WO2024120441A1 - 氧异吲哚-5-甲酰胺类化合物或其盐、溶剂合物的结晶形式或无定形形式 - Google Patents

氧异吲哚-5-甲酰胺类化合物或其盐、溶剂合物的结晶形式或无定形形式 Download PDF

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WO2024120441A1
WO2024120441A1 PCT/CN2023/136788 CN2023136788W WO2024120441A1 WO 2024120441 A1 WO2024120441 A1 WO 2024120441A1 CN 2023136788 W CN2023136788 W CN 2023136788W WO 2024120441 A1 WO2024120441 A1 WO 2024120441A1
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crystalline form
compound
xrpd
formula
graph
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PCT/CN2023/136788
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English (en)
French (fr)
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付利强
戚祖德
王峥
贾淼
张雷
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杭州格博生物医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention belongs to the field of medicine, and particularly relates to an oxoisoindole-5-carboxamide compound or its salt, a crystalline form or an amorphous form of a solvate thereof used as a CK1 ⁇ selective molecular glue degrading agent, and a preparation method and application thereof.
  • Casein kinase 1 ⁇ (CK1 ⁇ ), encoded by the gene CSNK1A1, is a ubiquitously expressed serine/threonine protein kinase in the CK1 kinase family.
  • CK1 ⁇ is involved in regulating a variety of physiological and pathological processes in cells and coordinates the orderly progress of life through different signal transduction pathways (Jiang et al., Cell Commun Signal (2016) 16: 23).
  • CK1 ⁇ as a key regulator of the Wnt/ ⁇ -catenin pathway, directly phosphorylates ⁇ -catenin at Ser45, making it a target for proteomic degradation (Liu et al., Cell (2002) 108: 837-847).
  • CK1 ⁇ is also thought to regulate the protein stability of the tumor suppressor p53 by regulating the activity of the MDM2/MDMX E3 ligase complex (Huart et al., J Biol Chem (2009) 284: 32384-94; Wu et al., Mol Cell Biol (2012) 32: 4821-4832).
  • CK1 ⁇ has been reported to be overexpressed in many types of human cancers, however, the exact role of CK1 ⁇ in the development of multiple tumor types has not been clearly elucidated (Richter et al., BMC Cancer (2016) 18: 140).
  • the Cancer Dependency Map (DepMap) database showed that inactivation of CK1 ⁇ by CRISPR/cas9-mediated gene knockout or shRNA-mediated gene inhibition significantly reduced the proliferation and/or survival of many cancer cell lines in multiple cancer types (Tsherniak et al., Cell (2017) 170: 564-576; Behan et al., Nature (2019) 568: 511-516).
  • CK1 ⁇ inhibition by using shRNA interference or D4476 was able to effectively inhibit the progression of MLL-AF9 leukemia and had little effect on normal hematopoietic stem and progenitor cells (HSPCs) (Jaras et al., J Exp Med (2014) 211 (4): 605-612).
  • HSPCs normal hematopoietic stem and progenitor cells
  • the compound of formula A is a new generation of CK1 ⁇ selective molecular glue degrader and is currently in the early clinical research stage.
  • polymorphism Due to the influence of various factors such as the configuration, conformation, molecular arrangement, molecular forces, and eutectic substances of the molecular structure, solid substances have different spatial arrangements of the molecular lattice, forming two or more different crystal structures. This phenomenon is called “polymorphism” or “isomorphism”. "Polymorphism” is widely present in solid drugs. There may be differences in the physical and chemical properties between different crystal forms of the same drug, such as appearance, density, hardness, melting point, solubility, stability, dissolution, dissolution rate, bioavailability, etc. This phenomenon is particularly evident in oral solid preparations. In addition, the existence form and quantity of polymorphic compounds are unpredictable. Different crystalline forms of the same drug have significant differences in solubility, melting point, density, stability, etc., which affect the uniformity, bioavailability, efficacy and safety of the drug to varying degrees.
  • some solid compounds may also exist in amorphous forms.
  • Amorphous refers to the structure of some non-completely crystalline amorphous regions (non-crystalline regions) or the composition of some amorphous solids (non-crystalline).
  • non-crystalline regions the structure of some amorphous solids
  • non-crystalline the composition of some amorphous solids
  • the present invention provides a crystalline form or amorphous form of an oxoisoindole-5-carboxamide compound or its salt or solvate used as a CK1 ⁇ selective molecular glue degrading agent, and a preparation method and application thereof.
  • the crystalline form or amorphous form of the present invention has very important value for drug development, formulation development and production.
  • the term "substantially as shown” when referring to, for example, an XRPD pattern, a TGA pattern, a DSC pattern, etc., refers to patterns that are not necessarily the same as those described herein, but that fall within the limits of experimental error or deviation when considered by one of ordinary skill in the art.
  • the present invention provides an amorphous form or a crystalline form of a compound of formula A or a pharmaceutically acceptable salt or a solvate thereof.
  • the chemical name of the compound is N-((S)-5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide.
  • the present invention includes, but is not limited to, crystalline form A1, crystalline form A2, crystalline form A3, crystalline form A4, crystalline form A5, crystalline form B, crystalline form C, crystalline form D1, crystalline form D2, crystalline form E, crystalline form F, crystalline form G, crystalline form H and amorphous form. Specifically as follows:
  • it is a solvate crystalline form A1 of a compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in an X-ray powder diffraction (XRPD) pattern expressed in 2 ⁇ angles: 6.54 ⁇ 0.2°, 19.64 ⁇ 0.2°, 9.21 ⁇ 0.2°, 16.35 ⁇ 0.2°, 18.48 ⁇ 0.2°, 9.79 ⁇ 0.2° and 17.23 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • it has XRPD characteristics substantially as shown in Table 1 below: peak:
  • the XRPD pattern is substantially as shown in Figure 1c, and optionally has one or more of the following characteristics:
  • it is a solvate crystalline form A2 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2 ⁇ angles: 18.57 ⁇ 0.2°, 19.67 ⁇ 0.2°, 16.38 ⁇ 0.2°, 9.28 ⁇ 0.2°, 17.38 ⁇ 0.2°, 25.18 ⁇ 0.2° and 13.11 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • it has XRPD characteristics substantially as shown in Table 2 below: peak:
  • the XRPD pattern is substantially as shown in Figure 2a, and optionally has one or more of the following characteristics:
  • it is a solvate crystalline form A3 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2 ⁇ angles: 19.61 ⁇ 0.2°, 18.45 ⁇ 0.2°9.22 ⁇ 0.2°, 16.33 ⁇ 0.2°, 6.54 ⁇ 0.2°, 17.24 ⁇ 0.2° and 9.80 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • it has XRPD characteristic peaks substantially at the positions shown in Table 3 below:
  • the XRPD pattern is substantially as shown in Figure 3a, and optionally has one or more of the following characteristics:
  • it is a solvate crystalline form A4 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2 ⁇ angles: 9.22 ⁇ 0.2°, 17.51 ⁇ 0.2°, 6.54 ⁇ 0.2°, 19.59 ⁇ 0.2°, 25.03 ⁇ 0.2°, 16.37 ⁇ 0.2° and 18.51 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the XRPD pattern is substantially as shown in Figure 4a, and optionally has one or more of the following characteristics:
  • it is a solvate crystalline form A5 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2 ⁇ angles: 16.43 ⁇ 0.2°, 19.74 ⁇ 0.2°, 6.58 ⁇ 0.2°, 9.27 ⁇ 0.2°, 18.53 ⁇ 0.2°, 17.37 ⁇ 0.2° and 9.88 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • it has XRPD characteristic peaks substantially at the positions shown in Table 5 below:
  • the XRPD pattern is substantially as shown in Figure 5a, and optionally has one or more of the following characteristics:
  • it is a crystalline form B of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2 ⁇ angles: 3.98 ⁇ 0.2°, 12.35 ⁇ 0.2°, 12.05 ⁇ 0.2°, 19.09 ⁇ 0.2°, 7.92 ⁇ 0.2°, 15.78 ⁇ 0.2° and 14.32 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • it has XRPD characteristic peaks substantially at the positions shown in Table 6 below:
  • the XRPD pattern is substantially as shown in Figure 6c, and optionally has one or more of the following characteristics:
  • it is a solvate crystalline form C of the compound of formula A, which has at least three, at least four, at least five At least six or seven characteristic peaks: 20.60 ⁇ 0.2°, 17.94 ⁇ 0.2°, 13.110 ⁇ 0.2°, 19.42 ⁇ 0.2°, 23.97 ⁇ 0.2°, 26.31 ⁇ 0.2° and 11.95 ⁇ 0.2°.
  • it has XRPD characteristic peaks substantially at the positions shown in Table 7 below:
  • the XRPD pattern is substantially as shown in Figure 7a, and optionally has one or more of the following characteristics:
  • it is a solvate crystalline form D1 of a compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in an X-ray powder diffraction (XRPD) pattern expressed in 2 ⁇ angles: 17.99 ⁇ 0.2°, 8.82 ⁇ 0.2°, 17.32 ⁇ 0.2°, 9.26 ⁇ 0.2°, 19.14 ⁇ 0.2°, 9.95 ⁇ 0.2° and 31.53 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the XRPD pattern is substantially as shown in Figure 8a, and optionally has one or more of the following characteristics:
  • it is a solvate crystalline form D2 of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2 ⁇ angles: 17.38 ⁇ 0.2°, 17.99 ⁇ 0.2°, 19.57 ⁇ 0.2°, 9.80 ⁇ 0.2°, 31.55 ⁇ 0.2°, 25.05 ⁇ 0.2° and 6.55 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the XRPD pattern is substantially as shown in Figure 9a, and optionally has one or more of the following characteristics:
  • it is a crystalline form E of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2 ⁇ angles: 11.14 ⁇ 0.2°, 15.76 ⁇ 0.2°, 12.59 ⁇ 0.2°, 19.71 ⁇ 0.2°, 9.56 ⁇ 0.2°, 17.83 ⁇ 0.2° and 13.58 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the XRPD pattern is substantially as shown in Figure 10c, and optionally has one or more of the following characteristics:
  • it is a crystalline form F of the compound of formula A, which has at least three, at least four, at least five, at least one, or more at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2 ⁇ angles: At least six or seven characteristic peaks: 17.70 ⁇ 0.2°, 21.46 ⁇ 0.2°, 27.66 ⁇ 0.2°, 19.20 ⁇ 0.2°, 17.17 ⁇ 0.2°, 19.44 ⁇ 0.2° and 22.01 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the XRPD pattern is substantially as shown in Figure 11a, and optionally has one or more of the following characteristics:
  • it is a crystalline form G of the compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in the X-ray powder diffraction (XRPD) pattern expressed in 2 ⁇ angles: 18.83 ⁇ 0.2°, 13.88 ⁇ 0.2°, 21.45 ⁇ 0.2°, 26.75 ⁇ 0.2°, 15.92 ⁇ 0.2°, 17.95 ⁇ 0.2° and 13.14 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the XRPD pattern is substantially as shown in Figure 12c, and optionally has one or more of the following characteristics:
  • it is a crystalline form H of a compound of formula A, which has at least three, at least four, at least five, at least six or seven characteristic peaks at the following positions in an X-ray powder diffraction (XRPD) pattern expressed in 2 ⁇ angles: 18.30 ⁇ 0.2°, 3.80 ⁇ 0.2°, 19.05 ⁇ 0.2°, 18.53 ⁇ 0.2°, 11.81 ⁇ 0.2°, 11.33 ⁇ 0.2° and 16.04 ⁇ 0.2°;
  • XRPD X-ray powder diffraction
  • the XRPD pattern is substantially as shown in Figure 13a, and optionally has one or more of the following characteristics:
  • it is an amorphous form as shown in FIG. 14d of the compound of formula A PLM, preferably, it has an XRPD pattern as shown in FIG. 14a, and optionally has one or more of the following characteristics:
  • the present invention provides a method for preparing a crystalline form or an amorphous form of a compound of formula A or a pharmaceutically acceptable salt or solvate thereof, comprising the steps of: suspending the compound of formula A or a pharmaceutically acceptable salt thereof, slowly cooling, rapidly cooling, slowly volatilizing, rapidly volatilizing, adding an antisolvent dropwise, adding an antisolvent reversely, vapor diffusion or heating-cooling DSC crystallization method, or spray drying, hot melt extrusion or solvent evaporation to obtain the crystalline form or amorphous form.
  • the compound of formula A is synthesized in the laboratory as described in the specific embodiment.
  • the solvent can be a commonly used solvent in the laboratory, for example, one or more of water, alkane solvents, alcohol solvents, ketone solvents, ester solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, nitrile solvents, ether solvents, aliphatic hydrocarbon solvents, polar aprotic solvents such as DMF and DMSO.
  • the mass volume ratio of the compound of formula A to the solvent can be 100 mg: (0.1-1 mL).
  • the present invention provides a method for preparing a crystalline form of a solvate of a compound of formula A, comprising the steps of mixing the compound of formula A with a solvent corresponding to the solvate type, separating the resulting solid and drying it, thereby obtaining a crystalline form of a solvate of the compound of formula A.
  • the solvent corresponding to the solvate type is, for example but not limited to, 1,4-dioxane, ethyl acetate, toluene, chloroform, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetone, N,N-dimethylformamide, acetonitrile, and the like.
  • the present invention provides a method for preparing an amorphous form of a compound of formula A, comprising the steps of mixing the compound of formula A with a solvent and spray drying the resulting solution, thereby obtaining an amorphous form of the compound of formula A.
  • the solvent may be a commonly used solvent in the laboratory, for example, one or more of water, alkane solvents, alcohol solvents, ketone solvents, ester solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, nitrile solvents, ether solvents, aliphatic hydrocarbon solvents, polar aprotic solvents such as DMF and DMSO.
  • Dichloromethane (DCM) is preferred.
  • the present invention provides a pharmaceutical composition comprising:
  • the crystalline form or amorphous form of the compound of formula A or its salt or solvate can be a therapeutically effective amount.
  • the pharmaceutically acceptable excipients can be excipients well known in the art, and in the case of solid preparations, they include but are not limited to: diluents, binders, disintegrants, lubricants, glidants, release rate control agents, plasticizers, preservatives, antioxidants, etc.
  • the present invention provides a pharmaceutical preparation comprising the above-mentioned pharmaceutical composition; wherein the pharmaceutical preparation may be a solid preparation, or may be a powder, granule, tablet, capsule, pill or film preparation.
  • the present invention provides the use of the above-mentioned crystalline form, amorphous form or pharmaceutical composition in the preparation of a medicament for treating a proliferative disease
  • the proliferative disease includes breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, gastric cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neuroblastoma, lymphoid organ cancer and hematological malignancies including leukemia (acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMOL), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large
  • the present invention provides a method for treating a proliferative disease, comprising the step of administering to a subject in need thereof a therapeutically effective amount of the form of the first aspect of the invention or the pharmaceutical composition of the third aspect of the invention or the pharmaceutical formulation of the fourth aspect of the invention.
  • the subject is a mammal, such as a human.
