CN106632253B - The crystal form and its pharmaceutical composition and purposes of a kind of substituted quinoline compound - Google Patents
The crystal form and its pharmaceutical composition and purposes of a kind of substituted quinoline compound Download PDFInfo
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- CN106632253B CN106632253B CN201610934836.8A CN201610934836A CN106632253B CN 106632253 B CN106632253 B CN 106632253B CN 201610934836 A CN201610934836 A CN 201610934836A CN 106632253 B CN106632253 B CN 106632253B
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The present invention relates to N- (the fluoro- 4- of 3- ((7- (2- hydroxy-2-methyl propoxyl group) quinolyl-4) oxygroup) phenyl) -1,5- dimethyl -3- oxo -2- phenyl -2, the crystal form C of 3- dihydro-1 h-pyrazole -4- formamide tosilate, preparation method, the pharmaceutical composition comprising the crystal form C and the crystal form C of the crystal form C and its pharmaceutical composition prevent, treat or mitigate patient antiproliferative disease drug in purposes.
Description
Invention field
The present invention relates to biomedicine fields, and in particular, to N- (the fluoro- 4- of 3- ((7- (2- hydroxy-2-methyl propoxyl group)
Quinolyl-4) oxygroup) phenyl) -1,5- dimethyl -3- oxo -2- phenyl -2,3- dihydro-1 h-pyrazole -4- formamide is to toluene
The crystal form of sulfonate, the preparation method of the crystal form, the pharmaceutical composition of the crystal form and the crystal form or its pharmaceutical composition
Object is preparing the purposes in anti-proliferative drugs.
Background of invention
Traditionally, treatment of cancer significantly improve it is related with the identification of therapeutic agent worked by new mechanism.It can be in cancer
A kind of mechanism utilized in disease treatment is regulatory protein kinase activity, because being tumour via protein kinase-activated signal transduction
The reason of many features of cell.Protein kinase signal transduction and, such as thyroid cancer, gastric cancer, head and neck cancer, lung cancer, breast cancer,
The growth of prostate cancer and colorectal cancer and Tumor cells and proliferation are especially relevant.
Protein kinase can be divided into receptor type and non-receptor type.Receptor type tyrosine kinase includes largely to have different biologies living
The transmembrane receptor of property.About being discussed in detail for receptor type tyrosine kinase, referring to " Structural biology of
protein tyrosine kinases",Cell.Mol.Life Sci.,2006(63),2608–2625.Due to protein kinase
And its ligand plays a crucial role in various cellular activities, and therefore, the dysregulation of protein kinase enzymatic activity
(dysregulation) it can lead to the change of cellularity, uncontrolled cell growth such as relevant to cancer.Therefore, albumen swashs
Enzyme is noticeable target in small-molecule drug research and development.It is particularly attractive relevant to anti-angiogenesis and antiproliferative activity
Small molecule adjust target include receptor type tyrosine kinase VEGFR, Flt3, c-Met, Axl and Mer or other.
Angiogenesis is from the process for prestoring blood vessels and being formed new capillary, this follows women/jenny reproduction
The allelotaxis of embryo plays critical effect in loop system, while also also playing to the healing of inflammatory disease and wound very heavy
The effect wanted.It is well known that certain diseases and associated angiogenesis out of control, such as eye neovascularization, retinopathy (including
Diabetic retinopathy), macular degeneration related with the age, fibrosis, psoriasis, hemangioblastoma, hemangioma, artery
Hardening, inflammatory disease, such as rheumatoid or rheumatic inflammatory disease, especially arthritis (rheumatoid arthritis), or
Other chronic inflammations, such as chronic asthma, artery or transplanting artery atherosis, mullerianosis and proliferative disease,
Such as the usually described entity tumor and liquid tumors (such as leukaemia).Entity tumor, depend particularly on angiogenesis come to
It supplies nutrition, nutrient and waste processing.In addition, angiogenesis can equally promote the life of cell or other positions metastatic tumour
It is long.
