Search

CN-121974890-A - Crystalline CSF-1R inhibitor acid salt and preparation method and application thereof

CN121974890ACN 121974890 ACN121974890 ACN 121974890ACN-121974890-A

Abstract

The invention provides a crystalline CSF-1R inhibitor acid salt, a preparation method and application thereof, wherein the CSF-1R inhibitor is a compound 3, 3-dimethyl-N- (6-methyl-5- ((2- (1-methyl-1H-pyrazol-4-yl) pyridine-4-yl) oxy) pyridine-2-yl) -2-oxo pyrrolidine-1-carboxamide with a structure shown in a formula (I), and the crystalline acid salt compound can greatly improve the dissolubility, hygroscopicity, chemical stability and other physical and chemical properties of the compound in a free state (I), meets the requirements of industrial production and meets the development requirements of clinical pharmaceutical preparations. The crystalline acid salt compound can be widely applied to the preparation of medicaments for treating cancers, tumors, autoimmune diseases, metabolic diseases or metastatic diseases.

Inventors

  • ZHANG LEI
  • ZHAO BAOWEI
  • YU HONGPING

Assignees

  • 上海和誉生物医药科技有限公司

Dates

Publication Date
20260505
Application Date
20220523
Priority Date
20210524

Claims (18)

  1. 1. A crystalline form of the acid salt of the compound of formula (I): 。
  2. 2. The crystalline form (I) compound acid salt according to claim 1, characterized in that the acid salt comprises an inorganic acid salt or an organic acid salt; the inorganic acid salt is selected from hydrochloride, sulfate, hydrobromide, hydrofluoric acid salt, hydroiodide or phosphate; the organic acid salt is selected from acetate, dichloroacetate, trichloroacetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, 4-chlorobenzenesulfonate, 1, 5-naphthalenedisulfonate, naphthalene-2-sulfonate, ethane-1, 2-disulfonate, methanesulfonate, ethanesulfonate, benzoate, caproate, caprylate, cinnamate, citrate, cyclohexanesulfinate, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, glutamate, isoascorbate, lactate, malate, mandelate, pyroglutamate, tartrate, dodecyl sulfate, dibenzoyltartrate, formate, fumarate, galactose, gentisate, acetohydroxamate, malonate, succinate, glutarate, adipate, sebacate, 2-ketoglutarate, glycolate, hippurate, isethionate, lactose, ascorbate, aspartate, laurate, maleate, nicotinate, oleate, orotate, oxalate, palmitate, pamoate, propionate, 4-acetamidate, 4-benzoate, 4-aminobenzoate, 2-hydroxy benzoate, 2-1-hydroxy-benzoate, 2-hydroxy-1-naphtalenate, 5-hydroxy-benzoate, stearate, thiocyanate, undecylenate or succinate.
  3. 3. The acid salt of the crystalline form (I) compound according to claim 2, characterized in that the crystalline form (I) compound is a hydrochloride salt, the X-ray powder diffraction pattern (XRPD) of which comprises four or more peaks at diffraction angles (2Θ) of 9.52 ± 0.2 °, 19.72 ± 0.2 °, 10.64 ± 0.2 °, 14.32 ± 0.2 °, 16.56 ± 0.2 °, 18.52 ± 0.2 ° and 27.20 ± 0.2 °, or comprises four or more peaks at diffraction angles (2Θ) of 24.32 ± 0.2 °, 17.78 ± 0.2 °, 24.58 ± 0.2 °, 19.96 ± 0.2 °, 10.18 ± 0.2 °, 21.34 ± 0.2 °, 18.06 ± 0.2 °, 28.10.10 ± 0.42 2 °, or comprises four or more peaks at diffraction angles (2Θ) of 18.74 ± 0.94 ± 0.2 °, 22.94 ± 0.4 ± 0.2 °, 24.38 ± 0.2 °, or the diffraction angles (2Θ) of the same as the diffraction angles (2Θ) of the crystalline form of the hydrochloride salt, preferably comprising the X-ray powder diffraction pattern of the four or more peaks at diffraction angles (2Θ) of 24.32 ± 0.2.2 °, 17.78 ± 0.2.2 °, 19.18.18 ± 0.18.18 ± 0.2.2 °, 18.18 ± 0.2.2.2 °, 18.18 2 ± 0.2X-0.0.2 °and 18 ± 0.0.32 2x-comprised.
  4. 4. The crystalline form (I) compound acid salt according to claim 2, wherein the crystalline form (I) compound acid salt is a sulfate salt, the X-ray powder diffraction pattern (XRPD) of which comprises four or more peaks at diffraction angles (2Θ) of 20.08±0.2 °, 23.22±0.2 °, 21.38±0.2 °, 24.86±0.2 °, 18.78±0.2 °, 20.46±0.2° and 9.38±0.2°, preferably the crystalline form sulfate salt X-ray powder diffraction pattern of which is substantially the same as the peak at diffraction angle (2Θ) shown in fig. 4.
