20 ℃ to 25 ℃ and stirring for 4 hours. The resulting solid was filtered and washed with 20mL of a 4: 1 acetone/water mixture. The filtered solid was dried at 50 ℃ to obtain 10g (yield: 93%) of the objective compound.

Moisture content: 7.5% (theoretical value of dihydrate: 6.83%)

Feature analysis

The analysis results of XRPD, ssNMR, DSC, and DVS of the crystalline form prepared in example 1 are shown in fig. 1A, fig. 2A, fig. 3A, and fig. 4A, respectively.

The relative intensities (I/I) of the crystalline forms in the XRPD spectrum are summarized in Table 1 below_o) 15% or more of the peaks. At I/I_oIn the case of peaks of ≧ 30% or more, peaks appear at diffraction angles (2 θ ± 0.2 °) of 9.4 °, 11.4 °, 13.0 °, 16.1 °, 18.5 °, 19.3 °, 24.9 °, and 26.3 °.

Table 1:

2θ(±0.2)	d	I/Io(％)	2θ(±0.2)	d	I/Io(％)
						9.4	9.4	100	20.8	4.3	28.9
11.4	7.7	40.1	21.4	4.1	23.4
						12.3	7.2	25.4	22.0	4.0	15.2
13.0	6.8	70.6	23.6	3.8	23.9
						15.6	5.7	21.8	24.4	3.6	18.8
16.1	5.5	35.5	24.9	3.6	40.6
						17.2	5.1	18.8	26.3	3.4	36.5
18.5	4.8	66.0	27.5	3.2	27.4
						19.3	4.6	43.1	28.5	3.1	33.5

2 θ: diffraction angle, d: the distance between the crystal planes is such that,

I/I_o(%): relative intensity (I: intensity of each peak; I)_o: intensity of maximum peak).

The crystalline forms are summarized in Table 2 below¹³Peak of chemical shift (ppm. + -. 0.5ppm) in C CP/MAS TOSS ssNMR spectrum.

Table 2:

chemical shifts (ppm. + -. 0.5 ppm).

The crystalline form shows a lowest point endothermic peak at about 100.7 ℃ when run from a start point of about 79 ℃ and a lowest point endothermic peak at about 190.8 ℃ when run from a start point of about 186.5 ℃, as measured by DSC (10 ℃/min). An endothermic peak at about 100.7 ℃ as measured by DSC indicates the dehydration point of the crystalline hydrate form of crystalline form I of the compound of formula (1) and an endothermic peak at about 190.8 ℃ indicates the melting point.

The crystalline form exhibited a moisture content of about 7.5% (theoretical moisture content of 6.83%) in a Karl-Fischer moisture analyzer and showed a condensation temperature of about 117 ℃ and 122 ℃ and a melting point of about 190 ℃ and 195 ℃.

The hygroscopicity of the crystalline form is about 2% to 5% in the relative humidity range of 10% to 90%, as measured by DVS.

Example 2 preparation of Anhydrous crystalline form of the Compound of formula (1) formula I

To 5.0g of the compound of formula (1) obtained by the method of example 1,50 mL of acetone was added, followed by stirring at 20-25 ℃ for 6 hours. The resulting solid was filtered and washed with 7.5mL of acetone. The filtered solid was dried at 50 ℃ to obtain 3.7g (yield: 80%) of the objective compound.

Moisture content: 0.1 percent of

Feature analysis

The analysis results of XRPD, ssNMR, DSC, and DVS of the crystalline form prepared in example 2 are shown in fig. 1B, fig. 2B, fig. 3B, and fig. 4B, respectively.

The relative intensities (I/I) of the crystalline forms in the XRPD spectrum are summarized in Table 3 below_o) 15% or more of the peaks. At I/I_oIn the case of peaks of ≧ 30% or more, peaks appear at diffraction angles (2 θ ± 0.2 °) of 6.0 °, 10.6 °, 10.9 °, 12.1 °, 16.0 °, 17.5 °, 18.3 °, 19.2 °, 20.3 °, 22.7 °, 23.7 °, and 26.3 °.

