CN117946168A

CN117946168A - New crystal forms, pharmaceutical compositions and applications of mesylate salt of phosphorus-containing pyrido [2,3-d ] pyrimidin-7-one

Info

Publication number: CN117946168A
Application number: CN202211324436.7A
Authority: CN
Inventors: 周鋆; 吕慧敏
Original assignee: Beijing Youhe Dingxin Equity Investment Management Co ltd
Current assignee: Beijing Youhe Dingxin Equity Investment Management Co ltd
Priority date: 2022-10-27
Filing date: 2022-10-27
Publication date: 2024-04-30

Abstract

The present application relates to novel crystalline forms, pharmaceutical compositions and uses of the mesylate salt of phosphorus-containing pyrido [2,3-d ] pyrimidin-7-one, having the structural formula (I), wherein the X-ray powder diffraction pattern of the novel crystalline form comprises diffraction angles selected from the group consisting of 5.0, 9.8, 11.6, 14.0, 16.5, 17.5, 19.8 and 23.2;

Description

New crystal forms, pharmaceutical compositions and applications of mesylate salt of phosphorus-containing pyrido [2,3-d ] pyrimidin-7-one

Technical Field

The application belongs to the technical field of medicines, and particularly relates to a novel crystal form, a pharmaceutical composition and application of mesylate containing phosphorus pyrido [2,3-d ] pyrimidine-7-one.

Background

Protein kinases are a class of phosphotransferases that function to transfer the gamma-phosphate group of ATP to specific amino acid residues of substrates, phosphorylate proteins, and perform their physiological and biochemical functions. Protein kinases are an important class of kinases that play a major role in signal transduction in two aspects: one is to modulate the activity of the protein by phosphorylation; and secondly, the signals are amplified step by step through the step-by-step phosphorylation of proteins, so that the cellular response is caused.

The abnormality of the protein kinase activity is not only closely related to the proliferation, apoptosis, metastasis, etc. of tumors and the abnormality of a certain link in a series of signal transduction pathways inside and outside cells, but also is a main cause of a series of other human diseases related to inflammation or proliferation reaction, such as rheumatoid arthritis, cardiovascular and nervous system diseases, asthma, psoriasis, etc. It is currently known that over four hundred human diseases are directly or indirectly associated with protein kinases, which makes protein kinases another major class of important drug targets following G-protein coupled receptors.

Phosphorus-containing pyrido [2,3-d ] pyrimidin-7-ones as inhibitors of protein kinases (e.g., PI3 ks) are useful in the treatment of diseases caused by aberrant protein kinase activity, and solid forms of the compounds may be important in the formulation of pharmaceutical compositions. For example, crystalline and amorphous forms of a compound may have different physical properties (e.g., stability, dissolution rate, density, etc.) that relate to their suitability for use in pharmaceutical compositions. The differences in physical properties may also affect the usefulness of the crystalline or amorphous forms, for example, as intermediates in the synthesis of forms suitable for use in pharmaceutical compositions.

Thus, there is an urgent need for a crystalline form of the mesylate salt of the phosphorus-containing pyrido [2,3-d ] pyrimidin-7-one that is thermodynamically stable and suitable for use in pharmaceutical compositions. There is also a need for crystalline forms of phosphorus-containing pyrido [2,3-d ] pyrimidin-7-ones that allow the physical properties of pharmaceutical compositions to be produced in high yields and purity.

Disclosure of Invention

In order to overcome the defects, the application provides a novel crystal form, a pharmaceutical composition and application of the mesylate salt of the phosphorus-containing pyrido [2,3-d ] pyrimidine-7-ketone, wherein the novel crystal form has good thermodynamic stability and is suitable for the pharmaceutical composition.

In a first aspect, the present application provides a novel crystalline form of a mesylate salt of a phosphorus-containing pyrido [2,3-d ] pyrimidin-7-one, the structure of the mesylate salt of a phosphorus-containing pyrido [2,3-d ] pyrimidin-7-one being as shown in formula (I), the novel crystalline form having an X-ray powder diffraction pattern comprising diffraction angles selected from the group consisting of 5.0 °, 9.8 °, 11.6 °, 14.0 °, 16.5 °, 17.5 °, 19.8 ° and 23.2 °;

In some embodiments, the new crystalline form exhibits an X-ray powder diffraction pattern as shown in fig. 1.

