CN109867671A - The crystal form and its pharmaceutical composition and purposes of a kind of pyrazoles [1,5-a] pyridine compounds - Google Patents
The crystal form and its pharmaceutical composition and purposes of a kind of pyrazoles [1,5-a] pyridine compounds Download PDFInfo
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Abstract
The present invention provides a kind of mono-sodium salt crystal form and application thereof of pyrazoles [1,5-a] pyridine compounds.The invention further relates to preparing the purposes in the drug for treating and preventing hyperproliferative disease comprising the crystal form or its pharmaceutical composition and the crystal form or described pharmaceutical composition.
Description
Invention field
The invention belongs to drug fields, are related to the base addition salts crystal form and its use of a kind of pyrazoles [1,5-a] pyridine compounds
On the way, and in particular to N- (5- (3- cyano pyrazole [1,5-a] pyridine -5- base) -2- methoxypyridine -3- base) -2,4- difluorobenzene sulphur
The mono-sodium salt crystal form and application thereof of amide (compound shown in formula (I)), further to the pharmaceutical composition comprising the crystal form.
The crystal form or described pharmaceutical composition can be used for inhibition or regulatory protein kinase activity in biological sample, can be used to
Protection, processing, treatment or the proliferative diseases or the pulmonary fibrosis that mitigate patient.
Background of invention
Phosphoinositide 3-kinase (PI3 kinases or PI3K), as a family of lipid kinase, in many cellular processes,
Such as the survival of cell, important adjustment effect is played in breeding and differentiation.As receptor tyrosine kinase and G-protein-coupling
Major influence factors in receptor downstream conduction, by generating phosphatide, PI3K is by the signal from all kinds of growth factors and the factor
It is transmitted to intracellular, activation Ser-ine-threonine protein kinase AKT (also referred to as protein kinase B (PKB)) and other downstream passages.Suppression
Oncogene or PTEN (homologous phosphatase-tensin) are most important reversed regulators in PI3K signal path
(“Small-molecule inhibitors of the PI3K signaling network.”Future Med
Chem.2011,3(5),549-565)。
According to structure and property, PI3K can be divided into three classes, wherein I class can be divided into two kinds of hypotypes of Ia and Ib again.II class
PI3K is a kind of macromolecule (170-210kDa) albumen, and the catalysis region of albumen can mediate classical Five Protein Kinase C Isoforms
Calcium/rouge bonding.Group III PI3K, using the Yeast protein encoded by VSP34 gene as representative, only phosphorylation PtdIns, promotes to generate
PtdIns(3)P；They be regarded as vesicle transport attemperator (" Targeting PI3K signaling in cancer:
opportunities,challenges and limitations.”Nature Review Cancer,2009,9,550)。
Ia type PI3K (PI3K α, PI3K β, PI3K γ and PI3K δ) be by catalytic subunit p110 (be p110 α respectively,
P110 β, p110 γ and p110 δ) and regulator subunit p85 (such as: p85 α, p85 β, p55 δ, p55 α and p50 α) composition dimerization
Body protein.P110 subunit with catalytic activity uses ATP phosphorylation Ptdlns, PtdIns4P and PtdIns (4,5) P2.
PI3K catalytic subunit α-subtype gene (PIK3CA) discovery, it was confirmed that important function of the Ia type PI3K in cancer.The base
Reason p110 α coding usually mutates and expands in human tumor, such as oophoroma (Campbell et al, Cancer
Res 2004,64,7678-7681；Levine et al.,Clin Cancer Res 2005,11,2875-2878；Wang et
al.,Hum Mutat 2005,25,322；Lee et al., Gynecol Oncol 2005,97,26-34), cervix cancer, cream
Cancer (Bachman, et al.Cancer Biol Ther 2004,3,772-775；Levine,et al.,supra；Li et
al.,Breast Cancer Res Treat 2006,96,91-95；Saal et al.,Cancer Res 2005,65,
2554-2559；Samuels and Velculescu, Cell Cycle 2004,3,1221-1224), colorectal cancer
(Samuels,et al.Science 2004,304,554；Velho et al.Eur J Cancer 2005,41,1649-
1654), carcinoma of endometrium (Oda et al.Cancer Res.2005,65,10669-10673), gastric cancer (Byun et al., M
J Cancer 2003,104,318-327；Li et al.,supra；Velho et al.,supra；Lee et al.,
Oncogene 2005,24,1477-1480), liver cancer (Lee et al., id), cellule and non-small cell lung cancer (Tang et
al.,Lung Cancer 2006,Jl,181-191；Massion et al.,Am J Respir Crit Care Meaf
2004,170,1088-1094), thyroid cancer (Wu et al, J Clin Endocrinol Met α b 2005,90,4688-
4693), acute myelocytic leukemia (AML) (Sujobert et al., Blood 1997,106,1063-1066), chronic marrow
Chronic myeloid leukemia (CML) (Hickey and Cotter J Biol Chem 2006,281,2441-2450) and colloid are female
Cytoma (Hartmann et al.Acta Neurop α thol (Berl) 2005,109,639-642；Samuels et al.,
supra)。
MTOR is highly conserved silk-threonine kinase, have lipid kinase activity, be PI3K/AKT access influence because
One of element.There are two kinds of completely different compounds, mTORC1 and mTORC2 by mTOR, and by adjusting nutrition supply and cell energy
Amount is horizontal, plays its important function in cell Proliferation.The downstream targets of mTORC1 are Ribosomal protein 1 and eukaryon
Both biological translation initiation factor 4E Binding Protein 1 plays an important role (" Present and to albumen synthesis
future of PI3K pathway inhibition in cancer:perspectives and limitations.”
