CN109867668B - Crystal form of pyrazolo [1,5-a ] pyridine compound, and pharmaceutical composition and application thereof - Google Patents
Crystal form of pyrazolo [1,5-a ] pyridine compound, and pharmaceutical composition and application thereof Download PDFInfo
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Abstract
The invention provides a monosodium salt crystal form of a pyrazolo [1,5-a ] pyridine compound and application thereof. The invention also relates to a medicine composition containing the crystal form or the medicine composition, and application of the crystal form or the medicine composition in preparing medicines for treating and preventing hyperproliferative diseases.
Description
Technical Field
The invention belongs to the field of medicines, and relates to a crystal form and application of a base addition salt of a pyrazolo [1,5-a ] pyridine compound, in particular to a crystal form and application of a monosodium salt of N- (5- (3-cyanopyrazole [1,5-a ] pyridine-5-yl) -2-methoxypyridine-3-yl) -2, 4-difluorobenzenesulfonamide (a compound shown in a formula (I)), and further relates to a pharmaceutical composition containing the crystal form. The crystalline form or the pharmaceutical composition may be used to inhibit or modulate protein kinase activity in a biological sample, and may be used to protect, treat or ameliorate a proliferative disease or pulmonary fibrosis in a patient.
Background
Phosphoinositide 3-kinases (PI3 kinase or PI3K), a family of lipid kinases, play important regulatory roles in many cellular processes, such as cell survival, proliferation and differentiation. As a major contributor to the downstream transduction of receptor tyrosine kinases and G protein-coupled receptors, PI3K transduces signals from various growth factors and factors into the cell by producing phospholipids, activating the serine-threonine protein kinase AKT (also known as protein kinase b (pkb)) and other downstream pathways. Cancer suppressor genes or PTEN (homologous phosphatase-tensin) are the most important inverse regulators in the PI3K signaling pathway ("Small-molecule inhibitors of the PI3K signaling network," Future Med chem.2011,3(5), 549-.
PI3K can be classified into three groups according to structure and properties, wherein the group I can be further classified into two subtypes, i.e., Ia and Ib. Class II PI3K is a large molecular weight (170-210kDa) protein whose catalytic domain mediates calcium/lipid binding of the classical protein kinase C subtype. Class III PI3K, represented by a yeast protein encoded by VSP34 gene, phosphorylates only PtdIns, promoting the production of PtdIns (3) P; they are considered to be regulators of vesicle trafficking ("Targeting PI3K signaling in Cancer: opportunities, changes and limitations," Nature Review Cancer,2009,9, 550).
Type Ia PI3K (PI3K α, PI3K β, PI3K γ and PI3K δ) are dimeric proteins consisting of the catalytic subunit p110 (p 110 α, p110 β, p110 γ and p110 δ, respectively) and the regulatory subunit p85 (e.g., p85 α, p85 β, p55 δ, p55 α and p50 α). The catalytically active P110 subunit was phosphorylated using ATP to Ptdlns, PtdIns4P and PtdIns (4,5) P2. The discovery of the PI3K catalytic subunit alpha-subtype gene (PIK3CA) confirms the important role of type Ia PI3K in cancer. The gene is encoded by p110 alpha, and is frequently mutated and amplified in human tumors, such as ovarian Cancer (Campbell et al, Cancer Res 2004,64,7678-, m J Cancer 2003,104, 318-; li et al, supra; velho et al, supra; lee et al, Oncogene 2005,24, 1477-; massion et al, Am J Respir Crit Care Meaf 2004,170, 1088-; samuels et al, supra).
mTOR is a highly conserved silk-threonine kinase, has lipid kinase activity, and is one of the contributing factors of the PI3K/AKT pathway. mTOR exists in two distinct complexes, mTORC1 and mTORC2 and plays its important role in cell proliferation by regulating nutrient supply and cellular energy levels. Downstream targets of mTORC1 are ribosomal protein S6 kinase 1 and eukaryotic translation initiation factor 4E binding protein 1, both of which have important roles in protein synthesis ("Present and future of PI3K pathway inhibition in cancer: perspectives and limitations," Current med. chem.2011,18, 2647-.
Conclusion dysregulation of mTOR signaling induced cancer came from studies of pharmacological interference with mTOR and the studied drugs included rapamycin, its homologs of sirolimus (CCI-779) and everolimus (RAD 001). Rapamycin is an mTOR inhibitor, inducing phase G1 arrest and apoptosis. The formation of a complex of rapamycin with FK-binding protein 12(FKBP-12) is believed to be associated with a rapamycin growth inhibition mechanism. These complexes bind specifically to mTOR, inhibit its activity, prevent protein translation and cell growth. The cellular role of mTOR inhibitors is also manifested in cells containing concomitantly inactivated PTEN. Thus, the anti-cancer activity of rapamycin is well recognized, and a range of rapamycin homologues, such as sirolimus and everolimus, are also approved by the U.S. food and drug administration for the treatment of some types of cancer.
Fibrosis is the excess fibrous connective tissue formed by an organ or tissue during repair or reaction. Fibrosis includes, but is not limited to, pulmonary fibrosis, liver fibrosis, skin fibrosis, and kidney fibrosis. Pulmonary fibrosis, also known as Idiopathic Pulmonary Fibrosis (IPF), interstitial diffuse pulmonary fibrosis, inflammatory pulmonary fibrosis or fibrotic alveolitis, is a heterogeneous syndrome characterized by abnormal generation of fibrous tissues between alveoli, which is caused by alveolitis and causes fibrosis due to infiltration of cells into the alveoli. The effects of idiopathic pulmonary fibrosis are chronic, progressive and often fatal.
