Crystal form of substituted 2-hydrogen-pyrazole derivative and preparation method thereof

Abstract

The invention relates to a crystal form of a substituted 2-hydrogen-pyrazole derivative (I) and a preparation method of the crystal form. The invention further discloses application of the crystal form in preparation of medicines for treating breast cancer and other cancers. # imgabs0 #

Description

A crystalline form of a substituted 2-hydrogen-pyrazole derivative and a preparation method thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims the benefit of and priority to Chinese invention patent application No. 202210971553.6 filed with the State Intellectual Property Office of the People's Republic of China on August 12, 2022, the entire contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present disclosure relates to a crystalline form of a substituted 2-hydrogen-pyrazole derivative and a preparation method thereof, and also includes the use of the crystalline form in the preparation of drugs for treating breast cancer and other cancers. Background Art

[0004] The cell cycle is primarily regulated by a series of serine / threonine kinases, also known as cyclin-dependent kinases (CDKs). These kinases, by binding to their corresponding regulatory subunits, cyclins, drive cell cycle progression, genetic transcription, and normal cell division and proliferation. CDK4 / 6 are key regulators of the cell cycle, triggering the transition from the growth phase (G1) to the DNA replication phase (S1). During cell proliferation, a complex formed by cyclin D and CDK4 / 6 phosphorylates the retinoblastoma protein (Rb). Phosphorylation of the tumor suppressor protein Rb releases the transcription factor E2F, to which it binds tightly in its unphosphorylated state. E2F activation further drives transcription through the cell cycle restriction point (R point) and progression from G1 to S phase, entering the cell proliferation cycle. Therefore, inhibiting CDK4 / 6 and preventing it from forming the Cyclin D-CDK4 / 6 complex can block the progression of the cell cycle from the G1 phase to the S phase, thereby inhibiting tumor proliferation. In estrogen receptor-positive (ER+) breast cancer (BC), overactivity of CDK4 / 6 is very common, and CDK4 / 6 is a key downstream target of ER signaling. Preclinical data show that dual inhibition of CDK4 / 6 and estrogen receptor (ER) signaling has a synergistic effect and can inhibit the growth of estrogen receptor-positive (ER+) breast cancer (BC) cells in the G1 phase.

[0005] WO2018045993A1 discloses a crystalline form of a substituted 2-hydrogen-pyrazole derivative, the structure of which is shown in the compound of formula (I), and discloses a crystalline form B of the compound of formula (I)

[0006] Summary of the Invention

[0007] In one aspect, the present disclosure provides crystals of a compound of formula (I),

[0008] The crystals of the compound of formula (I) described in the present disclosure may be in the form of a non-solvate or a solvate, such as a hydrate.

[0009] On the other hand, the present disclosure provides a crystalline compound A of formula (I), which has an X-ray powder diffraction pattern using Cu Kα radiation, comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 diffraction peaks at 2θ angles selected from the following: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.36±0.20°, 13.87±0.20°, 15.53±0.20°, 16.22±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20°, 20.87±0.20°, 21.10±0.20°, 23.52±0.20°, 24.09±0.20°, 25.24±0.20°, 26.21±0.20°, 26.61±0.20° and 27.91±0.20°.

[0010] In some embodiments of the present disclosure, the crystalline A of the compound of formula (I) comprises 3, 4, 5, 6, 7, 8, 9, 10 or 11 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.87±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20°, 23.52±0.20°, 24.09±0.20°, 25.24±0.20° and 26.61±0.20°.

[0011] In some embodiments of the present disclosure, the crystalline A of the compound of formula (I) comprises 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.87±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20° and 24.09±0.20°.

[0012] In another aspect, the present disclosure provides a crystalline compound A of formula (I), having an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, and 11.41±0.20°.

[0013] In some embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20° and 19.02±0.20°.

[0014] In some embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 17.25±0.20°, 19.02±0.20° and 24.09±0.20°.

[0015] In some embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.87±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20° and 24.09±0.20°.

[0016] In some embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.87±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20°, 23.52±0.20°, 24.09±0.20°, 25.24±0.20° and 26.61±0.20°.

[0017] In some embodiments of the present disclosure, the crystal A of the compound of formula (I) is prepared using Cu The X-ray powder diffraction pattern of Kα radiation has diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.36±0.20°, 13.87±0.20°, 15.53±0.20°, 16.22±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20°, 20.87±0.20°, 21.10±0.20°, 23.52±0.20°, 24.09±0.20°, 25.24±0.20°, 26.21±0.20°, 26.61±0.20° and 27.91±0.20°.