Current Med.Chem.2011,18,2647-2685)。
The imbalance of mTOR signal transduction induces research of the conclusion from pharmacology interference mTOR of cancer, and the drug of research includes
Rapamycin, homologue have temsirolimus (CCI-779) and everolimus (RAD001).Rapamycin is mTOR suppression
Preparation, the induction G1 phase blocks and Apoptosis.The formation of rapamycin and FK- Binding Protein 12 (FKBP-12) compound, is recognized
It is related to rapamycin growth inhibition mechanism.These compounds specifically bind mTOR, inhibit its activity, prevent protein translation
It is grown with cell.The cytosis of mTOR inhibitors is also manifested by the cell containing the PTEN with property inactivation.Therefore, thunder pa
The anticancer activity of mycin is accepted, and a series of rapamycin homologues, such as temsirolimus and Yi Weimo
Department is also ratified by United States Food and Drag Administration for treating some type of cancer.
Fibrosis is the extra fibrous connective tissue that organ or tissue is formed in reparation or reaction process.Fibrosis packet
Contain but be not limited to pulmonary fibrosis, liver fibrosis, fibrosis of skin and kidney fibrosis.Pulmonary fibrosis, also known as idiopathic pulmonary fibrosis
(idiopathic pulmonary fibrosis, IPF), chromic fibrous diffusivity pulmonary fibrosis, inflammatory pulmonary fibrosis or fibrosis
Property pulmonary alveolitis, belong to pneumonopathy, be it is a kind of by between alveolar fibr tissue extremely generate characterized by heterogeneous type combine disease, by
Pulmonary alveolitis causes, and cellular infiltration is into alveolar, so as to cause fibrosis.The influence of idiopathic pulmonary fibrosis is chronic, progressive
It is property and often fatefulue.
The clinical disease course of idiopathic pulmonary fibrosis is variable and is largely uncertain.Idiopathic lung is fine
Dimensionization be finally it is fatal, historical data shows to calculate since diagnosis, median survival interval be 2 to 3 years.Forced vital capacity
Decline can illustrate the progress of idiopathic fibrosis conditions of patients.The variation of forced vital capacity is in clinical test using most common
Terminal.Predicted value decline 5% or 10% of the forced vital capacity in 6-12 months is considered having with the increase of IPF mortality
It closes.
Our understandings pathogenetic for IPF start mainly to think that it belongs to inflammatory disease, think it for one kind later
By the complicated caused disease that interacts of epithelial cell damage and abnormal wound healing repeatedly, the trick including fibrocyte
It raises, be proliferated and break up, be finally the excess deposition of extracellular matrix.Change in this cognition is promoted as potential therapy
The change of type of compounds, so that the compound of specific passageways becomes focus during targeting fibrosis occurrence and development.
On IPF patient, PI3K/mTOR inhibitor is by inhibiting kinases, such as PI3Ks and mTOR to play a role.This leads
Cause the inactivation for participating in adjusting the cell receptor in pulmonary fibrosis development process.The proliferation of lung fibroblast is suppressed, cell
Epimatrix deposition reduces (" Update on diagnosis and treatment of idiopathic pulmonary
fibrosis",J Bras Pneumol.2015,41(5),454-466)。
CN 103965199A, WO 2014130375A1 and US 20140234254A1, which are disclosed, can be used to protect, locate
Reason, treatment or the compound for mitigating patient's proliferative diseases, wherein compound N-(5- (3- cyano pyrazole [1,5-a] pyridine -5-
Base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (compound shown in formula (I)) can effectively inhibit related protein kinase
Enzymatic activity and the occurrence and development for inhibiting tumour.
However, the different salt and solid forms of active pharmaceutical ingredient may have different property.Different salt or solid shape
The change of property caused by state can also improve final dosage form, for example, if bioavilability can be improved in this change.Together
When, the different salt and solid forms of active pharmaceutical ingredient can also generate polycrystalline or other crystal forms.
The present invention describes N- (5- (3- cyano pyrazole [1,5-a] pyridine -5- base) -2- methoxypyridine -3- base) -2,4-
The mono-sodium salt crystal form of difluorobenzenesulfonamide.
Summary of the invention
The present invention provide formula (I) shown in compound mono-sodium salt crystal form, can be used to inhibit, control and/or PI3K and/or
MTOR can also be used to treatment human pcna disease, such as cancer.The present invention also provides the methods for preparing this kind of crystal form.
On the one hand, the present invention provides the pharmaceutically acceptable base addition salts of one kind such as formula (I) compound represented,
In some embodiments, base addition salts of the present invention are inorganic base salts and organic alkali salt.
In other embodiments, inorganic base salts of the present invention be lithium salts, sodium salt, sylvite, calcium salt, magnesium salts or it
Any combination.
Also in some embodiments, organic alkali salt of the present invention is ammonium salt, choline salt, lysine salt, arginine
Salt, ethylaminoethanol salt, tromethamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, alkylbenzyldimethylasaltsum saltsum, piperazine salt, tert-butylamine salt, dicyclohexyl amine salt or
Their any combination.
In some embodiments, base addition salts of the present invention are the mono-sodium salt of compound shown in formula (I).
In other embodiments, base addition salts of the present invention include formula (I) shown in compound mono-sodium salt without
Setting and/or mono-sodium salt crystal form.
In some embodiments, base addition salts of the present invention are the mono-sodium salt crystal form of compound shown in formula (I),
X-ray powder diffraction pattern at the angle following 2 θ have diffraction maximum: 10.52 ° ± 0.2 °, 13.64 ° ± 0.2 °, 14.40 ° ±
0.2 °, 15.86 ° ± 0.2 °, 18.72 ° ± 0.2 °, 19.14 ° ± 0.2 ° and 24.68 ° ± 0.2 °.
In other embodiments, base addition salts of the present invention are the mono-sodium salt crystal form of compound shown in formula (I),
Its X-ray powder diffraction pattern at the angle following 2 θ have diffraction maximum: 10.52 ° ± 0.2 °, 13.64 ° ± 0.2 °, 14.40 ° ±
0.2°、15.86°±0.2°、18.72°±0.2°、19.14°±0.2°、19.47°±0.2°、20.31°±0.2°、21.16°
± 0.2 °, 23.94 ° ± 0.2 °, 24.68 ° ± 0.2 °, 26.21 ° ± 0.2 ° and 29.03 ° ± 0.2 °.