  • the crystalline form or amorphous form of the compound of formula A or its salt or solvate of the present invention has the following advantages: the present invention is the first to discover multiple unreported crystalline forms or amorphous forms of the compound of formula A or its salt or solvate, and the forms can serve as an important basis for subsequent drug development, formulation development and production.
  • Figure 1a shows the chemical purity spectrum of the crystalline form A1 of the compound of formula A.
  • FIG. 1 b shows the chiral purity spectrum of crystalline form A1 of the compound of formula A.
  • Figure 1c shows the X-ray powder diffraction pattern of the crystalline form A1 of the compound of formula A.
  • Figure 1d shows the differential scanning calorimetry graph of the crystalline form A1 of the compound of formula A.
  • FIG. 1e shows a thermogravimetric analysis of the crystalline form A1 of the compound of formula A.
  • FIG. 1 f shows the 1 H NMR spectrum of the crystalline form A1 of the compound of formula A.
  • Figure 2a shows the X-ray powder diffraction pattern of the crystalline form A2 of the compound of formula A.
  • Figure 2b shows a differential scanning calorimetry graph of the crystalline form A2 of the compound of formula A.
  • FIG. 2c shows a thermogravimetric analysis of the crystalline form A2 of the compound of formula A.
  • FIG. 2 d shows the 1 H NMR spectrum of the crystalline form A2 of the compound of formula A.
  • Figure 3a shows the X-ray powder diffraction pattern of the crystalline form A3 of the compound of formula A.
  • Figure 3b shows a differential scanning calorimetry graph of the crystalline form A3 of the compound of formula A.
  • FIG. 3c shows a thermogravimetric analysis of the crystalline form A3 of the compound of formula A.
  • FIG. 3 d shows the 1 H NMR spectrum of the crystalline form A3 of the compound of formula A.
  • Figure 4a shows the X-ray powder diffraction pattern of the crystalline form A4 of the compound of formula A.
  • Figure 4b shows a differential scanning calorimetry graph of the crystalline form A4 of the compound of formula A.
  • FIG. 4c shows a thermogravimetric analysis of the crystalline form A4 of the compound of formula A.
  • FIG. 4 d shows the 1 H NMR spectrum of the crystalline form A4 of the compound of formula A.
  • Figure 5a shows the X-ray powder diffraction pattern of the crystalline form A5 of the compound of formula A.
  • Figure 5b shows a differential scanning calorimetry graph of the crystalline form A5 of the compound of formula A.
  • Figure 5c shows the thermogravimetric analysis of the crystalline form A5 of the compound of formula A.
  • FIG5d shows the 1 H NMR spectrum of the crystalline form A5 of the compound of formula A.
  • FIG. 6a shows the chemical purity spectrum of crystalline form B of the compound of formula A.
  • FIG. 6b shows the chiral purity spectrum of crystalline form B of the compound of formula A.
  • FIG. 6c shows the X-ray powder diffraction pattern of crystalline form B of the compound of formula A.
  • FIG. 6d shows a differential scanning calorimetry graph of crystalline form B of the compound of formula A.
  • FIG. 6e shows a thermogravimetric analysis of crystalline form B of the compound of formula A.
  • FIG. 6 f shows the 1 H NMR spectrum of crystalline form B of the compound of formula A.
  • FIG. 7a shows an X-ray powder diffraction pattern of crystalline form C of the compound of formula A.
  • FIG. 7b shows a differential scanning calorimetry graph of crystalline form C of the compound of formula A.
  • FIG. 7c shows a thermogravimetric analysis of crystalline form C of the compound of formula A.
  • FIG. 7 d shows the 1 H NMR spectrum of crystalline form C of the compound of formula A.
  • Figure 8a shows the X-ray powder diffraction pattern of the crystalline form D1 of the compound of formula A.
  • Figure 8b shows the differential scanning calorimetry graph of the crystalline form D1 of the compound of formula A.
  • FIG8c shows a thermogravimetric analysis of the crystalline form D1 of the compound of formula A.
  • FIG8d shows the 1 H NMR spectrum of the crystalline form D1 of the compound of formula A.
  • Figure 9a shows the X-ray powder diffraction pattern of the crystalline form D2 of the compound of formula A.
  • Figure 9b shows the differential scanning calorimetry graph of the crystalline form D2 of the compound of formula A.
  • FIG. 9c shows a thermogravimetric analysis of the crystalline form D2 of the compound of Formula A.
  • FIG. 9 d shows the 1 H NMR spectrum of the crystalline form D2 of the compound of formula A.
  • Figure 10a shows the chemical purity spectrum of crystalline form E of the compound of formula A.
  • FIG. 10 b shows the chiral purity spectrum of crystalline form E of the compound of formula A.
  • FIG. 10c shows the X-ray powder diffraction pattern of crystalline form E of the compound of formula A.
  • Figure 10d shows a differential scanning calorimetry graph of crystalline form E of the compound of formula A.
  • FIG. 10e shows a thermogravimetric analysis of crystalline form E of the compound of formula A.
  • FIG. 10 f shows the 1 H NMR spectrum of crystalline form E of the compound of formula A.
  • Figure 11a shows the X-ray powder diffraction pattern of crystalline form F of the compound of formula A.
  • FIG. 11 b shows a differential scanning calorimetry graph of crystalline form F of the compound of formula A.
  • FIG. 11c shows a thermogravimetric analysis of crystalline form F of the compound of formula A.
  • FIG. 11 d shows the 1 H NMR spectrum of crystalline form F of the compound of formula A.
  • Figure 12a shows the chemical purity spectrum of crystalline form G of the compound of formula A.
  • Figure 12b shows the chiral purity spectrum of crystalline form G of the compound of formula A.
  • Figure 12c shows the X-ray powder diffraction pattern of crystalline form G of the compound of formula A.
  • Figure 12d shows the differential scanning calorimetry graph of crystalline form G of the compound of formula A.
  • Figure 12e shows the thermogravimetric analysis of crystalline form G of the compound of formula A.
  • FIG. 12f shows the 1 H NMR spectrum of crystalline form G of the compound of formula A.
  • Figure 13a shows the X-ray powder diffraction pattern of crystalline form H of the compound of formula A.
  • Figure 13b shows a differential scanning calorimetry graph of crystalline Form H of the compound of Formula A.
  • FIG. 13c shows a thermogravimetric analysis of crystalline form H of the compound of formula A.
  • FIG. 13 d shows the 1 H NMR spectrum of crystalline form H of the compound of formula A.
  • FIG. 14a shows the X-ray powder diffraction pattern of the amorphous form of the compound of Formula A.
  • FIG. 14 b shows a modulated differential scanning calorimetry (mDSC) graph of the amorphous form of the compound of Formula A.
  • mDSC modulated differential scanning calorimetry
  • FIG. 14c shows a thermogravimetric analysis of the amorphous form of the compound of Formula A.
  • Figure 14d shows a polarized light microscopy (PLM) image of the amorphous form of the compound of Formula A.
  • PLM polarized light microscopy
  • Figure 15a shows the chemical purity of crystalline form B of the compound of formula A.
  • FIG. 15b shows the chiral purity of crystalline Form B of the compound of Formula A.
  • Figure 15c shows the chemical purity of crystalline form B of the compound of formula A.
  • Figure 15d shows the chiral purity of crystalline Form B of the compound of formula A.
  • Figure 15e shows an X-ray powder diffraction stack of the stability test of the crystalline form B of the compound of formula A.
  • Figure 15f shows the chemical purity of crystalline form B of the compound of formula A.
  • Figure 15g shows the chiral purity of crystalline Form B of the compound of Formula A.
  • Figure 15h shows the chemical purity of crystalline form B of the compound of formula A.
  • Figure 15i shows the chiral purity of crystalline Form B of the compound of Formula A.
  • Figure 16a shows the chemical purity of crystalline Form E of the compound of formula A.
  • Figure 16b shows the chiral purity of crystalline Form E of the compound of Formula A.
  • Figure 16c shows the chemical purity of crystalline form E of the compound of formula A.
  • Figure 16d shows the chiral purity of crystalline Form E of the compound of Formula A.
  • Figure 16e shows an X-ray powder diffraction stack of the stability test of the crystalline form E of the compound of formula A.
  • Figure 16f shows the chemical purity of crystalline form E of the compound of formula A.
  • Figure 16g shows the chiral purity of crystalline Form E of the compound of Formula A.
  • Figure 16h shows the chemical purity of crystalline form E of the compound of formula A.
  • Figure 16i shows the chiral purity of crystalline Form E of the compound of Formula A.
  • Figure 17a shows the chemical purity of crystalline form G of the compound of formula A.
  • Figure 17b shows the chiral purity of crystalline Form G of the compound of Formula A.
  • Figure 17c shows an X-ray powder diffraction stack of the stability test of the crystalline form G of the compound of formula A.
  • Figure 17d shows the chemical purity of crystalline form G of the compound of formula A.
  • Figure 17e shows the chiral purity of crystalline Form G of the compound of Formula A.
  • Figure 17f shows the chemical purity of crystalline form G of the compound of formula A.
  • Figure 17g shows the chiral purity of crystalline Form G of the compound of Formula A.
  • FIG. 18a shows the DVS spectrum of crystalline form B of the compound of formula A.
  • Figure 18b shows the X-ray powder diffraction pattern of crystalline form B of the compound of formula A before and after the hygroscopicity experiment.
  • FIG. 19a shows the DVS spectrum of crystalline form E of the compound of formula A.
  • Figure 19b shows the X-ray powder diffraction pattern of crystalline form E of the compound of formula A before and after the hygroscopicity experiment.
  • Figure 20a shows the DVS spectrum of crystalline form G of the compound of formula A.
  • Figure 20b shows the X-ray powder diffraction pattern of crystalline form G of the compound of formula A before and after the hygroscopicity experiment.
  • Figure 21a shows an XRPD overlay of a sample of crystalline Form G obtained after simulated tableting experiment of the compound of Formula A.
  • the inventors have discovered various crystalline forms and amorphous forms of the compound of formula A or its pharmaceutically acceptable salt, or its solvate through long-term and in-depth research.
  • the crystalline forms and amorphous forms have better drug bioavailability, and the crystalline forms are high in purity and very stable, suitable for preparing pharmaceutical compositions for treating proliferative diseases, thereby being more conducive to treating diseases such as cancer, myeloproliferative and inflammatory diseases.
  • the crystalline forms and amorphous forms of the present invention are not easy to be raised, easy to collect, not easy to cause waste, and help protect the health of operators in the process of drug manufacturing such as packaging. On this basis, the inventors have completed the present invention.
  • the active ingredient refers to the amorphous form or crystalline form of the compound of formula A or its pharmaceutically acceptable salt or solvate thereof.
  • the active ingredient is the crystalline form A1, crystalline form A2, crystalline form A3, crystalline form A4, crystalline form A5, crystalline form B, crystalline form C, crystalline form D1, crystalline form D2, crystalline form E, crystalline form F, crystalline form G, crystalline form H and amorphous form as described above.
  • Solids exist in either amorphous or crystalline form.
  • the molecules are positioned in a three-dimensional lattice.
  • polymorphism a property known as "polymorphism"
  • Different polymorphs of a given substance may differ from one another in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystal shape, packing pattern, flowability and/or solid state stability.
  • Crystalline form A1 can be used as the starting material, the chemical purity is shown in Figure 1a, and the chiral purity is shown in Figure 1b.
  • the polymorphism of the compound of formula A was studied in the screening by suspension, slow cooling, fast cooling, slow evaporation, fast evaporation, anti-solvent dripping, anti-solvent reverse dripping, vapor diffusion or heating-cooling DSC crystallization method.
  • the compound of formula A exhibits complex polymorphic behavior, and 13 polymorphs and pseudo-polymorphs were found and identified, including 2 anhydrous crystalline forms, named crystalline form F and crystalline form G. 3 hydrates, named crystalline form B, crystalline form E and crystalline form H. 8 solvates, named crystalline form A1, crystalline form A2, crystalline form A3, crystalline form A4, crystalline form A5, crystalline form C, crystalline form D1 and crystalline form D2.
  • amorphous samples were obtained in solvent systems such as acetone and tetrahydrofuran in this study.
  • Crystalline Form A1, Crystalline Form A2, Crystalline Form A3, Crystalline Form A4 and Crystalline Form A5 have similar XRPD spectra, and it is speculated that they have similar crystal structures and are isomorphous solvates of each other.
  • Crystalline Form D1 and Crystalline Form D2 also have similar XRPD spectra, and it is speculated that they also have similar crystal structures and are another group of isomorphous solvates of each other.
  • room temperature generally refers to 4-30°C, preferably 20 ⁇ 5°C.
  • the present invention uses the following methods and instruments to characterize it: The quality was studied.
  • Methods for determining the X-ray powder diffraction of a crystalline form are known in the art. For example, a Bruker D8 Advance X-ray powder diffractometer is used at a scanning speed of 0.02° per minute using a Cu/K-Alpha 1 Radiation target acquisition map.
  • DSC Different Scanning Calorimetry
  • the DSC measurement method is known in the art.
  • a TA Discovery 2500 differential scanning calorimeter can be used to increase the temperature from 0°C to 250°C at a heating rate of 10°C per minute to obtain a DSC scan spectrum of the crystal form.
  • Nuclear magnetic resonance can also be used to assist in determining the crystalline structure, and its determination method is known in the art.
  • the present invention preferably uses Bruker Avance-AV-400MHz.
  • TGA Thermogravimetric analysis
  • the test is completed if the weight loss of the sample exceeds 20% by heating from room temperature to 300°C at a rate of 10°C/min under atmospheric conditions.
  • crystalline form of the present invention includes an amorphous form or a crystalline form of the compound of formula A or a pharmaceutically acceptable salt or a solvate thereof.
  • the present invention includes but is not limited to crystalline form A1, crystalline form A2, crystalline form A3, crystalline form A4, crystalline form A5, crystalline form B, crystalline form C, crystalline form D1, crystalline form D2, crystalline form E, crystalline form F, crystalline form G, and crystalline form H.
  • Amorphous or “amorphous form” refers to a substance formed when the particles (molecules, atoms, ions) of a substance are arranged in three-dimensional space without periodicity, characterized by a diffuse X-ray powder diffraction pattern without peaks. Amorphous is a special physical form of solid matter, and its locally ordered structural characteristics suggest that it is inextricably linked to crystalline substances.
  • the amorphous form of the present invention preferably has an XRPD pattern as shown in Figure 14a, and optionally has one or more of the following characteristics:
  • the present invention provides a method for preparing a crystalline form or an amorphous form of a compound of formula A or a pharmaceutically acceptable salt or solvate thereof, comprising the steps of: subjecting the compound of formula A or a pharmaceutically acceptable salt thereof to suspension, slow cooling, rapid cooling, slow volatilization, rapid volatilization, anti-solvent dripping, anti-solvent reverse dripping, vapor diffusion or heating-cooling DSC crystallization method, or spray drying, hot melt extrusion or solvent evaporation, thereby obtaining the crystalline form or amorphous form.