[0018] In some embodiments of the present disclosure, the XRPD pattern of the crystalline A of the compound of formula (I) using CuKα radiation is shown in FIG1 .

[0019] In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation, comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 diffraction peaks selected from the following 2θ angles: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 13.35±0.20°, 13.88±0.20°, 15.52±0.20°, 16.21±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20°, 20.77±0.20°, 21.09±0.20°, 23.63±0.20°, 24.07±0.20°, 25.19±0.20°, 26.19±0.20°, 26.60±0.20° and 27.89±0.20°.

[0020] In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) comprises 3, 4, 5, 6, 7, 8, 9, 10 or 11 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 13.88±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20°, 23.63±0.20°, 24.07±0.20°, 25.19±0.20° and 26.60±0.20°.

[0021] In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) comprises 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 13.88±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20° and 24.07±0.20°.

[0022] In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation with diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.45±0.20° and 11.40±0.20°.

[0023] In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation with diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.45±0.20°, 11.40±0.20° and 19.01±0.20°.

[0024] In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 17.24±0.20°, 19.01±0.20° and 24.07±0.20°.

[0025] In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 13.88±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20° and 24.07±0.20°.

[0026] In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 13.88±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20°, 23.63±0.20°, 24.07±0.20°, 25.19±0.20° and 26.60±0.20°.

[0027] In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 13.35±0.20°, 13.88±0.20°, 15.52±0.20°, 16.21±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20°, 20.77±0.20°, 21.09±0.20°, 23.63±0.20°, 24.07±0.20°, 25.19±0.20°, 26.19±0.20°, 26.60±0.20° and 27.89±0.20°.

[0028] In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 6.92±0.20°, 9.09±0.20°, 10.45±0.20°, 11.40±0.20°, 13.35±0.20°, 13.88±0.20°, 14.78±0.20°, 15.52±0.20°, 16.00±0.20°, 16.21±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20°, 19.66±0.20°, 20.77±0.20° , 21.09±0.20°, 21.55±0.20°, 22.22±0.20°, 22.55±0.20°, 23.63±0.20°, 24.07±0.20°, 25.19±0.20°, 26.19±0.20°, 26.60±0.20°, 27.21±0.20°, 27.89±0.20°, 28.74±0.20°, 29.55±0.20°, 29.88±0.20°, 30.38±0.20°, 31.36±0.20° and 31.85±0.20°.

[0029] In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 6.92, 9.09, 10.45, 11.40, 13.35, 13.88, 14.78, 15.52, 16.00, 16.21, 17.24, 18.18, 19.01, 19.66, 20.77, 21.09, 21.55, 22.22, 22.55, 23.63, 24.07, 25.19, 26.19, 26.60, 27.21, 27.89, 28.74, 29.55, 29.88, 30.38, 31.36 and 31.85.

[0030] In some other embodiments of the present disclosure, the XRPD pattern of the crystalline A of the compound of formula (I) using CuKα radiation is shown in FIG2 .

[0031] In other embodiments of the present disclosure, the XRPD pattern analysis data of the crystalline A of the compound of formula (I) using Cu Kα radiation are shown in Table 1.

[0032] Table 1: XRPD pattern analysis data of crystal A of compound of formula (I)

[0033] In some embodiments of the present disclosure, the crystalline A of the compound of formula (I) has a differential scanning calorimetry curve with endothermic peaks at 213.2±5.0°C and 228.5±5.0°C, respectively.

[0034] In some embodiments of the present disclosure, the DSC spectrum of the crystalline A of the compound of formula (I) is shown in FIG3 .

[0035] On the other hand, the present disclosure also provides a method for preparing the crystal A of the compound of formula (I), comprising the step of precipitating the compound of formula (I) from an organic solvent.

[0036] In some embodiments of the present disclosure, in the method for preparing the crystal A of the compound of formula (I), the organic solvent is selected from a mixed solvent of methanol and dichloromethane.

[0037] In some embodiments of the present disclosure, in the method for preparing the crystal A of the compound of formula (I), the volume ratio of methanol to dichloromethane is 1:5.