The clinical course of idiopathic pulmonary fibrosis is variable and largely unpredictable. Idiopathic pulmonary fibrosis is ultimately fatal, with historical data indicating a median survival of 2 to 3 years from the start of diagnosis. A decrease in maximal lung capacity may indicate the progression of the condition in patients with idiopathic fibrosis. Changes in maximal lung capacity are the most common endpoints used in clinical trials. A 5% or 10% reduction in the predicted value of maximum lung capacity within 6-12 months is considered to be associated with an increase in mortality in IPF patients.
Our understanding of the pathogenesis of IPF was initially primarily thought to be inflammatory disease, later thought to be a disease caused by a complex interaction of repeated epithelial cell injury and abnormal wound healing, including recruitment, proliferation and differentiation of fibroblasts, and finally excessive deposition of extracellular matrix. This cognitive change facilitates a change in the type of compound as a potential therapy, focusing on compounds that target specific pathways in the development of fibrosis.
In IPF patients, PI3K/mTOR inhibitors act by inhibiting kinases such as PI3Ks and mTOR. This results in the inactivation of cellular receptors involved in the regulation of the development of pulmonary fibrosis. Proliferation of lung fibroblasts is inhibited and extracellular matrix deposition is reduced ("Update on diagnosis and treatment of inflammatory pulmonary fibrosis", J Bras Pneumol.2015,41(5), 454-466).
CN 103965199A, WO 2014130375a1 and US 20140234254a1 disclose compounds that can be used for protecting, treating or alleviating proliferative diseases in a patient, wherein the compound N- (5- (3-cyanopyrazolo [1,5-a ] pyridin-5-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (a compound represented by formula (I)) is effective in inhibiting the activity of related protein kinases and inhibiting the development of tumors.
However, different salts and solid forms of a pharmaceutically active ingredient may have different properties. Changes in properties due to different salt or solid forms may also improve the final dosage form, for example, if such changes can improve bioavailability. At the same time, different salts and solid forms of the pharmaceutically active ingredient may also give rise to polymorphic or other crystalline forms.
Crystalline forms of the monosodium salt of N- (5- (3-cyanopyrazole [1,5-a ] pyridin-5-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide are described.
Disclosure of Invention
The present invention provides monosodium salt crystal forms of the compound of formula (I) which are useful for inhibiting, controlling and/or inhibiting PI3K and/or mTOR and for treating human proliferative diseases, such as cancer. The invention also provides methods of making such crystalline forms.
In one aspect, the invention provides a pharmaceutically acceptable base addition salt of a compound shown as a formula (I),
in some embodiments, the base addition salts described herein are inorganic base salts or organic base salts.
In other embodiments, the inorganic base salt of the present invention is a lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, or any combination thereof.
In still other embodiments, the organic base salt of the present invention is an ammonium salt, choline salt, lysine salt, arginine salt, aminoethanol salt, trometamol salt, N-methylglucamine salt, morpholine salt, piperazine salt, tert-butylamine salt, dicyclohexylamine salt, or any combination thereof.
In some embodiments, the base addition salt of the present invention is the monosodium salt of the compound of formula (I).
In other embodiments, the base addition salts of the present invention are amorphous or crystalline forms of the monosodium salt of the compound of formula (I).
In some embodiments, the base addition salt of the present invention is a crystalline form of the monosodium salt of the compound of formula (I) having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 14.73 ° ± 0.2 °, 14.93 ° ± 0.2 °, 21.77 ° ± 0.2 °, 22.59 ° ± 0.2 °, 23.29 ° ± 0.2 ° and 24.87 ° ± 0.2 °.
In other embodiments, the base addition salts of the present invention are crystalline forms of the monosodium salt of the compound of formula (I) having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 10.71 degrees +/-0.2 degrees, 14.73 degrees +/-0.2 degrees, 14.93 degrees +/-0.2 degrees, 19.01 degrees +/-0.2 degrees, 19.41 degrees +/-0.2 degrees, 21.57 degrees +/-0.2 degrees, 21.77 degrees +/-0.2 degrees, 22.59 degrees +/-0.2 degrees, 23.29 degrees +/-0.2 degrees, 24.87 degrees +/-0.2 degrees, 28.36 degrees +/-0.2 degrees and 30.18 degrees +/-0.2 degrees.