In some embodiments, the new crystalline form may be obtained by slurrying a crystalline form comprising diffraction angles selected from 4.7 °, 9.3 °, and 11.7 ° in acetonitrile solution by an X-ray powder diffraction pattern.

In some embodiments, the novel crystalline form may be obtained by suspension seeding of a crystalline form comprising diffraction angles selected from 10.8 °, 12.2 °, 16.0 °, 16.8 °, 25.6 °, and 26.8 ° in an ethanol solution by an X-ray powder diffraction pattern.

In some embodiments, the new crystalline form may be obtained by suspension seeding in an ethanol solution of a crystalline form comprising diffraction angles selected from 10.6 °, 16.0 °, and 25.5 ° by an X-ray powder diffraction pattern.

In some embodiments, the new crystalline form has a weight loss of 0.928% in a thermogravimetric analysis test at 250 ℃ to 300 ℃.

In some embodiments, the crystallinity of the new crystalline form is inversely related to the pressure applied.

In a second aspect, embodiments of the present application also provide a pharmaceutical composition comprising the novel crystalline form of the first aspect and a pharmaceutically acceptable additive.

In a third aspect, the present application provides the use of a pharmaceutical composition according to the second aspect for the treatment of a disease caused by aberrant activity of a protein kinase.

Compared with the prior art, the technical scheme has at least the following technical effects:

The application provides a new crystal form of mesylate of phosphorus-containing pyrido [2,3-d ] pyrimidine-7-ketone, which has excellent thermodynamic stability, and can provide a new way for the phosphorus-containing pyrido [2,3-d ] pyrimidine-7-ketone to be used in pharmaceutical compositions, so that the selection range of protein kinase inhibitors can be widened.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the application as claimed.

Drawings

FIG. 1 is an XRPD pattern for form I of the present application;

FIG. 2 is a ¹ H NMR spectrum of form I of the present application;

FIG. 3 is a TGA and DSC pattern of form I of the present application;

FIG. 4 is a comparison of XRPD patterns of form I of the present application before and after removal of the solvent;

FIG. 5 is a graph comparing the preparation of new crystal forms using a single solvent according to the present application;

FIG. 6 is a comparison of XRPD patterns for forms I, II, III and IV of the present application;

FIG. 7 is a graphical representation of XRPD patterns of a new crystalline form prepared according to the application using a single solvent beating experiment;

FIG. 8 is a 96-well plate XRPD pattern I for preparation of a new crystalline form using the mixed reagent of example 4 of the present application;

FIG. 9 is a 96-well plate XRPD pattern II for example 4 of the application using a mixed reagent to prepare a new crystal form;

FIG. 10 is a 96-well plate XRPD pattern III for preparation of a new crystalline form using the mixed reagent of example 4 of the present application;

FIG. 11 is a 96-well plate XRPD pattern IV for example 4 of the application using a mixed reagent to prepare a new crystal form;

FIG. 12 is a comparison of XRPD patterns of an A4 well sample of the application and an enlarged A4 sample prepared by enlargement thereof;

FIG. 13 is a comparison of XRPD patterns of an A1 well sample of the application and an enlarged A1 sample prepared by enlargement thereof;

FIG. 14 is a comparison of XRPD patterns for a SLURRY sample of the application and an enlarged SLURRY sample prepared by enlargement;

FIG. 15 is a TGA and DSC profile of an enlarged A4 sample of the present application;

FIG. 16 is a TGA and DSC profile of an enlarged A1 sample of the present application;

FIG. 17 is a TGA and DSC spectra of a sample of the present application at an enlarged scale SLURRY;

FIG. 18 is a comparison of XRPD patterns of an enlarged A4 sample of the application before and after solvent removal;

FIG. 19 is a comparison of XRPD patterns of an enlarged A1 sample of the application before and after solvent removal;

FIG. 20 is a comparison of XRPD patterns of a sample of the application before and after removal of solvent, magnified SLURRY;

FIG. 21 is a comparison of XRPD patterns of form I of the present application before and after physical milling.

Detailed Description

In order to better understand the technical solution of the present invention, the following detailed description of the embodiments of the present invention is provided with reference to the specific embodiments.