[0038] In other embodiments of the present disclosure, the method for preparing the crystal A of the compound of formula (I) comprises: (a) stirring the compound of formula (I), ethanol, water and hydrochloric acid together; (b) adding an aqueous solution of sodium hydroxide, heating and stirring for a period of time, then cooling to room temperature and filtering to obtain the crystal A of the compound of formula (I).

[0039] In some embodiments of the present disclosure, in the method for preparing the crystal A of the compound of formula (I), the heating in step (b) is to raise the temperature to 70-80°C.

[0040] In the present disclosure, in the method for preparing the crystal A of the compound of formula (I), the starting compound of formula (I) can be in any form, such as crystals, amorphous forms, hydrates, solvates, crude products, etc.

[0041] The present disclosure also provides a crystalline composition comprising Crystals A of the compound of formula (I), wherein Crystals A of the compound of formula (I) accounts for more than 50% by weight of the crystalline composition, preferably more than 75%, more preferably more than 90%, and most preferably more than 95%. In other embodiments of the present disclosure, in the crystalline composition comprising Crystals A of the compound of formula (I), Crystals A of the compound of formula (I) accounts for more than 96% by weight of the crystalline composition, or more than 97%, or more than 98%, or more than 99%. Each of the crystalline compositions may also contain a small amount of other crystalline or non-crystalline forms of the compound of formula (I).

[0042] In some embodiments of the present disclosure, in the crystalline composition comprising the crystalline A of the compound of formula (I), the remainder of the crystalline composition except the crystalline A of the compound of formula (I) is the non-crystalline A form of the compound of formula (I).

[0043] In some embodiments of the present disclosure, in the crystalline composition comprising crystal A of the compound of formula (I), the content of the compound of formula (I) in the crystalline composition may be greater than 95%, or greater than 99%, or greater than 99.9%, or greater than 99.99%.

[0044] In another aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Crystal A of the compound of formula (I), or a crystalline composition thereof; the pharmaceutical composition may comprise at least one pharmaceutically acceptable excipient. In addition, the pharmaceutical composition of the present application may further include one or more other therapeutic agents.

[0045] In some embodiments of the present disclosure, the pharmaceutical composition comprising the crystalline A of the compound of formula (I) is a solid pharmaceutical composition.

[0046] In some embodiments of the present disclosure, the excipients in the solid pharmaceutical composition comprising the crystalline A of the compound of formula (I) include at least one of a diluent, a binder, a disintegrant, and a lubricant.

[0047] In some embodiments of the present disclosure, the excipients in the solid pharmaceutical composition comprising the crystalline A of the compound of formula (I) include at least one of a filler, a glidant, and a lubricant.

[0048] In some embodiments of the present disclosure, the excipients in the solid pharmaceutical composition comprising the crystalline A of the compound of formula (I) include a filler, a glidant, and a lubricant.

[0049] In some embodiments of the present disclosure, the filler is selected from starch, pregelatinized starch, sucrose, lactose (e.g., lactose monohydrate), fructose, maltose, trehalose, pullulan, polydextrose, dextrin, maltodextrin, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cellulose acetate, ethyl cellulose, mannitol, sorbitol, erythritol, isomalt, lactitol, maltitol, polyethylene glycol, xylitol, sorbitol, calcium carbonate, calcium phosphate, anhydrous calcium hydrogen phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate, sodium chloride, or a mixture of any two or more thereof; preferably, the filler is selected from mannitol, microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropyl cellulose, anhydrous calcium hydrogen phosphate, lactose monohydrate, or a mixture thereof. a mixture of any two or more of the following: further preferably, the filler is selected from a mixture of any two of mannitol, microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropyl cellulose, anhydrous calcium hydrogen phosphate and lactose monohydrate; in some specific embodiments of the present disclosure, the filler is selected from a mixture of mannitol and microcrystalline cellulose, a mixture of mannitol and pregelatinized starch, a mixture of mannitol and low-substituted hydroxypropyl cellulose, a mixture of mannitol and anhydrous calcium hydrogen phosphate, or a mixture of crystalline cellulose and lactose monohydrate; in a specific embodiment of the present disclosure, the filler is selected from a mixture of mannitol and anhydrous calcium hydrogen phosphate; in a specific embodiment of the present disclosure, the filler is selected from a mixture of microcrystalline cellulose and lactose monohydrate.