  5. 5. The crystalline form (I) compound acid salt according to claim 2, wherein the crystalline form (I) compound acid salt is a phosphate salt, the X-ray powder diffraction pattern (XRPD) of which comprises four or more peaks at diffraction angles (2Θ) of 8.44 ± 0.2 °, 16.82 ± 0.2 °, 10.78 ± 0.2 °, 18.10 ± 0.2 °, 24.78 ± 0.2 °, 19.62 ± 0.2 ° and 23.24 ± 0.2 °, or four or more peaks at diffraction angles (2θ) of 10.86±0.2°, 8.48±0.2°, 17.02±0.2°, 10.46±0.2°, 18.38±0.2°, 7.98±0.2°, 23.82±0.2° and 16.06±0.2°, or four or more peaks at diffraction angles (2θ) of 10.84±0.2°, 8.54±0.2°, 17.14±0.2°, 16.76±0.2°, 10.36±0.2°, 18.26±0.2°, 27.88 ±0.2° and 22.34±0.2°; preferably, the crystalline phosphate salt thereof has an X-ray powder diffraction pattern substantially the same as the peak at the diffraction angle (2θ) shown in fig. 5, 6 or 7.
  6. 6. The crystalline form (I) compound acid salt according to claim 2, wherein the crystalline form (I) compound acid salt is a mesylate salt having an X-ray powder diffraction pattern (XRPD) comprising four or more peaks at diffraction angles (2Θ) of 16.28±0.2°, 20.82±0.2°, 7.78±0.2°, 26.68±0.2°, 23.36±0.2°, 26.30±0.2° and 23.62±0.2°, or comprising four or more peaks at diffraction angles (2Θ) of 8.64±0.2°, 21.02±0.2°, 16.34±0.2°, 23.34±0.2°, 18.48±0.2°, 7.84±0.2°, 26.00±0.2° and 10.82±0.2°, preferably wherein the crystalline form of the mesylate salt X-ray powder diffraction pattern is substantially the same as the diffraction angles (2Θ shown in figure 8 or figure 9.
  7. 7. The crystalline form (I) compound acid salt according to claim 2, wherein the crystalline form (I) compound acid salt is a citrate salt having an X-ray powder diffraction pattern (XRPD) comprising four or more peaks at diffraction angles (2Θ) of 16.14±0.2 °, 7.12±0.2 °, 14.86±0.2 °, 16.64±0.2 °, 21.34±0.2° and 13.70±0.2°, preferably having a crystalline form citrate X-ray powder diffraction pattern substantially the same as the peaks at diffraction angles (2Θ) shown in fig. 10.
  8. 8. The crystalline form (I) compound acid salt according to claim 2, wherein the crystalline form (I) compound acid salt is a malate salt having an X-ray powder diffraction pattern (XRPD) comprising four or more peaks at diffraction angles (2Θ) of 8.44±0.2 °, 27.82±0.2 °, 14.22±0.2 °, 9.72±0.2 °, 15.44±0.2 °, 18.96±0.2° and 19.28±0.2°, preferably having a crystalline malate salt X-ray powder diffraction pattern substantially the same as the peak at diffraction angle (2Θ) shown in fig. 11.
  9. 9. The crystalline form (I) compound acid salt according to claim 2, wherein the crystalline form (I) compound acid salt is a tartrate salt having an X-ray powder diffraction pattern (XRPD) comprising four or more peaks at diffraction angles (2Θ) of 9.16±0.2 °, 16.64±0.2 °, 19.80±0.2 °, 26.84±0.2 °, 18.96±0.2 °, 24.06±0.2° and 12.16±0.2°, preferably wherein the crystalline form tartrate salt X-ray powder diffraction pattern is substantially the same as the peak at diffraction angle (2Θ) shown in fig. 12.
  10. 10. The crystalline form (I) compound acid salt according to claim 2, wherein the crystalline form (I) compound acid salt is a fumarate salt having an X-ray powder diffraction pattern (XRPD) comprising four or more peaks at diffraction angles (2Θ) of 16.82±0.2 °, 18.28±0.2 °, 11.62±0.2 °, 15.10±0.2 °, 8.44±0.2 °, 21.54 ±0.2° and 27.58±0.2°, preferably having a crystalline form fumarate salt X-ray powder diffraction pattern substantially the same as the peak at diffraction angle (2Θ) shown in fig. 13.