It should be understood that the described embodiments are merely some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

The terminology used in the embodiments of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in this application and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

The crystalline forms provided herein can be identified based on characteristic peaks in X-ray powder diffraction (XRPD) analysis. XRPD is a scientific technology that measures X-rays, neutrons or electrons scattered by powder or microcrystalline materials as a function of scattering angle. XRPD can be used to identify and characterize crystalline solids because the diffraction pattern produced by a particular solid is typically different from that solid and can be used as a "fingerprint" to identify that solid. For example, an XRPD pattern or diffraction pattern substantially in accordance with a reference XRP pattern or diffraction pattern (e.g., a pattern or diffraction pattern generated by a sample (such as an unknown sample)) may be used to determine the identity of the sample material and the reference material. Both the position and relative intensity of the peaks in the XRPD diffractogram indicate the specific phase and consistency of the material.

Any 2θ angle described herein, except the 2θ angle described in the figures or examples, represents a specific value of ±0.2°. For example, when the described embodiments or claims describe 2θ of 4.4 °, it is understood that the 2θ angle is 4.4++0.2°, i.e. from 4.2 ° to 4.6 °.

Any temperature described herein in relation to DSC or TGA, except for the DSC or TGA temperatures described in the figures or examples, represents a specific value of ±5 ℃ or less. For example, when the examples or claims illustrate an endothermic peak at about 179 ℃, it is understood to mean 179 ℃ ± 5 ℃ or less, i.e. a temperature from 174 ℃ to 184 ℃. In a preferred embodiment, the DSC or TGA temperature is a specific value of +3℃, and in a more preferred embodiment is +2℃.

In the present application, "pharmaceutical composition" refers to a formulation prepared by mixing one or more of the compounds of the present application, a pharmaceutically acceptable salt or solvate or hydrate or prodrug, with another chemical ingredient (e.g., a pharmaceutically acceptable carrier or diluent). The purpose of the pharmaceutical composition is to facilitate the process of administration to animals. The pharmaceutical compositions may include, in addition to pharmaceutically acceptable carriers, pharmaceutically acceptable adjuvants such as: antibacterial, antifungal, antimicrobial, shelf-life agent, toner, solubilizing agent, thickener, surfactant, complexing agent, protein, amino acid, fat, saccharide, vitamin, mineral, trace element, sweetener, pigment, essence or combinations thereof, etc.

Example 1

The application provides a novel crystal form (hereinafter referred to as a crystal form I) of mesylate of phosphorus-containing pyrido [2,3-d ] pyrimidine-7-ketone, wherein the structural formula of the phosphorus-containing pyrido [2,3-d ] pyrimidine-7-ketone compound is shown as formula (I), the molecular formula is C ₂₆H₃₉N₆O₈ PS, and the molecular weight is 626.66.

XRPD assay was performed on the above crystalline form I under the following conditions: analysis was performed using a powder X-ray diffraction analyzer (Bruker D8 advance) equipped with a LynxEye detector. The 2 theta scan angle of the sample was from 3 deg. to 40 deg., the scan step size was 0.02 deg., and the tube voltage and tube current were 40KV and 40mA, respectively. The sample disk used for sample measurement is a zero background sample disk, and the obtained X-ray powder diffraction pattern is shown in fig. 1, and can be seen from fig. 1: the precipitated solid comprises diffraction angles selected from 5.0 °, 9.8 °, 11.6 °, 14.0 °, 16.5 °, 17.5 °, 19.8 ° and 23.2 °, the crystalline form I of the present application has a thermodynamically stable crystalline form which is not transformed in solvents such as ethanol, ethyl acetate and acetonitrile or high temperature environments, and which can be prepared in a reproducible form.

In this example, the present application provides a crystalline form that can be characterized by an X-ray powder diffraction pattern (XRPD) having characteristic peaks according to 2Θ. The relative intensities of the peaks may vary depending on the sample preparation technique, sample mounting procedure, and the particular instrument employed. In addition, instrument variations and other factors may affect the 2 theta value. In some embodiments, the XRPD peak assignment may vary by about 0.2 °.

In some embodiments, the present application form I is subjected to nuclear magnetic analysis (¹ H NMR).

The instrument used for the nuclear magnetic analysis is Bruker Advance 300 equipped with a B-ACS 120 automatic sample injection system, the nuclear magnetic analysis solvent adopts deuterated DMSO, the ¹ H NMR spectrum of the crystal form I is shown in figure 2,

In some embodiments, the present application form I is subjected to thermogravimetric analysis (TGA).