[0050] In some embodiments of the present disclosure, the glidant is selected from silicon dioxide, colloidal silicon dioxide, magnesium trisilicate, starch, powdered cellulose, micropowdered silica or talc or a mixture of any two or more thereof; preferably, the glidant is selected from silicon dioxide, colloidal silicon dioxide, micropowdered silica or talc; further preferably, the glidant is selected from colloidal silicon dioxide or talc; in a specific embodiment of the present application, the glidant is selected from colloidal silicon dioxide.

[0051] In some embodiments of the present disclosure, the lubricant is selected from stearic acid, calcium stearate, sodium stearate, zinc stearate, magnesium stearate, glyceryl monostearate, glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, palmitoylstearoyl glyceride, leucine, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate or talc; preferably, the lubricant is selected from magnesium stearate, glyceryl behenate, sodium lauryl sulfate or sodium stearyl fumarate; in a specific embodiment of the present application, the lubricant is selected from magnesium stearate.

[0052] In some embodiments of the present disclosure, the Crystalline A of the compound of formula (I) accounts for 10-90 wt% of the total weight of the solid pharmaceutical composition; preferably 20-85 wt%, 25-80 wt%, 25-75 wt%, 30-75 wt%, 40-75 wt%, 45-75 wt%, 45-65 wt%, 45-55 wt% or 50-55 wt%; more preferably 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt% or 55 wt%. In a specific embodiment of the present disclosure, the Crystalline A of the compound of formula (I) accounts for 50 wt% of the total weight of the solid pharmaceutical composition.

[0053] In some embodiments of the present disclosure, the filler accounts for 10-98 wt% of the total weight of the solid pharmaceutical composition; preferably 20-98 wt%, 25-80 wt%, 25-75 wt%, 30-75 wt%, 40-75 wt%, 45-75 wt%, 45-65 wt%, 45-55 wt% or 45-50 wt%; more preferably 45 wt%, 45.5 wt%, 46 wt%, 46.5 wt%, 46 wt%, 47.5 wt%, 48 wt%, 48.5 wt%, 49 wt%, 49.5 wt% or 50 wt%. In a specific embodiment of the present disclosure, the filler is selected from a mixture of mannitol and anhydrous calcium hydrogen phosphate, the weight ratio of mannitol to anhydrous calcium hydrogen phosphate is 1:0.5-2; preferably 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.0. In a specific embodiment of the present disclosure, the filler is selected from a mixture of mannitol and anhydrous calcium hydrogen phosphate, the mannitol and anhydrous calcium hydrogen phosphate account for 47.5wt% of the total weight of the solid pharmaceutical composition, and the weight ratio of mannitol to anhydrous calcium hydrogen phosphate is 1:1.0.

[0054] In some embodiments of the present disclosure, the glidant accounts for 0.5-5 wt% of the total weight of the solid pharmaceutical composition; preferably 0.8 wt%, 1.0 wt%, 1.2 wt%, 1.5 wt%, 2.0 wt%, 2.2 wt%, 2.5 wt%, 2.8 wt%, 3.0 wt%, 3.2 wt%, 3.5 wt%, 3.8 wt%, 4.0 wt%, 4.2 wt%, 4.5 wt% or 4.8 wt%; in a specific embodiment of the present disclosure, the glidant accounts for 1.0 wt% of the total weight of the solid pharmaceutical composition.

[0055] In some embodiments of the present disclosure, the lubricant accounts for 0.5-5 wt% of the total weight of the solid pharmaceutical composition; preferably 0.8 wt%, 1.0 wt%, 1.2 wt%, 1.5 wt%, 2.0 wt%, 2.2 wt%, 2.5 wt%, 2.8 wt%, 3.0 wt%, 3.2 wt%, 3.5 wt%, 3.8 wt%, 4.0 wt%, 4.2 wt%, 4.5 wt% or 4.8 wt%; in a specific embodiment of the present disclosure, the lubricant accounts for 1.5 wt% of the total weight of the solid pharmaceutical composition.

[0056] In one embodiment of the present disclosure, the solid pharmaceutical composition of Crystals A of the compound of formula (I) comprises: Crystals A of the compound of formula (I); mannitol and anhydrous calcium hydrogen phosphate; colloidal silicon dioxide; and magnesium stearate. In one embodiment of the present disclosure, the solid pharmaceutical composition of Crystals A of the compound of formula (I) comprises: 10-90 wt% of Crystals A of the compound of formula (I); 10-98 wt% of mannitol and anhydrous calcium hydrogen phosphate; 0.5-5 wt% of colloidal silicon dioxide; and 0.5-5 wt% of magnesium stearate.