  11. 11. A process for the preparation of an acid salt of a crystalline form of compound of formula (I) according to any one of claims 1 to 10, characterized in that it comprises the steps of: 1) Dissolving or dispersing the compound of formula (I) in the free form in an aqueous solvent or a suitable organic solvent, adding a liquid of an inorganic or organic acid or a solution of a solid acid to the system, or adding the compound of formula (I) in the free form to a solution of an acid; 2) Collecting solid products precipitated in the salt forming reaction process or obtaining crystalline products by creating the supersaturation degree in a salt system; the inorganic acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid; The organic acid is selected from acetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-chlorobenzenesulfonic acid, 1, 5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, ethane-1, 2-disulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, formic acid fumaric acid, galactonic acid, gentisic acid, acetohydroxamic acid, malonic acid, succinic acid, glutaric acid, adipic acid, sebacic acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, maleic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, salicylic acid, 4-aminosalicylic acid, 2, 5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, stearic acid, thiocyanic acid, undecylenic acid or succinic acid.
  12. 12. The method of claim 11, wherein the creating of the supersaturation in the salt system in step 2) comprises one or more of seeding, volatilizing the solvent, adding an anti-solvent, or cooling.
  13. 13. The process according to claim 11, wherein the suitable organic solvent is selected from alcohols, chlorinated alkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, sulfoxides or mixtures thereof, or aqueous solutions thereof, preferably the suitable organic solvent is selected from methanol, ethanol, N-propanol, isopropanol, dichloromethane, acetonitrile, acetone, 1, 4-dioxane, tetrahydrofuran, N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether or mixtures thereof, or aqueous solutions thereof.
  14. 14. A process for the preparation of an acid salt of a crystalline form of compound of formula (I) according to any one of claims 1 to 10, comprising the step of converting one form of the acid salt of the compound of formula (I) to the other form of the salt by a process of conversion of the form comprising heating or suspension crystallization in a suitable solvent selected from the group consisting of methanol, ethanol, N-propanol, isopropanol, dichloromethane, acetonitrile, acetone, 1, 4-dioxane, tetrahydrofuran, N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether or mixtures thereof, or an aqueous solution thereof.
  15. 15. A pharmaceutical composition comprising an acid salt of a crystalline form of a compound of formula (I) according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.
  16. 16. Use of an acid salt of a crystalline form of a compound of formula (I) according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment of a cancer, tumour, autoimmune disease, metabolic disease or metastatic disease associated with CSF-1R.
  17. 17. A crystalline form (I) compound acid salt according to any one of claims 1-10 for use as a medicament for the treatment of cancer, tumour, autoimmune disease, metabolic disease or metastatic disease associated with CSF-1R.
  18. 18. A crystalline form (I) compound of any one of claims 1-10 for use as a medicament in the treatment of ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, liver cancer, cervical cancer, bone metastatic cancer, papillary thyroid cancer, non-small cell lung cancer, colon cancer, gastrointestinal stromal tumor, solid tumor, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites, myeloproliferative diseases, leukemia, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, hypereosinophilic syndrome, mastocytosis or mast cell leukemia.

Description

Crystalline CSF-1R inhibitor acid salt and preparation method and application thereof The application relates to a crystalline CSF-1R inhibitor acid salt, a preparation method and application thereof, and a divisional application with the application number 202280012929.9, wherein the application date is 2022, 5 and 23. Technical Field The invention belongs to the field of drug development, and particularly relates to a crystalline CSF-1R inhibitor acid salt, a preparation method and application thereof. Background CSF-1R (cFMS) is known collectively as the cell colony stimulating factor-1 receptor. CSF-1R and cKIT, FLT3, PDGFR-a & b belong to three families of growth hormone receptors. The receptor is a membrane protein, expressed on the surfaces of macrophages and monocytes, and the extracellular segment of the receptor can be combined with macrophage colony stimulating factors, and intracellular segment tyrosine kinase can activate downstream cell growth and propagation signal paths of the macrophages and the monocytes, including MAPK, PI3K and the like. Thus, the CSF-1R signaling pathway has an important impact on megaphagy, monocyte development and differentiation, and the physiological function of Tumor-associated macrophages (Tumor-Associated Macrophage, TAM). With recent advances in tumor immunotherapy, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are thought to be directly involved in the formation of an immunosuppressive microenvironment within the tumor and angiogenesis supporting tumor growth. Meanwhile, clinical studies show that the TAM content is inversely related to prognosis of tumor patients. In the in vivo pharmacodynamic experiments of mice, the inhibition of the CSF-1R signal pathway can obviously reduce the number of macrophages with inhibition on immune system in tumors and improve the content of CD8 positive T cells. These experimental results indicate that CSF-1R small molecule inhibitors may reverse the immunosuppressive environment inside the tumor, promote activation of the immune system, and prolong the life of tumor patients. The Shanghai and Yu biomedical science and technology Co., ltd (Abbisko Therapeutics Co., ltd.) invented a novel structure of a small molecule compound having CSF-1R inhibitory effect (WO 2018214867A 1, international publication date: 2018, 11, 29) during a long-term study, and its representative compounds were as follows: ; The Chinese name is 3, 3-dimethyl-N- (6-methyl-5- ((2- (1-methyl-1H-pyrazol-4-yl) pyridin-4-yl) oxy) pyridin-2-yl) -2-oxo pyrrolidine-1-carboxamide (compound shown in formula (I)), and the compound can obviously improve the inhibition effect of CSF-1R target and the selectivity of other kinase receptors, improve the treatment window, reduce the clinical toxic and side effects, and meet the requirements of the current stage of tumor targeted treatment of lung cancer, breast cancer, prostate cancer, ovarian cancer, cervical cancer, melanoma, pancreatic cancer, head and neck cancer, glioma, tenosynovial giant cell tumor and the like. However, the patent WO2018214867A1 does not further research and develop the raw material form suitable for industrial production, does not develop the process method suitable for industrial application, and does not deeply research the aggregation state of the compound shown in the formula (I) to improve the physicochemical properties of the compound, thereby meeting the requirements of pharmaceutical or clinical application. WO2018214867A1 discloses an amorphous free or foamy solid compound prepared in example 1 by dropping a solution of 3, 3-dimethyl-2-oxopyrrolidine-1-carbonyl-chlorinated (0.33 mmol) in methylene chloride (10 mL) under ice bath into a solution of 6-methyl-5- ((2- (1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy) pyridin-2-amine (93 mg,0.33 mmol) and pyridine (78 mg,0.99 mmol) in methylene chloride (10 mL). The reaction was stirred at 5 ℃ for 30 minutes and then at room temperature for 2 hours. The organic phase was separated from the water by dichloromethane, washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered and concentrated to give the foam compound 3, 3-dimethyl-N- (6-methyl-5- ((2- (1-methyl-1H-pyrazol-4-yl) pyridin-4-yl) oxy) pyridin-2-oxopyrrolidine-1-carboxamide (42 mg, 30.4% yield). The inventor identifies the foam-like compound as an amorphous compound, which is easy to absorb moisture, soften and store, and is not suitable for clinical preparation development. Therefore, to meet the needs of clinical research and pharmaceutical formulations on the market, there is an urgent need to develop an aggregation form suitable for drug development to overcome the drawbacks of the prior art. Disclosure of Invention In order to solve the problems existing in the prior art, the inventor intensively researches different aggregation forms of the compound (3, 3-dimethyl-N- (6-methyl-5- ((2- (1-methyl-1H