Also in some embodiments, base addition salts of the present invention are the mono-sodium salt crystal form of compound shown in formula (I),
Its X-ray powder diffraction pattern at the angle following 2 θ have diffraction maximum: 5.24 ° ± 0.2 °, 5.61 ° ± 0.2 °, 8.88 ° ±
0.2°、9.54°±0.2°、10.52°±0.2°、13.64°±0.2°、14.40°±0.2°、14.78°±0.2°、15.86°±
0.2°、16.46°±0.2°、16.95°±0.2°、17.86°±0.2°、18.72°±0.2°、19.14°±0.2°、19.47°
±0.2°、20.31°±0.2°、20.74°±0.2°、21.16°±0.2°、22.09°±0.2°、22.61°±0.2°、
23.94°±0.2°、24.29°±0.2°、24.68°±0.2°、26.21°±0.2°、27.03°±0.2°、27.60°±
0.2°、28.32°±0.2°、29.03°±0.2°、30.10°±0.2°、31.73°±0.2°、31.94°±0.2°、33.86°
±0.2°、34.33°±0.2°、35.60°±0.2°、36.01°±0.2°、36.95°±0.2°、38.02°±0.2°、
38.86 ° ± 0.2 °, 40.32 ° ± 0.2 °, 41.00 ° ± 0.2 °, 42.08 ° ± 0.2 ° and 44.21 ° ± 0.2 °.
Again in some embodiments, base addition salts of the present invention are the mono-sodium salt crystal form of compound shown in formula (I),
Its X-ray powder diffraction figure is substantially as shown in.
On the other hand, the present invention relates to a kind of pharmaceutical composition, it includes the base addition salts of the above-mentioned any one of the present invention,
And pharmaceutically acceptable carrier, excipient, diluent, adjuvant or medium or their any combination.
In some embodiments, pharmaceutical composition of the present invention further includes additional therapeutic agent, described
Additional therapeutic agent is selected from chemotherapeutic agent, and antiproliferative is fine for treating the drug of atherosclerosis, or for treating lung
The drug or their combination of dimensionization.
In some embodiments, the base addition salts in pharmaceutical composition of the present invention can be any one of the salt
Kind of crystal form is specifically as follows any one crystal form of the salt, amorphous or their any combination.
In other embodiments, pharmaceutical composition of the present invention, involved in additional therapeutic agent be
Chlorambucil (chlorambucil), melphalan (melphalan), cyclophosphamide (cyclophosphamide), different ring phosphorus
Amide (ifosfamide), busulfan (busulfan), Carmustine (carmustine), lomustine (lomustine), chain
Urea helps rhzomorph (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin
(oxaliplatin), Dacarbazine (dacarbazine), Temozolomide (temozolomide), procarbazine
(procarbazine), methotrexate (MTX) (methotrexate), fluorouracil (fluorouracil), cytarabine
(cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine
(fludarabine), vincaleukoblastinum (vinblastine), vincristine (vincristine), vinorelbine
(vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), topotecan (topotecan), she
It is vertical to replace health (irinotecan), Etoposide (etoposide), tributidine (trabectedin), dactinomycin D
(dactinomycin), Doxorubicin (doxorubicin), epirubicin (epirubicin), daunomycin
(daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), mitomycin C
(mitomycin), Ipsapirone (ixabepilone), tamoxifen (tamoxifen), Flutamide (flutamide), dagger-axe that
Rayleigh analog (gonadorelin analogues), megestrol acetate (megestrol), prednisone (prednidone), ground plug
Meter Song (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon
α (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus
(temsirolimus), everolimus (everolimus), Afatinib (afatinib), alisertib, amuvatinib,
A Pa replaces Buddhist nun (apatinib), Axitinib (axitinib), bortezomib (bortezomib), bosutinib
(bosutinib), brivanib, cabozantinib, Si Dinibu (cediranib), crenolanib, gram Zhuo replace Buddhist nun
(crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), Tarceva
(erlotinib), ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), her horse
For Buddhist nun (imatinib), iniparib, Lapatinib (lapatinib), lenvatinib, Masitinib (masitinib), not
Te Saini (motesanib), linatinib (neratinib), nilotinib (nilotinib), niraparib,
Oprozomib, olaparib (olaparib), pazopanib (pazopanib), ponatinib, quizartinib,
Regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib,
Sorafenib (sorafenib), Sutent (sunitinib), tasocitinib, Telatinib (telatinib),
Tivozanib, tofacitinib, trametinib, Vande Thani (vandetanib), veliparib, Wei Luofeini
(vemurafenib), vismodegib, alemtuzumab (alemtuzumab), bevacizumab (bevacizumab),
Brentuximab vedotin, catumaxomab (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody
(denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab
(nimotuzumab), difficult to understand (ofatumumab), Victibix (panitumumab), Rituximab
(rituximab) or Herceptin (trastuzumab) or their combination.
On the other hand, base addition salts of the present invention or the pharmaceutical composition comprising base addition salts of the present invention can be used for preparing and be used for
Prevent, treat or mitigate patient's proliferative diseases, atherosclerosis or the drug of pulmonary fibrosis.
In some embodiments, proliferative diseases of the present invention are metastatic carcinomas, colon cancer, sdenocarcinoma of stomach, bladder cancer,
Breast cancer, kidney, liver cancer, lung cancer, cutaneum carcinoma, thyroid cancer, head and neck cancer, prostate cancer, cancer of pancreas, the cancer of central nervous system
Disease, glioblastoma or myeloproliferative disease.
On the other hand, the present invention relates to use the pharmaceutical composition of base addition salts of the present invention or base addition salts of the present invention to prepare
For inhibiting or the purposes of the drug of regulatory protein kinase activity.