Table 3:

2θ(±0.2)	d	I/Io(％)	2θ(±0.2)	d	I/Io(％)
						6.0	14.6	75.6	20.3	4.4	58.1
10.6	8.3	47.1	20.8	4.3	18.6
						10.9	8.1	48.8	22.1	4.0	26.7
12.1	7.3	62.2	22.7	3.9	100
						13.0	6.8	25.0	23.7	3.8	55.2
16.0	5.5	57.6	24.2	3.7	15.1
						17.5	5.1	32.0	26.3	3.4	62.2
18.3	4.9	85.5	28.1	3.2	18.0
						18.7	4.7	23.3	32.1	2.8	17.4
19.2	4.6	36.0

2 θ: diffraction angle, d: the distance between the crystal planes,

I/I_o(%): relative intensity (I: intensity of each peak; I)_o: intensity of maximum peak).

The crystalline forms are summarized in Table 4 below¹³Peak of chemical shift (ppm. + -. 0.5ppm) in C CP/MAS TOSS ssNMR spectrum.

Table 4:

chemical shifts (ppm +0.5 ppm).

The above crystalline form exhibits a lowest-point endothermic peak at about 190.8 ℃ when run from a starting point of about 185.8 ℃, and the endothermic peak at about 190.8 ℃ represents the melting point, as measured by DSC (10 ℃/min).

The crystalline form exhibited a moisture content of about 0.1% as measured by a Karl-Fischer moisture analyzer and showed a melting point at about 190 ℃. and 195 ℃.

The hygroscopicity of the crystalline form, as measured by DVS, is at a level of about 0.3% to 0.5% in the relative humidity range of 10% to 50%, which is very low, and at a level of about 3% in the range of 50% to 90%.

Example 3 preparation of Anhydrous crystalline form II of the Compound of formula (1)

To 2.0g of the compound of formula (1) of example 2, 20mL of acetonitrile was added, followed by heating at 70-80 ℃ and stirring for 2 hours, and then stirring at 20-25 ℃ for 12 hours. The resulting solid was filtered and washed with 5mL of acetonitrile. The filtered solid was dried at 50 ℃ to obtain 1.7g (yield: 85%) of the objective compound.

Moisture content: 0.3 percent.

Feature analysis

The analysis results of XRPD, ssNMR, DSC, and DVS of the crystalline form prepared in example 3 are shown in fig. 1C, fig. 2C, fig. 3C, and fig. 4C, respectively.

The relative intensities (I/I) of the crystalline forms in the XRPD spectrum are summarized in Table 5 below_o) 15% or higher peak. At I/I_oIn the case of the peaks of ≧ 30% or more, peaks appear at diffraction angles (2 θ ± 0.2 °) of 4.9 °, 5.9 °, 11.8 °, 18.8 °, and 19.9 °.

Table 5:

2θ(±0.2)	d	I/Io(％)	2θ(±0.2)	d	I/Io(％)
						4.9	18.2	50.3	19.5	4.6	25.7
5.9	15.1	35.6	19.9	4.5	32.6
						11.8	7.5	100	22.0	4.0	17.3
13.9	6.4	24.5	25.2	3.5	26.1
						14.7	6.0	24.3	25.5	3.5	23.3
16.1	5.5	24.3	27.0	3.3	18.5
						18.8	4.7	38.6

2 θ: diffraction angle, d: the distance between the crystal planes,

I/I_o(%): relative intensity (I: intensity of each peak; I)_o: intensity of maximum peak).

The crystalline forms are summarized in Table 6 below¹³Peak of chemical shift (ppm. + -. 0.5ppm) in C CP/MAS TOSS ssNMR spectrum.

Table 6:

chemical shifts (ppm. + -. 0.5 ppm).

The above crystalline form exhibits a lowest point endothermic peak at about 184.8 ℃ when run from a starting point of about 181.3 ℃ as measured by DSC (10 ℃/min), and the endothermic peak at about 184.8 ℃ represents the melting point.

The crystalline form exhibited a moisture content of about 0.3% as measured by a Karl-Fischer moisture analyzer and showed a melting point of about 183-.

The hygroscopicity of the crystalline form is at a level of about 0.7% in the relative humidity range of 10% to 90%, as measured by DVS, which is very low. The crystalline form is sufficiently stable under long term storage conditions (e.g., 25 ℃ and 60% relative humidity), accelerated conditions (e.g., 40 ℃ and 75% relative humidity), and harsh conditions (e.g., 60 ℃).

Example 4 crystalline monohydrochloride monohydrate (1HCl 1H) of compound of formula (1)₂Preparation of form O) to 10g of the compound prepared by the method of reference example or examples 1 to 3, 100mL of a mixed solvent of ethanol: water (9: 1) was added. 4.9mL of 35% concentrated HCl was added and stirred at room temperature for 6 hours. The resulting solid was filtered and washed with 30mL of ethanol. The filtered solid was dried at 50 ℃ to obtain 9.1g (yield: 82%) of the objective compound.