[0057] In one embodiment of the present disclosure, the solid pharmaceutical composition of Crystalline A of Compound of Formula (I) comprises: 50-55 wt% of Crystalline A of Compound of Formula (I); 45-50 wt% of mannitol and anhydrous calcium hydrogen phosphate; 1.0 wt% of colloidal silicon dioxide; and 1.2 wt% of magnesium stearate.

[0058] In some embodiments, in the solid pharmaceutical composition of Crystalline Compound A of Formula (I), Crystalline Compound A of Formula (I) serves as an active ingredient, mannitol and anhydrous calcium hydrogen phosphate serve as fillers, colloidal silicon dioxide serves as a glidant, and magnesium stearate serves as a lubricant.

[0059] In one embodiment of the present disclosure, the solid pharmaceutical composition of Crystalline A of Compound of Formula (I) comprises: Crystalline A of Compound of Formula (I); microcrystalline cellulose and lactose monohydrate; colloidal silicon dioxide; and magnesium stearate.

[0060] In some embodiments, the crystalline A of the compound of formula (I) is used as the active ingredient, microcrystalline cellulose and lactose monohydrate are used as fillers, colloidal silicon dioxide is used as a glidant, and magnesium stearate is used as a lubricant.

[0061] The solid pharmaceutical composition of the present disclosure can be formed into a variety of dosage forms suitable for oral administration to humans, such as tablets, pills, capsules, powders or granules, etc. In some embodiments of the present disclosure, the solid pharmaceutical composition is in the form of a capsule.

[0062] In some embodiments of the present disclosure, the solid pharmaceutical composition of crystalline A of compound of formula (I) is in the form of a capsule, the capsule shell of the capsule is selected from a plant capsule shell or a gelatin capsule shell, and the plant capsule shell is selected from a hollow capsule of hypromellose.

[0063] In some embodiments of the present disclosure, in the solid pharmaceutical composition of Crystal A of the compound of formula (I), the particle size distribution of Crystal A of the compound of formula (I) satisfies X50≤5μm, X90≤15μm; preferably, the particle size distribution of Crystal A of the compound of formula (I) satisfies X50=1~5μm, X90=3~15μm.

[0064] In some embodiments of the present disclosure, the solid pharmaceutical composition formulation of Crystalline Compound A of Formula (I) is a capsule containing 50 mg of Crystalline Compound A of Formula (I) per unit.

[0065] In some embodiments of the present disclosure, the formulation is a capsule containing 60 mg of Crystalline A of the compound of Formula (I) per unit.

[0066] In some embodiments of the present disclosure, each unit of the solid pharmaceutical composition of Crystalline A of Compound of Formula (I) comprises 50 mg of Crystalline A of Compound of Formula (I), 23.75 mg of mannitol, 23.75 mg of anhydrous calcium hydrogen phosphate, 1 mg of colloidal silicon dioxide, and 1.5 mg of magnesium stearate.

[0067] In some embodiments of the present disclosure, each unit of the solid pharmaceutical composition of Crystalline A of Compound of Formula (I) comprises 60 mg of Crystalline A of Compound of Formula (I), 28.5 mg of mannitol, 28.5 mg of anhydrous calcium hydrogen phosphate, 1.2 mg of colloidal silicon dioxide, and 1.8 mg of magnesium stearate.

[0068] On the other hand, the present disclosure provides the use of Crystalline A of the compound of formula (I), a crystalline composition of Crystalline A of the compound of formula (I), or a solid pharmaceutical composition of Crystalline A of the compound of formula (I) in the preparation of a medicament for treating or preventing diseases associated with selective CDK4 / 6 inhibition, wherein the diseases associated with selective CDK4 / 6 inhibition include breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer, and acute myeloid leukemia.

[0069] On the other hand, the present disclosure provides the use of Crystalline A of the compound of formula (I), a crystalline composition of Crystalline A of the compound of formula (I), or a solid pharmaceutical composition of Crystalline A of the compound of formula (I) for treating or preventing diseases related to selective CDK4 / 6 inhibition, wherein the selective CDK4 / 6 inhibition-related diseases include breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer and acute myeloid leukemia.