In still other embodiments, the base addition salts of the present invention are crystalline forms of the monosodium salt of the compound of formula (I) having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.59 +/-0.2 DEG, 9.33 +/-0.2 DEG, 10.71 +/-0.2 DEG, 11.21 +/-0.2 DEG, 14.73 +/-0.2 DEG, 14.93 +/-0.2 DEG, 15.39 +/-0.2 DEG, 16.55 +/-0.2 DEG, 17.36 +/-0.2 DEG, 17.64 +/-0.2 DEG, 18.42 +/-0.2 DEG, 19.01 +/-0.2 DEG, 19.41 +/-0.2 DEG, 19.66 +/-0.2 DEG, 19.84 +/-0.2 DEG, 20.26 +/-0.2 DEG, 21.57 +/-0.2 DEG, 21.77 +/-0.2 DEG, 22.34 +/-0.2 DEG, 22.59 +/-0.2 DEG, 23.29 +/-0.2 DEG, 24.15 +/-0.2 DEG, 24.87 +/-0.25 +/-0.2.2 DEG +/-0.26 DEG +/-0.27 DEG, 27 DEG, 2 DEG, 2.32 DEG, 2 DEG, 2.31 +/-0.32 DEG, 2 DEG, 2.32 DEG, 2 DEG, 2.31 +/-0.32 DEG, 2 DEG, 2.31 +/-0.31 DEG, 2 DEG, 2.31 DEG, 2 DEG, 2.32 DEG, 2 DEG, 2.31 +/-0.32 DEG, 2 DEG, 0.3 +/-0.3 DEG, 2.3 +/-0.3 DEG, 0.32 DEG, 0.3 +/-0, 38.40 ° ± 0.2 °, 38.83 ° ± 0.2 °, 39.49 ° ± 0.2 °, 40.04 ° ± 0.2 °, 41.32 ° ± 0.2 °, 42.80 ° ± 0.2 °, 43.89 ° ± 0.2 ° and 45.77 ° ± 0.2 °.
In still other embodiments, the base addition salts of the present invention are crystalline forms of the monosodium salt of the compound of formula (I) having an X-ray powder diffraction pattern substantially as shown in figure 1.
In another aspect, the present invention relates to a pharmaceutical composition comprising a base addition salt according to any one of the above, together with a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or vehicle, or any combination thereof.
In some embodiments, the pharmaceutical composition of the present invention, further comprising an additional therapeutic agent selected from a chemotherapeutic agent, an antiproliferative agent, an agent for treating atherosclerosis, or an agent for treating pulmonary fibrosis, or a combination thereof.
In some embodiments, the base addition salt in the pharmaceutical composition of the present invention may be any one of the crystalline forms of the salt, in particular, any one of the crystalline forms, amorphous form or any combination thereof of the salt.
In still other embodiments, the pharmaceutical compositions of the invention wherein the additional therapeutic agent is chlorambucil (chlorembucil), melphalan (melphalan), cyclophosphamide (cyclophosphamide), ifosfamide (ifomide), busulfan (busufan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptacin), cisplatin (cissplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), dacarbazine (dacarbazine), temozolomide (temozolomide), procarbazine (procarbazine), methotrexate (methotrexate), fluorouracil (ufloracicine), cytarabine (cytarabine), gemcitabine (gemcitabine), mercaptopurine (mercaptopurine), fludarabine (fludarabine), vinorexin (vinorelbine), vinorelbine (paclitaxel), vinpocetine), dactinomycin (dactinomycin), doxorubicin (doxorubicin), epirubicin (epirubicin), daunorubicin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), mitomycin C (mitomycin), ixabepilone (ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analogs (gonadorelin analogs), megestrol (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methyprenidolone), thalidomide (thalidomide), interferon alpha (interferon alfa), calcium folinate (leucovorin), sirolimus (sirolimus), ceritinib (texilitins), interferon alpha (interferon alfa), sunitinib (acinib, albertinib (acin), zeanib (acinib ), acinib (acinib, acinitine, acinib (acinitine, acinib), acinib (acinib ), erlotinib (erlotinib), ganetespib, gefitinib (gefitinib), ibrutinib, icotinib (icotinib), imatinib (imatinib), inib, lapatinib (lapatinib), lenvatinib (lentitinib), masitinib (macitinib), motesanib (motesanib), neratinib (neratinib), nilotinib (nilotinib), nilapanib (nilotinib), niraparib, oprozomib, olaparib (olaparib), pazopanib (pazopanib), ponatinib, quintzatinib, regorafenib, rigoteib, rucapanib, xorulitinib, saratanib (saratatinib), sorafenib (sorafenib), sunitinib (sunitinib), velutib (rucatinib), bevacizumab (bletematinib), bevacizumab (bletemab), bevacizumab (blevacizumab), bevacizumab (bletemab), bevacizumab (bevacizumab), rituximab (rituximab), or trastuzumab (trastuzumab), or a combination thereof.
In another aspect, the base addition salts of the present invention or pharmaceutical compositions comprising the base addition salts of the present invention may be used in the preparation of a medicament for preventing, treating or ameliorating a proliferative disease, atherosclerosis or pulmonary fibrosis in a subject.
In some embodiments, the proliferative disease described herein is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, cancer of the central nervous system, glioblastoma or myeloproliferative disease.
In another aspect, the present invention relates to the use of a base addition salt according to the invention or a pharmaceutical composition of a base addition salt according to the invention for the preparation of a medicament for inhibiting or modulating the activity of a protein kinase.
In some embodiments, the protein kinase of the invention is phosphoinositide 3-kinase (PI3 kinase or PI3K) and/or mTOR.
In another aspect, the invention relates to a process for the preparation of a base addition salt of a compound of formula (I).
The crystal form of the base addition salt can be prepared by a conventional preparation method, wherein certain crystal forms can also be prepared by a crystal form conversion method.
The solvent used in the method for preparing the salt of the present invention is not particularly limited, and any solvent that can dissolve the starting materials to some extent and does not affect the properties thereof is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention. The invention provides a preferable solvent used in each reaction step.