The thermal gravimetric analysis uses a TA TGA Q500 instrument, 2 mg-3 mg of crystal form I sample is placed in an equilibrated aluminum sample tray, the sample mass is automatically weighed in a TGA heating furnace, the sample is heated to 250-300 ℃ at a speed of 10 ℃/min for weightless treatment, in the test process, the nitrogen flow of nitrogen to a balance chamber and a sample chamber is 40mL/min and 60mL/min respectively, and the obtained TGA map is shown in figure 3, and the obtained TGA map is calculated by the following steps: the weight loss rate of the crystal form I before and after weight loss is 0.928%, and the weight loss rate of the crystal form I is lower, so that the crystal form I has good stability.

In some embodiments, form I was heated to 150 ℃ using a TA TGA Q500 instrument to remove residual solvent to obtain desolvated form I, which was characterized by XRPD using an X-ray diffraction analyzer (Bruker D8 advance), and the desolvated XRPD pattern was compared to the pattern of the non-desolvated form, as shown in fig. 4, and no change in the characteristic peak of form I after desolvation was found, indicating that the solvent remaining in form I had no effect on the form of the mesylate salt of the phosphorus-containing pyrido [2,3-D ] pyrimidin-7-one.

In some embodiments, the present application form I is subjected to differential scanning calorimetric analysis (DSC).

The instrument used for differential scanning calorimetric analysis was TA DSC Q200, and the standard sample used for calibration was indium.

Placing 2 mg-3 mg of the crystal form I sample in a TA DSC sample tray, recording the accurate mass of the sample, heating the sample to 250-300 ℃ in a nitrogen flow of 50mL/min at a heating rate of 10 ℃/min, and obtaining a DSC graph shown in figure 3, wherein the DSC graph is shown in figure 3: before the temperature of the crystal form I reaches the decomposition temperature of the crystal form I, no obvious melting peak exists, which indicates that the melting point of the crystal form I is higher than the decomposition temperature, and further indicates that the crystal form I is relatively stable.

The chemical formula of the phosphorus-containing pyrido [2,3-d ] pyrimidine-7-ketone is as follows: 2-amino-8- [4- (diethoxyphosphorylmethylamino) cyclohexyl ] -6- (6-methoxy-3-pyridinyl) -4-methylpyridin [2,3-d ] pyrimidin-7-one, the preparation of the above compound is as follows:

a) To a solution of trans-2-amino-8- (4-hydroxycyclohexyl) -6- (6-methoxy-3-pyridinyl) -4-methylpyridin-7-one (1-11, 1.5g,3.93mmol and sodium acetate (640 mg,7.8 mmol) in dichloromethane (15 mL) at 0deg.C) was added PCC (1.1 g,4.7 mmol) and the resulting mixture was stirred at room temperature for 4 hours, filtered, concentrated under reduced pressure and the crude product was purified by silica gel column chromatography using a petroleum ether/ethyl acetate mixture (70/30) as eluent to give the compound 2-amino-6- (6-methoxy-3-pyridinyl) -4-methyl-8- (4-oxocyclohexyl) pyridin-2, 3-d pyrimidin-7-one (2-1, 1g, yield: 67%). Mass spectrometry analysis results: m/z 380.30[ M+H ] ₊.

B) A solution of 2-amino-6- (6-methoxy-3-pyridinyl) -4-methyl-8- (4-oxocyclohexyl) pyridin [2,3-d ] pyrimidin-7-one (2-1, 1.5g,4.0 mmol) and triethylamine (1.2 g,11.8 mmol) in THF (15 mL) was stirred at room temperature for 1 hour, ti (OPr-i) ₄ (5 mL) and diethoxyphosphorylmethylamine (2-2, 1.5g,5.9 mmol) were added and the resulting mixture was stirred at room temperature for 2 hours, sodium borohydride (0.75 g,19.8 mmol) was added and stirred overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL), extracted with dichloromethane (3X 100 mL), the organic phase dried over magnesium sulfate, filtered, concentrated, and the residue purified by HPLC to give 2-amino-8- [4- (diethoxyphosphorylmethylamino) cyclohexyl ] -6- (6-methoxy-3-pyridinyl) -4-methylpyridin-7-one (2-3, 400mg, yield: 19%) as a trans/cis mixture, which was further separated by Supercritical Fluid Chromatography (SFC) to give 226mg of cis product and 50mg of trans product.