Moisture content: 3.2% (theoretical value of monohydrate: 3.3%)

Ion chromatography: 6.5% (theoretical value of monohydrochloride: 6.92%)

Feature analysis

The results of the XRPD, ssNMR, DSC, and DVS analyses of the crystalline form prepared in example 4 are shown in fig. 1D, fig. 2D, fig. 3D, and fig. 4D, respectively.

The relative intensities (I/I) of the crystalline form in the XRPD spectrum are summarized in Table 7 below_o) 15% or higher peak. At I/I_oIn the case of a peak of ≧ 30% or more, peaks appear at diffraction angles (2 θ ± 0.2 °) of 8.9 °, 13.4 °, 14.1 °, 16.0 °, 19.8 °, 21.1 °, 21.7 °, 23.5 °, 25.7 °, and 32.7 °.

Table 7:

2θ(±0.2)	d	I/Io(％)	2θ(±0.2)	d	I/Io(％)
						8.9	10.0	61.5	21.7	4.1	42.0
10.5	8.4	18.3	22.0	4.0	18.3
						12.3	7.4	28.4	22.4	4.0	15.4
12.6	7.0	17.8	23.5	3.8	100
						13.4	6.6	94.7	24.2	3.7	21.3
14.1	6.3	35.5	25.7	3.5	52.1
						16.0	5.5	36.1	27.5	3.2	20.7
16.4	5.4	17.8	28.0	3.2	17.2
						17.3	5.1	21.3	28.7	3.1	20.1
18.1	4.9	27.2	29.9	3.0	25.4
						19.3	4.6	18.3	30.6	2.9	21.9
19.8	4.5	32.0	32.3	2.7	20.1
						21.1	4.2	92.3	32.7	2.7	30.2

2 θ: diffraction angle, d: the distance between the crystal planes,

I/I_o(%): relative intensity (I: intensity of each peak; I)_o: intensity of maximum peak).

The crystalline forms are summarized in Table 8 below¹³Peak of chemical shift (ppm. + -. 0.5ppm) in C CP/MAS TOSS solid-state nuclear magnetic resonance (ssNMR) spectrum.

Table 8:

chemical shifts (ppm. + -. 0.5 ppm).

The crystalline form exhibits an endothermic peak at about 151.0 ℃ with a lowest point, and an endothermic peak at about 177.7 ℃ when run from a starting point of about 126.7 ℃ as measured by DSC (10 ℃/min). The endothermic peak at about 151.0 ℃ as measured by DSC represents the dehydration point of the crystalline monohydrochloride monohydrate form and the endothermic peak at about 177.7 ℃ represents the melting point.

The crystalline form exhibited a moisture content of about 3.2% as measured by a Karl-Fischer moisture analyzer and showed a melting point of about 187-193 ℃.

The hygroscopicity of this crystalline form is at a level of about 0.4% in the relative humidity range of 10% to 90%, as measured by DVS, which is very low. It is expected that the crystalline form will absorb moisture under long term storage conditions (e.g., a temperature of 25 ℃ and a relative humidity of 60%) and accelerated conditions (e.g., a temperature of 40 ℃ and a relative humidity of 75%) to maintain the crystalline form of the monohydrate.

Example 5 preparation of Anhydrous crystalline Mono hydrochloride (1HCl) form of the Compound of formula (1)

To 20g of anhydrous compound 1 prepared by a method similar to example 2, 60mL of DMSO was added. 5.1mL of 35% concentrated HCl was added, and the mixture was stirred at room temperature for 6 hours. The resulting solid was filtered off and washed with 40mL of DMSO. The filtered solid was then dried at 50 ℃ to obtain 18.3g (yield: 85%) of the objective compound.

Moisture content: 0.1 percent of

Ion chromatography: 6.6% (theoretical value of monohydrochloride: 6.92%)

In addition, to 20g of anhydrous compound 1 prepared by a method similar to example 2, 60mL of DMF was added. 5.1mL of 35% concentrated HCl was added and stirred at room temperature for 6 hours. The resulting solid was filtered off and washed with 40mL of DMF. The filtered solid was dried at 50 ℃ to obtain 16.6g (yield: 77%) of the objective compound.