The experiments for the preparation of the salts according to the invention are described in detail in the examples section. Meanwhile, the invention provides an activity test experiment (such as a pharmacokinetic experiment), a solubility experiment, a stability experiment (comprising a high temperature, high humidity and illumination experiment), a hygroscopicity experiment and the like of the salt. The experimental result shows that the salt has good bioactivity, good solubility and high stability, and is suitable for pharmaceutical use.
The salt of the invention is tested according to a conventional experimental method, wherein the description of the hygroscopicity characteristics and the definition of the hygroscopicity increase (the guideline of the hygroscopicity test of medicaments 9103 in the appendix of the year edition of Chinese pharmacopoeia 2015, the experimental conditions: 25 ℃ +/-1 ℃ and 80% +/-2% relative humidity) are shown in the table below.
Characterization of hygroscopicity and definition of hygroscopicity increase
The salt is not easy to deliquesce under the influence of high humidity, and is convenient to store for a long time.
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
The crystalline form may be considered in the present invention to be characterized by graphical data "depicted" in the figures. These data include, for example, X-ray single crystal diffraction patterns, X-ray powder diffraction patterns, raman spectra, fourier transform-infrared spectra, DSC curves, and solid state NMR spectra. The skilled artisan will appreciate that the graphical representation of such data may undergo small changes (e.g., peak relative intensities and peak positions) due to factors such as instrument response changes and sample concentration and purity changes, as is well known to the skilled artisan. Nevertheless, the skilled person is able to compare the graphical data in the figures herein with the graphical data generated for an unknown crystal form and can confirm whether the two sets of graphical data represent the same crystal form.
"XRD" refers to X-ray diffraction.
The term "amorphous" or "amorphous form" as used herein is intended to mean that the substance, component or product in question lacks a characteristic crystalline shape or crystalline structure, is substantially not crystalline or the substance, component or product in question when determined, for example, by XRPD (X-ray powder diffraction), is not birefringent or cubic, for example, when viewed using polarized light microscopy, or has an X-ray powder diffraction pattern without sharp peaks. In certain embodiments, a sample comprising an amorphous form of a substance may be substantially free of other amorphous forms and/or crystalline forms.
The term "substantially pure" means that a crystalline form is substantially free of one or more additional crystalline forms, i.e., the crystalline form is at least 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or contains additional crystalline forms in the crystalline form, the percentage of which in the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%. By X-ray powder diffraction (XRPD), Differential Scanning Calorimetry (DSC), or thermogravimetric analysis (TGA) "substantially the same" is meant that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks are shown in the X-ray powder diffraction pattern, Differential Scanning Calorimetry (DSC), or thermogravimetric analysis (TGA).
The term "2 θ value" or "2 θ" refers to the peak position in degrees of an experimental setup based on X-ray diffraction experiments and is the common abscissa unit of the diffraction pattern. The experimental setup required that if the reflection was diffracted when the incident beam formed an angle θ (θ) with a certain crystal, the reflected beam was recorded at an angle 2 θ (2 θ). It is to be understood that reference herein to specific 2 θ values for a particular polymorph is intended to refer to the 2 θ values (in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, a radiation source (Cu, K α, K α 1) is used
1.540598；Kα2
1.544426, respectively; the K alpha 2/K alpha 1 intensity ratio: 0.50).
The term "X-ray powder diffraction pattern" or "XRPD pattern" refers to the experimentally observed diffraction pattern or parameters derived therefrom. The powder X-ray diffraction pattern is characterized by the peak position (abscissa) and the peak intensity (ordinate). The relative peak heights of XRPD patterns depend on many factors related to sample preparation and instrument geometry, while peak positions are relatively insensitive to experimental details. Thus, in some embodiments, the crystalline compounds of the invention are characterized by XRPD patterns having certain peak positions, with substantially the same characteristics as the XRPD patterns provided in the figures of the invention. According to the condition of the instrument used in the test, the diffraction peak has error tolerance of +/-0.1 DEG, +/-0.2 DEG, +/-0.3 DEG, +/-0.4 DEG or +/-0.5 DEG; in some embodiments the diffraction peaks have a margin of error of ± 0.2 °.
The melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline compounds of the present invention are characterized by a DSC profile with characteristic peak positions having substantially the same properties as the DSC profile provided in the figures of the present invention. Depending on the conditions of the instrument used in this test, melting peaks have a tolerance of + -1 deg. + -. 2 deg. + -. 3 deg. + -. 4 deg. or + -5 deg.. In some embodiments the melting peak has a margin of error of ± 3 ℃.
The term "relative intensity" refers to the ratio of the intensity of the first strong peak to the intensity of the other peaks when the intensity of the first strong peak is 100% of all the diffraction peaks of an X-ray powder diffraction pattern (XRPD).
When referring to a spectrogram or/and data appearing in a graph, "peak" refers to a feature that one skilled in the art would recognize as not being attributable to background noise.
In the context of the present invention, when used or whether the word "about" or "approximately" is used, there may be a difference of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, or 20% between the numerical values representing each number.
General preparation of crystalline forms
The crystalline form may be prepared by a variety of methods including, but not limited to, for example, crystallization or recrystallization from a suitable solvent mixture; sublimation; solid state conversion from another phase; crystallization from a supercritical fluid; and spraying. Techniques for crystallization or recrystallization of crystalline forms of solvent mixtures include, but are not limited to, for example, solvent evaporation; reducing the temperature of the solvent mixture; seeding (crystal seeding) of a supersaturated solvent mixture of a compound and/or salt thereof; freeze drying the solvent mixture; and an anti-solvent (antisolvent) is added to the solvent mixture. Crystalline forms, including polymorphs, can be prepared using high throughput crystallization techniques.