(2) Adding the product obtained in the step (1) into a 25mL single-port bottle, adding 12mL of ethanol, putting into an oil bath, heating to 50 ℃ and stirring, adding 244.6 mu L of methanesulfonic acid liquid into the solution after the sample is dissolved, heating to 70 ℃ for reaction for 1h, naturally cooling, gradually precipitating solids, cooling to room temperature, and stirring for 1 h.

Example 2

The sulfonate of phosphorus-containing pyrido [2,3-d ] pyrimidine-7-ketone is dissolved by adopting a single solvent, wherein the single solvent comprises any one of methanol, ethanol, isopropanol, isobutanol, 2-butanone, tetrahydrofuran, acetonitrile, methyl tertiary butyl ether, acetone, water, toluene, ethyl acetate and isopropyl acetate.

Specifically, the sulfonate containing phosphorus pyrido [2,3-d ] pyrimidine-7-ketone is weighed and placed in 13 glass bottles, the solvent in 13 is added into the glass bottles respectively, one solvent corresponds to one glass bottle, 13 different mixed liquid medicines are obtained, 2mL of liquid medicine in each bottle is taken out and filtered into 13 centrifuge tubes, and the 13 obtained filtrate and the residual suspension after filtration are used in the later experiments. In the process of preparing the crude drug solution, the mass of the weighed crude drug, the volume of the solvent and experimental phenomena in preparation are shown in table 1.

TABLE 1 proportion of the compound of EXAMPLE 1 and solvent formulation of Mixed liquor

The 13 filtrates are distributed in 13 centrifuge tubes, the 13 centrifuge tube openings are placed in a fume hood for natural volatilizing, the samples with obvious solids are separated out, the samples with too little solids and no obvious solids are analyzed and identified by XRPD, the samples with too little solids and no obvious solids are not characterized, and the identification results are shown in Table 2 and FIG. 5.

TABLE 2 XRPD results for samples obtained by crystallization in 13 solvents

Four crystalline solids were found in total in the 13 single solvents identified above, STOCK, STOCK2, STOCK 3 and STOCK 10, respectively, as identified by XRPD analysis. XRPD measurements were performed on each of the four crystalline solids, under the following conditions: analysis was performed using a powder X-ray diffraction analyzer (Bruker D8 advance) equipped with a LynxEye detector. The 2 theta scan angle of the sample was from 3 deg. to 40 deg., the scan step size was 0.02 deg., and the tube voltage and tube current were 40KV and 40mA, respectively. The sample pan used for the sample measurement was a zero background sample pan. The crystal forms STOCK, STOCK 3 and STOCK were determined to be identical and were designated as form II, the X-ray powder diffraction pattern of form II including diffraction angles selected from 10.8 °, 12.2 °, 16.0 °, 16.8 °, 25.6 ° and 26.8 °, and the X-ray powder diffraction pattern of form II being shown in fig. 6. STOCK 2A 2 comprises a mixed crystal of two crystal forms, one of which is form II and the other of which is designated as form III, the X-ray powder diffraction pattern of form III comprising diffraction angles selected from 10.6 °, 16.0 °, and 25.5 °, the X-ray powder diffraction pattern of form III being as shown in FIG. 6, example 3

13 Bottles of the different mixed liquor in example 2 were stirred and beaten at room temperature, stirred and preserved after 3 days, the suspended liquor was sequentially filtered and analyzed and identified by XRPD, and the identification results are shown in table 3 and fig. 7.

TABLE 3 XRPD results for samples obtained by beating in a single solvent

The crystal forms SLURRY to SLURRY, SLURRY8, SLURRY, SLURRY to SLURRY13 are identical to the crystal form I according to XRPD analysis and identification. SLURRY7 is a new crystalline form, hereinafter designated form IV, the X-ray powder diffraction pattern of which includes diffraction angles selected from 4.7 °, 9.3 ° and 11.7 °, the XRPD pattern of which is shown in figure 6.

In this embodiment, form IV is in the form of a solvate, "solvate" refers to a compound formed by the interaction of a solute (e.g., a compound having structural formula I) and one or more solvents (e.g., acetonitrile, water). Thus, "solvate" includes a single type of solvate containing a solvent molecule, as well as more than one type of solvate containing a solvent molecule (mixed solvate). Typically, one or more solvents in the solvates described herein are organic solvents, or combinations of organic solvents, and exemplary solvates of the present application include acetonitrile solvates.