[0070] On the other hand, the present disclosure provides a method for treating or preventing diseases related to selective CDK4 / 6 inhibition, which comprises administering a therapeutically effective amount of Crystalline A of the compound of formula (I), a crystalline composition of Crystalline A of the compound of formula (I), or a solid pharmaceutical composition of Crystalline A of the compound of formula (I) to a mammal in need thereof, wherein the diseases related to selective CDK4 / 6 inhibition include breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer, and acute myeloid leukemia.

[0071] On the other hand, the present disclosure provides a crystalline compound A of formula (I), a crystalline composition of crystalline compound A of formula (I), or a solid pharmaceutical composition of crystalline compound A of formula (I) for treating or preventing diseases related to selective CDK4 / 6 inhibition, wherein the diseases related to selective CDK4 / 6 inhibition include breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer, and acute myeloid leukemia.

[0072] In some embodiments of the present disclosure, the mammal is a human.

[0073] In another aspect, the present disclosure provides a method for preparing a solid pharmaceutical composition of the crystalline A of the compound of formula (I), comprising the following steps:

[0074] 1) sieving and mixing the crystals A of the compound of formula (I), a filler, a glidant and a lubricant;

[0075] 2) dry granulating the mixed mixture and mixing it with a lubricant;

[0076] 3) Capsule filling.

[0077] In some embodiments of the present disclosure, the filler in the method for preparing the solid pharmaceutical composition of the crystalline A of the compound of formula (I) is as described above, for example, the filler is a mixture of mannitol and anhydrous calcium hydrogen phosphate, or a mixture of microcrystalline cellulose and lactose monohydrate.

[0078] In some embodiments of the present disclosure, the glidant in the method for preparing the solid pharmaceutical composition of the crystalline A of the compound of formula (I) is as described above, for example, the glidant is colloidal silicon dioxide.

[0079] In some embodiments of the present disclosure, the internal lubricant and the external lubricant in the preparation method of the solid pharmaceutical composition of the crystal A of the compound of formula (I) are the same, and the lubricant is as described above, for example, the lubricant is magnesium stearate.

[0080] In the present disclosure, the X-ray powder diffraction spectrum of the sample is measured under the following conditions: Instrument: Bruker D8advance X-ray diffractometer.

[0081] It should be noted that the positions or relative intensities of peaks in X-ray powder diffraction spectra may vary due to factors such as the measuring instrument, measurement method, and conditions. For any particular crystal, the peak positions may have errors, and the measurement error of the 2θ value is ±0.2. Therefore, this error should be taken into account when determining the value of each crystal, and any value within this error is within the scope of this application.

[0082] It should be noted that for the same crystal, the position of the DSC endothermic peak may vary due to factors such as the measuring instrument, measurement method / conditions, etc. For any particular crystal, the position of the endothermic peak may have an error of ±5°C. Therefore, this error should be taken into account when determining the crystallinity of each crystal, and any error within this error is within the scope of this application.

[0083] In the present disclosure, the XRPD spectra of crystal A of compound of formula (I) are shown in Figures 1 and 2, both representing the test results of different batches of the same crystal.

[0084] Technical Effects

[0085] The crystals A of the compound of formula (I) described in the present disclosure have good solubility, show good stability under conditions such as high humidity, high temperature, illumination, air flow crushing and high pressure grinding, and also show good stability under long-term test conditions. The crystals A of the compound of formula (I) described in the present disclosure and its pharmaceutical composition have advantages in terms of pharmaceutical activity, pharmacokinetics, bioavailability, hygroscopicity, stability, melting point, solubility, formulation dissolution, excipient compatibility, purity, and ease of preparation, so as to meet the needs of drugs in production, storage, transportation and formulation. For example, the crystals A of the compound of formula (I) have better water solubility than the crystals B of the compound of formula (I), and show better dissolution in formulation, and also show better pharmacokinetic properties.

[0086] Definition and Description

[0087] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be construed as ambiguous or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0088] "Mammal" includes humans and domestic animals such as laboratory mammals and household pets (e.g., cats, dogs, pigs, sheep, cattle, goats, horses, rabbits), and non-domesticated mammals, such as wild mammals.

[0089] The term "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal, such as a human. The medium includes all pharmaceutically acceptable carriers for use therewith. Pharmaceutical compositions facilitate administration of the compound to an organism.