Crystals (including polymorphs), methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.R.Byrn, R.R.Pfeiffer, and J.G.Stowell, second edition, SSCI, West Lafayette, Indiana (1999).
In crystallization techniques in which a solvent is utilized, the solvent is generally selected based on one or more factors including, but not limited to, for example, the solubility of the compound, the crystallization technique used, and the vapor pressure of the solvent. Combinations of solvents may be utilized. For example, the compound may be solubilized in a first solvent to obtain a solution, and then an anti-solvent is added to reduce the solubility of the compound in the solution and precipitate the crystal formation. An antisolvent is a solvent in which the compound has low solubility.
Seed crystals may be added to any crystallization mixture to facilitate crystallization. Seeding may be used to control the growth of a particular polymorph, and/or to control the grain size distribution of the crystallized product. Therefore, the calculation of the amount of seeds required depends on the size of the available seeds and the desired size of the average product particles, as described in "Programmed Chemical Batch crystals", J.W.Mullin and J.Nyvlt, Chemical Engineering Science,1971,26, 369-. Small sized seeds are generally required to effectively control crystal growth in the batch. Small size seeds can be produced by large crystals sieving, milling or micronization, or by solution microcrystallization. In crystal milling or micronization, care should be taken to avoid changing crystallinity from the desired crystalline form (i.e., to amorphous or other polymorphic forms).
The cooled crystallization mixture can be filtered under vacuum and the isolated solid product washed with a suitable solvent (e.g., cold recrystallization solvent). After washing, the product can be dried under a nitrogen purge to give the desired crystalline form. The product may be analyzed by suitable spectroscopic or analytical techniques including, but not limited to, for example, Differential Scanning Calorimetry (DSC), X-ray powder diffraction (XRPD), and thermogravimetric analysis (TGA) to ensure that a crystalline form of the compound has been formed. The resulting crystalline form may be produced in an isolated yield of greater than about 70% by weight, preferably greater than about 90% by weight, based on the weight of the compound initially used in the crystallization process. The product may optionally be de-agglomerated by co-grinding or by passing through a mesh screen.
X-ray powder diffraction (XRPD) study: x-ray powder diffraction (XRPD) patterns were collected on a PANalytical Empyrean X-ray diffractometer in the netherlands equipped with a transmission-reflection sample stage with an automated 3X 15 zero background sample holder. The radiation source used is (Cu, K alpha, K alpha 1)
1.540598；Kα2
1.544426, respectively; the K alpha 2/K alpha 1 intensity ratio: 0.50) with the voltage set at 45KV and the current set at 40mA, the beam divergence of the X-rays, i.e., the effective size of the X-ray confinement on the sample, is 10mm, and an effective 2 theta range of 3 to 40 ° is obtained using a theta-theta continuous scanning mode. Taking a proper amount of sample at the position of the circular groove of the zero-background sample rack under the environmental condition (about 18-32 ℃), lightly pressing the sample with a clean glass slide to obtain a flat plane, and fixing the zero-background sample rack. The sample (typically 1-2 mg) is scanned in a scan step of 0.0167 ° in the range of 3-40 ° 2 θ ± 0.2 °. The software used for Data collection was a Data Collector, and Data was analyzed and presented using Data Viewer and HighScore Plus.
Differential Scanning Calorimetry (DSC) analysis: DSC measurements in TA InstrumentsTMModel Q2000 was performed using a sealed disk apparatus. Samples (approximately 2-6 mg) were weighed in aluminum pans, capped with Tzero, precision recorded to one hundredth of a milligram, and transferred to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data were collected between room temperature and 300 ℃ at a heating rate of 10 ℃/min. The endothermic peak was plotted downward, and the data was analyzed and displayed using TA Universal Analysis.
Thermogravimetric analysis (TGA): TGA measurements in TA InstrumentsTMModel Q500 was performed using an open set-up. The sample (about 10mg to 30mg) was placed in a platinum crucible that was previously peeled. The instrument precisely weighs the sample and thousandths of a milligram is recorded by the instrument. The balance was purged with nitrogen at 40mL/min and the sample was purged with nitrogen at 60 mL/min. Data were collected at a heating rate of 10 ℃/min between room temperature and 300 ℃ and analyzed and presented using TA Universal Analysis.
1H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer. Solid state13C NMR spectra were obtained using Bruker 100MHz nuclear magnetic resonance at ambient temperature (from 21 ℃ to 25 ℃).1H NMR Spectrum in CDC13、DMSO-d6、CD3OD or acetone-d6TMS (0ppm) or chloroform (7.25ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constant J, in Hertz (Hz).
The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-MS (column model: Zorbax SB-C18, 2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase 5% -95% (CH with 0.1% formic acid)3CN) in (H containing 0.1% formic acid)2O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.
The method adopts inductively coupled plasma mass spectrometry (ICP-MS) to analyze and determine the salt forming proportion of the compound shown in the formula (I) and inorganic base. The measurement conditions were: an Agilent 7800ICP-MS system, using He mode, Sc45 as an internal standard element.