New angiogenesis is highly complex and hight coordinate a process, it is required that there is a large amount of growth factor to pierce
Swash, but vascular endothelial growth factor (VEGFR) signal response usually represented in physiology and pathology angiogenesis it is key
Rate-limiting step.VEGF is combined and activated receptor type tyrosine kinase.There are three types of the VEGFR hypotypes confirmed by the mankind:
VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4).VEGFR-2 mediates the main cell of VEGF to answer
It answers, especially mitosis and angiogenesis.VEGFR-1 adjust VEGFR-2 signal transduction or as virtual/decoy receptor every
From VEGF and VEGFR-2.The expression of VEGFR-1 is adjusted by anoxic forward direction, and mechanism is similar by HIF-1 adjusting with VEGF；It
Type and developing stage of the function based on cell and change.(Stuttfeld E,Ballmer-Hofer K(September
2009)."Structure and function of VEGF receptors".IUBMB Life 61(9):915–22.)。
VEGFR-2 is the mitosis and survival of main mediate vascular endothelial cell (EC), at the same keep angiogenesis and
The permeability of capilary.Therefore, directly inhibit the activity of kinases VEGFR-2 that will reduce the growth of angiogenesis and tumour, and
And inhibit VEGFR-2 targeting in the activity of host epithelial cells more stable on science of heredity, and the tumour of non-inhibited mutability
Tissue, it will reduce the probability of resistance development.Some drug targetings act on the response of VEGFR signal, are either administered alone,
Or it is combined with other chemotherapeutic agents, effective to patients with advanced malignant tumor (" VEGF-targeted therapy:
mechanisms of anti-tumor activity."Nature Reviews Cancer,2008,8,579；
“Molecular basis for sunitinib efficacy and future clinical development.”
Nature Reviews Drug Discovery,2007,6,734；"Angiogenesis:an organizing
principle for drug discovery”Nature Reviews Drug Discovery,2007,6,273)。
FLT3 (Flt3, FMS sample tyrosine kinase 3), also referred to as FLK2 (fetal liver kinase..2) and STK1
(human stem cell kinase.1), is a kind of receptor tyrosine kinase, belongs to KIT, PDGFR, FMS and FLT1
Type III receptor tyrosine kinase family, (Stirewalt DL, et al., Nat.Rev.Cancer, 2003,3:650-665).
FLT3 is related to hematopoietic disorder, including myeloproliferative disorder such as thrombocythemia, primary thrombocytosis (ET),
The preceding malign disorders, thin of myelofibrosis (MF), chronic idiopathic myelofibrosis (IMF) and polycythemia vera (PV)
Born of the same parents reduce and preceding pernicious myelodysplastic syndrome.Malignant hematologic disease includes leukaemia, lymthoma (non-Hodgkin's lymph
Tumor), it is Hodgkin's disease (being also Hodgkin lymphoma) and myeloma such as acute lymphatic leukemia (ALL), acute myelogenous
Leukaemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic granulocyte are white
Blood disease (CML), chronic neutrophil leukemia (CNL) (Matthew C.Stubbs and Scott A.Armstrong,
“FLT3as a Therapeutic Target in Childhood Acute Leukemia.”Current Drug
Targets,2007,8,703-714)。
FLT3 is in the case where the 70-100% of acute myeloid leukaemia (AML), the T- acute lymphoblastic of He Gao percentage
In leukaemia (ALL) situation of cell with it is each it is horizontal be overexpressed (Griffin JD, et al., Haematol J., 2004,5:
188-190).In primitive cell crisis, also it is overexpressed in the smaller hypotype of chronic myelogenous leukemia (CML).Research is
Display B pedigree leukaemia ALL and AML cell continually co-express FL, set up cause FLT3 composing type activate autocrine or
Paracrine signal transduction recycles (Zheng R, et.al., Blood., 2004,103:267-274) and is suffering from Langerhans tissue
It is found in the serum of the patient of cellular proliferative disorder (Langerhans cell histocytosis) and systemic loupus erythematosus high
Horizontal FLT3 ligand, this further proves the FLT3 in those autoimmune diseases in the dysregulation of dendritic cells resistance cell
Signal transduction (Rolland et al., J.Immunol., 2005,174:3067-3071；Engen et al.,"Targeted
Therapy of FLT3 in Treatment of AML—Current Status and Future Directions.”
J.Clin.Med.,2014,3,1466-1489)。
C-Met, i.e. hepatocyte growth factor receptor (HGFR), its main function point and are had proven in endothelial cell
It is in endothelial cell, myogenous cells, has expression in hematopoietic cell and motor neuron.C-Met natural ligand is liver cell
Growth factor (HGF) is a multi-functional growth factor, i.e. dispersion factor (SF).In fetus and adult, c-Met is activated
It can promote the formation of certain forms, for example, invasive growth will will lead to the fast-growth of cell, intercellular division, and thin
Born of the same parents to migration around it (" From Tpr-Met to Met, tumorigenesis and tubes. " Oncogene 2007,
26,1276；"Met Receptor Tyrosine Kinase as a Therapeutic Anticancer Target."