Example 4

The 13 filtrates obtained in example 2 were distributed in 96-well plates, and the specific distribution is shown in the solvent distribution matrix of Table 4. Sealing the 96-well plate by using a sealing film, and naturally volatilizing after punching. After evaporation of the solvent, samples with significant solids precipitated were suitably identified by XRPD analysis, and samples with too little and no significant solids were not characterized, and the XRPD measurements are shown in table 5 and fig. 8-11.

TABLE 4 distribution of solvents in 96 well plates

TABLE 5 XRPD assay results for samples in 96 well plates

Through the XRPD analysis and identification, a total of 2 crystal forms were found in this example, and the two crystal forms are the same as crystal form II and crystal form III, respectively, and some samples were mixed crystal of crystal form II and crystal form III.

In the following, a small scale up experiment was performed with the A1 site sample representing form III, the A4 site sample representing form II and SLURRY representing form IV to prepare samples, designated as scale up A1, scale up A4 and scale up SLURRY7 in order for subsequent investigation, and XRPD, TGA and DSC characterization and XRPD characterization after solvent removal of the prepared solid. The solvent removal was achieved by heating to 150 ℃ using TGA.

(1) Preparation of A1 hole site sample

45.28Mg of the sulfonate sample prepared in example 1 was weighed, 1.5mL of methanol was added for dissolution, the mixture was filtered and distributed to 96-well plates, 200. Mu.L of each well was added, the mixture was sealed with a sealing film and then was left to open, the mixture was naturally volatilized in a fume hood, and the obtained solids were combined and named amplified A1 for XRPD, DSC and TGA characterization and XRPD characterization after solvent removal.

(2) Preparation of A4 hole site sample

The sulfonate sample 30.77mg prepared in example 1 was weighed separately, 1.0mL of methanol was added, 10.45mg of isobutanol was added, after sufficient shaking, filtration and distribution to 96-well plates was performed, two filtrates each 100 μl were added, sealing film was capped, then the wells were pricked, placed in a fume hood for natural evaporation, the resulting solids were combined, named amplified A4, subjected to XRPD, DSC and TGA characterization and XRPD characterization after solvent removal.

(3) Preparation SLURRY of sample

The sulfonate sample prepared in example 1, 20.05mg, was weighed, 2.0mL of acetonitrile was added, stirred at room temperature for 3 days, and the resulting solid from the suspension was filtered and designated as an enlarged SLURRY, and XRPD, DSC and TGA characterization and XRPD characterization after removal of the solvent were performed.

The three amplified samples were subjected to XRPD characterization and compared to prior to amplification, and the comparative XRPD patterns are shown in fig. 12-14, which show no change in the crystalline form.

The TGA and DSC were measured on the amplified samples A4, A1 and SLURRY, respectively, and the TGA and DSC spectra are shown in fig. 15 to 17, and as can be seen from fig. 15 to 17: the solvent residues of the crystal form II, the crystal form III and the crystal form IV are higher.

The samples of the amplification A4, the amplification A1 and the amplification SLURRY were subjected to XRPD characterization after removal of the solvent, and the characterization results are shown in FIGS. 18 to 20, and can be seen from FIGS. 18 to 19: amplification A4 (form II) and amplification A1 (form III) did not change; as can be seen from fig. 20: the SLURRY7 sample (form IV) was amplified to remove the solvent and converted to form I, confirming that form IV is a solvate.

Example 5

Suspension seeding experiments were performed on the four crystalline forms obtained in examples 1 to 4.

Equal amounts of the weighed samples of form I, form II, form III and form IV were placed in an 8mL glass bottle, solvent was added to make a suspension, the suspension was stirred in solvent at room temperature for 1 day, and the solid was filtered and subjected to XRPD analysis to determine the conversion of the form. The specific experimental conditions and samples are shown in table 6.

TABLE 6 suspension transformation experimental conditions and details

Through the above crystal transformation experiment, XRPD analysis is performed on the crystal transformed sample, and it is found that: the crystal form I, the crystal form II and the crystal form III are all converted into the crystal form I after crystal transformation, which shows that the crystal form I is the most stable crystal form, and the crystal form I is subjected to physical grinding and characterization to determine the transformation of the crystal form.

About 10mg of form I sample was taken and manually milled in a mortar for 5 minutes, the solid powder was subjected to XRPD characterization, the XRPD characterization spectrum being shown in fig. 21, and as can be seen in fig. 21, form I was significantly reduced in crystallinity after physical milling, thus indicating that form I was relatively sensitive to pressure.