Drawings
FIG. 1 is an X-ray powder diffraction (XRPD) pattern of the monosodium salt crystalline form of the compound of formula (I).
FIG. 2 is a Differential Scanning Calorimetry (DSC) curve of the monosodium salt crystal form of the compound of formula (I).
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Detailed description of the invention
Specific synthesis of the compound N- (5- (3-cyanopyrazole [1,5-a ] pyridin-5-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide reference is made to example 3 of patent CN 103965199a and the content thereof is incorporated in its entirety in the present invention.
Examples
EXAMPLE 1 crystalline form of the monosodium salt of N- (5- (3-cyanopyrazole [1,5-a ] pyridin-5-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide
1.Preparation method I of crystal form of title monosodium salt
Adding acetone (5400mL) and N- (5- (3-cyanopyrazole [1,5-a ] pyridin-5-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (600.00g, 1359mmol) into a reaction kettle, stirring at room temperature, adding a water (600mL) solution of sodium hydroxide (59.81g, 1495mmol), heating to 60 + -5 deg.C, stirring for 30 minutes, cooling to 25 + -5 deg.C, vacuum-filtering, adding filtrate into the reaction kettle, controlling the temperature to 25 + -5 deg.C, adding isopropanol (12000mL), cooling to 0 + -5 deg.C, stirring for 1h, vacuum-filtering, drying the solid at 60 deg.C for 24h to obtain N- (5- (3-cyanopyrazole [1,5-a ] pyridin-5-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide sodium salt crude product.
Adding the crude product of N- (5- (3-cyanopyrazole [1,5-a ] pyridin-5-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide sodium salt and absolute ethanol (5500mL) into a reaction kettle, heating to 78 +/-5 ℃, stirring for 4h, cooling to 0 +/-5 ℃, stirring for 1h, and filtering to obtain a solid, drying at 60 ℃ for 24h to obtain a light yellow solid (475g, 86.4%).
2.Preparation of the title monosodium salt crystal form II
Anhydrous ethanol (8mL) and N- (5- (3-cyanopyrazole [1,5-a ] pyridin-5-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (500mg, 1.13mmol) were added to a reaction flask, stirred at room temperature, added a solution of sodium hydroxide (50mg, 1.25mmol) in ethanol (2mL), warmed to 80 + -5 deg.C and stirred for 30 minutes, cooled to 25 + -5 deg.C, filtered with suction, and the solid was dried at 60 deg.C for 24 hours to give a pale yellow solid (446mg, 84.97%).
3.Identification of the crystalline form of the title monosodium salt
(1) Through inductively coupled plasma mass spectrometry, the salt formation ratio of the compound of formula (I) to sodium hydroxide is 1: 1.
(2) the X-ray powder diffraction pattern of the crystalline form of the title monosodium salt, as shown in figure 1, may have a margin of error of ± 0.2 ° as analyzed by Empyrean X-ray powder diffraction (XRPD).
(3) The differential scanning calorimetry curve of the crystalline form of the title monosodium salt, as analyzed by TA Q2000 Differential Scanning Calorimetry (DSC), is shown in figure 2, which contains an endothermic peak at 307.72 ℃ with a margin of error of ± 3 ℃.
Example 2 pharmacokinetic experiments
The LC/MS/MS system for analysis included an Agilent 1200 series vacuum degassing furnace, a binary injection pump, an orifice plate autosampler, a column oven, an Agilent G6430 three-stage quadrupole mass spectrometer with an electrospray ionization (ESI) source. The quantitative analysis was performed in MRM mode, with the parameters of the MRM transition as shown in table a:
table a:
| multiple reaction detection scan | 490.2→383.1 |
| Fragmentation electricPress and press | 230V |
| Capillary voltage | 55V |
| Temperature of drying |
350℃ |
| Atomizer | 40psi |
| Dry air flow rate | 10L/min |
Analysis 5. mu.L of sample was injected using an Agilent XDB-C18, 2.1X 30mm, 3.5. mu.M column. Analysis conditions were as follows: the mobile phase was 0.1% aqueous formic acid (A) and 0.1% methanolic formic acid (B). The flow rate was 0.4 mL/min. Mobile phase gradients are shown in table B:
table B:
| Time | gradient of mobile phase B |
| 0.5min | 5％ |
| 1.0min | 95％ |
| 2.2min | 95％ |
| 2.3min | 5％ |
| 5.0min | Terminate |
Also used for the analysis was an Agilent 6330 series LC/MS spectrometer equipped with a G1312A binary syringe pump, a G1367A auto sampler and a G1314C UV detector; the LC/MS/MS spectrometer uses an ESI radiation source. The appropriate cation model treatment and MRM conversion for each analyte was performed using standard solutions for optimal analysis. During the analysis a Capcell MP-C18 column was used, with the specifications: 100X 4.6mm I.D., 5. mu.M (Phenomenex, Torrance, California, USA). The mobile phase was 5mM ammonium acetate, 0.1% aqueous methanol (a): 5mM ammonium acetate, 0.1% methanolic acetonitrile solution (B) (70/30, v/v); the flow rate is 0.6 mL/min; the column temperature was kept at room temperature; 20 μ L of sample was injected.