[0090] The term "therapeutically effective amount" refers to a non-toxic amount of a drug or pharmaceutical agent sufficient to achieve the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0091] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0092] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0093] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0094] The term "prevention" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0095] As used herein, "pharmaceutically acceptable carrier" refers to a carrier that is administered with an active ingredient, has no significant irritating effect on an organism, and does not impair the biological activity and properties of the active compound. For additional information on carriers, see Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0096] The word "comprise" or "comprises" and its English variations such as comprises or comprising or equivalents should be understood as having an open, non-exclusive meaning, that is, "including but not limited to", meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

[0097] Herein, singular terms encompass plural referents and vice versa unless the context clearly dictates otherwise.

[0098] Unless otherwise indicated herein, each parameter value (including 2θ values, reaction conditions) is considered to be modified by the term "about" to reflect the measurement error that exists in each value, for example, an error of ±5% relative to the given value.

[0099] For the purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely for their disclosure prior to the filing date of the present application. All statements regarding the dates of these documents or the representations of their contents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications become part of the common general knowledge in the art in any country. BRIEF DESCRIPTION OF THE DRAWINGS

[0100] Figures 1 and 2 are XRPD spectra of crystal A of compound of formula (I).

[0101] FIG3 is a DSC spectrum of crystal A of compound of formula (I).

[0102] FIG4 is a comparison of the dissolution rates of the crystalline capsules of the compound of formula (I) A and the crystalline capsules of the compound of formula (I) B. DETAILED DESCRIPTION

[0103] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any adverse way. The compound of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining the specific embodiments with other chemical synthesis methods, and equivalent replacement modes well known to those skilled in the art, and preferred embodiments include but are not limited to the examples of the present invention. It will be apparent to those skilled in the art that various changes and improvements will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0104] Example 1 Preparation of Crystalline Compound A of Formula (I)

[0105] Method 1:

[0106] At 20°C, 1.877 kg of the compound of formula (I), 12.5 L of dichloromethane, and 2.5 L of methanol were added sequentially to a 50 L reactor and stirred until the solid was completely dissolved. The reaction system was heated to 30°C and stirred at this temperature for 22 hours. The mixture was filtered, and the filter cake was washed with 5 L of dichloromethane. The filtrate was concentrated to dryness under reduced pressure, and the resulting solid was dried in a vacuum oven at 45°C for 72 hours to obtain Crystal A of the compound of formula (I).

[0107] Method 2:

[0108] Prepare sodium hydroxide solution: add 4.2 kg of sodium hydroxide and 29.2 kg of water into the reaction tank and stir until dissolved. Control the temperature at 15-25°C and filter before use.

[0109] 14.62 kg of the compound of formula (I), 115.4 kg of anhydrous ethanol, 146.2 kg of water, and 5.5 L of hydrochloric acid were stirred until dissolved, then filtered. The filtrate was cooled to 0-10°C, and the sodium hydroxide solution prepared above was added, and stirred for 10 minutes. The temperature was raised to 70-80°C, and stirred for 1.5 hours. After cooling to room temperature, the mixture was filtered to obtain crystalline compound A of formula (I).

[0110] Example 2 Preparation of Capsules of Crystals A and B of Compound of Formula (I)

[0111] Preparation of capsules of compound crystals A of formula (I)

[0112] Crystalline compound A of formula (I), mannitol, anhydrous calcium hydrogen phosphate, colloidal silicon dioxide, and magnesium stearate were mixed and sieved to obtain mixture I; mixture I was dry granulated; magnesium stearate was added to the dry granulated material and mixed; and the mixture was divided into capsules and filled to obtain capsules of crystalline compound A of formula (I) according to Table 2.

[0113] Table 2

[0114] Preparation of capsules of compound of formula (I) crystal B

[0115] Referring to the preparation method of capsules of compound crystals A of formula (I), only the compound crystals A of formula (I) are replaced with compound crystals B of formula (I) (i.e., the B form of the compound of formula (I) disclosed in WO2018045993A1) to obtain capsules of compound crystals B of formula (I).

[0116] Experimental Example 1 Dissolution

[0117] The dissolution medium was pH 4.5 acetate buffer, the medium volume was 900 ml, the temperature was 37 ± 0.5 °C, and the medium was kept at 150 rpm. The basket method was used. 10 ml of samples were taken at 10, 15, 20, and 30 min. The same volume of medium was replenished. The sample was filtered, an appropriate amount of the primary filtrate was discarded, and the subsequent filtrate was accurately measured for dilution and shaken. The absorbance was measured by UV spectrophotometry and the dissolution rate was calculated. The results are shown in Figure 4.