  • the compound of formula A is synthesized in the laboratory as described in the specific embodiment.
  • the solvent can be a commonly used solvent in the laboratory, for example, one or more of water, alkane solvents, alcohol solvents, ketone solvents, ester solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, nitrile solvents, ether solvents, aliphatic hydrocarbon solvents, polar aprotic solvents such as N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).
  • the mass volume ratio of the compound of formula A to the solvent can be 100 mg: (0.1-1 mL).
  • the present invention provides a method for preparing a crystalline form of a solvate of a compound of formula A, comprising the steps of mixing the compound of formula A with a solvent corresponding to the solvate type, separating the resulting solid and drying it, thereby obtaining a crystalline form of a solvate of the compound of formula A.
  • the preparation method of crystalline form A1 comprises: mixing and slurrying the compound of formula A with MTBE, separating, and drying to obtain crystalline form A1.
  • the preparation method of crystalline form A2 comprises: suspending crystalline form A1 and 1,4-dioxane, and separating to obtain crystalline form A2.
  • the preparation method of crystalline form A3 comprises: suspending crystalline form A1 and toluene, and separating to obtain crystalline form A3.
  • the preparation method of crystalline form A4 comprises: mixing crystalline form A1 with dichloromethane, and rapidly volatilizing the mixture to obtain crystalline form A4.
  • the preparation method of crystalline form A5 comprises: suspending crystalline form A1 with ethyl acetate, and separating to obtain crystalline form A5.
  • the preparation method of crystalline form B comprises: suspending crystalline form A1 with ethanol, separating, and drying to obtain crystalline form B.
  • the preparation method of crystalline form C comprises: suspending crystalline form A1 and dimethyl sulfoxide, and separating to obtain crystalline form C.
  • the preparation method of crystalline form D1 comprises: suspending crystalline form A1 and isopropanol, and separating to obtain crystalline form D1.
  • DMSO: water 24:76, v/v
  • the preparation method of crystalline form F comprises: suspending crystalline form A1 with water, and separating to obtain crystalline form F.
  • the preparation method of crystalline form H comprises: mixing crystalline form E with methanol, heating-cooling, and separating to obtain crystalline form H.
  • the solvent corresponding to the solvate type is, for example but not limited to, 1,4-dioxane, ethyl acetate, toluene, chloroform, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetone, N,N-dimethylformamide, acetonitrile, and the like.
  • the solvent used in the method for preparing the amorphous phase of the present invention is not particularly limited.
  • the present invention includes any solvent that can dissolve the starting material and does not affect its properties.
  • many similar modifications, equivalent replacements, or solvents, solvent combinations, and different proportions of solvent combinations that are equivalent to those described in the present invention are considered to be within the scope of the present invention.
  • the present invention provides preferred solvents used in each reaction step.
  • the present invention provides a method for preparing an amorphous form of a compound of formula A, comprising the steps of mixing the compound of formula A with a solvent and spray drying the resulting solution, thereby obtaining an amorphous form of the compound of formula A.
  • the solvent can be a commonly used solvent in the laboratory, for example: the solvent is one or more of water, alcohol solvents, ester solvents, ketone solvents, halogenated hydrocarbon solvents, nitrile solvents and ether solvents, wherein the alcohol solvent is preferably ethanol and/or methanol; the ester solvent is preferably ethyl acetate; the ketone solvent is preferably acetone; the halogenated hydrocarbon solvent is preferably dichloromethane; the nitrile solvent is preferably acetonitrile; the ether solvent is preferably tetrahydrofuran; preferably, the solvent is one or more of ethyl acetate, acetone, tetrahydrofuran, methyl tert-butyl ether and acetonitrile.
  • the solvent is one or more of ethyl acetate, acetone, tetrahydrofuran, methyl tert-butyl ether and acetonit
  • the separation is performed by centrifugal filtration using a 0.45 ⁇ m nylon filter membrane centrifuge tube at a certain rotation speed (eg, 14,000 rpm).
  • the crystalline form and amorphous form of the present invention have excellent effects in treating proliferative diseases
  • the crystalline form and amorphous form of the present invention and pharmaceutical compositions containing the crystalline form and amorphous form of the present invention as main active ingredients can be used to treat, prevent and alleviate proliferative diseases.
  • the form described in the present invention can be used to treat the following diseases: cancer, myeloproliferative and inflammatory diseases, etc.
  • the pharmaceutical composition of the present invention comprises a safe and effective amount of the crystalline form or amorphous form of the present invention and a pharmaceutically acceptable excipient and/or carrier.
  • the crystalline and amorphous forms of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the pharmaceutical composition can be in a dosage form suitable for human administration, such as tablets, capsules, granules, powders, or pills, etc., preferably tablets, capsules, granules, disintegrating tablets, sustained-release or controlled-release tablets, etc.
  • the pharmaceutical composition of the present invention can be prepared by various methods well known in the art, which can be prepared by mixing a therapeutically effective amount of the compound of formula A or one or more of its salts, crystalline forms or amorphous forms of solvates with one or more pharmaceutically acceptable excipients into a dosage form suitable for human administration, such as tablets, capsules, granules, etc.
  • “Therapeutically effective amount” refers to an amount of a compound form according to the invention that, when administered to a patient in need thereof, is sufficient to achieve treatment of a disease state, condition or disorder for which the compound has utility. Such an amount will be sufficient to elicit the biological or medical response of a tissue system or patient sought by a researcher or clinician.
  • the pharmaceutical composition contains 0.1-2000 mg of the crystalline form and amorphous form of the present invention per dose, and more preferably, contains 0.1-200 mg of the crystalline form and amorphous form of the present invention per dose.
  • the "one dose” is one capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be mixed with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients.
  • Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • administration mode of the crystalline form and amorphous form or pharmaceutical composition of the present invention is not particularly limited, and representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • a safe and effective amount of the crystalline form and amorphous form of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 0.1 to 2000 mg, preferably 0.1 to 200 mg.
  • the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill range of skilled physicians.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, cross-linked polyvidone, cross-linked sodium carboxymethyl cellulose; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, par
  • Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active ingredient in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active ingredient can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottons
  • composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances.
  • compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms of the crystalline and amorphous forms of the invention for topical administration include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the obtained amorphous form or crystalline form has excellent stability, solubility and bioavailability.
  • Preparation method Prepare the compound of formula A by referring to the method of Example 15 of PCT/CN2022/097236, then Then MTBE was slurried to obtain crystalline form A1.
  • the chemical name of the compound of formula A is N-((S)-5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide.
  • the compound of formula A (4.9 g) was slurried in MTBE (25 ml) at room temperature for 24 h, filtered and dried to obtain 4.41 g of a white solid with a yield of 90%.
  • XRPD ( FIG. 1 c ) identified the solid as crystalline form A1.
  • FIG1a Its chemical purity diagram is shown in FIG1a , its chiral purity diagram is shown in FIG1b , its X-ray powder diffraction diagram is shown in FIG1c , the parameters of each peak are shown in Table 1 , its differential scanning calorimetry diagram (DSC) diagram is shown in FIG1d , its thermogravimetric analysis diagram is shown in FIG1e , and its 1 H NMR spectrum is shown in FIG1f .
  • DSC differential scanning calorimetry diagram
  • Preparation method Weigh about 40 mg of crystalline form A1, add 0.2-1 mL of 1,4-dioxane, and stir and suspend at 25°C at 300 rpm for 2 weeks. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 ⁇ m nylon filter centrifuge tube to obtain crystalline form A2.
  • FIG2a Its X-ray powder diffraction pattern is shown in FIG2a , the parameters of each peak are shown in Table 2 , the differential scanning calorimetry (DSC) pattern is shown in FIG2b , the thermogravimetric analysis pattern is shown in FIG2c , and the 1 H NMR spectrum is shown in FIG2d .
  • DSC differential scanning calorimetry
  • Preparation method Weigh about 40 mg of crystalline form A1, add 0.2-1 mL of toluene, and suspend under stirring at 25°C and 300 rpm for 2 weeks. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 ⁇ m nylon filter centrifuge tube to obtain crystalline form A3.
  • FIG3a Its X-ray powder diffraction pattern is shown in FIG3a , the parameters of each peak are shown in Table 3 , the differential scanning calorimetry (DSC) pattern is shown in FIG3b , the thermogravimetric analysis pattern is shown in FIG3c , and the 1 H NMR spectrum is shown in FIG3d .
  • DSC differential scanning calorimetry
  • Preparation method Weigh about 30 mg of crystalline form A1, add 5 mL of DCM to fully dissolve, and filter through a 0.45 ⁇ m nylon filter syringe filter to obtain a clear solution. The obtained clear solution is purged with nitrogen at room temperature to quickly evaporate the solvent. Collect the solid obtained after the solvent evaporates to obtain crystalline form A4.
  • FIG4a Its X-ray powder diffraction pattern is shown in FIG4a , the parameters of each peak are shown in Table 4 , the differential scanning calorimetry (DSC) pattern is shown in FIG4b , the thermogravimetric analysis pattern is shown in FIG4c , and the 1 H NMR spectrum is shown in FIG4d .
  • DSC differential scanning calorimetry
  • Preparation method Weigh about 60 mg of crystalline form A1, add 0.2-1 mL of ethyl acetate, and stir at 50°C and 300 rpm for 1 week. Centrifuge the resulting suspension using a 0.45 ⁇ m nylon filter centrifuge tube at 14,000 rpm to obtain crystalline form A5.
  • Preparation method Weigh 410 mg of Form A1 and place it in an 8 mL glass bottle. Add 5 mL of ethanol and stir at 25 ° C to obtain a suspension. Add about 5 mg of Form B seed crystals to the above suspension, stir at 25 ° C for about 5 days, collect the solid by filtration, and vacuum dry the obtained solid at 50 ° C for about 8 hours and at 25 ° C for about 3 hours. About 350 mg of Form B off-white powder is prepared, and the yield is about 87%.
  • Preparation method Weigh about 40 mg of crystalline form A1, add 0.2-1 mL of DMSO, and suspend at 25°C at 300 rpm for 2 weeks. Centrifuge the resulting suspension at 14,000 rpm using a 0.45 ⁇ m nylon filter centrifuge tube to obtain crystalline form C.
  • FIG7a Its X-ray powder diffraction pattern is shown in FIG7a , the parameters of each peak are shown in Table 7 , the differential scanning calorimetry (DSC) pattern is shown in FIG7b , the thermogravimetric analysis pattern is shown in FIG7c , and the 1 H NMR spectrum is shown in FIG7d .
  • DSC differential scanning calorimetry
  • Preparation method Weigh about 40 mg of crystalline form A1, add 0.2-1 mL of IPA, and suspend with stirring at 25°C and 300 rpm for 2 weeks. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 ⁇ m nylon filter centrifuge tube to obtain crystalline form D1.
  • DMSO water
  • v/v a mixed solution
  • FIG9a Its X-ray powder diffraction pattern is shown in FIG9a , the parameters of each peak are shown in Table 9 , the differential scanning calorimetry (DSC) pattern is shown in FIG9b , the thermogravimetric analysis pattern is shown in FIG9c , and the 1 H NMR spectrum is shown in FIG9d .
  • DSC differential scanning calorimetry
  • FIG10a Its chemical purity is shown in FIG10a , its chiral purity is shown in FIG10b , its X-ray powder diffraction pattern is shown in FIG10c , the parameters of each peak are shown in Table 10 , its differential scanning calorimetry (DSC) pattern is shown in FIG10d , its thermogravimetric analysis pattern is shown in FIG10e , and its 1 H NMR spectrum is shown in FIG10f .
  • DSC differential scanning calorimetry
  • Preparation method Weigh about 40 mg of crystalline form A1, add 0.2-1 mL of water, and suspend at 25°C at 300 rpm for 2 weeks. Centrifuge the resulting suspension at 14,000 rpm using a 0.45 ⁇ m nylon filter centrifuge tube to obtain crystalline form F.
  • FIG11a Its X-ray powder diffraction pattern is shown in FIG11a , the parameters of each peak are shown in Table 11, the differential scanning calorimetry (DSC) pattern is shown in FIG11b , the thermogravimetric analysis pattern is shown in FIG11c , and the 1 H NMR spectrum is shown in FIG11d .
  • DSC differential scanning calorimetry
  • the compound of formula A was prepared by referring to the method of Example 15 of PCT/CN2022/097236, and then the compound was ring-closed under acidic conditions and crystallized in acetonitrile-water to obtain crystalline form G.
  • the compound of formula A was identified as crystalline form G by XRPD ( FIG. 12 c ).
  • FIG12a Its chemical purity diagram is shown in FIG12a , its chiral purity diagram is shown in FIG12b , its X-ray powder diffraction diagram is shown in FIG12c , the parameters of each peak are shown in Table 12 , its differential scanning calorimetry diagram (DSC) diagram is shown in FIG12d , its thermogravimetric analysis diagram is shown in FIG12e , and its 1 H NMR spectrum is shown in FIG12f .
  • DSC differential scanning calorimetry diagram
  • Preparation method Weigh about 60 mg of crystalline form E, add 0.2-1 mL of methanol, and stir at 50°C and 300 rpm for 1 week. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 ⁇ m nylon filter centrifuge tube to obtain crystalline form H.
  • Preparation method 1 Weigh about 40 mg of crystalline form A1, add 0.2-1 mL of EA, and suspend at 25° C. and 300 rpm for 2 weeks. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 ⁇ m nylon filter centrifuge tube to obtain the amorphous form of the compound of formula A.
  • Preparation method 2 Weigh about 40 mg of crystalline form A1, add 0.2-1 mL of acetone, and suspend at 25°C at 300 rpm for 2 weeks. The resulting suspension is centrifuged at 14,000 rpm using a 0.45 ⁇ m nylon filter centrifuge tube to obtain the amorphous form of the compound of formula A.
  • Preparation method 3 About 40 mg of crystalline form A1 was weighed, 0.2-1 mL of THF was added, and the mixture was suspended at 25° C. and 300 rpm for 2 weeks. The obtained suspension was centrifuged at 14,000 rpm using a 0.45 ⁇ m nylon filter centrifuge tube to obtain the amorphous form of the compound of formula A.
  • Preparation method 4 About 50 mg of crystalline form A1 was weighed, 0.2-1 mL of EA was added, and 10 heating and cooling cycles were performed between 5°C and 50°C at a rate of 0.2°C/min, while suspending with a magnetic stirrer at 300 rpm. The resulting suspension was centrifuged and filtered at 14,000 rpm at 5°C using a 0.45 ⁇ m nylon filter centrifuge tube to obtain the amorphous form of the compound of formula A.
  • Preparation method 5 A crude product was obtained according to the method of Example 1, and then the crude product was treated with EA (5 mL) and MTBE (5 mL) to obtain a filter cake. The filter cake was added to 30 mL of acetonitrile and ultrasonicated for 5 minutes to uniformly disperse it into a slurry solution, and then 70 mL of water was added to make the whole solution clear and transparent, and after freeze-drying, an amorphous off-white solid compound of formula A was obtained.