The prepared sodium salt crystal form is mixed with preparation auxiliary materials and then filled into capsules, after the mixture is respectively gavaged to a beagle dog at about 2.5mg/kg, 5.0mg/kg, 7mg/kg or 10mg/kg, blood (0.3mL) is taken at time points of 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours to prepare medicine-containing blood plasma, and the medicine-containing blood plasma is centrifuged at 3,000 or 4,000rpm for 2-10 minutes. Drug concentrations in plasma were analyzed by LC-MS/MS (using Agilent 1200 or Agilent G6430 series LC/MS/MS spectrometers) and pharmacokinetic parameters were calculated using WinNonlin software non-compartmental modeling. The specific parameters are shown in Table 1.
Table 1: pharmacokinetic data of sodium salt crystal form prepared by the invention in beagle dog
And (4) conclusion: as can be seen from the results in Table 1, crystalline form C of the monosodium salt of the present inventionmax、AUClastAre all larger than the compound shown in the formula (I), which indicates that the monosodium salt crystal of the inventionThe type has large exposure in beagle dogs, good absorption and remarkably superior pharmacokinetic property to the compound shown in the formula (I).
Example 3 stability test
Taking a proper amount of sample (100-200 mg), spreading in a clean culture dish to form a thin layer with thickness less than or equal to 5mm, respectively irradiating at high temperature (60 + -2 deg.C), high humidity (25 + -2 deg.C, 90% + -5% relative humidity), and visible light (4500 lx + -500 lx, ultraviolet light not less than 0.7 W.h/m)225 +/-2 ℃, 60% +/-5% relative humidity) and normal temperature (25 +/-2 ℃, 65% +/-5% relative humidity), sampling for inspection on days 5 and 10 respectively, and calculating the impurity content by a peak area normalization method by using an HPLC instrument, wherein the instrument and the test conditions are shown in Table 2.
Table 2: instrument and test conditions
And (4) experimental conclusion: experimental results show that the sodium salt crystal form prepared by the invention has no obvious change in appearance and purity under the conditions of high temperature (60 ℃) and high humidity (25 ℃ and RH 90% +/-5%), has good stability effect and is suitable for pharmaceutical application.
Example 4 hygroscopicity test
A proper amount of the sodium salt crystal form test sample prepared by the invention is taken, and the hygroscopicity of the sample is tested by adopting a dynamic moisture adsorption instrument. The experimental results prove that the salt is not easy to deliquesce under the influence of high humidity.
Example 5 solubility test
Weighing about 5mg of the monosodium salt, placing the monosodium salt into a 30mL penicillin bottle, adding 15mL of purified water, shaking the penicillin bottle in a 37 ℃ water bath shaking tank, observing the dissolution condition in the penicillin bottle, and if the dissolution is complete, adding a small amount of test sample for many times until the solution is saturated and can not be dissolved continuously. And after continuing shaking for 24h/48h, taking a proper amount of saturated solution at 37 ℃ in a penicillin bottle, filtering the saturated solution by using a filter membrane (polyethersulfone, 0.45 mu m, 13mm and Jinteng), discarding 2mL of primary filtrate, respectively quickly and precisely measuring 600 mu L of secondary filtrate and 600 mu L of acetonitrile, and uniformly mixing to obtain a sample solution with balanced solubility, and detecting by using an external standard method to obtain the solubility of the test sample.
The assay used an Agilent ZORBAX SB-C18, 4.6X 50mM, 5. mu.M column (or other suitable chromatography column) with a UV detector, a detection wavelength of 264nm, a flow rate of 1.0mL/min, a column temperature of 35 ℃, a sample size of 10. mu.L, a mobile phase of 10mM sodium dihydrogen phosphate buffer (pH 3.0), acetonitrile 50:50, run time 7 min.
And (4) conclusion: the solubility of the monosodium salt is better.
The foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity and understanding. The invention has been described with reference to various specific and preferred embodiments and techniques. It should be understood, however, that many variations and modifications may be made while remaining within the spirit and scope of the invention. It will be apparent to those skilled in the art that variations and modifications can be effected within the scope of the claims. Accordingly, it is to be understood that the above description is intended to be illustrative, and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but instead should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.
Claims (11)
1. A crystal form of monosodium salt of a compound shown as a formula (I),
characterized in that the X-ray powder diffraction pattern of the crystal form has diffraction peaks at the following 2 theta angles: 14.73 ° ± 0.2 °, 14.93 ° ± 0.2 °, 21.77 ° ± 0.2 °, 22.59 ° ± 0.2 °, 23.29 ° ± 0.2 ° and 24.87 ° ± 0.2 °.
2. The crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 10.71 degrees +/-0.2 degrees, 14.73 degrees +/-0.2 degrees, 14.93 degrees +/-0.2 degrees, 19.01 degrees +/-0.2 degrees, 19.41 degrees +/-0.2 degrees, 21.57 degrees +/-0.2 degrees, 21.77 degrees +/-0.2 degrees, 22.59 degrees +/-0.2 degrees, 23.29 degrees +/-0.2 degrees, 24.87 degrees +/-0.2 degrees, 28.36 degrees +/-0.2 degrees and 30.18 degrees +/-0.2 degrees.