In some embodiments, protein kinase of the present invention is phosphoinositide 3-kinase (PI3 kinases or PI3K)
And/or mTOR.
On the other hand, the present invention relates to the preparation methods of the base addition salts of compound shown in formula (I).
The crystal form of base addition salts of the present invention can be prepared by conventional preparation method, wherein the present invention
In certain crystal forms can also be prepared by the method for crystal transfer.
Solvent used in the preparation method of salt of the present invention is not particularly limited, any to a certain extent
It dissolution starting material and does not influence the solvent of its property and is included in the present invention.In addition, many similar changes of this field,
Equivalent replacement, or it is equal to solvent described in the invention, the different proportion of solvent combination and solvent combination is accordingly to be regarded as this hair
Bright scope.The present invention gives preferable solvents used in each reaction step.
The preparation experiment of salt of the present invention will be described in detail in embodiment part.Meanwhile the present invention provides
The active testing experiment (such as pharmacokinetic studies) of the salt, solubility experiment, stability experiment (including high temperature, high humidity
And illumination experiment) and hygroscopicity test etc..According to the experimental results, salt of the present invention has preferable bioactivity, and molten
Solution property is good, and stability is high, is suitble to pharmaceutical applications.
The hygroscopicity test of salt of the present invention is tested according to routine experiment method, wherein about drawing moist feature
It describes and draws the defining of moist weight gain (Chinese Pharmacopoeia 9103 drug draws moist test guideline of version annex in 2015 tests item
Part: 25 DEG C ± 1 DEG C, 80% ± 2% relative humidity) as in the table below.
Draw moist feature description and draws defining for moist weight gain
Salt of the present invention is not influenced vulnerable to high humility and is deliquesced, and convenient long-term storage is placed.
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This
Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim
In range.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method and material described herein
Trample the present invention.The present invention is not limited to method described herein and material.The one of the document, patent and the similar material that are combined
Or more it is different from the application or in the case where contradicting it is (including but not limited to defined term, term application, described
Technology, etc.), be subject to the application.
Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's
It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference
It is bright.
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise
Content.
Crystal form is regarded as being characterized by the graph data of chart " description " in the present invention.These data include, such as X-
Ray single crystal diffraction map, X-ray powder diffraction collection, Raman spectrum, Fourier transform-infrared spectroscopy, DSC curve and solid
State NMR spectra.The skilled person will understand that small variation (such as peak relative intensity and peak can occur for the graphical representation of this kind of data
Position), the reason is that such as instrument response variation and sample concentration and the factor of purity variation, this is known for technical staff
's.Nevertheless, the graph data that technical staff can compare the graph data in this texts and pictures and generate to unknown crystalline form, and can
Confirm whether two group picture graphic datas characterize identical crystalline form.
" XRD " refers to X-ray diffraction.
Term " amorphous " used in the present invention or " amorphous form " be intended to mean that discussed substance, component or
Product, the crystal shape or crystalline texture of lacking in individuality property, substantially when for example being measured by XRPD (X-ray powder diffraction)
It is not crystal or the substance discussed, component or product, such as when being watched using polarization microscope is not birefringent
Perhaps cube or X-ray powder diffraction figure do not have spike.In certain embodiments, the amorphous shape comprising substance
The sample of formula can be substantially free of other amorphous forms and/or crystal form.
Term " substantially pure " refers to a kind of crystal form substantially free of another or a variety of crystal forms, the i.e. purity of crystal form
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 extremely
Lack and contain other crystal forms in 99.9% or crystal form, percentage of the other crystal forms in the total volume of crystal form or total weight is few
In 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 it is few
In 0.01%.X-ray powder diffraction (XRPD), differential scanning calorimetric curve (DSC) or thermal gravimetric analysis curve (TGA) are " substantially
It is identical " refer to X-ray powder diffraction figure, differential scanning calorimetric curve (DSC) or thermal gravimetric analysis curve (TGA) 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% peak is shown in figure
In.
Term " 2 θ numerical value " or " 2 θ " refer to by X-ray diffraction experiment experimental provision by spend in terms of peak position and
It is the common abscissa unit of diffracting spectrum.If the test setting requirements form angle θ (θ) in incident beam and a certain crystal face
When reflection be diffracted, then with 2 θ of angle (2 θ) record reflection light beam.It should be understood that specific polymorphous specific 2 θ number mentioned by this paper
Value is intended to refer to the 2 θ numerical value measured using X-ray diffraction experiment condition as described herein (in terms of spending).For example, as herein
It is described, using radiation source (Cu, k α,1.540598； 1.544426；1 intensity of K α 2/K α: 0.50).
Term " X-ray powder diffraction collection " or " XRPD map " refer to the diffraction pattern that experimental observation arrives or from its
Parameter.Powder x-ray diffraction map is characterized by peak position (abscissa) and peak intensity (ordinate).XRPD map it is opposite
Peak height depends on many factors related with sample preparation and instrument geometry, and peak position is relatively unwise to experimental detail
Sense.Therefore, in some embodiments, crystalline compounds of the invention are characterized by having the XRPD figure of certain peak positions,
With scheming substantially the same feature with the XRPD provided in attached drawing of the present invention.According to this test instrument situation, diffraction maximum
In the presence of ± 0.1 °, ± 0.2 °, ± 0.3 °, ± 0.4 ° or ± 0.5 ° of error margin；Diffraction maximum exists in some embodiments
± 0.2 ° of error margin.
The melting peak height of DSC curve depends on many factors related with sample preparation and instrument geometry, and peak position
It sets to experimental detail relative insensitivity.Therefore, in some embodiments, crystalline compounds of the invention are characterized by having
The DSC of characteristic peak positions schemes, and has and schemes substantially the same property with the DSC provided in attached drawing of the present invention.According to this test institute
With apparatus status, melting peak presence ± 1 °, ± 2 °, ± 3 °, the error margins of ± 4 ° or ± 5 °.It melts in some embodiments
The error margin of peak presence ± 3 DEG C.