  • Preparation method 6 A crude product is obtained according to the method of Example 1, and then the crude product is spray-dried with a solvent such as DCM and EtOH, with the air inlet temperature set at 80°C to 120°C to obtain an amorphous compound of formula A.
  • a solvent such as DCM and EtOH
  • Crystalline Form B chemical purity is shown in Figure 15a
  • chiral purity is shown in Figure 15b.
  • the open container was placed at 25°C/92%RH and 40°C/75%RH for 13 days, respectively, and the sealed container was placed at 60°C for 13 days.
  • the stability sample was tested by XRPD and HPLC and the sample was observed for color change. The data is shown in Table 14.
  • Crystalline Form E chemical purity is shown in Figure 16a
  • chiral purity is shown in Figure 16b.
  • the open container was placed at 25°C/92%RH and 40°C/75%RH for 13 days, respectively, and the sealed container was placed at 60°C for 13 days.
  • the stability sample was tested by XRPD and HPLC and the sample was observed for color change. The data is shown in Table 15.
  • Crystalline Form G chemical purity is shown in Figure 12a
  • chiral purity is shown in Figure 12b.
  • the open container was placed at 25°C/92%RH and 40°C/75%RH for 13 days, respectively, and the sealed container was placed at 60°C for 13 days.
  • the stability sample was tested by XRPD and HPLC and the sample was observed for color change. The data is shown in Table 16.
  • the above substances are mixed evenly and filled into ordinary gelatin capsules to obtain 10,000-100,000 capsules.
  • Example 23 Pharmacokinetic evaluation of the crystalline form G and amorphous form of the compound of formula A in mice by oral administration
  • CD1 male mice were selected and the test compound was administered orally.
  • the plasma drug concentration at different time points was quantitatively determined by LC/MS/MS to evaluate the pharmacokinetic characteristics of the test drug in mice.
  • test compound was prepared in 25 mM citrate buffer (pH 3) containing 5% Tween 80 and orally administered to CD1 mice (free access to food and water).
  • Blood was collected from the dorsal plantar vein at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration, placed in an anticoagulant tube containing EDTA-K2 and mixed, and centrifuged at 4 ° C and 4000 g for 5 minutes.
  • the blood drug concentration was determined by LC-MS/MS, and the relevant pharmacokinetic parameters were calculated by the non-compartmental model Linear/log trapezoidal method using Phoenix WinNonlin 6.3 pharmacokinetic software.
  • the pharmacokinetic parameters of the compound of formula A in vivo are good, and the area under the drug-time curve is 3 to 4 times that of the crystalline form G.
  • Tables 14, 15 and 16 the stability of crystalline forms B, E and G is good, and the crystal form has not changed.
  • the stability of crystalline forms B, E and G is good, and the crystal form has not changed.
  • the crystalline form G when tableted at 2MPa, 5MPa and 10MPa pressures, respectively, as shown in Table 20, has no significant change in crystallinity. Therefore, the form described in the present invention is very suitable for use in pharmaceutical compositions.
  • the crystalline form and amorphous form of the present invention are not easy to be lifted up, easy to collect, and not easy to cause waste during the drug manufacturing process such as packaging, which helps to protect the health of operators.

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Abstract

涉及一种氧异吲哚-5-甲酰胺类化合物或其盐、溶剂合物的结晶形式或无定形形式。还公开了含有该结晶形式或无定形形式的组合物，及制备方法和应用。得到的结晶形式或无定形形式具有良好的固体稳定性，对药物开发、制剂开发和生产具有十分重要的价值。

Description

氧异吲哚-5-甲酰胺类化合物或其盐、溶剂合物的结晶形式或无定形形式 技术领域
本发明属于医药领域，特别涉及一种用作CK1α选择性分子胶降解剂的氧异吲哚-5-甲酰胺类化合物或其盐、溶剂合物的结晶形式或无定形形式，及其制备方法和应用。
背景技术
酪蛋白激酶1α(CK1α)，由基因CSNK1A1编码，是CK1激酶家族中一个普遍表达的丝氨酸/苏氨酸蛋白激酶。CK1α参与调节细胞的多种生理和病理过程，并通过不同的信号转导途径协调生命的有序进行(Jiang et al.,Cell Commun Signal(2018)16:23)。例如，CK1α作为Wnt/β-catenin途径的关键调控器，直接将β-catenin的Ser45处磷酸化，从而使其成为蛋白体降解的靶标(Liu et al.,Cell(2002)108:837-847)。CK1α也被认为通过调节MDM2/MDMX E3连接酶的活性复合物来调节肿瘤抑制因子p53的蛋白质稳定性(Huart et al.,J Biol Chem(2009)284:32384-94；Wu et al.,Mol Cell Biol(2012)32:4821-4832)。据报道，CK1α在许多类型的人类癌症中过度表达，然而，CK1α在多种肿瘤类型的发展中的确切作用还没有得到明确的阐明(Richter et al.,BMC Cancer(2018)18:140)。癌症依赖性图谱(DepMap)数据库显示，通过CRISPR/cas9介导的基因敲除或shRNA介导的基因抑制使CK1α的失活，显著降低了多种癌症类型的许多癌细胞系的增殖和/或存活(Tsherniak et al.,Cell(2017)170:564-576；Behan et al.,Nature(2019)568:511-516)。此外，通过使用shRNA干扰或D4476(一种CK1α抑制剂)抑制CK1α活性，该方法能够有效抑制MLL-AF9白血病的进展，而且对正常造血干细胞和祖细胞(HSPCs)影响小(Jaras et al,J Exp Med(2014)211(4):605-612)。总之，这些数据表明CK1α是潜在治疗血液***恶性癌症和实体瘤适应症的潜在靶点。
式A化合物作为新一代CK1α选择性分子胶降解剂，现已处于早期临床研究阶段。
然而，未见关于式A化合物或其盐、溶剂合物的结晶形式或无定形形式及其制备方法和应用、制剂等的任何研究与报道。
固体物质由于分子结构的构型、构象、分子排列、分子作用力、共晶物质等各种因素影响，致使分子晶格空间排列不同，形成两种或两种以上不同的晶体结构，这种现象被称为“多晶现象”(Polymorphism Phenomenon)或“同质异晶现象”。“多晶现象”在固体药物中广泛存在，同一药物的不同晶型之间理化性质可能存在差异，如外观、密度、硬度、熔点、溶解度、稳定性、溶出度、溶出速率、生物利用度等方面可能会有显著不同，此现象在口服固体制剂上表现得尤为明显。此外，多晶型化合物的存在形态和数量是不可预期的，同一药物的不同结晶形式在溶解度、熔点、密度、稳定性等方面存在显著的差异，从而不同程度地影响药物的均一性、生物利用度、疗效和安全性等。
除了多晶型以外，一些固体化合物还可能存在无定形形式，无定形是指一些非完全晶体无定形区(非晶区)的结构或者一些无定形固体(非晶体)的构成方式。对于特定固体药物而言，其无定形形式的存在形态和数量同样是不可预期的，并同样可能对该药物的溶解度、熔点、密度、稳定性等产生显著影响。
因此，在新药研发过程中需要对药物化合物进行全面筛选，从多重因素进行考虑。特别地，对于上述用于治疗增值性病症的式A化合物而言，开发该化合物或其衍生物、晶型、无定形、或其药学上可接受的盐、水合物或溶剂合物的可能具有药用价值的剂型，对提高化合物的稳定性、溶解度、生物利用度等特性具有潜在的药用和临床价值。
发明内容
本发明提供了一种用作CK1α选择性分子胶降解剂的氧异吲哚-5-甲酰胺类化合物或其盐、溶剂合物的结晶形式或无定形形式及其制备方法和应用。本发明的结晶形式或无定形形式对药物开发、制剂开发和生产具有十分重要的价值。
在以下描述中，阐述了某些具体细节以便提供对本发明各种实施方式的透彻理解。然而，本领域技术人员将理解，可以在没有这些细节的情况下实践本发明。以下对若干实施方式的描述是在理解本公开被视为所要求保护的主题的示例的情况下进行的，并且无意于将所附权利要求限制于所示的特定实施方式。贯穿本发明使用的标题仅是为了方便而提供的，不应被解释为以任何方式限制权利要求。在任何标题下示出的实施方式可以与在任何其他标题下示出的实施方式组合。
此外，当提及例如XRPD图、TGA图、DSC图等时，术语“基本上如...所示”是指不一定与本文描述的那些相同，但当由本领域普通技术人员考虑时，落入实验误差或偏差的限度内的图谱。
在一个方面中，本发明提供了式A化合物或其药学上可接受的盐或其溶剂合物的无定形形式或结晶形式。
所述化合物的化学名为N-((S)-5-氯吡啶-2-基)(环丁基)甲基)-2-((S)-2,6-二氧哌啶-3-基)-1-氧异吲哚-5-甲酰胺(N-((S)-(5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide)。
本发明包括但不限于结晶形式A1、结晶形式A2、结晶形式A3、结晶形式A4、结晶形式A5、结晶形式B、结晶形式C、结晶形式D1、结晶形式D2、结晶形式E、结晶形式F、结晶形式G、结晶形式H和无定形形式。具体如下：
式A化合物的溶剂合物结晶形式A1
在一个实施方式中，其为式A化合物的溶剂合物结晶形式A1，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：6.54±0.2°，19.64±0.2°，9.21±0.2°，16.35±0.2°，18.48±0.2°，9.79±0.2°和17.23±0.2°。
在一些优选实施方式中，其具有基本上如下表1中所示位置处的XRPD特征 峰：
表1
在一些优选实施方式中，基本上如图1c所示的XRPD图，并任选地具有以下一个或多个特征：
1)在DSC图中，在147.77℃±2℃处有1个吸热峰，在159.25℃±2℃处有1个吸热峰；
2)在TGA图中，在240℃之前有10.64±0.2重量％的失重；
3)基本上如图1d所示的DSC图；和/或
4)基本上如图1e所示的TGA图。
式A化合物的溶剂合物结晶形式A2
在一个实施方式中，其为式A化合物的溶剂合物结晶形式A2，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：18.57±0.2°，19.67±0.2°，16.38±0.2°，9.28±0.2°，17.38±0.2°，25.18±0.2°和13.11±0.2°。
在一些优选实施方式中，其具有基本上如下表2中所示位置处的XRPD特征 峰：
表2
在一些优选实施方式中，基本上如图2a所示的XRPD图，并任选地具有以下一个或多个特征：
1)在DSC图中，在153.88℃±2℃处有1个吸热峰，在178.46℃±2℃处有1个吸热峰；
2)在TGA图中，在165.00℃之前有11.32±0.2重量％的失重，在165.00℃至230.00℃之间具有2.83±0.2重量％的失重；
3)基本上如图2b所示的DSC图；和/或
4)基本上如图2c所示的TGA图。
式A化合物的溶剂合物结晶形式A3
在一个实施方式中，其为式A化合物的溶剂合物结晶形式A3，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：19.61±0.2°，18.45±0.2°9.22±0.2°，16.33±0.2°，6.54±0.2°，17.24±0.2°和9.80±0.2°。