Cancer Letter,2009,280,1-14)。
There are lasting c-Met to stimulate for the human malignancies being widely present, is overexpressed or makes a variation, including breast cancer, liver
Cancer, lung cancer, oophoroma, kidney, thyroid cancer, colon cancer, glioblastoma, prostate cancer etc..C-Met equally involves artery congee
Sample hardening and tissue fibrosis such as pulmonary fibrosis.By the interaction of mesenchyma stroma of tumors, including HGF/c-Met approach, make these
The invasive growth speed of cancer cell thoroughly improves.Therefore, a large amount of evidences show the response of c-Met signal and certain cancers disease
Development speed it is related, and improve its with using c-Met as major target class cancer drug exploitation in role status
(“Molecular cancer therapy:can our expectation be MET.”Euro.J.Cancer,2008,44,
641-651；"Targeting the c-Met Signaling Pathway in Cancer."Clin.Cancer
Res.2006,12,3657).Agents targeting c-Met signaling pathway are now under
clinical investigation.(“Novel Therapeutic Inhibitors of the c-Met Signaling
Pathway in Cancer.”Clinical Cancer Research,2009,15,2207).“Drug development
of MET inhibitors:targeting oncogene addiction and expedience.”Nature Review
Drug Discovery,2008,7,504)。
TYRO3 in receptor tyrosine kinase, Axl (being also UFO) and MERTK (being also Mer) (TAM) family are to send out recently
Existing kinase families.The kinase domain of the member of this family all has and has similar overall structure domain and highly relevant
Kwiaies conserved sequence.TAM receptor tyrosine kinase ectopic expression or overexpression and is in various human tumors
Tumour cell provides survival advantage.In experimental model, Axl and MerTK can be carcinogenic.Although MerTK and Axl can be with activating criteria
Cell proliferation path (member of ERK, AKT, signal transduction and activating transcription factor (STAT) family), but their output
It usually promotes cells survival rather than rises in value.These kinases may be that dual anticancer target spot has been opened first in tumour cell
A kind of TAMRTK survival-signal of non-oncogene habituation is issued, then in microenvironment, the inhibition of MerTK and Axl may be reversed
Congenital immunity inhibits (" The TAM family:phosphatidylserine-sensing receptor tyrosine
kinases gone awry in cancer.”Nature Review Cancer,2014,14,769)。
Recently some researches show that Mer and Axl often in some tumor cell lines it is (such as thin in various non-small cell lung cancers
In born of the same parents' strain) it over-expresses or activates.Mer the or Axl activation of ligand-dependent can stimulate MAPK, AKT and FAK signal path,
It shows receptor tyrosine kinase and plays key player in a variety of oncogenic processes.The exception table of Axl silencing (knockdown)
It reaches and activates by accelerating Apoptosis to improve external non-small cell lung cancer to the sensibility of chemotherapy agents.Compare Mer and Axl
The effect of silencing (knockdown) finds that Mer inhibition can more completely block tumour growth and simultaneously silencing Axl
(knockdown) chemosensitivity is more effectively improved simultaneously.Therefore, Axl, Mer or double inhibition is inhibited to be likely to be targeting cancer
A kind of therapeutic strategy of cell.(Rachel et al.,"Mer or Axl Receptor Tyrosine Kinase
inhibition promotes apoptosis,blocks growth,and enhances chemosensitivity of
human non-small cell lung cancer”,Oncogene,2013,32(29),3420-3431).
Therefore, specifically inhibit, adjust and/or adjustment kinases (particularly including above-mentioned VEGFR, Flt3, c-Met, Axl and
Mer the small molecule compound of signal transduction) is for treating or preventing and the illness of abnormal cell proliferation and associated angiogenesis
Be it is special it is desirable that.Small molecule compound as one of which is N- (the fluoro- 4- of 3- ((7- (the third oxygen of 2- hydroxy-2-methyl
Base) quinolyl-4) oxygroup) phenyl) -1,5- dimethyl -3- oxo -2- phenyl -2,3- dihydro-1 h-pyrazole -4- formamide, it
With following chemical structure:
2012118632 A1 of patent application WO discloses N- (the fluoro- 4- of 3- ((7- (2- hydroxy-2-methyl propoxyl group) quinoline
Quinoline -4- base) oxygroup) phenyl) -1,5- dimethyl -3- oxo -2- phenyl -2,3- dihydro-1 h-pyrazole -4- formamide (embodiment
1) and its corresponding salt, such as hydrochloride (embodiment 5), maleate (embodiment 6), tosilate (embodiment 7), benzene
Sulfonate (embodiment 8)；Also disclose the treatment of the inhibition of these compounds, the signal transduction for adjusting and/or adjusting protein kinase
Activity.
The different salt and solid forms of active pharmaceutical ingredient may have different property.Different salt and solid forms are in property
Change in terms of matter can provide improved formulations, for example, being readily synthesized or handling, improve dissolution rate or improve stability and guarantee the quality
Phase.The change of the property caused by different salt or solid forms can also improve final dosage form, for example, if this change
Bioavilability can be improved.The different salt and solid forms of active pharmaceutical ingredient can also generate polycrystalline or other crystal forms, from
And more chances are provided to assess the change of properties of the active pharmaceutical ingredient of a solid.