Term " relative intensity " refers to the intensity at the last the first peak in all diffraction maximums of X-ray powder diffraction figure (XRPD)
When being 100%, the ratio of the intensity of the intensity and the last the first peak at other peaks.
When referring to spectrogram or/and appearing in the data in figure, what " peak " referred to that those skilled in the art can identify will not
Belong to a feature of background noise.
In the context of the present invention, when using or when the wordings such as " about " or " about " whether or not using, indicate every
One digital numerical value is possible to will appear 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15% or 20%
Etc. differences.
The general preparation method of crystal type
Crystal type can be prepared by a variety of methods, including but not limited to for example be tied from suitable solvent mixture crystallization or again
It is brilliant；Distillation；From another mutually solid state transformed；From crystalization in supercritical fluid；With it is spraying.The crystallization of crystal type for solvent mixture
Or the technology of recrystallization includes but is not limited to that such as solvent evaporates；Reduce the temperature of solvent mixture；Compound and/or its salt
The seeding (crystal seeding) of supersaturated solvent mixture；Solvent mixture freeze-drying；Add with anti-solvent (anti-solvent)
To solvent mixture.Crystal type, including polymorphs body can be prepared with high yield crystallization technique.
The characterization of the crystal (including polymorphs body) of drug, preparation method and medicine crystal is discussed at Solid-State
Chemistry of Drugs, S.R.Byrn, R.R.Pfeiffer and J.G.Stowell, the second edition, SSCI, West
Lafayette,Indiana(1999)。
In the crystallization technique for wherein utilizing solvent, solvent is generally selected according to one or more factors, the factor packet
Include but be not limited to the solubility of such as compound, the vapour pressure of crystallization technique used and solvent.Using the combination of solvent.Example
Such as, compound solubilising in the first solvent can be made anti-solvent to be added then to reduce the molten of compound in solution to obtain solution
Xie Du, and precipitating crystalline formation.Anti-solvent is the solvent that wherein compound has low solubility.
Crystal seed can be added to any crystalline mixture to promote to crystallize.The growth of specific polymorphs body can be controlled with seeding,
And/or the grain size distribution of control crystallized product.Therefore, the calculating of the amount of required crystal seed depend on available crystal seed size and
The desired size of average product particle, such as " Programmed Cooling Batch Crystallizers ", J.W.Mullin
And described in J.Nyvlt, Chemical Engineering Science, 1971,26,369-377.Generally require the crystalline substance of small size
Kind, effectively to control the crystal growth in batch of material.By the sieving of big crystal, grinding or micronization, or pass through solution controlled micro crystallization,
It can produce the crystal seed of small size.In crystal grinds or is micronized, it should be noted that crystallinity is avoided to change from desired crystal type
(that is, becoming armorphous or other polymorphics).
It can filter under vacuum through cooling crystalline mixture, separated solid product is with suitable solvent (for example, cold
Recrystallization solvent) washing.After washing, product can be dried under nitrogen purging to obtain required crystal type.Product can be by being suitble to
Spectrum or analytical technology analysis, including but not limited to such as differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD)
With thermogravimetric analysis (TGA), to guarantee that the crystal type of compound has been formed.Resulting crystal type can be by based on first in crystallization process
Begin to generate using the amount of the separation yield of greater than about 70% weight of compound by weight, the separation of preferably greater than about 90% weight produces
Rate.It can be optionally by being co-mulled and made into or making product deblocking by mesh screen.
X-ray powder diffraction (XRPD) research: in the Transflective sample for being equipped with automation zero Background Samples frame of 3*15
X-ray powder diffraction (XRPD) pattern is collected on the Dutch PANalytical Empyrean x-ray diffractometer of platform.It is used
Radiation source be (Cu, k α, 1.540598；1.544426；1 intensity of K α 2/K α: 0.50), wherein voltage
It is set in 45KV, electric current is set in 40mA, the divergence of X-ray, i.e., the effective dimensions that X-ray constrains on sample is
10mm obtains 3 °~40 ° of effective 2 θ range using θ-θ continuous scanning mode.Take appropriate amount of sample at ambient conditions (about 18
DEG C~32 DEG C) at zero Background Samples frame circular groove, it is gently pressed with clean glass slide, obtains a smooth plane, and will
Zero Background Samples frame is fixed.By sample (usually 1~2mg) with 0.0167 ° of scanning step in 3~40 ° of 2 θ ± 0.2 ° range
Interior scanning.Software for data collection is Data Collector, and data are with Data Viewer and HighScore Plus points
Analysis and displaying.
Differential scanning calorimetry (DSC) analysis: dsc measurement is in TA InstrumentsTMIt is filled in model Q2000 with seal disc
Set progress.Sample (about 2~6mg) is weighed in aluminium dish, with Tzero gland, precision is recorded 1 percent milligrams, and by sample
Product are transferred in instrument and measure.Instrument is purged with nitrogen with 50mL/min.Room temperature between 300 DEG C with 10 DEG C/min's
The rate of heat addition collects data.It is drawn downwards with endothermic peak, data are analyzed and shown with TA Universal Analysis.
Thermogravimetric analysis (TGA): TGA is measured in TA InstrumentsTMIt is carried out in model Q500 with opening device.By sample
(about 10mg~30mg) is put into the platinum crucible removed the peel in advance.Instrument precision weighs the weight of sample, and by instrument record to thousand points
One of milligram.Balance is purged with nitrogen with 40mL/min, and sample is purged with nitrogen with 60mL/min.In room temperature between 300 DEG C
Data are collected with the rate of heat addition of 10 DEG C/min, data are analyzed and shown with TA Universal Analysis.