Feature analysis

The results of the XRPD, ssNMR, DSC, and DVS analyses of the crystalline form prepared in example 5 are shown in fig. 1E, fig. 2E, fig. 3E, and fig. 4E, respectively.

The relative intensities (I/I) of the crystalline form in the XRPD spectrum are summarized in Table 9 below_o) 15% or higher peak. At I/I_oIn the case of a peak of not less than 30% or higher, peaks appear at diffraction angles (2 θ ± 0.2 °) of 9.5 °, 12.3 °, 13.0 °, 13.5 °, 14.2 °, 21.4 °, 23.0 °, 23.2 °, 23.5 °, 27.2 ° and 27.5 °.

Table 9:

2θ(±0.2)	d	I/Io(％)	2θ(±0.2)	d	I/Io(％)
						9.5	9.3	100	23.0	3.9	59.3
10.7	8.3	17.5	23.2	3.8	57.5
						12.3	7.2	34.4	23.5	3.8	52.1
13.0	6.8	39.2	24.7	3.6	17.8
						13.5	6.5	32.7	25.2	3.5	20.9
14.2	6.2	33.6	27.2	3.3	36.9
						16.1	5.5	20.2	27.5	3.2	40.7
17.5	5.1	20.0	28.9	3.1	15.4
						18.9	4.7	26.0	29.1	3.1	16.4
20.0	4.4	15.2	30.1	3.0	20.3
						20.3	4.4	16.4	30.4	2.9	17.8
21.4	4.1	42.2	34.8	2.6	16.5
						22.2	4.0	15.3

2 θ: diffraction angle, d: the distance between the crystal planes,

I/I_o(%): relative intensity (I: intensity of each peak; I)_o: intensity of maximum peak).

The crystalline forms are summarized in Table 10 below¹³Peak of chemical shift (ppm. + -. 0.5ppm) in C CP/MAS TOSS solid-state nuclear magnetic resonance (ssNMR) spectrum.

Table 10:

chemical shifts (ppm. + -. 0.5 ppm).

The above crystalline form exhibits an endothermic peak with a lowest point at about 230.1 ℃ when run from a starting point of about 200.7 ℃ as measured by DSC (10 ℃/min). The endothermic peak at about 230.1 ℃ represents the melting point.

The crystalline form exhibited a moisture content of about 0.1% as measured by a Karl-Fischer moisture analyzer and showed a melting point of about 238-.

The hygroscopicity of this crystalline form is at a level of about 0.35% in the relative humidity range of 10% to 90%, as measured by DVS, which is very low. The crystalline form does not absorb moisture under long term storage conditions (e.g., a temperature of 25 ℃ and a relative humidity of 60%) and accelerated conditions (e.g., a temperature of 40 ℃ and a relative humidity of 75%) to maintain the anhydrous crystalline form.

Example 6 preparation of the monohydrochloride (1HCl) amorphous form of the Compound of formula (1)

5g of the compound of chemical formula 1 obtained in example 5 in the form of anhydrous crystals was dissolved in 150mL of methanol. The solution was filtered through a filter to remove foreign substances, and the filtrate was concentrated under reduced pressure to obtain 4.9g (yield: 98%) of the objective compound as a solid.

Moisture content: 1.2 percent of

Feature analysis

The results of the XRPD, DVS and ssNMR analyses of the amorphous form prepared in example 6 are shown in fig. 1F, fig. 2F and fig. 4F, respectively.

Amorphous form does not show any diffraction values in the XRPD spectrum.

In addition, the amorphous form exhibits very high hygroscopicity, as measured by DVS, in the relative humidity range of 10-90%. In this way, it is expected that absorption of moisture under long-term storage conditions (25 ℃ temperature and 60% relative humidity) and accelerated conditions (40 ℃ temperature and 75% relative humidity) will lead to instability. Actually, the moisture absorption was confirmed to be 7 to 9% under the conditions of 25 ℃ and 60% relative humidity and under the conditions of 40 ℃ and 75% relative humidity.

In addition, the moisture content of the amorphous form was 1.2% as measured by a Karl-Fischer moisture analyzer, and no characteristic melting point was observed.

Test example 1: comparative testing of the solubility of amorphous and crystalline polymorphs of the hydrochloride salt

In order to compare the solubilities of the amorphous form of hydrochloride and the crystalline polymorph of hydrochloride, samples were prepared using the polymorphic and amorphous forms of hydrochloride of the compound of formula (1) prepared in examples 4 to 6 according to nonionic water and acidity (pH) under the following conditions. Thereafter, each solution was analyzed by High Performance Liquid Chromatography (HPLC) according to the conditions for measuring the content of the compound of formula (1), and the amount of dissolution (LOD: 0.1. mu.g/mL) was measured based on the compound of formula (1). The results calculated from the measured values are shown in table 11 below.

Specifically, 5mg of each polymorph was added to 5mL of water and mixed using Voltamixer at 20-25 ℃. Thereafter, a filtrate obtained by filtration using GH Polypro membrane Acrodisc, PALL (pore size 0.2 μm) was diluted with a dilution solvent for High Performance Liquid Chromatography (HPLC) at a ratio of 1/100 to obtain a sample.

Table 11:

as shown in table 11 above, the solubility of the hydrochloride salt of the compound of formula (1) is significantly higher than that of the compound of formula (1) (less than 1.0 μ g/mL), and the anhydrous crystalline form of the hydrochloride salt form in the crystalline polymorph has the highest solubility in water.

Therefore, in terms of pharmaceutical compositions, anhydrous crystalline hydrochloride forms of the compound of formula (1) are expected to be most advantageous when elution or the like is considered.

Test example 2: comparative stability testing of amorphous and crystalline polymorphs of the hydrochloride salt

To compare the stability of the amorphous form of the hydrochloride salt and the crystalline polymorph of the hydrochloride salt, each sample of the polymorph and amorphous form of the hydrochloride salt of the compound of formula (1) prepared in examples 4 to 6 was left for 4 weeks under long-term conditions (e.g., a temperature of 25 ± 2 ℃ and a relative humidity of 60 ± 5%) and accelerated conditions (e.g., a temperature of 40 ℃ and a relative humidity of 75%). Each sample was analyzed by High Performance Liquid Chromatography (HPLC) according to the purity measuring conditions of the compound of formula (1). Purity measurements (%) are shown in table 12 below.

Table 12:

as shown in table 12, the crystalline hydrochloride form of the compound of formula (1) is stable compared to the amorphous hydrochloride form of the compound of formula (1), and particularly the anhydrous crystalline form of the hydrochloride salt of the compound of formula (1) shows the best results.

Thus, by comparing tests 1 and 2, the anhydrous crystalline hydrochloride salt form of the compound of formula (1) is expected to be most advantageous for pharmaceutical compositions when considering various physicochemical properties (e.g., solubility, purity, stability, hygroscopicity, melting point, etc.).

Claims (24)

1. A crystalline form of a compound of formula (1):

[ chemical formula (1) ]

Wherein the crystalline form has a chemical purity of greater than about 80%, an

Wherein the crystalline form is selected from

(a) A dihydrate crystalline form of the compound of formula (1) that has an X-ray powder diffraction pattern comprising peaks at diffraction angle 2 Θ values of 9.4 ° ± 0.2 °, 13.0 ° ± 0.2 ° and 18.5 ° ± 0.2 ° when illuminated with a Cu-K α light source;

(b) anhydrous form I of the compound of formula (1) having an XRPD pattern comprising peaks at diffraction angle 2 Θ values of 6.0 ° ± 0.2 °, 18.3 ° ± 0.2 ° and 22.7 ° ± 0.2 ° when illuminated with a Cu-ka light source;

(c) anhydrous form II of the compound of formula (1) having an XRPD pattern comprising peaks at diffraction angle 2 Θ values of 4.9 ° ± 0.2 °, 5.9 ° ± 0.2 ° and 11.8 ° ± 0.2 ° when illuminated with a Cu-ka light source;

(d) monohydrochloride monohydrate (1HCl · 1H) of compound of formula (1)₂O) a crystalline form having an XRPD pattern comprising peaks at diffraction angle 2 Θ values of 8.9 ° ± 0.2 °, 13.4 ° ± 0.2 °, 21.1 ° ± 0.2 ° and 23.5 ° ± 0.2 ° when illuminated with a Cu-ka light source; and

(e) a crystalline form of the anhydrous monohydrochloride salt of a compound of formula (1) having an XRPD pattern comprising peaks at diffraction angle 2 Θ values of 9.5 ° ± 0.2 °, 23.0 ° ± 0.2 °, 23.2 ° ± 0.2 ° and 23.5 ° ± 0.2 ° when illuminated with a Cu-ka light source.

2. The crystalline form of the compound of formula (1) according to claim 1, wherein the chemical purity of the crystalline form is greater than 95%.

3. The crystalline form of claim 1, wherein the crystalline form is as in (a).

4. The crystalline form of claim 1, wherein the crystalline form is as in (b).

5. The crystalline form of claim 1, wherein the crystalline form is as in (c).

6. The crystalline form of claim 1, wherein the crystalline form is as in (d).

7. The crystalline form of claim 1, wherein the crystalline form is as in (e).

8. The crystalline form of claim 1, wherein the crystalline form is as in (a), wherein the crystalline form has peaks comprising the following chemical shifts¹³C solid state nuclear magnetic resonance spectrum (ssNMR): 147.7 + -0.5, 156.2 + -0.5 and 165.4 + -0.5 ppm.

9. The crystalline form of claim 1, wherein the crystalline form is as in (b), wherein the crystalline form has peaks comprising the following chemical shifts¹³C ssNMR spectrum: 54.3 + -0.5, 127.3 + -0.5, 146.9 + -0.5 and 156.7 + -0.5 ppm.

10. The crystalline form of claim 1, wherein the crystalline form is as in (c), wherein the crystalline form has peaks comprising the following chemical shifts¹³C ssNMR spectrum: 129.2 + -0.5, 153.1 + -0.5, 156.7 + -0.5 and 165.2 + -0.5 ppm.

11. The crystalline form of claim 1, wherein the crystalline form is as in (d), wherein the crystalline form has peaks comprising the following chemical shifts¹³C ssNMR spectrum: 145.8 + -0.5, 157.8 + -0.5 and 164.5 + -0.5 ppm.

12. The crystalline form of claim 1, wherein the crystalline form is as in (e), wherein the crystalline form has peaks comprising the following chemical shifts¹³C ssNMR spectrum: 146.9 + -0.5, 158.7 + -0.5 and 163.0 + -0.5 ppm.

13. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 12, and at least one pharmaceutically acceptable carrier or diluent.

14. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition is for the treatment of cancer induced by tyrosine kinase or a mutant thereof.

15. The pharmaceutical composition of claim 14, wherein the cancer is a solid cancer.

16. The pharmaceutical composition of claim 13, wherein the crystalline form is chemically pure greater than about 95%.

17. The pharmaceutical composition of claim 13, further comprising a non-metallic salt lubricant selected from the group consisting of glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl trimyristate, glyceryl tristearate, sucrose fatty acid ester, palmitic acid, palmitoyl alcohol, stearic acid, stearyl alcohol, fumaric acid, polyethylene glycol 4000, polyethylene glycol 6000, polytetrafluoroethylene, starch, talc, hydrogenated castor oil, mineral oil, hydrogenated vegetable oil, silicon dioxide, and any combination thereof.

18. The pharmaceutical composition of claim 13, further comprising a metal salt lubricant.

19. A process for preparing the dihydrate (2H) of claim 3₂O) a crystalline form, comprising:

(a) adding the compound of chemical formula 1 to a mixture of acetone and water in such a ratio that the compound is not completely dissolved in the mixture at room temperature;

(b) heating the mixture to a temperature at which the compound is completely dissolved; and

(c) cooling the mixture and removing the acetone and water to obtain the dihydrate (2H) of the compound₂O)。

20. A process for preparing the anhydrous form I of claim 4 comprising

(a) Dihydrate (2H) of the compound of claim 3₂O) mixing with acetone; and

(b) isolating the anhydrous form I of the compound.

21. A process for preparing the anhydrous form II of claim 5, comprising

(a) Combining anhydrous form I of the compound of claim 4 with acetonitrile;

(b) heating to above about 80 ℃; and

(c) cooling and isolating the anhydrous form II of the compound.

22. A process for preparing the monohydrochloride monohydrate (1 HCl.1H) of claim 6₂O) process comprising

(a) Mixing the compound of chemical formula 1 with ethanol, water and an aqueous hydrochloric acid solution; and

(b) isolation of the monohydrochloride monohydrate (1 HCl.1H) of said compound₂O)。

23. A process for preparing the crystalline form of the anhydrous monohydrochloride of claim 7 comprising

(a) Mixing the anhydrous compound of chemical formula 1 with an aprotic polar solvent and hydrochloric acid having a concentration of about 30% or more; and

(b) isolating the anhydrous monohydrochloride salt of the compound.

24. The method of claim 23, wherein the aprotic polar solvent is DMSO or DMF.