For above-mentioned N- (the fluoro- 4- of 3- ((7- (2- hydroxy-2-methyl propoxyl group) quinolyl-4) oxygroup) phenyl) -1,
5- dimethyl -3- oxo -2- phenyl -2,3- dihydro-1 h-pyrazole -4- formamide, different salt, solid forms, different salt crystalline substance
Type still needs researcher and further develops and improve.
Abstract of invention
Only summarize some aspects of the invention below, it is not limited to this.These aspects and other parts are later
There is more complete explanation.All bibliography in this specification are incorporated in this by whole.Work as the disclosure of the specification
When variant with citation, it is subject to the disclosure of the specification.
The present invention provides N- (the fluoro- 4- of 3- ((7- (2- hydroxy-2-methyl propoxyl group) quinolyl-4) oxygroup) phenyl)-
A kind of crystal form of 1,5- dimethyl -3- oxo -2- phenyl -2,3- dihydro-1 h-pyrazole -4- formamide tosilate, at this
Crystal form C is named as in application.Crystal form C can be effectively used for treatment proliferative diseases.Present invention provides the sides for preparing crystal form C
Method treats mammal, the especially method of human pcna disease, and the pharmaceutical composition comprising crystal form C using crystal form C
Object.The crystal form C that the application proposes is compared to its amorphous forms, and stability is higher, body absorption is more preferable, has more excellent medicine
For kinetic property.
On the one hand, the present invention provides the crystal form of compound shown in formula (I),
Its X-ray powder diffraction collection be included in 2 θ be 7.20 ° ± 0.2 °, 10.06 ° ± 0.2 °, 17.40 ° ± 0.2 °,
17.75 ° ± 0.2 °, 18.65 ° ± 0.2 °, 19.48 ° ± 0.2 ° and 20.13 ° ± 0.2 ° of peak.
In some embodiments, the X-ray powder diffraction collection of the crystal form be included in 2 θ values be 7.20 ° ± 0.2 °,
10.06°±0.2°、14.96±0.2°、16.76±0.2°、17.40°±0.2°、17.75°±0.2°、18.65°±0.2°、
19.48°±0.2°、20.13°±0.2°、20.90°±0.2°、21.71°±0.2°、22.69°±0.2°、23.37°±
0.2 °, 24.40 ° ± 0.2 °, 25.52 ° ± 0.2 °, 26.29 ° ± 0.2 ° and 28.41 ° ± 0.2 ° of peak.
In other embodiments, the X-ray powder diffraction collection of the crystal form and Fig. 1 are substantially the same.
In some embodiments, the differential scanning calorimetric curve of the crystal form is included in 168 DEG C ± 3 DEG C and 219 DEG C ± 3
DEG C two endothermic peaks.
In other embodiments, the differential scanning calorimetric curve of the crystal form and Fig. 2 are substantially the same.
In some embodiments, when being heated to 185 DEG C, the thermal gravimetric analysis curve of the crystal form includes about 3.5%
Weight loss.
In other embodiments, the thermal gravimetric analysis curve of the crystal form and Fig. 3 are substantially the same.
In some embodiments, the crystal form is substantially pure.
On the other hand, the present invention provides a kind of pharmaceutical composition, and it includes the crystal forms of compound shown in the formula (I).
In some embodiments, wherein the pharmaceutical composition, further includes pharmaceutically acceptable figuration
Agent, carrier, adjuvant, solvent or their combination.