1H H NMR spectroscopy is recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.Solid-state13C H NMR spectroscopy uses
Bruker 100MHz nuclear-magnetism is at room temperature (from 21~25 DEG C).1H H NMR spectroscopy is with CDC13、DMSO-d6、CD3OD or acetone-d6It is molten
Agent (as unit of ppm) uses TMS (0ppm) or chloroform (7.25ppm) as reference standard.It, will when there is multiplet
Use following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet,
Multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), dt (doublet of
Triplets, double triplets).Coupling constant J, unit are indicated with hertz (Hz).
The determination condition of low resolution mass spectrometry (MS) data is: 6120 level four bars HPLC-MS of Agilent (column model:
Zorbax SB-C18,2.1 × 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase: 5%~95% (contains 0.1%
The CH of formic acid3CN) in (H containing 0.1% formic acid2O the ratio in)), using electrospray ionisation (ESI), at 210nm/254nm,
It is detected with UV.
The present invention using inductivity coupled plasma mass spectrometry (ICP-MS) analyze and determine formula (I) shown in compound with it is inorganic
Alkali at salt ratio.Determination condition are as follows: Agilent 7800ICP-MS system, using He mode, Sc45 is as internal standard element.
Detailed description of the invention
Fig. 1 is X-ray powder diffraction (XRPD) figure of the mono-sodium salt crystal form of compound shown in formula (I).
Fig. 2 is differential scanning calorimetry (DSC) curve of the mono-sodium salt crystal form of compound shown in formula (I).
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, does not therefore limit the present invention to the implementation
Among example range.
Specific implementation method
Compound N-(5- (3- cyano pyrazole [1,5-a] pyridine -5- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene
Content therein is integrally incorporated by the specific synthetic method of sulfonamide referring to the embodiment 3 in patent CN 103965199A
In the present invention.
Embodiment
1 N- of embodiment (5- (3- cyano pyrazole [1,5-a] pyridine -5- base) -2- methoxypyridine -3- base) -2,4- difluoro
The mono-sodium salt crystal form of benzsulfamide
1.The preparation of title mono-sodium salt crystal form
N- (5- (3- cyano pyrazole [1,5-a] pyridine -5- base) -2- methoxypyridine -3- base) -2 is added into reaction flask,
4- difluorobenzenesulfonamide sodium salt (1.00g, 2.16mmol), water (2mL) and dehydrated alcohol (8mL), being heated to reflux keeps solid molten
Clearly.44 DEG C are cooled to, solid is precipitated.It filters, filter cake for 24 hours, obtains light yellow solid (0.35g, 35.0%) in 60 DEG C of dryings.
2.The identification of title mono-sodium salt crystal form
(1) it is analyzed by inductivity coupled plasma mass spectrometry, formula (I) compound and sodium hydroxide are at salt ratio
1:1.
(2) it is analyzed by Empyrean X-ray powder diffraction (XRPD), the X-ray powder of title mono-sodium salt crystal form spreads out
Figure is penetrated as shown in Figure 1, ± 0.2 ° of error margin may be present.
(3) it is analyzed by TA Q2000 differential scanning calorimetry (DSC), the differential scanning calorimetric curve of title mono-sodium salt crystal form
As shown in Fig. 2, there is ± 3 DEG C of error margin it includes 215.76 DEG C of endothermic peak.
2 pharmacokinetic studies of embodiment
The LC/MS/MS system of analysis includes the serial vacuum degassing furnace of Agilent 1200, and binary syringe pump, orifice plate is certainly
Dynamic sampler, column insulating box, charged spray ionize the Agilent G6430 three-level level four bars mass spectrograph in the source (ESI).Quantitative analysis
It is carried out under MRM mode, the parameter of MRM conversion is as in Table A:
Table A:
| More reaction detection scannings | 490.2→383.1 |
| Fragmentation voltage | 230V |
| Capillary voltage | 55V |
| Dry temperature degree | 350℃ |
| Atomizer | 40psi |
| Dry gas stream speed | 10L/min |
Analysis uses μM column of Agilent XDB-C18,2.1 × 30mm, 3.5, injects 5 μ L samples.Analysis condition: mobile phase
For 0.1% aqueous formic acid (A) and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient such as table
Shown in B:
Table B:
| Time | The gradient of Mobile phase B |
| 0.5min | 5% |
| 1.0min | 95% |
| 2.2min | 95% |
| 2.3min | 5% |
| 5.0min | It terminates |
In addition, the also 6330 series LC/MS/MS spectrometer of Agilent for analysis, is infused equipped with G1312A binary
Penetrate pump, G1367A automatic sampler and G1314C UV detector；LC/MS/MS spectrometer uses ESI radioactive source.Use titer
Suitable cationic model treatment is carried out to each analyte and MRM conversion carries out optimal analysis.It uses during analysis
Capcell MP-C18 column, specification are as follows: 100 × 4.6mm I.D., 5 μM (Phenomenex, Torrance, California,
USA).Mobile phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70/
30, v/v)；Flow velocity is 0.6mL/min；Column temperature is maintained at room temperature；Inject 20 μ L samples.
It is poured into capsule after the sodium salt crystal form of preparation is mixed with pharmaceutical adjunct, respectively to be about 2.5mg/kg, 5.0mg/
It is 0.25,0.5,1.0,2.0,3.0,4.0,6.0 at time point after beasle dog is given in kg, 7mg/kg or 10mg/kg stomach-filling,
Blood (0.3mL) is taken within 8.0,12 and 24 hours, plasma containing drug is prepared, and is centrifuged 2~10 minutes at 3,000 or 4,000rpm.With
Drug in LC-MS/MS analysis (using Agilent 1200 or Agilent G6430 series LC/MS/MS spectrometer) blood plasma is dense
Degree calculates pharmacokinetic parameters using the non-compartment model method of WinNonlin software.Design parameter is shown in Table 1.
Table 1: pharmacokinetic data of the sodium salt crystal form prepared by the present invention in beasle dog
Conclusion: from 1 result of table as it can be seen that the C of mono-sodium salt crystal form of the present inventionmax、AUClastThan compound shown in formula (I)
Greatly, show that mono-sodium salt crystal form of the invention is big in the intracorporal exposed amount of beasle dog, absorb well, pharmacokinetic property is significant
Better than compound shown in formula (I).