在一些优选实施方式中，其具有基本上如下表3中所示位置处的XRPD特征峰：
表3
在一些优选实施方式中，基本上如图3a所示的XRPD图，并任选地具有以下一个或多个特征：
1)在DSC图中，在90.56℃±2℃处有1个放热峰，在152.55℃±2℃和177.33℃±2℃处各有1个吸热峰；
2)在TGA图中，在165.00℃之前有12.08±0.2重量％的失重，在165.00℃至230.00℃之间具有2.12±0.2重量％的失重；
3)基本上如图3b所示的DSC图；和/或
4)基本上如图3c所示的TGA图。
式A化合物的溶剂合物结晶形式A4
在一个实施方式中，其为式A化合物的溶剂合物结晶形式A4，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：9.22±0.2°，17.51±0.2°，6.54±0.2°，19.59±0.2°，25.03±0.2°，16.37±0.2°和18.51±0.2°。
在一些优选实施方式中，其具有基本上如下表4中所示位置处的XRPD特征峰：
表4
在一些优选实施方式中，基本上如图4a所示的XRPD图，并任选地具有以下一个或多个特征：
1)在DSC图中，在149.48℃±2℃处有1个吸热峰；
2)在TGA图中，在160℃之前有3.01±0.2重量％的失重；
3)基本上如图4b所示的DSC图；和/或
4)基本上如图4c所示的TGA图。
式A化合物的溶剂合物结晶形式A5
在一个实施方式中，其为式A化合物的溶剂合物结晶形式A5，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：16.43±0.2°，19.74±0.2°，6.58±0.2°，9.27±0.2°，18.53±0.2°，17.37±0.2°和9.88±0.2°。
在一些优选实施方式中，其具有基本上如下表5中所示位置处的XRPD特征峰：
表5
在一些优选实施方式中，基本上如图5a所示的XRPD图，并任选地具有以下一个或多个特征:
1)在DSC图中，在154.86℃±2℃处有1个吸热峰；
2)在TGA图中，在220℃之前有6.75±0.2重量％的失重；
3)基本上如图5b所示的DSC图；和/或
4)基本上如图5c所示的TGA图。
式A化合物的结晶形式B
在一个实施方式中，其为式A化合物的结晶形式B，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：3.98±0.2°，12.35±0.2°，12.05±0.2°，19.09±0.2°，7.92±0.2°，15.78±0.2°和14.32±0.2°。
在一些优选实施方式中，其具有基本上如下表6中所示位置处的XRPD特征峰：
表6
在一些优选实施方式中，基本上如图6c所示的XRPD图，并任选地具有以下一个或多个特征：
1)在DSC图中，在25.54℃±2℃处有1个吸热峰，在183.52℃±2℃处有1个吸热峰；
2)在TGA图中，在100℃之前有1.03±0.2重量％的失重；
3)基本上如图6d所示的DSC图；和/或
4)基本上如图6e所示的TGA图。
式A化合物的溶剂合物结晶形式C
在一个实施方式中，其为式A化合物的溶剂合物结晶形式C，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五 个、至少六个或七个特征峰：20.60±0.2°，17.94±0.2°，13.110±0.2°，19.42±0.2°，23.97±0.2°，26.31±0.2°和11.95±0.2°。
在一些优选实施方式中，其具有基本上如下表7中所示位置处的XRPD特征峰：
表7
在一些优选实施方式中，基本上如图7a所示的XRPD图，并任选地具有以下一个或多个特征：
1)在DSC图中，在127.33℃±2℃处有1个吸热峰；
2)在TGA图中，在160.00℃之前有16.21±0.2重量％的失重，在160.00℃至260.00℃之间具有9.29±0.2重量％的失重；
3)基本上如图7b所示的DSC图；和/或
4)基本上如图7c所示的TGA图。
式A化合物的溶剂合物结晶形式D1
在一个实施方式中，其为式A化合物的溶剂合物结晶形式D1，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：17.99±0.2°，8.82±0.2°，17.32±0.2°，9.26±0.2°，19.14±0.2°，9.95±0.2°和31.53±0.2°。
在一些优选实施方式中，其具有基本上如下表8中所示位置处的XRPD特征峰：
表8
在一些优选实施方式中，基本上如图8a所示的XRPD图，并任选地具有以下一个或多个特征:
1)在DSC图中，在161.17℃±2℃处有1个吸热峰；
2)在TGA图中，在210℃之前有11.30±0.2重量％的失重；
3)基本上如图8b所示的DSC图；和/或
4)基本上如图8c所示的TGA图。
式A化合物的溶剂合物结晶形式D2
在一个实施方式中，其为式A化合物的溶剂合物结晶形式D2，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：17.38±0.2°，17.99±0.2°，19.57±0.2°，9.80±0.2°，31.55±0.2°，25.05±0.2°和6.55±0.2°。
在一些优选实施方式中，其具有基本上如下表9中所示位置处的XRPD特征峰：
表9
在一些优选实施方式中，基本上如图9a所示的XRPD图，并任选地具有以下一个或多个特征：
1)在DSC图中，在83.30℃±2℃处有1个吸热峰，在126.89℃±2℃处有1个吸热峰；
2)在TGA图中，在110.00℃之前有12.51±0.2重量％的失重，在110.00℃至250.00℃之间具有12.26±0.2重量％的失重；
3)基本上如图9b所示的DSC图；和/或
4)基本上如图9c所示的TGA图。
式A化合物的结晶形式E
在一个实施方式中，其为式A化合物的结晶形式E，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：11.14±0.2°，15.76±0.2°，12.59±0.2°，19.71±0.2°，9.56±0.2°，17.83±0.2°和13.58±0.2°。
在一些优选实施方式中，其具有基本上如下表10中所示位置处的XRPD特征峰：
表10
在一些优选实施方式中，基本上如图10c所示的XRPD图，并任选地具有以下一个或多个特征:
1)在DSC图中，在37.94℃±2℃处有1个吸热峰，在190.71℃±2℃处有1个吸热峰；
2)在TGA图中，在130℃之前有1.17±0.2重量％的失重；
3)基本上如图10d所示的DSC图；和/或
4)基本上如图10e所示的TGA图。
式A化合物的结晶形式F
在一个实施方式中，其为式A化合物的结晶形式F，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至 少六个或七个特征峰：17.70±0.2°，21.46±0.2°，27.66±0.2°，19.20±0.2°，17.17±0.2°，19.44±0.2°和22.01±0.2°。
在一些优选实施方式中，其具有基本上如下表11中所示位置处的XRPD特征峰：
表11
在一些优选实施方式中，基本上如图11a所示的XRPD图，并任选地具有以下一个或多个特征：
1)在DSC图中，在216.58℃±2℃处有1个吸热峰；
2)在TGA图中，在100℃之前有0.598±0.2重量％的失重；
3)基本上如图11b所示的DSC图；和/或
4)基本上如图11c所示的TGA图。
式A化合物的结晶形式G
在一个实施方式中，其为式A化合物的结晶形式G，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：18.83±0.2°，13.88±0.2°，21.45±0.2°，26.75±0.2°，15.92±0.2°，17.95±0.2°和13.14±0.2°。
在一些优选实施方式中，其具有基本上如下表12中所示位置处的XRPD特征峰：
表12
在一些优选实施方式中，基本上如图12c所示的XRPD图，并任选地具有以下一个或多个特征：
1)在DSC图中，在236.59℃±2℃处有1个吸热峰；
2)在TGA图中，在150℃之前有0.52±0.2重量％的失重；
3)基本上如图12d所示的DSC图；和/或
4)基本上如图12e所示的TGA图。
式A化合物的结晶形式H
在一个实施方式中，其为式A化合物的结晶形式H，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：18.30±0.2°，3.80±0.2°，19.05±0.2°，18.53±0.2°，11.81±0.2°，11.33±0.2°和16.04±0.2°；
在一些优选实施方式中，其具有基本上如下表13中所示位置处的XRPD特征峰：
表13
在一些优选实施方式中，基本上如图13a所示的XRPD图，并任选地具有以下一个或多个特征：
1)在DSC图中，在77.45℃±2℃处有1个吸热峰，在154.75℃±2℃处有1个吸热峰；
2)在TGA图中，在120℃之前有0.19±0.2重量％的失重；
3)基本上如图13b所示的DSC图；和/或
4)基本上如图13c所示的TGA图。
式A化合物PLM图14d所示的无定形形式
在一个实施方式中，其为式A化合物PLM图14d所示的无定形形式，优选地，其具有如图14a所示的XRPD图，并任选地具有以下一个或多个特征：
1)在mDSC图中，在129.30℃±2.0℃处有1个玻璃化转变温度；
2)在TGA图中，在210℃±2.0℃之前有2.7重量％的失重；
3)基本上如图14b所示的mDSC图；和/或
4)基本上如图14c所示的TGA图。
在第二方面中，本发明提供了式A化合物或其药学上可接受的盐、溶剂合物的结晶形式或无定形形式的制备方法，包括步骤：将式A所示化合物或其药学上可接受的盐通过混悬、缓慢冷却、快速冷却、缓慢挥发、快速挥发、反溶剂滴加、反溶剂反向滴加、蒸气扩散或加热-冷却DSC结晶方法，或喷雾干燥、热熔挤出或溶剂蒸发，从而得到所述的结晶形式或无定形形式。
在所述制备方法中，所述式A化合物如具体实施例所述的方法实验室合成。所述溶剂可以是实验室常用的溶剂，例如：水、烷烃类溶剂、醇类溶剂、酮类溶剂、酯类溶剂、芳香烃类溶剂、卤代烃类溶剂、腈类溶剂、醚类溶剂、脂肪烃类溶剂、极性非质子类溶剂如DMF、DMSO中的一种或多种。其中式A化合物与溶剂的质量体积比可为100mg：(0.1～1mL)。
在一个实施方式中，本发明提供了式A化合物的溶剂合物的结晶形式的制备方法，其包括如下步骤：将式A化合物与对应于溶剂合物类型的溶剂混合，分离所得的固体并干燥，由此得到式A化合物的溶剂合物的结晶形式。
在一些优选实施方式中，所述对应于溶剂合物类型的溶剂例如但不限于1,4-二氧六环、乙酸乙酯、甲苯、氯仿、2-甲基四氢呋喃、甲基叔丁基醚、丙酮、N,N-二甲基甲酰胺、乙腈等。
在一个实施方式中，本发明提供了式A化合物的无定形形式的制备方法，其包括如下步骤：将式A化合物与溶剂混合，并将所得溶液喷雾干燥，由此得到式A化合物的无定形形式。
在一些优选实施方式中，所述溶剂可以是实验室常用的溶剂，例如：水、烷烃类溶剂、醇类溶剂、酮类溶剂、酯类溶剂、芳香烃类溶剂、卤代烃类溶剂、腈类溶剂、醚类溶剂、脂肪烃类溶剂、极性非质子类溶剂如DMF、DMSO中的一种或多种。优选二氯甲烷(DCM)。
在第三方面中，本发明提供了一种药物组合物，包含：
(a)第一方面所述的形式；和
(b)药学上可接受的载体或赋形剂。
所述式A化合物或其盐、溶剂合物的结晶形式或无定形形式可为治疗有效量。所述药学上可接受的辅料可为本领域熟知的辅料，在固体制剂的情况下，其包括但不限于：稀释剂、粘合剂、崩解剂、润滑剂、助流剂、释放速度控制剂、增塑剂、防腐剂、抗氧化剂等。
在第四方面中，本发明提供了一种药物制剂，其包含上述药物组合物；其中，所述的药物制剂可为固体制剂，也可为散剂、颗粒剂、片剂、胶囊剂、滴丸剂或膜剂。
在第五方面中，本发明提供上述的结晶形式、无定形形式或药物组合物在制备治疗增殖性疾病的药物中的应用，所述增殖性疾病包括乳腺癌、结肠癌症、脑癌、***癌、肾癌、胰腺癌、卵巢癌、头部以及颈部癌、黑色素瘤、结直肠癌、胃癌、鳞状细胞癌、小细胞癌肺癌、非小细胞肺癌、睾丸癌、Merkel细胞癌、胶质母细胞瘤、神经母细胞瘤，淋巴器官癌和血液恶性肿瘤包括白血病(急性淋巴细胞白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)、慢性粒细胞白血病(CML)、急性单核细胞白血病(AMOL)、毛细胞白血病(HCL)、T细胞前淋巴细胞白血病(T-PLL)、大颗粒淋巴细胞白血病、成人T细胞白血病)、淋巴瘤(小淋巴细胞淋巴瘤(SLL)、霍奇金淋巴瘤(结节性硬化，混合细胞、富含淋巴细胞、淋巴细胞耗竭或未耗竭以及结节淋巴细胞为主的霍奇金淋巴瘤)、非霍奇金淋巴瘤(所有亚型)，慢性淋巴细胞白血病/小淋巴细胞淋巴瘤，B细胞前淋巴细胞白血病、淋巴瘤(如巨球蛋白血症)、脾边缘区淋巴瘤、浆细胞肿瘤(浆细胞骨髓瘤、浆细胞瘤、单克隆免疫球蛋白沉积疾病、重链疾病)、***外边缘区B细胞淋巴瘤(MALT淋巴瘤)、淋巴瘤(NMZL)、滤泡性淋巴瘤、套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性积液淋巴瘤、伯基特淋巴瘤/白血病、T细胞前淋巴细胞白血病、T细胞大颗粒淋巴细胞白血病、侵袭性NK细胞白血病、成人T细胞白血病/淋巴瘤、结外NK/T细胞淋巴瘤(鼻型)、肠病T型细胞淋巴瘤、肝脾T细胞淋巴瘤、母细胞NK细胞淋巴瘤、真菌病蕈样肉芽肿/塞扎里综合征、原发性皮肤CD30阳性T细胞淋巴瘤疾病、原发性皮肤间变性大细胞淋巴瘤、淋巴瘤样丘疹病、血管免疫母细胞T细胞淋巴瘤、外周T 细胞淋巴瘤(非特定的)、间变性大细胞淋巴瘤、多发性骨髓瘤(浆细胞骨髓瘤或Kahler病)。
在第六方面中，本发明提供一种治疗增殖性疾病的方法，包括步骤：给有需要的对象施用治疗有效量的本发明第一方面的形式或本发明第三方面的药物组合物或本发明第四方面的药物制剂。
在一些优选实施方式中，所述的对象为哺乳动物，如人。
本发明式A化合物或其盐、溶剂合物的结晶形式或无定形形式具有如下优点，本发明首次发现了式A化合物或其盐、溶剂合物的多种未见报道的结晶形式或无定形形式，所述形式可作为后续药物开发、制剂开发和生产的重要基础。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1a显示了式A化合物结晶形式A1的化学纯度谱图。
图1b显示了式A化合物结晶形式A1的手性纯度谱图。
图1c显示了式A化合物结晶形式A1的X-射线粉末衍射图。
图1d显示了式A化合物结晶形式A1的差示扫描量热法图。
图1e显示了式A化合物结晶形式A1的热重分析图。
图1f显示了式A化合物结晶形式A1的1HNMR图。
图2a显示了式A化合物结晶形式A2的X-射线粉末衍射图。
图2b显示了式A化合物结晶形式A2的差示扫描量热法图。
图2c显示了式A化合物结晶形式A2的热重分析图。
图2d显示了式A化合物结晶形式A2的1HNMR图。
图3a显示了式A化合物结晶形式A3的X-射线粉末衍射图。
图3b显示了式A化合物结晶形式A3的差示扫描量热法图。
图3c显示了式A化合物结晶形式A3的热重分析图。
图3d显示了式A化合物结晶形式A3的1HNMR图。
图4a显示了式A化合物结晶形式A4的X-射线粉末衍射图。
图4b显示了式A化合物结晶形式A4的差示扫描量热法图。
图4c显示了式A化合物结晶形式A4的热重分析图。
图4d显示了式A化合物结晶形式A4的1HNMR图。
图5a显示了式A化合物结晶形式A5的X-射线粉末衍射图。
图5b显示了式A化合物结晶形式A5的差示扫描量热法图。
图5c显示了式A化合物结晶形式A5的热重分析图。
图5d显示了式A化合物结晶形式A5的1HNMR图。
图6a显示了式A化合物结晶形式B的化学纯度谱图。
图6b显示了式A化合物结晶形式B的手性纯度谱图。
图6c显示了式A化合物结晶形式B的X-射线粉末衍射图。
图6d显示了式A化合物结晶形式B的差示扫描量热法图。
图6e显示了式A化合物结晶形式B的热重分析图。