3. The crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.59 +/-0.2 DEG, 9.33 +/-0.2 DEG, 10.71 +/-0.2 DEG, 11.21 +/-0.2 DEG, 14.73 +/-0.2 DEG, 14.93 +/-0.2 DEG, 15.39 +/-0.2 DEG, 16.55 +/-0.2 DEG, 17.36 +/-0.2 DEG, 17.64 +/-0.2 DEG, 18.42 +/-0.2 DEG, 19.01 +/-0.2 DEG, 19.41 +/-0.2 DEG, 19.66 +/-0.2 DEG, 19.84 +/-0.2 DEG, 20.26 +/-0.2 DEG, 21.57 +/-0.2 DEG, 21.77 +/-0.2 DEG, 22.34 +/-0.2 DEG, 22.59 +/-0.2 DEG, 23.29 +/-0.2 DEG, 24.15 +/-0.2 DEG, 24.87 +/-0.25 +/-0.2.2 DEG +/-0.26 DEG +/-0.27 DEG, 27 DEG, 2 DEG, 2.32 DEG, 2 DEG, 2.31 +/-0.32 DEG, 2 DEG, 2.32 DEG, 2 DEG, 2.31 +/-0.32 DEG, 2 DEG, 2.31 +/-0.31 DEG, 2 DEG, 2.31 DEG, 2 DEG, 2.32 DEG, 2 DEG, 2.31 +/-0.32 DEG, 2 DEG, 0.3 +/-0.3 DEG, 2.3 +/-0.3 DEG, 0.32 DEG, 0.3 +/-0, 38.40 ° ± 0.2 °, 38.83 ° ± 0.2 °, 39.49 ° ± 0.2 °, 40.04 ° ± 0.2 °, 41.32 ° ± 0.2 °, 42.80 ° ± 0.2 °, 43.89 ° ± 0.2 ° and 45.77 ° ± 0.2 °.
4. The crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction pattern substantially as shown in figure 1.
5. A pharmaceutical composition comprising the crystalline form of any one of claims 1-4; it further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or any combination thereof.
6. The pharmaceutical composition of claim 5, further comprising an additional therapeutic agent selected from a chemotherapeutic agent, an antiproliferative agent, an agent for treating atherosclerosis, or an agent for treating pulmonary fibrosis, or a combination thereof.
7. The pharmaceutical composition of claim 6, wherein the additional therapeutic agent is chlorambucil (chlorambucil), melphalan (melphalan), cyclophosphamide (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busufan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozotocin), cisplatin (cissplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), dacarbazine (dacarbazine), temozolomide (temozolomide), procarbazine (procarbazine), methotrexate (methotrexate), fluorouracil (fluoroouracil), cytarabine (cytarabine), gemcitabine (gemcitabine), mercaptopurine (mercandopurin), fludarabine (fluocine), vinorelbine (vincristine (vinorelbine), vinorelbine (neomycin), vinorelbine (paclitaxel), vinpocetine (neovinpocetine), doxorubicin (doxorubicin), epirubicin (epirubicin), daunorubicin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), mitomycin C (mitomycin), ixabepilone (ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analogs (gonadorelin analoges), megestrol (megestrol), prednisone (prednidogen), dexamethasone (dexamethosone), methylprednisolone (methylprednisone), thalidomide (thalidomide), interferon alpha (interferon alfa), calcium folinate (leucovororin), sirolimus (sirolimus), rosins (teibrimonis), sirolimus (temolimus), everolimus (everitinib), erlotinib (aritinib), bortinib (aridinib), aripiptinib (aridinib), tacrolinib (arinib, arinib (arinib), aribixin (valtinib), aribixin (aridinib, aridinib (aridinib), aridinib (aridinib, aridinib (tacrolib), tacrolib, aridinib (aridinib, aridinib (aridinib), aridinib), ganetespib, gefitinib (gefitinib), ibrutinib, Icotinib (icotinib), imatinib (imatinib), iniparib, lapatinib (lapatinib), lenvatinib, masitinib (masitinib), motesanib (motesanib), neratinib (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib (olaparib), pazopanib (pazopanib), ponatinib, quinzattinib, regorafenib, rigagortib, rucapaparib, ruxolitinib, saracanib (saratinib), saridegibereib, sorafenib (sorafenib), sunitinib (sunitinib), testatinib (testatinib), tenertuzumab (siderabucinib), bevacizumab (sorafenib), netovatuzumab (ritnib), bevacizumab (netovatuzumab), bevacizumab (netovanib), bevacizumab (netovatuzumab), bevacizumab (netovatuzumab), bevacizb (netovatezomib), bevacizumab), bevacizb), bevacizumab (netovanib), bevacizumab), bevacizb), bevacizumab (netovatebuclizumab), bevacizb (e (netovatebuclizumab), bevacizb), bevacizumab), bevacizb (netovatebuclizumab), bevacizb), bevacizumab), bevacizb (e (bevacizb), bevacizumab), bevacizb), bevacizumab (e (bevacizumab), bevacizb, or trastuzumab (trastuzumab), or any combination thereof.
8. Use of the crystalline form of any one of claims 1-4 or the pharmaceutical composition of any one of claims 5-7 in the manufacture of a medicament for preventing, treating or ameliorating a proliferative disorder, atherosclerosis or pulmonary fibrosis in a subject.
9. The use according to claim 8, wherein the proliferative disease is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, cancer of the central nervous system, glioblastoma or myeloproliferative disease.
10. Use of the crystalline form of any one of claims 1-4 or the pharmaceutical composition of any one of claims 5-7 for the preparation of a medicament for inhibiting or modulating protein kinase activity.
11. The use of claim 10, wherein the protein kinase is PI3K and/or mTOR.
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