3 stability test of embodiment
It takes sample appropriate (100~200mg), is laid in clean culture dish, spread out into thickness≤5mm thin layer, exist respectively
High temperature (60 ± 2 DEG C), high humidity (25 ± 2 DEG C, 90% ± 5% relative humidity), illumination (visible light 4500lx ± 500lx, ultraviolet light
Not less than 0.7Wh/m2, 25 ± 2 DEG C, 60% ± 5% relative humidity) and room temperature (25 ± 2 DEG C, 65% ± 5% relative humidity)
Under the conditions of carry out stability test (high temperature, high humidity illumination and normal temperature condition are placed 10 days), respectively at the 5th day, 10 days sample into
Performing check calculates impurity content by areas of peak normalization method using HPLC instrument, and instrument and test condition are shown in Table 2.
Table 2: instrument and test condition
Experiment conclusion: the experimental results showed that, sodium salt crystal form prepared by the present invention high temperature (60 DEG C), high humidity (25 DEG C, RH
90% ± 5%) under the conditions of, appearance and purity have no significant change, and stabilizing effect is good, are suitble to pharmaceutical applications.
4 draws moist test of embodiment
Take sodium salt crystal form test sample prepared by the present invention appropriate, using dynamic water adsorption instrument test its draw it is moist.It is real
It tests the results show that salt of the present invention is not influenced vulnerable to high humility and deliquesced.
5 solubility experiment of embodiment
Mono-sodium salt of the present invention about 5mg is weighed, is placed in 30mL cillin bottle, 15mL purified water is added, in 37 DEG C of water-baths
It is shaken in concussion slot, observes in cillin bottle and dissolve situation, if dissolution completely, can be added test sample to solution on a small quantity several times and satisfy
With can not continue to dissolve.Continue shake for 24 hours/48h after, take 37 DEG C of saturated solutions in cillin bottle appropriate, with filter membrane (polyether sulfone,
0.45 μm, 13mm, saliva is risen) filtering, primary filtrate 2mL is abandoned, and precision measures 600 μ L subsequent filtrates rapidly respectively and 600 μ L acetonitriles are mixed
It closes uniformly to get equilbrium solubility test solution, detects to obtain the solubility of test sample using external standard method.
Analysis uses Agilent ZORBAX SB-C18,4.6 × 50mm, 5 μM column (or other applicable chromatographic columns), inspection
Survey device is UV detector, and Detection wavelength 264nm, flow velocity 1.0mL/min, 35 DEG C of column temperature, sample volume is 10 μ L, and mobile phase is
10mM phosphate sodium dihydrogen buffer solution (pH 3.0): acetonitrile=50:50, runing time 7min.
Conclusion: the solubility of mono-sodium salt of the present invention is preferable.
For purposes of clarity and understanding, disclosed above have been illustrated by is retouched in some details with embodiment
It states.The present invention has referred to different specific and preferred embodiments and techniques and has been described.It will be appreciated, however, that being maintained at
While within spirit and scope of the invention, many modifications may be made to and modification.Within the scope of the claims it is implementable variation and
It would have been obvious for a person skilled in the art for modification.It is therefore to be understood that above description be intended to it is illustrative, not for
It is restrictive.Therefore, the scope of the present invention should not be determined with reference to above description, and should be with reference to claim together with these rights
It is required that complete scope of equal value and determine.
Claims (11)
1. the crystal form of the mono-sodium salt such as formula (I) compound represented,
It is characterized in that, the X-ray powder diffraction pattern of the crystal form is at the angle following 2 θ with diffraction maximum: 10.52 ° ±
0.2 °, 13.64 ° ± 0.2 °, 14.40 ° ± 0.2 °, 15.86 ° ± 0.2 °, 18.72 ° ± 0.2 °, 19.14 ° ± 0.2 ° and 24.68 °
±0.2°。
2. crystal form according to claim 1, wherein the X-ray powder diffraction pattern of the crystal form has at the angle following 2 θ
Have a diffraction maximum: 10.52 ° ± 0.2 °, 13.64 ° ± 0.2 °, 14.40 ° ± 0.2 °, 15.86 ° ± 0.2 °, 18.72 ° ± 0.2 °,
19.14°±0.2°、19.47°±0.2°、20.31°±0.2°、21.16°±0.2°、23.94°±0.2°、24.68°±
0.2 °, 26.21 ° ± 0.2 ° and 29.03 ° ± 0.2 °.
3. crystal form according to claim 1, wherein the X-ray powder diffraction pattern of the crystal form has at the angle following 2 θ
There is a diffraction maximum: 5.24 ° ± 0.2 °, 5.61 ° ± 0.2 °, 8.88 ° ± 0.2 °, 9.54 ° ± 0.2 °, 10.52 ° ± 0.2 °, 13.64 °
±0.2°、14.40°±0.2°、14.78°±0.2°、15.86°±0.2°、16.46°±0.2°、16.95°±0.2°、
17.86°±0.2°、18.72°±0.2°、19.14°±0.2°、19.47°±0.2°、20.31°±0.2°、20.74°±
0.2°、21.16°±0.2°、22.09°±0.2°、22.61°±0.2°、23.94°±0.2°、24.29°±0.2°、24.68°
±0.2°、26.21°±0.2°、27.03°±0.2°、27.60°±0.2°、28.32°±0.2°、29.03°±0.2°、
30.10°±0.2°、31.73°±0.2°、31.94°±0.2°、33.86°±0.2°、34.33°±0.2°、35.60°±
0.2°、36.01°±0.2°、36.95°±0.2°、38.02°±0.2°、38.86°±0.2°、40.32°±0.2°、41.00°
± 0.2 °, 42.08 ° ± 0.2 ° and 44.21 ° ± 0.2 °.