图6f显示了式A化合物结晶形式B的1HNMR图。
图7a显示了式A化合物结晶形式C的X-射线粉末衍射图。
图7b显示了式A化合物结晶形式C的差示扫描量热法图。
图7c显示了式A化合物结晶形式C的热重分析图。
图7d显示了式A化合物结晶形式C的1HNMR图。
图8a显示了式A化合物结晶形式D1的X-射线粉末衍射图。
图8b显示了式A化合物结晶形式D1的差示扫描量热法图。
图8c显示了式A化合物结晶形式D1的热重分析图。
图8d显示了式A化合物结晶形式D1的1HNMR图。
图9a显示了式A化合物结晶形式D2的X-射线粉末衍射图。
图9b显示了式A化合物结晶形式D2的差示扫描量热法图。
图9c显示了式A化合物结晶形式D2的热重分析图。
图9d显示了式A化合物结晶形式D2的1HNMR图。
图10a显示了式A化合物结晶形式E的化学纯度谱图。
图10b显示了式A化合物结晶形式E的手性纯度谱图。
图10c显示了式A化合物结晶形式E的X-射线粉末衍射图。
图10d显示了式A化合物结晶形式E的差示扫描量热法图。
图10e显示了式A化合物结晶形式E的热重分析图。
图10f显示了式A化合物结晶形式E的1HNMR图。
图11a显示了式A化合物结晶形式F的X-射线粉末衍射图。
图11b显示了式A化合物结晶形式F的差示扫描量热法图。
图11c显示了式A化合物结晶形式F的热重分析图。
图11d显示了式A化合物结晶形式F的1HNMR图。
图12a显示了式A化合物结晶形式G的化学纯度谱图。
图12b显示了式A化合物结晶形式G的手性纯度谱图。
图12c显示了式A化合物结晶形式G的X-射线粉末衍射图。
图12d显示了式A化合物结晶形式G的差示扫描量热法图。
图12e显示了式A化合物结晶形式G的热重分析图。
图12f显示了式A化合物结晶形式G的1HNMR图。
图13a显示了式A化合物结晶形式H的X-射线粉末衍射图。
图13b显示了式A化合物结晶形式H的差示扫描量热法图。
图13c显示了式A化合物结晶形式H的热重分析图。
图13d显示了式A化合物结晶形式H的1HNMR图。
图14a显示了式A化合物无定形形式的X-射线粉末衍射图。
图14b显示了式A化合物无定形形式的调制差示扫描量热分析(mDSC)图。
图14c显示了式A化合物无定形形式的热重分析图。
图14d显示了式A化合物无定形形式的偏振光显微镜(PLM)图。
图15a显示了式A化合物结晶形式B的化学纯度。
图15b显示了式A化合物结晶形式B的手性纯度。
图15c显示了式A化合物结晶形式B的化学纯度。
图15d显示了式A化合物结晶形式B的手性纯度。
图15e显示了式A化合物结晶形式B稳定性实验的X-射线粉末衍射叠图。
图15f显示了式A化合物结晶形式B的化学纯度。
图15g显示了式A化合物结晶形式B的手性纯度。
图15h显示了式A化合物结晶形式B的化学纯度。
图15i显示了式A化合物结晶形式B的手性纯度。
图16a显示了式A化合物结晶形式E的化学纯度。
图16b显示了式A化合物结晶形式E的手性纯度。
图16c显示了式A化合物结晶形式E的化学纯度。
图16d显示了式A化合物结晶形式E的手性纯度。
图16e显示了式A化合物结晶形式E稳定性实验的X-射线粉末衍射叠图。
图16f显示了式A化合物结晶形式E的化学纯度。
图16g显示了式A化合物结晶形式E的手性纯度。
图16h显示了式A化合物结晶形式E的化学纯度。
图16i显示了式A化合物结晶形式E的手性纯度。
图17a显示了式A化合物结晶形式G的化学纯度。
图17b显示了式A化合物结晶形式G的手性纯度。
图17c显示了式A化合物结晶形式G稳定性实验的X-射线粉末衍射叠图。
图17d显示了式A化合物结晶形式G的化学纯度。
图17e显示了式A化合物结晶形式G的手性纯度。
图17f显示了式A化合物结晶形式G的化学纯度。
图17g显示了式A化合物结晶形式G的手性纯度。
图18a显示了式A化合物结晶形式B的DVS谱图。
图18b显示了式A化合物引湿性实验前后结晶形式B的X-射线粉末衍射图。
图19a显示了式A化合物结晶形式E的DVS谱图。
图19b显示了式A化合物引湿性实验前后结晶形式E的X-射线粉末衍射图。
图20a显示了式A化合物结晶形式G的DVS谱图。
图20b显示了式A化合物引湿性实验前后结晶形式G的X-射线粉末衍射图。
图21a显示了式A化合物模拟压片实验后结晶形式G所得样品的XRPD叠图。
具体实施方式
本发明人通过长期而深入的研究，发现了式A化合物或其药学上可接受的盐，或其溶剂合物的多种结晶形式和无定形形式，所述结晶形式和无定形形式具有更佳的药物生物利用度，且所述结晶形式纯度高，且非常稳定，适合用于制备治疗增殖性疾病的药物组合物，从而更有利于治疗癌症、骨髓增殖性和炎症等疾病。此外，本发明的结晶形式和无定形形式在分装等药品制造过程中，不易扬起，易收集，不易造成浪费，且有助于保护操作人员的身体健康。在此基础上，发明人完成了本发明。
活性成分
本发明中，活性成分是指式A化合物或其药学上可接受的盐或其溶剂合物的无定形形式或结晶形式。优选地，活性成分为如上所述的结晶形式A1、结晶形式A2、结晶形式A3、结晶形式A4、结晶形式A5、结晶形式B、结晶形式C、结晶形式D1、结晶形式D2、结晶形式E、结晶形式F、结晶形式G、结晶形式H和无定形形式。
缩写

多晶型物
固体不是以无定形的形式就是以结晶的形式存在。在结晶形式的情况下，分子定位于三维晶格格位内。当化合物从溶液或浆液中结晶出来时，它能以不同的空间点阵排列结晶(这种性质被称作“多晶型现象”)，形成具有不同的结晶形式的晶体，这各种结晶形式被称作“多晶型物”。给定物质的不同多晶型物可在一个或多个物理属性方面(如溶解度和溶解速率、真比重、晶形、堆积方式、流动性和/或固态稳定性)彼此不同。
晶型筛选
可以结晶形式A1为起始原料，化学纯度见附图1a，手性纯度见附图1b。筛选中通过混悬、缓慢冷却、快速冷却、缓慢挥发、快速挥发、反溶剂滴加、反溶剂反向滴加、蒸气扩散或加热-冷却DSC结晶方法研究了式A化合物的多晶现象。
式A化合物呈现出复杂的多晶型行为，发现并鉴别出13种多晶型及伪多晶型，包括2种无水晶型，命名为结晶形式F和结晶形式G。3种水合物，命名为结晶形式B、结晶形式E和结晶形式H。8种溶剂合物，命名为结晶形式A1、结晶形式A2、结晶形式A3、结晶形式A4、结晶形式A5、结晶形式C、结晶形式D1和结晶形式D2。此外，本研究中在丙酮和四氢呋喃等溶剂体系中得到了无定形样品。
结晶形式A1、结晶形式A2、结晶形式A3、结晶形式A4和结晶形式A5具有相似的XRPD谱图，推测它们晶体结构相似，互为类质同晶溶剂合物。结晶形式D1和结晶形式D2也具有相似的XRPD谱图，推测它们也具有相似的晶体结构，互为另一组类质同晶溶剂合物。
如本文所用，术语“室温”一般指4-30℃，较佳地指20±5℃。
本发明在制备式A化合物的多晶型物后，采用如下多种方式和仪器对其性 质进行了研究。
X射线粉末衍射
测定晶型的X射线粉末衍射的方法在本领域中是已知的。例如使用Bruker D8 Advance型号的X射线粉末衍射仪，以0.02°每分钟的扫描速度，采用Cu/K-Alpha1辐射靶获取图谱。
如本领域所熟知的，由于实验变化性，当在不同的仪器上测量X射线衍射图时，如果两个θ(2θ)值相差在0.2°(即，±0.2°)内，则假定峰的位置相等。例如，美国药典规定，如果10个最强衍射峰的角度设定与参照材料的角度设定相差在±0.2°内，并且峰的相对强度变化不大于20％，则确认相同。因此，假定在本文所列举的位置的0.2°内的峰位置是相同的。除非另有说明，否则本文所列举的所有X射线衍射角度均基于铜K-α源。
示差扫描量热分析
又称“差示量热扫描分析”(DSC)，是在加热过程中，测量被测物质与参比物之间的能量差与温度之间关系的一种技术。DSC图谱上的峰位置、形状和峰数目与物质的性质有关，故可以定性地用来鉴定物质。本领域常用该方法来检测物质的相变温度、玻璃化转变温度、反应热等多种参数。
DSC测定方法在本领域中是已知的。例如可使用TA Discovery 2500差示扫描量热计，以10℃每分钟的升温速率，从0℃升温至250℃，获得晶型的DSC扫描图谱。
核磁
也可采用核磁共振(NMR)来辅助确定晶型结构，其测定方法在本领域中是已知的。本发明优选地采用Bruker Avance-AV-400MHz。
热重分析(TGA)测定
将样品(2～5mg)放在铝盘上，按以下方法运行：
在大气条件下以10℃/min的速率从室温加热至300℃，如果样品的失重超过20％，则测试完成。
偏振光显微镜(PLM)测定
-尼康LV100POL配备500万像素CCD
-物理镜头：10倍～50倍。
动态水分吸附(DVS)测定
-DVS Intrinsic动态水蒸汽吸附仪
-气体流速200sccm，炉温25℃。
本发明的结晶形式
如本文所用，术语“本发明的结晶形式”包括式A化合物或其药学上可接受的盐或其溶剂合物的无定形形式或结晶形式。
优选地，本发明包括但不限于结晶形式A1、结晶形式A2、结晶形式A3、结晶形式A4、结晶形式A5、结晶形式B、结晶形式C、结晶形式D1、结晶形式D2、结晶形式E、结晶形式F、结晶形式G、结晶形式H。
无定形形式
“无定形”或“无定形形式”是指物质的质点(分子、原子、离子)在三维空间排列无周期性时形成的物质，其特征是具有漫射的不具尖峰的X射线粉末衍射图。无定形是固体物质的一种特殊的物理形式，其局部有序的结构特征，提示其与晶型物质有着千丝万缕的联系。
本发明优选地无定形具有如图14a所示的XRPD图，并任选地具有以下一个或多个特征：
1)在mDSC图中，在129.30℃±2.0℃处有1个玻璃化转变温度；
2)在TGA图中，在210℃±2.0℃之前有2.7重量％的失重；
3)基本上如图14b所示的mDSC图；和/或
4)基本上如图14c所示的TGA图。
本发明结晶形式或无定形的制备方法
本发明提供了式A化合物或其药学上可接受的盐、溶剂合物的结晶形式或无定形形式的制备方法，包括步骤：将式A所示化合物或其药学上可接受的盐通过混悬、缓慢冷却、快速冷却、缓慢挥发、快速挥发、反溶剂滴加、反溶剂反向滴加、蒸气扩散或加热-冷却DSC结晶方法，或喷雾干燥、热熔挤出或溶剂蒸发，从而得到所述的结晶形式或无定形形式。
在所述制备方法中，所述式A化合物如具体实施例所述的方法实验室合成。所述溶剂可以是实验室常用的溶剂，例如：水、烷烃类溶剂、醇类溶剂、酮类溶剂、酯类溶剂、芳香烃类溶剂、卤代烃类溶剂、腈类溶剂、醚类溶剂、脂肪烃类溶剂、极性非质子类溶剂如N,N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)中的一种或多种。其中式A化合物与溶剂的质量体积比可为100mg：(0.1～1mL)。
在一个实施方式中，本发明提供了式A化合物的溶剂合物的结晶形式的制备方法，其包括如下步骤：将式A化合物与对应于溶剂合物类型的溶剂混合，分离所得的固体并干燥，由此得到式A化合物的溶剂合物的结晶形式。
优选地，结晶形式A1的制备方法包括：将式A化合物与MTBE混合打浆，分离，干燥，得结晶形式A1。
优选地，结晶形式A2的制备方法包括：将结晶形式A1与1,4-二氧六环混悬，分离，得结晶形式A2。
优选地，结晶形式A3的制备方法包括：将结晶形式A1与甲苯混悬，分离，得结晶形式A3。
优选地，结晶形式A4的制备方法包括：将结晶形式A1与二氯甲烷混合，快速挥发，得结晶形式A4。
优选地，结晶形式A5的制备方法包括：将结晶形式A1与乙酸乙酯混悬，分离，得结晶形式A5。
优选地，结晶形式B的制备方法包括：将结晶形式A1与乙醇混悬，分离，干燥，得结晶形式B。
优选地，结晶形式C的制备方法包括：将结晶形式A1与二甲基亚砜混悬，分离，得结晶形式C。
优选地，结晶形式D1的制备方法包括：将结晶形式A1与异丙醇混悬，分离，得结晶形式D1。
优选地，结晶形式D2的制备方法包括：将结晶形式A1与混合溶液(DMSO:水＝24:76，v/v)混悬，分离，得结晶形式D2。
优选地，结晶形式E的制备方法包括：将结晶形式A1与乙腈/水(v:v＝80:20)混合溶液混合，加热-冷却，分离，干燥，得结晶形式E。
优选地，结晶形式F的制备方法包括：将结晶形式A1与水混悬，分离，得结晶形式F。
优选地，结晶形式H的制备方法包括：将结晶形式E与甲醇混合，加热-冷却，分离，得结晶形式H。
在一些优选实施方式中，所述对应于溶剂合物类型的溶剂例如但不限于1,4-二氧六环、乙酸乙酯、甲苯、氯仿、2-甲基四氢呋喃、甲基叔丁基醚、丙酮、N,N-二甲基甲酰胺、乙腈等。
发明所述的无定形的制备方法中所使用的溶剂没有特别限制，任何在程度 上能溶解起始原料并且不影响其性质的溶剂均包含在本发明中。另外，本领域的许多类似改动，等同替换，或等同于本发明所描述的溶剂，溶剂组合，及溶剂组合的不同比例，均视为本发明的包含范围。本发明给出了各反应步骤所使用的较佳的溶剂。
在一个实施方式中，本发明提供了式A化合物的无定形形式的制备方法，其包括如下步骤：将式A化合物与溶剂混合，并将所得溶液喷雾干燥，由此得到式A化合物的无定形形式。
在一些优选实施方式中，所述溶剂可以是实验室常用的溶剂，例如：所述溶剂为水、醇类溶剂、酯类溶剂、酮类溶剂、卤代烃溶剂、腈类溶剂和醚类溶剂中的一种或多种，其中，所述醇类溶剂优选为乙醇和/或甲醇；所述酯类溶剂优选为乙酸乙酯；所述酮类溶剂优选为丙酮；所述卤代烃溶剂优选为二氯甲烷；所述腈类溶剂优选为乙腈；所述醚类溶剂优选为四氢呋喃；较佳地，所述溶剂为乙酸乙酯、丙酮、四氢呋喃、甲基叔丁基醚、乙腈中的一种或多种。
优选地，所述分离是用0.45μm尼龙滤膜离心管在一定转速(如14,000rpm)下离心过滤。
药物组合物
由于本发明的结晶形式和无定形形式具有优异的治疗增殖性疾病的作用，因此本发明的结晶形式和无定形形式以及含有本发明的结晶形式和无定形形式为主要活性成分的药物组合物可用于治疗、预防以及缓解增殖性疾病。根据现有技术，本发明所述的形式可用于治疗以下疾病：癌症，骨髓增殖性和炎症等等。
本发明的药物组合物包含安全有效量范围内的本发明的结晶形式或无定形形式及药学上可以接受的赋形剂和/或载体。
本发明的结晶形式和无定形形式可以单独给药，或者与其他药学上可接受的化合物联合给药。
所述药物组合物可以选择适合人体服用的剂型，例如：片剂、胶囊剂、颗粒剂、散剂、或丸剂等，优选片剂、胶囊剂、颗粒剂、崩解片、缓释或控释片剂等。
本发明所述药物组合物可以采用本领域所熟知的各种方法制备，其可将治疗有效量的所述式A化合物或其盐、溶剂合物的结晶形式或无定形形式中的一种或多种与一种或多种药学上可接受的辅料混合制备成适合人体服用的剂型，例如：片剂、胶囊剂、颗粒剂等。
“治疗有效量”是指根据本发明的化合物形式的量，其当施用至有此需要的患者时，足以实现对于化合物具有效用的疾病状态、病症或障碍的治疗。这样的量将足以引起研究人员或临床医生所寻求的组织***或患者的生物或医学反应。
“安全有效量”指的是：化合物(多晶型物)的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有0.1～2000mg本发明的结晶形式和无定形形式/剂，更佳地，含有0.1～200mg本发明的结晶形式和无定形形式/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的结晶形式和无定形形式或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
使用药物组合物时，是将安全有效量的本发明的结晶形式和无定形形式适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为0.1～2000mg，优选0.1～200mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，微晶纤维素、淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、碳酸钠、交联聚维酮、交联羧甲基纤维素钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高 岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明的结晶形式和无定形形式的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明的主要优点包括：
1.提供了一系列新颖的N-((S)-5-氯吡啶-2-基)(环丁基)甲基)-2-((S)-2,6-二氧哌啶-3-基)-1-氧异吲哚-5-甲酰胺或其盐、溶剂合物的结晶形式或无定形形式。
2.所得到的无定形形式或结晶形式具有优异的稳定性、溶解度、生物利用度。
实施例1结晶形式A1的制备
制备方法参照PCT/CN2022/097236实施例15的方法制备式A化合物，然 后MTBE打浆得结晶形式A1。
在含有二甲基乙酰胺(DMAc)(50mL)的圆底烧瓶中，加入化合物1(3.25g，12.3mmol，盐酸盐)，化合物2(4.67g，12.9mmol)，NMM(6.2g，61.3mmol)和T3P(5.6g，17.6mmol)。将混合物脱气并用N2吹扫3次。混合物在N2环境下25℃搅拌12小时。将混合物倒入饱和氯化钠水溶液(100mL)，然后过滤并用水(100mL)洗涤。然后滤饼溶于DCM(200mL)中，用饱和NaHCO3水溶液(100mL)洗涤，用无水Na2SO4干燥有机相，减压过滤浓缩，得到化合物3(6.5g，以化合物1计收率99.7％)白色固体。
将化合物3(6.5g)溶于CH3CN(13mL)，加入苯磺酸(1.1g，6.95mmol)。在N2环境下，将混合物在70℃下搅拌14小时，混合物用DCM(60mL)稀释，用饱和NaHCO3水溶液(30mLⅹ2)洗涤，然后用H2O(30mLⅹ2)洗涤，用无水Na2SO4干燥有机相，过滤并减压浓缩，得到粗产物。然后将粗产物用EA(5mL)和MTBE(5mL)在25℃下打浆0.5h，得到式A化合物(4.9g)，白色固体，以化合物1计，产率87％。所述式A化合物的化学名为N-((S)-5-氯吡啶-2-基)(环丁基)甲基)-2-((S)-2,6-二氧哌啶-3-基)-1-氧异吲哚-5-甲酰胺(N-((S)-(5-chloropyridin-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide)。
上述式A化合物(4.9g)在MTBE(25ml)中室温打浆24h，过滤干燥得白色固体4.41g，收率90％。经XRPD(图1c)鉴定，为结晶形式A1。
其化学纯度图见图1a,手性纯度图见图1b，X-射线粉末衍射图见图1c，各个峰的参数如表1所示，差示扫描量热法图(DSC)见图1d，热重分析图见图1e，1H NMR的图谱见图1f。
表1
实施例2结晶形式A2的制备
制备方法。称取约40mg结晶形式A1，加入0.2-1mL的1,4-二氧六环，在25℃以300rpm的转速搅拌混悬2周。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，得结晶形式A2。
其X-射线粉末衍射图见图2a，各个峰的参数如表2所示，差示扫描量热法图(DSC)见图2b，热重分析图见图2c，1H NMR的图谱见图2d。
表2
实施例3结晶形式A3的制备
制备方法。称取约40mg结晶形式A1，加入0.2-1mL的甲苯，在25℃以300rpm的转速在搅拌混悬2周。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，得结晶形式A3。
其X-射线粉末衍射图见图3a，各个峰的参数如表3所示，差示扫描量热法图(DSC)见图3b，热重分析图见图3c，1H NMR的图谱见图3d。
表3
实施例4结晶形式A4的制备
制备方法。称取约30mg结晶形式A1，加入5mL的DCM充分溶解，经0.45μm尼龙滤膜针头式过滤器过滤得澄清溶液。将所得澄清溶液在室温下由氮气吹扫快速挥发溶剂。收集溶剂挥发后所得固体，得结晶形式A4。
其X-射线粉末衍射图见图4a，各个峰的参数如表4所示，差示扫描量热法图(DSC)见图4b，热重分析图见图4c，1H NMR的图谱见图4d。
表4
实施例5结晶形式A5的制备
制备方法。称取约60mg结晶形式A1，加入0.2-1mL乙酸乙酯，在50℃以300rpm转速搅拌1周。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，得结晶形式A5。
其X-射线粉末衍射图见图5a，各个峰的参数如表5所示，差示扫描量热法图(DSC)见图5b，热重分析图见图5c，1H NMR的图谱见图5d。
表5
实施例6结晶形式B的制备
制备方法。称取410mg的晶型A1，置于8mL玻璃瓶中。加入5mL乙醇，置于25℃下搅拌得到混悬液。向上述混悬液中加入约5mg晶型B晶种，在25℃搅拌约5天后，通过过滤收集固体，所得固体在50℃真空干燥约8小时，在25℃真空干燥约3小时。制备得到晶型B灰白色粉末约350mg，产率约为87％。
其化学纯度见图6a，手性纯度见图6b，X-射线粉末衍射图见图6c，各个 峰的参数如表6所示，差示扫描量热法图(DSC)见图6d，热重分析图见图6e，1H NMR的图谱见图6f。
表6
实施例7结晶形式C的制备
制备方法。称取约40mg结晶形式A1，加入0.2-1mL的DMSO，在25℃以300rpm的转速搅拌混悬2周。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，得结晶形式C。
其X-射线粉末衍射图见图7a，各个峰的参数如表7所示，差示扫描量热法图(DSC)见图7b，热重分析图见图7c，1H NMR的图谱见图7d。
表7
实施例8结晶形式D1的制备
制备方法。称取约40mg结晶形式A1，加入0.2-1mL的IPA，在25℃以300rpm的转速搅拌混悬2周。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，得结晶形式D1。
其X-射线粉末衍射图见图8a，各个峰的参数如表8所示，差示扫描量热法图(DSC)见图8b，热重分析图见图8c，1H NMR的图谱见图8d。
表8
实施例9结晶形式D2的制备
制备方法。称取约40mg结晶形式A1，加入0.2-1mL的混合溶液(DMSO:水＝24:76，v/v)，在25℃以300rpm的转速搅拌混悬2周。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，得结晶形式D2。
其X-射线粉末衍射图见图9a，各个峰的参数如表9所示，差示扫描量热法图(DSC)见图9b，热重分析图见图9c，1H NMR的图谱见图9d。
表9
实施例10结晶形式E的制备
制备方法。称860mg结晶形式A1，在50℃溶解在10mL ACN/water(v:v＝80:20)混合溶液中。所得溶液经0.45μm尼龙滤膜针头式过滤器以得到澄清溶液。澄清溶液以0.1℃/min的速率降温到5℃。降温到约30℃时加入约5mg结晶形式E晶种，得到的混悬液继续以0.1℃/min的速率降温到5℃，并维持在5℃搅拌1天。固体通过在5℃过滤的方式收集，所得固体在50℃真空干燥约4.5小时。制备得到结晶形式E灰白色粉末约350mg，产率约为41％。
其化学纯度见图10a，手性纯度见图10b，X-射线粉末衍射图见图10c，各个峰的参数如表10所示，差示扫描量热法图(DSC)见图10d，热重分析图见图10e，1H NMR的图谱见图10f。
表10
实施例11结晶形式F的制备
制备方法。称取约40mg结晶形式A1，加入0.2-1mL的水，在25℃以300rpm的转速搅拌混悬2周。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，得结晶形式F。
其X-射线粉末衍射图见图11a，各个峰的参数如表11所示，差示扫描量热法图(DSC)见图11b，热重分析图见图11c，1H NMR的图谱见图11d。
表11
实施例12结晶形式G的制备
制备方法。参照PCT/CN2022/097236实施例15的方法制备式A化合物，然后在酸性条件下关环并在乙腈-水中结晶，得结晶形式G。
化合物1(32.5g，121mmol)和化合物2(56g，155mmol)加入DMAc(500mL) 中，加入T3P(46.7g，147mmol)和NMM(62g，613mmol)。将混合物脱气并用N2吹扫3次。混合物在N2环境下25℃搅拌12小时。将混合物倒入饱和氯化钠水溶液(1000mL)，然后过滤并用水(1000mL)洗涤。滤饼溶于DCM(2000mL)中，用饱和NaHCO3水溶液(1000mL)洗涤，无水Na2SO4干燥有机相，减压过滤浓缩，得到化合物3(66g)，白色固体(纯度大于98％，手性纯度大于98％)。
将化合物3(66g)溶于CH3CN(660mL)，加入苯磺酸(57.4g，363mmol)。在N2气环境下，将混合物在50℃下搅拌16小时，降温至0℃，用7％NaHCO3调pH至7-8，将上述溶液缓慢滴加入水(3300mL)中，搅拌3h，抽滤，用水(300mL)洗滤饼，滤饼真空干燥得到式A化合物(50g)，白色固体，两步的产率为89％。
上述式A化合物经XRPD(图12c)鉴定，为结晶形式G。
其化学纯度图见图12a，手性纯度图见图12b，X-射线粉末衍射图见图12c，各个峰的参数如表12所示，差示扫描量热法图(DSC)见图12d，热重分析图见图12e，1H NMR的图谱见图12f。
表12
实施例13结晶形式H的制备
制备方法。称取约60mg结晶形式E，加入0.2-1mL甲醇，在50℃以300rpm转速搅拌1周。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤，得结晶形式H。
其X-射线粉末衍射图见图13a，各个峰的参数如表13所示，差示扫描量热法图(DSC)见图13b，热重分析图见图13c，1H NMR的图谱见图13d。
表13
实施例14式A化合物无定形的制备
制备方法1。称取约40mg结晶形式A1，加入0.2-1mL的EA，在25℃以300rpm的转速搅拌混悬2周。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤得式A化合物的无定形。
制备方法2。称取约40mg结晶形式A1，加入0.2-1mL丙酮，在25℃以300rpm的转速搅拌混悬2周。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤得式A化合物的无定形。
制备方法3。称取约40mg结晶形式A1，加入0.2-1mL的THF，在25℃以300rpm的转速搅拌混悬2周。将所得混悬液用0.45μm尼龙滤膜离心管在14,000rpm下离心过滤得式A化合物的无定形。
制备方法4。称取约50mg结晶形式A1，加入0.2-1mL的EA，在5℃至50℃之间以0.2℃/min的速率进行10个升降温循环，同时用300rpm磁力搅拌进行混悬。将所得混悬液用0.45μm尼龙滤膜离心管在5℃以14,000rpm离心过滤得式A化合物的无定形。
制备方法5。按照实施例1方法得到粗产物，然后将粗产物用EA(5mL)和MTBE(5mL)，得到滤饼。将滤饼加入到30mL乙腈中，超声波处理5分钟，使其均匀分散成浆状溶液，再加入70mL水，使得整个溶液澄清透明，冻干后得到类白色固体式A化合物的无定形。
制备方法6。按照实施例1方法得到粗产物，然后将粗产物与溶剂，如DCM和EtOH，进行喷雾干燥，进风温度设定80℃～120℃，得式A化合物的无定形。
式A化合物的无定形的X-射线粉末衍射图见图14a。
实施例15结晶形式B的稳定性实验
结晶形式B，化学纯度见附图15a，手性纯度见附图15b。敞口容器分别放置于25℃/92％RH和40℃/75％RH中13天，密闭容器放置于60℃中13天。稳定性样品进行XRPD、HPLC检测并观察样品是否具有颜色变化。数据见表14。
表14
实施例16结晶形式E的稳定性实验
结晶形式E，化学纯度见附图16a，手性纯度见附图16b。敞口容器分别放置于25℃/92％RH和40℃/75％RH中13天，密闭容器放置于60℃中13天。稳定性样品进行XRPD、HPLC检测并观察样品是否具有颜色变化。数据见表15。
表15

实施例17结晶形式G的稳定性实验
结晶形式G，化学纯度见附图12a，手性纯度见附图12b。敞口容器分别放置于25℃/92％RH和40℃/75％RH中13天，密闭容器放置于60℃中13天。稳定性样品进行XRPD、HPLC检测并观察样品是否具有颜色变化。数据见表16。
表16
实施例18结晶形式B的引湿性实验
结晶形式B的吸水和脱水行为用DVS进行了研究。湿度程序：25℃，40-0-95-0-40％RH,dm/dt 0.002,最短平衡时间为60min，最长平衡时间为360min。并对DVS测试后的样品进行了XRPD检测，以判断是否发生晶型转变。结果见表17。
表17
注释“N/A”:未实施。
实施例19结晶形式E的引湿性实验
结晶形式E的吸水和脱水行为用DVS进行了研究。湿度程序：25℃，40-0-95-0-40％RH,dm/dt 0.002,最短平衡时间为60min，最长平衡时间为360min。并对DVS测试后的样品进行了XRPD检测，以判断是否发生晶型转变。结果见表18。
表18

注释“N/A”:未实施。
实施例20结晶形式G的引湿性实验
结晶形式G的吸水和脱水行为用DVS进行了研究。湿度程序：25℃，40-0-95-0-40％RH,dm/dt 0.002,最短平衡时间为60min，最长平衡时间为360min。并对DVS测试后的样品进行了XRPD检测，以判断是否发生晶型转变。结果见表19。
表19

注释“N/A”:未实施。
实施例21模拟压片实验
称取约10mg结晶形式G，分别在2MPa、5MPa和10MPa压力下压制5min。通过XRPD表征研究晶型转变以及结晶度的变化情况。见表20。
表20
实施例22药物组合物
表21
按常规方法，根据表21所示，将上述物质混合均匀，装入普通明胶胶囊，得到10000-100000颗胶囊。
实施例23式A化合物结晶形式G和无定形的小鼠灌胃药代动力学评价
选用CD1雄性小鼠，经口灌胃给予测试化合物后，应用LC/MS/MS法定量测定不同时间点的血浆药物浓度，以评价受试药物在小鼠体内的药代动力学特征。
实验材料：CD1Mouse小鼠(雄性，20-30g，6-8周龄，浙江维通利华)。
实验操作：根据表22所示，将测试化合物配制于含5％Tween 80的25mM柠檬酸盐缓冲液(pH 3)，经口灌胃给予CD1小鼠(自由饮食饮水)。于给药后0.25h、0.5h、1h、2h、4h、6h、8h和24h从跖背静脉采血，置于含EDTA-K2的抗凝管中并混合，在4℃、4000g下离心5分钟。采用LC-MS/MS法测定血药浓度，使用Phoenix WinNonlin 6.3药动学软件，以非房室模型Linear/log trapezoidal法计算相关药代动力学参数。
表22
由表22所示，式A化合物体内药代动力学参数好，药时曲线下面积是结晶形式G的3～4倍。由表14、表15和表16所示，结晶形式B、结晶形式E和结晶形式G的稳定性好，晶型未见转变。由表17、表18和表19引湿性试验所示，结晶形式B、结晶形式E和结晶形式G的稳定性好，晶型未见转变。尤其是结晶形式G，分别在2MPa、5MPa和10MPa压力下压片，如表20所示，结晶度无明显变化。因此，本发明所述的形式非常适合用于药物组合物。而且本发明的结晶形式和无定形形式在分装等药品制造过程中，不易扬起，易收集，不易造成浪费，有助于保护操作人员的身体健康。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (19)

  1. 式A化合物或其药学上可接受的盐或其溶剂合物的无定形形式或结晶形式
  2. 如权利要求1所述的形式，其特征在于，其为式A化合物的结晶形式G，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：18.83±0.2°，13.88±0.2°，21.45±0.2°，26.75±0.2°，15.92±0.2°，17.95±0.2°和13.14±0.2°；优选地，其具有基本上如表12中所示位置处的XRPD特征峰；更优选地，其具有基本上如图12c所示的XRPD图；并任选地具有以下一个或多个特征：
    1)在DSC图中，在236.59℃±2℃处有1个吸热峰；
    2)在TGA图中，在150℃之前有0.52±0.2重量％的失重；
    3)基本上如图12d所示的DSC图；和/或
    4)基本上如图12e所示的TGA图。
  3. 如权利要求1所述的形式，其特征在于，其为式A化合物的溶剂合物结晶形式A1，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：6.54±0.2°，19.64±0.2°，9.21±0.2°，16.35±0.2°，18.48±0.2°，9.79±0.2°和17.23±0.2°；优选地，其具有基本上如表1中所示位置处的XRPD特征峰；更优选地，其具有基本上如图1c所示的XRPD图；并任选地具有以下一个或多个特征：
    1)在DSC图中，在147.77℃±2℃处有1个吸热峰，在159.25℃±2℃处有1个吸热峰；
    2)在TGA图中，在240℃之前有10.64±0.2重量％的失重；
    3)基本上如图1d所示的DSC图；和/或
    4)基本上如图1e所示的TGA图。
  4. 如权利要求1所述的形式，其特征在于，其为式A化合物的溶剂合物结晶形式A2，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：18.57±0.2°，19.67±0.2°，16.38±0.2°，9.28±0.2°，17.38±0.2°，25.18±0.2°和13.11±0.2°；优选地，其具有基本上如表2中所示位置处的XRPD特征峰；更优选地，其具有基本上如图2a所示的XRPD图；并任选地具有以下一个或多个特征：
    1)在DSC图中，在153.88℃±2℃处有1个吸热峰，在178.46℃±2℃处有1个吸热峰；
    2)在TGA图中，在165.00℃之前有11.32±0.2重量％的失重，在165.00℃至230.00℃之间具有2.83±0.2重量％的失重；
    3)基本上如图2b所示的DSC图；和/或
    4)基本上如图2c所示的TGA图。
  5. 如权利要求1所述的形式，其特征在于，其为式A化合物的溶剂合物结晶形式A3，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：19.61±0.2°，18.45±0.2°9.22±0.2°，16.33±0.2°，6.54±0.2°，17.24±0.2°和9.80±0.2°；优选地，其具有基本上如表3中所示位置处的XRPD特征峰；更优选地，其具有基本上如图3a所示的XRPD图；并任选地具有以下一个或多个特征：
    1)在DSC图中，在90.56℃±2℃处有1个放热峰，在152.55℃±2℃和177.33℃±2℃处各有1个吸热峰；
    2)在TGA图中，在165.00℃之前有12.08±0.2重量％的失重，在165.00℃至230.00℃之间具有2.12±0.2重量％的失重；
    3)基本上如图3b所示的DSC图；和/或
    4)基本上如图3c所示的TGA图。
  6. 如权利要求1所述的形式，其特征在于，其为式A化合物的溶剂合物结晶形式A4，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：9.22±0.2°，17.51±0.2°，6.54±0.2°，19.59±0.2°，25.03±0.2°，16.37±0.2°和18.51±0.2°；优选地，其具有基本上如表4中所示位置处的XRPD特征峰；更优选地，其具有基本上如图4a所示的XRPD图；并任选地具有以下一个或多个特征：
    1)在DSC图中，在149.48℃±2℃处有1个吸热峰；
    2)在TGA图中，在160℃之前有3.01±0.2重量％的失重；
    3)基本上如图4b所示的DSC图；和/或
    4)基本上如图4c所示的TGA图。
  7. 如权利要求1所述的形式，其特征在于，其为式A化合物的溶剂合物结晶形式A5，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：16.43±0.2°，19.74±0.2°，6.58±0.2°，9.27±0.2°，18.53±0.2°，17.37±0.2°和9.88±0.2°；优选地，其具有基本上如表5中所示位置处的XRPD特征峰；更优选地，其具有基本上如图5a所示的XRPD图；并任选地具有以下一个或多个特征：
    1)在DSC图中，在154.86℃±2℃处有1个吸热峰；
    2)在TGA图中，在220℃之前有6.75±0.2重量％的失重；
    3)基本上如图5b所示的DSC图；和/或
    4)基本上如图5c所示的TGA图。
  8. 如权利要求1所述的形式，其特征在于，其为式A化合物的结晶形式B，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：3.98±0.2°，12.35±0.2°，12.05±0.2°，19.09±0.2°，7.92±0.2°，15.78±0.2°和14.32±0.2°；优选地，其具有基本上如表6中所示位置处的XRPD特征峰：更优选地，其具有基本上如图6c所示的XRPD图；并任选地具有以下一个或多个特征：
    1)在DSC图中，在25.54℃±2℃处有1个吸热峰，在183.52℃±2℃处有1个吸热峰；
    2)在TGA图中，在100℃之前有1.03±0.2重量％的失重；
    3)基本上如图6d所示的DSC图；和/或
    4)基本上如图6e所示的TGA图。
  9. 如权利要求1所述的形式，其特征在于，其为式A化合物的溶剂合物结晶形式C，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：20.60±0.2°，17.94±0.2°，13.11±0.2°，19.42±0.2°，23.97±0.2°，26.31±0.2°和11.95±0.2°；优选地，其具有基 本上如表7中所示位置处的XRPD特征峰；更优选地，其具有基本上如图7a所示的XRPD图；并任选地具有以下特征：
    1)在DSC图中，在127.33℃±2℃处有1个吸热峰；
    2)在TGA图中，在160.00℃之前有16.21±0.2重量％的失重，在160.00℃至260.00℃之间具有9.29±0.2重量％的失重；
    3)基本上如图7b所示的DSC图；和/或
    4)基本上如图7c所示的TGA图。
  10. 如权利要求1所述的形式，其特征在于，其为式A化合物的溶剂合物结晶形式D1，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：17.99±0.2°，8.82±0.2°，17.32±0.2°，9.26±0.2°，19.14±0.2°，9.95±0.2°和31.53±0.2°；优选地，其具有基本上如表8中所示位置处的XRPD特征峰；更优选地，其具有基本上如图8a所示的XRPD图；并任选地具有以下一个或多个特征：
    1)在DSC图中，在161.17℃±2℃处有1个吸热峰；
    2)在TGA图中，在210℃之前有11.30±0.2重量％的失重；
    3)基本上如图8b所示的DSC图；和/或
    4)基本上如图8c所示的TGA图。
  11. 如权利要求1所述的形式，其特征在于，其为式A化合物的溶剂合物结晶形式D2，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：17.38±0.2°，17.99±0.2°，19.57±0.2°，9.80±0.2°，31.55±0.2°，25.05±0.2°和6.55±0.2°；优选地，其具有基本上如表9中所示位置处的XRPD特征峰；更优选地，其具有基本上如图9a所示的XRPD图；并任选地具有以下一个或多个特征：
    1)在DSC图中，在83.30℃±2℃处有1个吸热峰，在126.89℃±2℃处有1个吸热峰；
    2)在TGA图中，在110.00℃之前有12.51±0.2重量％的失重，在110.00℃至250.00℃之间具有12.26±0.2重量％的失重；
    3)基本上如图9b所示的DSC图；和/或
    4)基本上如图9c所示的TGA图。
  12. 如权利要求1所述的形式，其特征在于，其为式A化合物的结晶形式E，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：11.14±0.2°，15.76±0.2°，12.59±0.2°，19.71±0.2°，9.56±0.2°，17.83±0.2°和13.58±0.2°；优选地，其具有基本上如表10中所示位置处的XRPD特征峰：更优选地，其具有基本上如图10c所示的XRPD图；并任选地具有以下一个或多个特征：
    1)在DSC图中，在37.94℃±2℃处有1个吸热峰，在190.71℃±2℃处有1个吸热峰；
    2)在TGA图中，在130℃之前有1.17±0.2重量％的失重；
    3)基本上如图10d所示的DSC图；和/或
    4)基本上如图10e所示的TGA图。
  13. 如权利要求1所述的形式，其特征在于，其为式A化合物的结晶形式F，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：17.70±0.2°，21.46±0.2°，27.66±0.2°，19.20±0.2°，17.17±0.2°，19.44±0.2°和22.01±0.2°；优选地，其具有基本上如表11中所示位置处的XRPD特征峰；更优选地，其具有基本上如图11a所示的XRPD图；并任选地具有以下一个或多个特征：
    1)在DSC图中，在216.58℃±2℃处有1个吸热峰；
    2)在TGA图中，在100℃之前有0.598±0.2重量％的失重；
    3)基本上如图11b所示的DSC图；和/或
    4)基本上如图11c所示的TGA图。
  14. 如权利要求1所述的形式，其特征在于，其为式A化合物的结晶形式H，其在以2θ角表示的X射线粉末衍射(XRPD)图中的以下位置处具有至少三个、至少四个、至少五个、至少六个或七个特征峰：18.30±0.2°，3.80±0.2°，19.05±0.2°，18.53±0.2°，11.81±0.2°，11.33±0.2°和16.04±0.2°；优选地，其具有基本上如表13中所示位置处的XRPD特征峰：更优选地，其具有基本上如图13a所示的XRPD图；并任选地具有以下一个或多个特征：
    1)在DSC图中，在77.45℃±2℃处有1个吸热峰，在154.75℃±2℃处有1个吸热峰；
    2)在TGA图中，在120℃之前有0.19±0.2重量％的失重；
    3)基本上如图13b所示的DSC图；和/或
    4)基本上如图13c所示的TGA图。
  15. 如权利要求1所述的形式，其特征在于，其为式A化合物的无定形形式，优选地，其具有如图14a所示的XRPD图，更优选地，其还任选地具有以下一个或多个特征：
    1)在mDSC图中，在129.30℃±2.0℃处有1个玻璃化转变温度；
    2)在TGA图中，在210℃±2.0℃之前有2.7重量％的失重；
    3)基本上如图14b所示的mDSC图；和/或
    4)基本上如图14c所示的TGA图。
  16. 一种制备如权利要求1-15中任一项所述的形式的方法，其特征在于，包括步骤：将式A所示化合物或其药学上可接受的盐通过混悬、缓慢冷却、快速冷却、缓慢挥发、快速挥发、反溶剂滴加、反溶剂反向滴加、蒸气扩散或加热-冷却DSC结晶方法，或喷雾干燥、热熔挤出或溶剂蒸发，从而得到权利要求1-15中任一项所述的形式。
  17. 一种药物组合物，其特征在于，包含：
    (a)权利要求1-15中任一项所述的形式；和
    (b)药学上可接受的载体或赋形剂。
  18. 一种药物制剂，其包含如权利要求17所述的药物组合物；其中，所述的药物制剂可为固体制剂，所述固体制剂的剂型选自下组：散剂、颗粒剂、片剂、胶囊剂、滴丸剂或膜剂。
  19. 一种如权利要求1-15中任一项所述的形式、或如权利要求17所述的药物组合物或如权利要求18所述的药物制剂在制备治疗增殖性疾病的药物中的用途，优选地，所述增殖性疾病选自：乳腺癌、结肠癌症、脑癌、***癌、肾癌、胰腺癌、卵巢癌、头部以及颈部癌、黑色素瘤、结直肠癌、胃癌、鳞状细胞癌、小细胞癌肺癌、非小细胞肺癌、睾丸癌、Merkel细胞癌、胶质母细胞瘤、神经母细胞瘤，淋巴器官癌和血液恶性肿瘤包括白血病(急性淋巴细胞白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)、慢性粒细胞白血病(CML)、急性单核细胞白血病(AMOL)、毛细胞白血病(HCL)、T细胞前淋巴 细胞白血病(T-PLL)、大颗粒淋巴细胞白血病、成人T细胞白血病)、淋巴瘤(小淋巴细胞淋巴瘤(SLL)、霍奇金淋巴瘤(结节性硬化，混合细胞、富含淋巴细胞、淋巴细胞耗竭或未耗竭以及结节淋巴细胞为主的霍奇金淋巴瘤)、非霍奇金淋巴瘤(所有亚型)，慢性淋巴细胞白血病/小淋巴细胞淋巴瘤，B细胞前淋巴细胞白血病、淋巴瘤(如巨球蛋白血症)、脾边缘区淋巴瘤、浆细胞肿瘤(浆细胞骨髓瘤、浆细胞瘤、单克隆免疫球蛋白沉积疾病、重链疾病)、***外边缘区B细胞淋巴瘤(MALT淋巴瘤)、淋巴瘤(NMZL)、滤泡性淋巴瘤、套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性积液淋巴瘤、伯基特淋巴瘤/白血病、T细胞前淋巴细胞白血病、T细胞大颗粒淋巴细胞白血病、侵袭性NK细胞白血病、成人T细胞白血病/淋巴瘤、结外NK/T细胞淋巴瘤(鼻型)、肠病T型细胞淋巴瘤、肝脾T细胞淋巴瘤、母细胞NK细胞淋巴瘤、真菌病蕈样肉芽肿/塞扎里综合征、原发性皮肤CD30阳性T细胞淋巴瘤疾病、原发性皮肤间变性大细胞淋巴瘤、淋巴瘤样丘疹病、血管免疫母细胞T细胞淋巴瘤、外周T细胞淋巴瘤(非特定的)、间变性大细胞淋巴瘤、多发性骨髓瘤(浆细胞骨髓瘤或Kahler病)。
PCT/CN2023/136788 2022-12-07 2023-12-06 氧异吲哚-5-甲酰胺类化合物或其盐、溶剂合物的结晶形式或无定形形式 WO2024120441A1 (zh)

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WO2020118098A1 (en) * 2018-12-05 2020-06-11 Vividion Therapeutics, Inc. Substituted isoindolinones as modulators of cereblon-mediated neo-substrate recruitment
CN113423701A (zh) * 2018-11-13 2021-09-21 拜欧斯瑞克斯公司 取代的异吲哚啉酮
CN114269729A (zh) * 2019-05-31 2022-04-01 细胞基因公司 经取代1-氧代-异吲哚啉-5-羧酰胺化合物，其组合物，及以此治疗的方法
WO2022257897A1 (en) * 2021-06-08 2022-12-15 Hangzhou Glubio Pharmaceutical Co., Ltd. Isoindolinone compounds, and uses thereof

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CN113423701A (zh) * 2018-11-13 2021-09-21 拜欧斯瑞克斯公司 取代的异吲哚啉酮
WO2020118098A1 (en) * 2018-12-05 2020-06-11 Vividion Therapeutics, Inc. Substituted isoindolinones as modulators of cereblon-mediated neo-substrate recruitment
CN114269729A (zh) * 2019-05-31 2022-04-01 细胞基因公司 经取代1-氧代-异吲哚啉-5-羧酰胺化合物，其组合物，及以此治疗的方法
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