In other embodiments, wherein the pharmaceutical composition, wherein further including antiproliferative, institute
Stating antiproliferative is melphalan (melphalan), cyclophosphamide (cyclophosphamide), ifosfamide
(ifosfamide), busulfan (busulfan), Carmustine (carmustine), lomustine (lomustine), chain urea assistant
Rhzomorph (streptozocin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), reaches cis-platinum (cisplatin)
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), tesirolimus
(temsirolimus), everolimus (everolimus), Afatinib (afatinib), Axitinib (axitinib), rich
It relaxes to win for Buddhist nun (bosutinib), card and replaces Buddhist nun for Buddhist nun (cabozantinib), Ceritinib (ceritinib), gram Zhuo
(crizotinib), dabrafenib (dabrafenib), Dasatinib (dasatinib), Tarceva (erlotinib), Ji
It is non-for Buddhist nun (gefitinib), according to Shandong for Buddhist nun (ibrutinib), hydrochloric acid Conmana (icotinib hydrochloride), she
Imatinib (imatinib), Lapatinib (lapatinib), nilotinib (nilotinib), pazopanib (pazopanib),
Piperazine Jia Tani (pegaptanib), Ponatinib (ponatinib) draw and replace Buddhist nun (radotinib), Rui Gefeini more
(regorafenib), Luso benefit replaces Buddhist nun (ruxolitinib), Sorafenib (sorafenib), Sutent
(sunitinib), tropsch imatinib (tofacitinib), Trimetinib (trametinib), Vande Thani (vandetanib),
Wei Luofeini (vemurafenib), methanesulfonic acid Ah pa for Buddhist nun (apatinib mesylate), Masitinib (masitinib),
Alanine Bu Linibu (brivanib alaninate), Si Dinibu (cediranib), up to can for Buddhist nun (dacomitinib),
Good fortune he replace Buddhist nun (fostamatinib), motesanibdiphosphate (motesanib diphosphate), linatinib
(neratinib), department's beauty replaces Buddhist nun for Buddhist nun (selumetinib), for pyrrole method Buddhist nun, Ba Fei for Buddhist nun (bafetinib), multidimensional
(dovitinib), saracatinib (saracatinib), Telatinib (telatinib), for Wo Zhani (tivozanib), Ah
Logical sequence monoclonal antibody (alemtuzumab), bevacizumab (bevacizumab), the appropriate monoclonal antibody Wei Duoting (brentuximab in Belém
Vedotin), catumaxomab (catumaxomab), Cetuximab (cetuximab), promise monoclonal antibody (denosumab), lucky
Trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), difficult to understand
(ofatumumab), Victibix (panitumumab), Rituximab (rituximab), tositumomab
(tositumomab), Herceptin (trastuzumab), idelalisib, duvelisib, gilteritinib,
buparlisib、taselisib、copanlisib、voxtalisib、pilaralisib、sonolisib、perifosine、
alectinib、ibrutinib、pertuzumab、nintedanib、cobimetinib、temsirolimus、sirolimus、
Pixantrone or their any combination.
On the other hand, the crystalline substance the present invention provides the crystal form of compound shown in formula (I) and comprising compound shown in formula (I)
The purposes of the pharmaceutical composition of type in medicine preparation, the drug is for preventing, treating or mitigating patient's proliferative diseases.
In some embodiments, wherein the proliferative diseases are colon and rectum carcinoma, gastric cancer, sdenocarcinoma of stomach, pancreas
Cancer, bladder cancer, gallbladder cancer, breast cancer, kidney, clear-cell carcinoma, liver cancer, hepatocellular carcinoma, lung cancer, cutaneum carcinoma, melanoma, first shape
Gland cancer, osteosarcoma, soft tissue sarcoma, head and neck cancer, central nerve neuroma, glioma, glioblastoma, ovary
Cancer, uterine cancer, carcinoma of endometrium, prostate cancer, acute myelogenous leukemia or acute lymphoblastic leukemia or their turn
Move cancer.
In some embodiments, wherein the drug is for inhibiting receptor tyrosine kinase activity.
In other embodiments, wherein the receptor tyrosine kinase is VEGFR, Flt3, c-Met, Axl or Mer.
Detailed description of the invention
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 " 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, use radiation source (Cu, k α, K α 11.540598；Kα21.544426；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 DEG C, ± 2 DEG C, ± 3 DEG C, the error margins of ± 4 DEG C or ± 5 DEG C.In some embodiments
The error margin of middle melting 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.
Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments
Disease or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In other embodiments
In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another
In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stable body
Parameter) or above-mentioned two aspect adjust disease or illness.In other embodiments, " treatment ", which refers to, prevents or delays disease or disease
Breaking-out, generation or the deterioration of disease.
The detailed description of formula (I) compound crystal form C of the present invention
Disclosed by the invention is N- (the fluoro- 4- of 3- ((7- (2- hydroxy-2-methyl propoxyl group) quinolyl-4) oxygroup) benzene
Base) -1,5- dimethyl -3- oxo -2- phenyl -2,3- dihydro-1 h-pyrazole -4- formamide tosilate crystal form C, this
Invention further relates to the composition containing disclosed crystal form C.The therapeutical uses of the crystal form C and therapeutic combination containing it
Represent the individual aspect of the disclosure.Technology for characterizing crystal type C describes in the examples below.These technologies can individually or
Combination is for characterizing crystal type disclosed herein.Crystal type is see also drawing features disclosed herein.
On the one hand, the present invention provides the crystal form C of compound shown in formula (I),
Wherein the X-ray powder diffraction collection of the crystal form be included in 2 θ values be 7.20 ° ± 0.2 °, 10.06 ° ± 0.2 °,
17.40 ° ± 0.2 °, 17.75 ° ± 0.2 °, 18.65 ° ± 0.2 °, 19.48 ° ± 0.2 ° and 20.13 ° ± 0.2 ° of peak.
In some embodiments, wherein the X-ray powder diffraction collection of the crystal form C be included in 2 θ values be 7.20 ° ±
0.2°、10.06°±0.2°、14.96±0.2°、16.76±0.2°、17.40°±0.2°、17.75°±0.2°、18.65°±
0.2°、19.48°±0.2°、20.13°±0.2°、20.90°±0.2°、21.71°±0.2°、22.69°±0.2°、23.37°
± 0.2 °, 24.40 ° ± 0.2 °, 25.52 ° ± 0.2 °, 26.29 ° ± 0.2 ° and 28.41 ° ± 0.2 ° of peak.
In other embodiments, the X-ray powder diffraction collection of the crystal form C and Fig. 1 are substantially the same.
In some embodiments, the differential scanning calorimetric curve of the crystal form C be included in 168 DEG C ± 3 DEG C and 219 DEG C ±
3 DEG C of two endothermic peaks.
In other embodiments, the differential scanning calorimetric curve of the crystal form C and Fig. 2 are substantially the same.
In some embodiments, when being heated to 185 DEG C, the thermal gravimetric analysis curve of the crystal form C includes about 3.5%
Weight loss.
In other embodiments, the thermal gravimetric analysis curve of the crystal form C and Fig. 3 are substantially the same.
In some embodiments, the crystal form C is substantially pure.
On the other hand, the present invention provides a kind of pharmaceutical composition, and it includes the crystal form C of compound shown in the formula (I).
In some embodiments, wherein the pharmaceutical composition, further includes pharmaceutically acceptable figuration
Agent, carrier, adjuvant, solvent or their combination.
In other embodiments, wherein the pharmaceutical composition, wherein further including antiproliferative, institute
Stating antiproliferative is melphalan (melphalan), cyclophosphamide (cyclophosphamide), ifosfamide
(ifosfamide), busulfan (busulfan), Carmustine (carmustine), lomustine (lomustine), chain urea assistant
Rhzomorph (streptozocin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), reaches cis-platinum (cisplatin)
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), tesirolimus
(temsirolimus), everolimus (everolimus), Afatinib (afatinib), Axitinib (axitinib), rich
It relaxes to win for Buddhist nun (bosutinib), card and replaces Buddhist nun for Buddhist nun (cabozantinib), Ceritinib (ceritinib), gram Zhuo
(crizotinib), dabrafenib (dabrafenib), Dasatinib (dasatinib), Tarceva (erlotinib), Ji
It is non-for Buddhist nun (gefitinib), according to Shandong for Buddhist nun (ibrutinib), hydrochloric acid Conmana (icotinib hydrochloride), she
Imatinib (imatinib), Lapatinib (lapatinib), nilotinib (nilotinib), pazopanib (pazopanib),
Piperazine Jia Tani (pegaptanib), Ponatinib (ponatinib) draw and replace Buddhist nun (radotinib), Rui Gefeini more
(regorafenib), Luso benefit replaces Buddhist nun (ruxolitinib), Sorafenib (sorafenib), Sutent
(sunitinib), tropsch imatinib (tofacitinib), Trimetinib (trametinib), Vande Thani (vandetanib),
Wei Luofeini (vemurafenib), methanesulfonic acid Ah pa for Buddhist nun (apatinib mesylate), Masitinib (masitinib),
Alanine Bu Linibu (brivanib alaninate), Si Dinibu (cediranib), up to can for Buddhist nun (dacomitinib),
Good fortune he replace Buddhist nun (fostamatinib), motesanibdiphosphate (motesanib diphosphate), linatinib
(neratinib), department's beauty replaces Buddhist nun for Buddhist nun (selumetinib), for pyrrole method Buddhist nun, Ba Fei for Buddhist nun (bafetinib), multidimensional
(dovitinib), saracatinib (saracatinib), Telatinib (telatinib), for Wo Zhani (tivozanib), Ah
Logical sequence monoclonal antibody (alemtuzumab), bevacizumab (bevacizumab), the appropriate monoclonal antibody Wei Duoting (brentuximab in Belém
Vedotin), catumaxomab (catumaxomab), Cetuximab (cetuximab), promise monoclonal antibody (denosumab), lucky
Trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), difficult to understand
(ofatumumab), Victibix (panitumumab), Rituximab (rituximab), tositumomab
(tositumomab), Herceptin (trastuzumab), idelalisib, duvelisib, gilteritinib,
buparlisib、taselisib、copanlisib、voxtalisib、pilaralisib、sonolisib、perifosine、
alectinib、ibrutinib、pertuzumab、nintedanib、cobimetinib、temsirolimus、sirolimus、
Pixantrone or their any combination.
On the other hand, the crystalline substance the present invention provides the crystal form C of compound shown in formula (I) and comprising compound shown in (I)
The purposes of the pharmaceutical composition of type C in medicine preparation, the drug is for preventing, treating or mitigating patient's proliferative diseases.
In some embodiments, wherein the proliferative diseases are colon and rectum carcinoma, gastric cancer, sdenocarcinoma of stomach, pancreas
Cancer, bladder cancer, gallbladder cancer, breast cancer, kidney, clear-cell carcinoma, liver cancer, hepatocellular carcinoma, lung cancer, cutaneum carcinoma, melanoma, first shape
Gland cancer, osteosarcoma, soft tissue sarcoma, head and neck cancer, central nerve neuroma, glioma, glioblastoma, ovary
Cancer, uterine cancer, carcinoma of endometrium, prostate cancer, acute myelogenous leukemia or acute lymphoblastic leukemia or their turn
Move cancer.
In some embodiments, wherein the drug is for inhibiting receptor tyrosine kinase activity.
In other embodiments, wherein the receptor tyrosine kinase be VEGFR, Flt3, c-Met, Axl, Mer or
A combination thereof.
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.
Read it is described in detail below after, the feature of the disclosure and excellent can be more easily to understand in those of ordinary skill in the art
Point.It should be understood that for clarity reasons, in the above and below upper and lower certain features of the present invention described in the text of independent embodiment
It can also combine to form single embodiment.On the contrary, for succinct reason, described in the context of single embodiment originally
Disclosed different characteristic also may be combined to form their sub-portfolio.The disclosure is further illustrated by examples hereinbelow, these realities
Applying example should not be construed as the scope of the present disclosure or spirit being limited to the wherein described specific steps.
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.
Brief description
Fig. 1: the crystal form C of formula (I) compound X-ray powder diffraction (XRPD) figure.
Fig. 2: the crystal form C of formula (I) compound differential scanning calorimetry (DSC) curve.
Fig. 3: the crystal form C of formula (I) compound thermogravimetric analysis (TGA) curve.
Fig. 4: the solid-state of the crystal form C of formula (I) compound13C NMR spectra.
Specific embodiment
Specific embodiment of the invention below, the embodiment described rather than are limited to further describe the present invention
The system present invention.
Prepare embodiment
Raw material N- (the fluoro- 4- of 3- ((7- (2- hydroxy-2-methyl propoxyl group) quinolyl-4) oxygroup) phenyl) -1,5- diformazan
The preparation of base -3- oxo -2- phenyl -2,3- dihydro-1 h-pyrazole -4- formamide refer to 2012118632 A1 of WO, and by its
In content be integrally incorporated in the present invention.
Embodiment 1:N- (the fluoro- 4- of 3- ((7- (2- hydroxy-2-methyl propoxyl group) quinolyl-4) oxygroup) phenyl) -1,5-
The preparation of the crystal form C of dimethyl -3- oxo -2- phenyl -2,3- dihydro-1 h-pyrazole -4- formamide P-TOLUENE SULFO ACID 99's salt
By N- (the fluoro- 4- of 3- ((7- (2- hydroxy-2-methyl propoxyl group) quinolyl-4) oxygroup) phenyl) -1,5- dimethyl -
3- oxo -2- phenyl -2,3- dihydro-1 h-pyrazole -4- formamide (1.0g, 1.80mmol) is dissolved in methanol (30mL) and dichloro
The in the mixed solvent of methane (15mL) is slowly added to the methanol of 4- toluenesulfonic acid hydrate (360mg, 1.88mmol) thereto
(2mL) solution.It is stirred at room temperature 1 hour, solvent is removed under reduced pressure, obtain light yellow oil, then in 20 DEG C at methanol (20mL)
Middle crystallization, obtaining title compound is white solid (1.26g, 96%).
Solid phase13CNMR(101MHz)δ(ppm):167.64,164.19,160.94,154.29,153.10,148.14,
143.69,141.50,133.53,130.18,129.05,127.25,124.80,114.78,107.19,100.84,98.55,
96.78,76.79,70.95,31.86,29.15,27.06,21.98,9.17。
Characterize embodiment
1. powder x-ray diffraction (XRPD) is studied
In the Dutch PANalytical for the Transflective sample stage for being equipped with automation zero Background Samples frame of 3*15
X-ray powder diffraction (XRPD) pattern is collected on Empyrean x-ray diffractometer.Radiation source used is (Cu, k α, K α 1
1.540598；Kα21.544426；1 intensity of K α 2/K α: 0.50), wherein voltage is set in 45KV, and electric current is set in
The divergence of 40mA.X- ray, i.e., the effective dimensions that X-ray constrains on sample use θ-θ continuous scanning mould for 10mm.