In summary, 13 solvents and binary mixtures thereof are used for the mesylate of the phosphorus-containing pyrido [2,3-d ] pyrimidine-7-one, and the polymorphic form screening of the mesylate of the phosphorus-containing pyrido [2,3-d ] pyrimidine-7-one is completed by using multiple ways such as a mixed solvent crystallization method, a single solvent crystallization method, a suspension crystal transformation method, a grinding crystal transformation method and the like, and all solid samples obtained in the screening process are subjected to powder X-ray diffraction analysis (XRPD), so that the crystal form I is the most stable crystal of the mesylate of the phosphorus-containing pyrido [2,3-d ] pyrimidine-7-one, and the thermodynamically stable crystal form can obtain advantages in preparation, such as being stable enough to be stored for a long time, and has great significance for the compound to the environments such as temperature, light, humidity and the like for the phosphorus-containing pyrido [2,3-d ] pyrimidine-7-one to be used for pharmacy.

Example 6

The novel crystals of the mesylate salt of phosphopyrido [2,3-d ] pyrimidin-7-one obtained in the above examples can be used to prepare pharmaceutical compositions comprising the novel crystalline forms described above and pharmaceutically acceptable additives.

Such additives include lubricants, disintegrants, emulsifiers, surfactants, buffers, preservatives, antioxidants and the like commonly used in pharmaceuticals.

The pharmaceutical composition of the present application may be in the form of an oral formulation such as a tablet, capsule, granule or inhalant; the external preparation may be, for example, suspension, aerosol, suppository, ointment, ear drop, injection, or the like.

The pharmaceutical composition of the application can be used for treating diseases caused by abnormal activity of protein kinases including PI 3K-alpha, PI 3K-beta, PI 3K-gamma and PI 3K-delta. The disease may be psoriasis, liver cirrhosis, tracheitis, diabetes, diseases involving angiogenesis, eye diseases, immune system diseases, cardiovascular diseases, epilepsy or neurodegenerative diseases. The disease may also be a tumor, such as one or a combination of several of lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, sarcoma of soft tissue, cancer of the urinary tract, penile cancer, prostate cancer, chronic or acute leukemia, bladder cancer, renal or ureteral cancer, neoplasms of the central nervous system, spinal axis tumors, gastrointestinal stromal tumors, mastocytosis, glioma, sarcoma, and lymphoma.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims

1. A novel crystalline form of a mesylate salt of a phosphorus-containing pyrido [2,3-d ] pyrimidin-7-one, characterized in that the mesylate salt of a phosphorus-containing pyrido [2,3-d ] pyrimidin-7-one has the structural formula (I), the novel crystalline form having an X-ray powder diffraction pattern comprising diffraction angles selected from the group consisting of 5.0 °, 9.8 °, 11.6 °, 14.0 °, 16.5 °, 17.5 °, 19.8 ° and 23.2 °;

2. The new crystalline form according to claim 1, characterized in that it exhibits an X-ray powder diffraction pattern as shown in figure 1.

3. The new crystalline form according to claim 1, characterized in that it is obtainable by beating a crystalline form comprising diffraction angles selected from 4.7 °, 9.3 ° and 11.7 ° in acetonitrile solution by means of an X-ray powder diffraction pattern.

4. The new crystalline form according to claim 1, characterized in that it is obtainable by suspension seeding of a crystalline form comprising diffraction angles selected from 10.8 °, 12.2 °, 16.0 °, 16.8 °, 25.6 ° and 26.8 ° in ethanol solution by means of an X-ray powder diffraction pattern.

5. The new crystalline form according to claim 1, characterized in that it is obtainable by suspension seeding in an ethanol solution of a crystalline form comprising diffraction angles selected from 10.6 °, 16.0 ° and 25.5 ° by an X-ray powder diffraction pattern.

6. The new crystalline form according to claim 1, characterized by a weight loss of 0.928% in thermogravimetric analysis test at 250 ℃ to 300 ℃.

7. The new crystalline form of claim 1, wherein the crystallinity of the new crystalline form is inversely related to the pressure applied.

8. A pharmaceutical composition comprising the novel crystalline form of any one of claims 1 to 7 and a pharmaceutically acceptable additive.

9. Use of a pharmaceutical composition according to claim 8 for the treatment of a disease caused by abnormal activity of a protein kinase.