4. crystal form according to claim 1, wherein the X-ray powder diffraction pattern of the crystal form is substantially such as Fig. 1 institute
Show.
5. a kind of pharmaceutical composition, it includes crystal forms described in claim 1-4 any one；It, which is further included, pharmaceutically may be used
Carrier, excipient, diluent, adjuvant or their any combination of receiving.
6. pharmaceutical composition according to claim 5, further includes additional therapeutic agent, the additional therapeutic agent is selected from
Chemotherapeutic agent, antiproliferative, for treating the drug of atherosclerosis, or the drug for treating pulmonary fibrosis, or
Their combination.
7. pharmaceutical composition according to claim 6, wherein the additional therapeutic agent is Chlorambucil
(chlorambucil), melphalan (melphalan), cyclophosphamide (cyclophosphamide), ifosfamide
(ifosfamide), busulfan (busulfan), Carmustine (carmustine), lomustine (lomustine), chain urea assistant
Rhzomorph (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin) reach
Carbazine (dacarbazine), Temozolomide (temozolomide), procarbazine (procarbazine), methotrexate (MTX)
(methotrexate), fluorouracil (fluorouracil), cytarabine (cytarabine), gemcitabine
(gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vincaleukoblastinum
(vinblastine), vincristine (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel),
Docetaxel (docetaxel), topotecan (topotecan), Irinotecan (irinotecan), Etoposide
(etoposide), tributidine (trabectedin), dactinomycin D (dactinomycin), Doxorubicin
(doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone
(mitoxantrone), bleomycin (bleomycin), mitomycin C (mitomycin), Ipsapirone
(ixabepilone), tamoxifen (tamoxifen), Flutamide (flutamide), Gonadorelin analog
(gonadorelin analogues), megestrol acetate (megestrol), prednisone (prednidone), dexamethasone
(dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon-' alpha '
(interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus
(temsirolimus), everolimus (everolimus), Afatinib (afatinib), alisertib, amuvatinib,
A Pa replaces Buddhist nun (apatinib), Axitinib (axitinib), bortezomib (bortezomib), bosutinib
(bosutinib), brivanib, cabozantinib, Si Dinibu (cediranib), crenolanib, gram Zhuo replace Buddhist nun
(crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), Tarceva
(erlotinib), ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), her horse
For Buddhist nun (imatinib), iniparib, Lapatinib (lapatinib), lenvatinib, Masitinib (masitinib), not
Te Saini (motesanib), linatinib (neratinib), nilotinib (nilotinib), niraparib,
Oprozomib, olaparib (olaparib), pazopanib (pazopanib), ponatinib, quizartinib,
Regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib,
Sorafenib (sorafenib), Sutent (sunitinib), tasocitinib, Telatinib (telatinib),
Tivozanib, tofacitinib, trametinib, Vande Thani (vandetanib), veliparib, Wei Luofeini
(vemurafenib), vismodegib, alemtuzumab (alemtuzumab), bevacizumab (bevacizumab),
Brentuximab vedotin, catumaxomab (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody
(denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab
(nimotuzumab), difficult to understand (ofatumumab), Victibix (panitumumab), Rituximab
(rituximab) or Herceptin (trastuzumab) or their any combination.
8. pharmaceutical composition described in crystal form described in claim 1-4 any one or claim 5-7 any one is being made
Purposes in standby drug, wherein the drug for prevent, treat or mitigate patient's proliferative diseases, atherosclerosis or
Pulmonary fibrosis.
9. purposes according to claim 8, wherein the proliferative diseases are metastatic carcinoma, colon cancer, sdenocarcinoma of stomach, bladder
Cancer, breast cancer, kidney, liver cancer, lung cancer, cutaneum carcinoma, thyroid cancer, head and neck cancer, prostate cancer, cancer of pancreas, central nervous system
Cancer, glioblastoma or myeloproliferative disease.
10. pharmaceutical composition described in crystal form described in claim 1-4 any one or claim 5-7 any one is being made
Purposes in standby drug, wherein the drug is for inhibition or regulatory protein kinase activity.
11. purposes according to claim 10, wherein the protein kinase is PI3K and/or mTOR.
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| CN112321505A (en) * | 2019-10-25 | 2021-02-05 | 杭州中美华东制药有限公司 | Bosutinib crystal form and preparation method thereof |
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| CN103965199A (en) * | 2013-02-02 | 2014-08-06 | 广东东阳光药业有限公司 | Aromatic heterocyclic compounds, pharmaceutical composition containing compounds and application of pharmaceutical composition |
| US20140234254A1 (en) * | 2013-02-21 | 2014-08-21 | Sunshine Lake Pharma Co., Ltd. | Heteroaromatic compounds as pi3 kinase modulators and methods of use |
| US20150258076A1 (en) * | 2011-12-12 | 2015-09-17 | Dr. Reddy's Laboratories Ltd. | Substituted pyrazolo[1,5-a] pyridine as tropomyosin receptor kinase (trk) inhibitors |
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2018
- 2018-11-30 CN CN201811451913.XA patent/CN109867671B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150258076A1 (en) * | 2011-12-12 | 2015-09-17 | Dr. Reddy's Laboratories Ltd. | Substituted pyrazolo[1,5-a] pyridine as tropomyosin receptor kinase (trk) inhibitors |
| CN103965199A (en) * | 2013-02-02 | 2014-08-06 | 广东东阳光药业有限公司 | Aromatic heterocyclic compounds, pharmaceutical composition containing compounds and application of pharmaceutical composition |
| US20140234254A1 (en) * | 2013-02-21 | 2014-08-21 | Sunshine Lake Pharma Co., Ltd. | Heteroaromatic compounds as pi3 kinase modulators and methods of use |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112321505A (en) * | 2019-10-25 | 2021-02-05 | 杭州中美华东制药有限公司 | Bosutinib crystal form and preparation method thereof |
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Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |