A crystalline form of a substituted 2-hydro-pyrazole derivative and a process for its preparation

Abstract

The present disclosure relates to a crystal form of substituted 2-hydro-pyrazole derivative (I) and a preparation method thereof, and also includes the use of the crystal form in the preparation of drugs for treating breast cancer and other cancers.

Description

[0001] Cross-reference to related applications

[0002] This disclosure claims the benefit and priority of Chinese 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 herein by reference. Technical Field

[0003] This disclosure relates to a crystalline form of a substituted 2-hydropyrazole derivative and a method for preparing the same, as well as the use of the crystalline form in the preparation of drugs for treating breast cancer and other cancers. Background Technology

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

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

[0006] Summary of the Invention

[0007] On the one hand, this disclosure provides crystallization of the compound of formula (I),

[0008]

[0009] The crystals of the compounds of formula (I) described in this disclosure can be in the form of a nonsolvent or a solvate, such as a hydrate.

[0010] On the other hand, this disclosure provides a crystalline form A of compound (I) whose X-ray powder diffraction pattern using Cu Kα radiation contains 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°, 10.47±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°.

[0011] In some embodiments of this disclosure, the crystal A of the compound of formula (I) contains, in its X-ray powder diffraction pattern using Cu Kα radiation, 3, 4, 5, 6, 7, 8, 9, 10, or 11 diffraction peaks selected from 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°.

[0012] In some embodiments of this disclosure, the crystal A of the compound of formula (I) contains 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°.

[0013] On the other hand, this disclosure provides a crystal of compound (I) A, whose 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°.

[0014] In some embodiments of this disclosure, the crystal A of the compound of formula (I) has diffraction peaks at 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°, and 19.02±0.20°.

[0015] In some embodiments of this disclosure, the crystal A of the compound of formula (I) has diffraction peaks at 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°, 17.25±0.20°, 19.02±0.20°, and 24.09±0.20°.

[0016] In some embodiments of this disclosure, the crystal A of the compound of formula (I) has diffraction peaks at 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°.

[0017] In some embodiments of this disclosure, the crystal A of the compound of formula (I) has diffraction peaks at 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°.

[0018] In some embodiments of this disclosure, the crystal A of the compound of formula (I) is obtained using Cu. The X-ray powder diffraction pattern of Kα radiation shows 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°.

[0019] In some embodiments of this disclosure, the crystal A of compound (I) has an XRPD pattern obtained using CuKα radiation as shown in the figure. Figure 1 As shown.

[0020] In other embodiments of this disclosure, the crystal A of the compound of formula (I) contains, in its X-ray powder diffraction pattern using Cu Kα radiation, 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°.

[0021] In other embodiments of this disclosure, the crystal A of the compound of formula (I) contains, in its X-ray powder diffraction pattern using Cu Kα radiation, 3, 4, 5, 6, 7, 8, 9, 10, or 11 diffraction peaks selected from 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°.

[0022] In other embodiments of this disclosure, the crystal A of the compound of formula (I) contains, in its X-ray powder diffraction pattern using Cu Kα radiation, 3, 4, 5, 6, 7, or 8 diffraction peaks selected from 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°.

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

[0024] In other embodiments of this disclosure, the crystal A of the compound of formula (I) has diffraction peaks at 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° and 19.01±0.20°.

[0025] In other embodiments of this disclosure, the crystal A of the compound of formula (I) has diffraction peaks at 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°, 17.24±0.20°, 19.01±0.20°, and 24.07±0.20°.

[0026] In other embodiments of this disclosure, the crystal A of the compound of formula (I) has diffraction peaks at 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°.

[0027] In other embodiments of this disclosure, the crystal A of the compound of formula (I) has diffraction peaks at 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°.

[0028] In other embodiments of this disclosure, the crystal A of the compound of formula (I) is obtained using Cu. The X-ray powder diffraction pattern of Kα radiation has 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°.

[0029] In other embodiments of this disclosure, the crystal A of the compound of formula (I) exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 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°, and 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°.

[0030] In other embodiments of this disclosure, the crystal A of the compound of formula (I) has diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 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.

[0031] In other embodiments of this disclosure, the crystal A of the compound of formula (I), whose XRPD pattern using CuKα radiation is as follows: Figure 2 As shown.

[0032] In some other embodiments of this disclosure, the crystals A of the compound of formula (I) are shown in Table 1, with XRPD spectral resolution data obtained using Cu Kα radiation.

[0033] Table 1: XRPD spectrum analysis data of crystal A of compound (I)

[0034]

[0035]

[0036] In some embodiments of this disclosure, the crystal A of the compound of formula (I) has differential scanning calorimetry curves with peak values ​​of endothermic peaks at 213.2±5.0℃ and 228.5±5.0℃, respectively.

[0037] In some embodiments of this disclosure, the DSC spectrum of crystal A of compound (I) is as follows: Figure 3 As shown.

[0038] On the other hand, this disclosure also provides a method for preparing crystals A of the compound of formula (I), comprising the step of precipitating the compound of formula (I) from an organic solvent.

[0039] In some embodiments of this disclosure, the method for preparing crystallized A of compound (I) uses an organic solvent selected from a mixture of methanol and dichloromethane.

[0040] In some embodiments of this disclosure, the method for preparing crystallized A of compound (I) uses a volume ratio of methanol to dichloromethane of 1:5.

[0041] In some other embodiments of this disclosure, the method for preparing crystal A of the compound of formula (I) includes: (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, and then cooling to room temperature and filtering to obtain crystal A of the compound of formula (I).

[0042] In some embodiments of this disclosure, the method for preparing crystallized A of compound (I) involves heating to 70–80°C in step (b).

[0043] In this disclosure, the starting compound of formula (I) can be in any form, such as crystals, amorphous substances, hydrates, solvates, crude products, etc., in the method for preparing crystallized A of the compound of formula (I).

[0044] This disclosure also provides crystalline compositions comprising crystalline A of compound (I), wherein crystalline A of compound (I) comprises 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 some other embodiments of this disclosure, the crystalline compositions comprising crystalline A of compound (I) comprise more than 96%, or more than 97%, or more than 98%, or more than 99% by weight of the crystalline composition. Each of the crystalline compositions may also contain small amounts of other crystalline or amorphous forms of compound (I).

[0045] In some embodiments of this disclosure, the crystalline composition comprising crystalline A of compound (I) is wherein the remainder of the crystalline composition other than crystalline A of compound (I) is the non-crystalline A form of compound (I).

[0046] In some embodiments of this disclosure, the content of the compound of formula (I) in the crystalline composition comprising crystal A may be 95% or more, or 99% or more, or 99.9% or more, or 99.99% or more.

[0047] On the other hand, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline A of a compound of formula (I), or a crystalline composition thereof; said pharmaceutical composition may contain at least one pharmaceutically acceptable excipient. Furthermore, the pharmaceutical compositions of this application may further comprise one or more other therapeutic agents.

[0048] In some embodiments of this disclosure, the pharmaceutical composition comprising crystalline A of compound (I) is a solid pharmaceutical composition.

[0049] In some embodiments of this disclosure, the excipients in the solid pharmaceutical composition comprising crystalline A of compound (I) include at least one of a diluent, a binder, a disintegrant, and a lubricant.

[0050] In some embodiments of this disclosure, the excipients in the solid pharmaceutical composition comprising crystalline A of compound (I) include at least one of a filler, a flow aid, and a lubricant.

[0051] In some embodiments of this disclosure, the excipients in the solid pharmaceutical composition comprising crystalline A of compound (I) include fillers, flow aids, and lubricants.

[0052] In some embodiments of this 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, isomaltitol, 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 any two or more mixtures thereof; preferably, the filler is selected from mannitol, microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropyl cellulose, anhydrous calcium hydrogen phosphate, lactose monohydrate, or any mixtures thereof. The filler is selected from any two or more of the following: a mixture of mannitol, microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropyl cellulose, anhydrous dicalcium phosphate, and lactose monohydrate; in some specific embodiments of this 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 dicalcium phosphate, or a mixture of microcrystalline cellulose and lactose monohydrate; in one specific embodiment of this disclosure, the filler is selected from a mixture of mannitol and anhydrous dicalcium phosphate; in another specific embodiment of this disclosure, the filler is selected from a mixture of microcrystalline cellulose and lactose monohydrate.

[0053] In some embodiments of this disclosure, the flow aid is selected from silica, colloidal silica, magnesium trisilicate, starch, powdered cellulose, micronized silica gel, or talc, or any two or more of these; preferably, the flow aid is selected from silica, colloidal silica, micronized silica gel, or talc; more preferably, the flow aid is selected from colloidal silica or talc; in one specific embodiment of this application, the flow aid is selected from colloidal silica.

[0054] In some embodiments of this 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 stearoyl fumarate, or talc; preferably, the lubricant is selected from magnesium stearate, glyceryl behenate, sodium lauryl sulfate, or sodium stearoyl fumarate; in one specific embodiment of this application, the lubricant is selected from magnesium stearate.

[0055] In some embodiments of this disclosure, the crystals A of the compound of formula (I) comprise 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 one specific embodiment of this disclosure, the crystals A of the compound of formula (I) comprise 50 wt% of the total weight of the solid pharmaceutical composition.

[0056] In some embodiments of this disclosure, the filler comprises 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 one specific embodiment of this disclosure, the filler is selected from a mixture of mannitol and anhydrous calcium hydrogen phosphate, wherein the weight ratio of mannitol to anhydrous calcium hydrogen phosphate is 1:0.5 to 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 another specific embodiment of this disclosure, the filler is selected from a mixture of mannitol and anhydrous calcium hydrogen phosphate, wherein the mannitol and anhydrous calcium hydrogen phosphate account for 47.5 wt% of the total weight of the solid pharmaceutical composition, and the weight ratio of mannitol to anhydrous calcium hydrogen phosphate is 1:1.0.

[0057] In some embodiments of this disclosure, the flow aid comprises 0.5 to 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 one specific embodiment of this disclosure, the flow aid comprises 1.0 wt% of the total weight of the solid pharmaceutical composition.

[0058] In some embodiments of this disclosure, the lubricant comprises 0.5 to 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 one specific embodiment of this disclosure, the lubricant comprises 1.5 wt% of the total weight of the solid pharmaceutical composition.

[0059] In one embodiment of this disclosure, the solid pharmaceutical composition of crystalline A of compound (I) comprises: crystalline A of compound (I); mannitol and anhydrous calcium hydrogen phosphate; colloidal silica; and magnesium stearate. In another embodiment of this disclosure, the solid pharmaceutical composition of crystalline A of compound (I) comprises: 10–90 wt% crystalline A of compound (I); 10–98 wt% mannitol and anhydrous calcium hydrogen phosphate; 0.5–5 wt% colloidal silica; and 0.5–5 wt% magnesium stearate.

[0060] In one embodiment of this disclosure, the solid pharmaceutical composition of crystalline A of compound (I) comprises: 50-55 wt% crystalline A of compound (I); 45-50 wt% mannitol and anhydrous calcium hydrogen phosphate; 1.0 wt% colloidal silica; and 1.2 wt% magnesium stearate.

[0061] In some embodiments, in the solid pharmaceutical composition of crystalline A of the compound of formula (I), crystalline A of the compound of formula (I) is used as the active ingredient, mannitol and anhydrous calcium hydrogen phosphate are used as fillers, colloidal silica is used as a flow aid, and magnesium stearate is used as a lubricant.

[0062] In one embodiment of this disclosure, the solid pharmaceutical composition of crystalline A of compound (I) comprises: crystalline A of compound (I); microcrystalline cellulose and lactose monohydrate; colloidal silica; and magnesium stearate.

[0063] In some embodiments, crystalline A of the compound of formula (I) is used as the active ingredient, microcrystalline cellulose and lactose monohydrate are used as fillers, colloidal silica is used as a flow aid, and magnesium stearate is used as a lubricant.

[0064] The solid pharmaceutical compositions disclosed herein can be formulated in various forms suitable for oral administration to humans, including tablets, pills, capsules, powders, or granules. In some embodiments of this disclosure, the solid pharmaceutical composition is formulated as a capsule.

[0065] In some embodiments of this disclosure, the solid pharmaceutical composition of crystalline A of formula (I) is formulated as a capsule, wherein the capsule shell is selected from plant capsule shells or gelatin capsule shells, and the plant capsule shell is selected from hydroxypropyl methylcellulose empty capsules.

[0066] In some embodiments of this disclosure, in the solid pharmaceutical composition of crystal A of compound (I), the particle size distribution of crystal A of compound (I) satisfies X50≤5μm, X90≤15μm; preferably, the particle size distribution of crystal A of compound (I) satisfies X50=1~5μm, X90=3~15μm.

[0067] In some embodiments of this disclosure, the solid pharmaceutical composition formulation of crystalline A of compound (I) is a capsule containing 50 mg of crystalline A of compound (I) per unit.

[0068] In some embodiments of this disclosure, the formulation is a capsule containing 60 mg of crystalline A of formula (I) per unit.

[0069] In some embodiments of this disclosure, each unit of the solid pharmaceutical composition of crystalline A of the compound of formula (I) comprises 50 mg of crystalline A of the compound of formula (I), 23.75 mg of mannitol, 23.75 mg of anhydrous calcium hydrogen phosphate, 1 mg of colloidal silica, and 1.5 mg of magnesium stearate.

[0070] In some embodiments of this disclosure, each unit of the solid pharmaceutical composition of crystalline A of the compound of formula (I) comprises 60 mg of crystalline A of the compound of formula (I), 28.5 mg of mannitol, 28.5 mg of anhydrous calcium hydrogen phosphate, 1.2 mg of colloidal silica, and 1.8 mg of magnesium stearate.

[0071] On the other hand, this disclosure provides the use of crystal A of compound (I), a crystalline composition of crystal A of compound (I), or a solid pharmaceutical composition of crystal A of compound (I) in the preparation of a medicament for treating or preventing selective CDK4 / 6 inhibition-related diseases, including breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer, and acute myeloid leukemia.

[0072] On the other hand, this disclosure provides the use of crystal A of compound (I), a crystalline composition of crystal A of compound (I), or a solid pharmaceutical composition of crystal A of compound (I) for the treatment or prevention of selective CDK4 / 6 inhibition-related diseases, including breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer, and acute myeloid leukemia.

[0073] On the other hand, this disclosure provides a method for treating or preventing selective CDK4 / 6 inhibition-related diseases, comprising administering to a mammal in need a therapeutically effective amount of crystal A of the compound of formula (I), a crystalline composition of crystal A of the compound of formula (I), or a solid pharmaceutical composition of crystal A of the compound of formula (I), the selective CDK4 / 6 inhibition-related diseases including breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer, and acute myeloid leukemia.

[0074] On the other hand, this disclosure provides a crystalline A of a compound of formula (I), a crystalline composition of crystalline A of compound of formula (I), or a solid pharmaceutical composition of crystalline A of compound of formula (I) for treating or preventing selective CDK4 / 6 inhibition-related diseases, including breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer, and acute myeloid leukemia.

[0075] In some embodiments of this disclosure, the mammal is a human.

[0076] On the other hand, this disclosure provides a method for preparing a solid pharmaceutical composition of crystalline A of the compound of formula (I), comprising the following steps:

[0077] 1) The crystalline A of compound (I) is sieved and mixed with filler, flow aid and lubricant;

[0078] 2) After dry granulation of the mixture, it is mixed with the lubricant;

[0079] 3) Capsule filling.

[0080] In some embodiments of this disclosure, the filler in the preparation method of 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.

[0081] In some embodiments of this disclosure, the flow aid in the preparation method of the solid pharmaceutical composition of the crystalline A of the compound of formula (I) is as described above, for example, the flow aid is colloidal silica.

[0082] In some embodiments of this disclosure, the internal and external lubricants in the method for preparing the solid pharmaceutical composition of the crystalline A of the compound of formula (I) are the same, and the lubricant is as described above, for example, magnesium stearate.

[0083] In this disclosure, the X-ray powder diffraction spectra of the samples were determined under the following conditions: Instrument: Bruker D8 Advance X-ray diffractometer.

[0084] It should be noted that in X-ray powder diffraction spectroscopy, the position or relative intensity of peaks may vary due to factors such as the measuring instrument, method / conditions, etc. For any given crystal, the peak position may have errors, with a 2θ value measurement error of ±0.2. Therefore, this error should be taken into account when determining the position of each crystal, and such errors are within the scope of this application.

[0085] It should be noted that for the same crystal, the position of the endothermic peak in DSC may vary due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal, the position of the endothermic peak may have an error, which can be ±5℃. Therefore, this error should be taken into account when determining the position of each crystal, and such errors are also within the scope of this application.

[0086] In this disclosure, the XRPD spectrum of crystallized compound A of formula (I) is as follows: Figure 1 and Figure 2 As shown, the two represent test results from different batches of the same crystal.

[0087] Technical effect

[0088] Crystalline A of compound (I) of this disclosure exhibits good solubility and good stability under conditions of high humidity, high temperature, light exposure, air jet milling, and high-pressure grinding, as well as good stability under long-term experimental conditions. Crystalline A of compound (I) of this disclosure and its pharmaceutical compositions possess advantages in terms of drug activity, pharmacokinetics, bioavailability, hygroscopicity, stability, melting point, solubility, formulation dissolution, excipient compatibility, purity, and ease of preparation, thus meeting the needs of drug production, storage, transportation, and formulation. For example, crystalline A of compound (I) exhibits better water solubility and better dissolution in formulations compared to crystalline B of compound (I), and also demonstrates superior pharmacokinetic properties.

[0089] Definitions and Explanations

[0090] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0091] "Mammals" include humans and livestock such as laboratory mammals and domestic pets (e.g., cats, dogs, pigs, sheep, cattle, sheep, goats, horses, rabbits), as well as non-domesticated mammals such as wild mammals.

[0092] The term "pharmaceutical composition" refers to a formulation of the compounds disclosed herein and a medium generally accepted in the art for delivering biologically active compounds to mammals, such as humans. The medium includes all pharmaceutically acceptable carriers for use therein. Pharmaceutical compositions facilitate the administration of compounds to organisms.

[0093] The term "therapeutic effective dose" refers to a sufficient amount of a non-toxic drug or agent that achieves the desired effect. The determination of the effective dose varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective dose in a case can be determined by a person skilled in the art based on routine testing.

[0094] The term "treatment" means administering the compounds or preparations described in this disclosure to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0095] (i) Suppress the disease or disease state, that is, curb its development;

[0096] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0097] The term “prevention” means administering the compounds or preparations described in this disclosure to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0098] In this disclosure, "pharmaceuticalally acceptable carriers" refers to carriers that are administered co-administered with the active ingredient, do not cause significant irritation to the organism, and do not impair the biological activity and properties of the active compound. Further information regarding carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0099] The word “comprise” or “comprise” and its English variants such as comprises or comprising or equivalents should be understood in an open, non-exclusive sense, meaning “including but not limited to”, implying that it may cover other unspecified elements, components and steps in addition to those listed.

[0100] In this document, unless the context clearly indicates otherwise, singular terms encompass plural referents, and vice versa.

[0101] In this document, unless otherwise stated, all parameter values ​​(including 2θ values ​​and reaction conditions) are considered to be modified by the term “about” to reflect measurement errors, such as ±5% error relative to a given value.

[0102] For purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publication is part of the general knowledge in the art. Attached Figure Description

[0103] Figure 1 and Figure 2 The image shows the XRPD spectrum of compound A of formula (I) crystallization.

[0104] Figure 3 The image shows the DSC spectrum of compound A of formula (I) crystallization.

[0105] Figure 4 A comparison chart of the dissolution rates of crystalline capsules of compound (I) A and crystalline capsules of compound (I). Detailed Implementation

[0106] The present application is described in detail below through examples, but this does not imply any adverse limitation on the present application. The compounds of this application can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of this application without departing from the spirit and scope of this application.

[0107] Example 1: Preparation of crystallized compound A of formula (I)

[0108] Method 1:

[0109] At 20°C, 1.877 kg of compound (I), 12.5 L of dichloromethane, and 2.5 L of methanol were sequentially added to a 50 L reactor and stirred until the solid was completely dissolved. The reaction system was then 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 crystalline form A of compound (I).

[0110] Method 2:

[0111] Preparation of sodium hydroxide solution: Add 4.2 kg of sodium hydroxide and 29.2 kg of water to the reaction vessel and stir until dissolved. Control the temperature at 15-25℃. Filter before use.

[0112] 14.62 kg of compound (I), 115.4 kg of anhydrous ethanol, 146.2 kg of water, and 5.5 L of hydrochloric acid were stirred until dissolved and then filtered. The filtrate was cooled to 0–10 °C, and the prepared sodium hydroxide solution 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 A of compound (I).

[0113] Example 2: Preparation of capsules containing crystals A and B of formula (I)

[0114] Preparation of capsules of crystalline compound A of formula (I)

[0115] The crystalline compound A of formula (I), mannitol, anhydrous calcium hydrogen phosphate, colloidal silica and magnesium stearate were mixed and then sieved to obtain mixture I; mixture I was dry granulated; magnesium stearate was added to the dry granulated material and mixed; it was then dispensed into capsules for filling to obtain capsules of crystalline compound A of formula (I) as shown in Table 2.