[0118] Experimental Example 2 Pharmacokinetics in rats

[0119] a) Grouped administration

[0120] SD rats weighing 180-220 g were acclimated for 3-5 days and randomly divided into two groups of four. Crystalline Form A of Compound I and Crystalline Form B of Compound I were administered orally at a dose of 12 mg / kg. The rats were fasted for 12 hours before dosing and given food 4 hours after dosing. Water was freely available before, during, and after the experiment.

[0121] b) Sampling

[0122] The blood was collected at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 24h, 30h, and 48h after administration. About 0.3mL of blood was collected from the orbital venous plexus and placed in a centrifuge tube containing EDTA-K2. The tubes were stored at 4°C and centrifuged at 4000rpm for 10min within 1h. The tubes were then stored at -20°C for testing.

[0123] 50 μL of plasma sample to be tested was taken, 300 μL of acetonitrile solution containing internal standard was added, the mixture was shaken and mixed for 10 min, centrifuged at 13000 rpm for 10 min, 80 μL of supernatant was taken, 80 μL of 50% acetonitrile aqueous solution was added, and 2 μL was taken for LC / MS / MS analysis.

[0124] c) Detection method

[0125] Liquid chromatography-tandem mass spectrometry (LC-MS / MS) was used, with diazepam as the internal standard (IS). The analytes and IS were extracted from plasma by protein precipitation, separated by a reversed-phase column, and quantified by electrospray ionization (ESI) on a tandem quadrupole mass spectrometer.

[0126] The results are shown in Table 3.

[0127] Table 3 Pharmacokinetic results

Claims

1. A crystal of a compound of formula (I), wherein the X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20° and 11.41±0.20°, 2. The crystal of the compound of formula (I) according to claim 1, having an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 17.25±0.20°, 19.02±0.20° and 24.09±0.20°.

3. The crystal of the compound of formula (I) according to claim 1, wherein the X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.87±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20°, 23.52±0.20°, 24.09±0.20°, 25.24±0.20° and 26.61±0.20°.

4. The crystal of the compound of formula (I) according to claim 1, wherein Cu The X-ray powder diffraction pattern of Kα radiation has diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.36±0.20°, 13.87±0.20°, 15.53±0.20°, 16.22±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20°, 20.87±0.20°, 21.10±0.20°, 23.52±0.20°, 24.09±0.20°, 25.24±0.20°, 26.21±0.20°, 26.61±0.20° and 27.91±0.20°.

5. A crystalline compound of formula (I), wherein the X-ray powder diffraction pattern using Cu Kα radiation comprises 3, 4, 5, 6, 7 or 8 diffraction peaks at 2θ angles selected from the group consisting of: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 13.88±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20° and 24.07±0.20°. 6 . The crystal of the compound of formula (I) according to claim 5 , whose XRPD pattern using Cu Kα radiation is shown in FIG2 .

7. A crystal of the compound of formula (I), wherein the differential scanning calorimetry curve has endothermic peaks at 213.2±5.0°C and 228.5±5.0°C, respectively.

8. A method for preparing a crystal of the compound of formula (I) according to any one of claims 1 to 7, comprising: A step of precipitating the compound of formula (I) from an organic solvent.

9. A crystalline composition of the compound of formula (I) according to any one of claims 1 to 7, wherein the crystals A of the compound of formula (I) account for more than 50% by weight of the crystalline composition, preferably more than 75%, more preferably more than 90%, and most preferably more than 95%.

10. A pharmaceutical composition comprising a therapeutically effective amount of a crystal of the compound of formula (I) according to any one of claims 1 to 7, or a crystalline composition thereof; the pharmaceutical composition may comprise at least one pharmaceutically acceptable excipient.

11. Use of the crystal of the compound of formula (I) according to any one of claims 1 to 7, the crystalline composition of the crystal of the compound of formula (I) according to claim 9, or the solid pharmaceutical composition of the crystal of the compound of formula (I) according to claim 10 in the preparation of a medicament for treating or preventing diseases associated with selective CDK4 / 6 inhibition, wherein the diseases associated with selective CDK4 / 6 inhibition include breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer and acute myeloid leukemia.

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