[0116] Table 2

[0117]

[0118] Preparation of capsules of compound B crystallized from formula (I)

[0119] Following the method for preparing capsules of compound crystal A of formula (I), only the compound crystal A of formula (I) is replaced with compound crystal B of formula (I) (i.e., the B crystal form of compound (I) disclosed in WO2018045993A1) to obtain capsules of compound crystal B of formula (I).

[0120] Example 1 Dissolution

[0121] Using pH 4.5 acetate buffer as the dissolution medium (900 ml), at 37 ± 0.5℃ and 150 rpm, using the basket method, 10 ml samples were taken at 10, 15, 20, and 30 min. The same volume of medium was added back, the samples were filtered, and an appropriate amount of the initial filtrate was discarded. The subsequent filtrate was accurately measured, diluted, and mixed well. The absorbance was measured by UV spectrophotometry, and the dissolution rate was calculated. The results are as follows: Figure 4 As shown.

[0122] Experimental Example 2: Pharmacokinetics in Rats

[0123] a) Grouped administration

[0124] SD rats, weighing 180–220 g, were randomly divided into two groups of four rats each after acclimatization for 3–5 days. Each group was administered compound I crystal form A and compound I crystal form B by gavage at a dose of 12 mg / kg. Rats were fasted for 12 hours before administration and given food 4 hours after administration. Water was provided freely before, during, and after the experiment.

[0125] b) Sampling

[0126] Blood was collected at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 24h, 30h, and 48h after drug administration. Approximately 0.3mL of blood was collected from the orbital venous plexus and placed in centrifuge tubes containing EDTA-K2. The tubes were stored at 4℃ and centrifuged at 4℃, 4000rpm, for 10min within 1 hour. The tubes were then stored at -20℃ for analysis.

[0127] Take 50 μL of the plasma sample to be tested, add 300 μL of acetonitrile solution containing internal standard, shake to mix for 10 min, centrifuge at 13000 rpm for 10 min, take 80 μL of supernatant, add 80 μL of 50% acetonitrile aqueous solution, and take 2 μL for LC / MS / MS analysis.

[0128] c) Detection methods

[0129] Liquid chromatography-tandem mass spectrometry (LC-MS / MS) was used, with diazepam as the internal standard (IS). The analytes and internal standard were extracted from plasma using protein precipitation. A reversed-phase column was used to separate the compounds and the internal standard. Quantitative analysis of the analytes was performed using electrospray ionization (ESI) on a tandem quadrupole mass spectrometer.

[0130] The results are shown in Table 3.

[0131] Table 3 Pharmacokinetic Results

[0132]

[0133]

Claims

1. The crystals of compound (I), whose X-ray powder diffraction patterns using Cu Kα radiation show 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°. 。 2. The crystallization 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°, 10.45±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°.

3. The crystallization of the compound of formula (I) according to claim 2, wherein Cu is used. The X-ray powder diffraction pattern of Kα radiation has 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°.

4. The crystallization of the compound of formula (I) according to any one of claims 1-3, the XRPD pattern of which is obtained by Cu Kα radiation is shown in Figure 2.

5. A crystalline composition of the compound of formula (I) according to any one of claims 1-3, wherein the crystals of the compound of formula (I) account for more than 50% by weight of the crystalline composition.

6. The crystalline composition according to claim 5, wherein the crystals of the compound of formula (I) account for more than 75% by weight of the crystalline composition.

7. The crystalline composition according to claim 6, wherein the crystals of the compound of formula (I) account for more than 90% by weight of the crystalline composition.

8. The crystalline composition according to claim 7, wherein the crystals of the compound of formula (I) account for more than 95% by weight of the crystalline composition.

9. A pharmaceutical composition comprising a therapeutically effective amount of crystals of the compound of formula (I) according to any one of claims 1-3, or a crystalline composition according to any one of claims 5-8; said pharmaceutical composition may contain at least one pharmaceutically acceptable excipient.

10. Use of the crystallization of the compound of formula (I) according to any one of claims 1-3, the crystalline composition according to any one of claims 5-8, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating or preventing selective CDK4 / 6 inhibition-related diseases, said selective CDK4 / 6 inhibition-related diseases including breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer, and acute myeloid leukemia.

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