Formula obtains 3 °~40 ° of effective 2 θ range.Take appropriate amount of sample at ambient conditions (about 18 DEG C~32 DEG C) in zero Background Samples frame
At circular groove, is gently pressed with clean glass slide, obtain a smooth plane, and zero Background Samples frame is fixed.By sample
(usually 1~2mg) generates traditional XRPD pattern with 0.0167 ° of scanning step within the scope of 3 °~40 ° ± 0.2 ° of 2 θ
(as shown in Figure 1).Software for data collection is Data Collector, data Data Viewer and HighScore
Plus analysis and displaying, such as table 1.
The X-ray powder diffraction of the crystal form C of 1 formula of table (I) compound analyzes result
2. differential scanning calorimetry (DSC) is analyzed
Dsc measurement is in TA InstrumentsTMIt is carried out in model Q2000 with sealed disk assembly.By sample (about 2~6mg)
It is weighed in aluminium dish, with Tzero gland, precision is recorded 1 percent milligrams, and sample is transferred in instrument and is measured.
Instrument is purged with nitrogen with 50mL/min.Data are collected with the rate of heat addition of 10 DEG C/min between 300 DEG C in room temperature.With heat absorption
Peak is drawn downwards, and data are analyzed and shown with TA Universal Analysis.
The differential scanning calorimetric curve of the crystal form C of formula (I) compound is as shown in Fig. 2, it includes 168 DEG C and 219 DEG C two
± 3 DEG C of error margin may be present in endothermic peak.
3. weight analysis (TGA)
TGA is measured in TA InstrumentsTMIt is carried out in model Q500 with opening device.By sample (about 10mg~30mg)
It is put into the platinum crucible removed the peel in advance.Instrument precision weighs the weight of sample, and by instrument record to one thousandth milligram.Balance is used
Nitrogen is purged with 40mL/min, and sample is purged with nitrogen with 60mL/min.Room temperature between 300 DEG C with the heating of 10 DEG C/min
Rate collection data, data are analyzed and are shown with TA Universal Analysis.
The thermal gravimetric analysis curve of the crystal form C of formula (I) compound is as shown in figure 3, when being heated to 185 DEG C, and it includes 3.5%
Weight loss.
4. stability experiment
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 (90% ± 5% relative humidity), (visible light 4500lx ± 500lx, ultraviolet light are not less than for illumination
0.7W·h/m2, 25 ± 2 DEG C, 60% ± 5% relative humidity) and room temperature (25 ± 2 DEG C, 65% ± 5% relative humidity) under the conditions of
Stability test (high temperature, high humidity illumination and normal temperature condition are placed 10 days) is carried out, is tested respectively at the 5th day, sampling in 10 days,
Impurity content is calculated by areas of peak normalization method using HPLC instrument, instrument and test condition are shown in Table 2, and data result is shown in Table 3.
Table 2
Table 3
Conclusion: 3 data of table can be seen that the crystal form C of formula (I) compound and amorphous in high temperature, high humidity and normal temperature condition
Lower to place 10 days, related substance has no significant change, and illustrates the crystal form C of formula (I) compound and amorphous in high temperature, high humidity and normal
It is stable under the conditions of temperature.
Under illumination condition, compared with 0 day, the main peak decline 0.14% of the crystal form C of formula (I) compound；Formula (I) compound
Unbodied main peak decline 0.42%；Under illumination condition, the crystal form C of formula (I) compound is than amorphous stabilization.
5. hygroscopicity test
Empty weighing bottle jump a queue son weight be denoted as m1, crystal form C or amorphous (about 1.0g) addition of formula (I) compound is added
In weighing bottle, and cap, weight are denoted as m2.Then weighing bottle is placed in lower part and is placed with saturation NH by unlimited bottle stopper4Cl aqueous solution
Container in (80% ± 2%RH), placed 10 days under the conditions of 25 DEG C ± 1 DEG C, took one bottle of detection, weighing bottle respectively in 5,10 days
Weight be denoted as m3, draw it is moist calculated according to following formula, the results are shown in Table 5.
The version of table 4 2015 years " Chinese Pharmacopoeia " is to drawing moist feature description and draw wet weight gain and define
| Draw wet feature | Draw wet rate of body weight gain |
| It is moist | It absorbs enough moisture and forms liquid |
| It is great draw it is moist | Draw wet weight gain not less than 15% |
| Have draw it is moist | Draw wet weight gain less than 15% but not less than 2% |
| Slightly draw moist | Draw wet weight gain less than 2% but not less than 0.2% |
| Nothing is moist almost without drawing | Draw wet weight gain less than 0.2% |
The crystal form C of 5 formula of table (I) compound and unbodied draw wet test result
Conclusion: as can be seen from the results in table 5 above, the crystal form C of formula (I) compound slightly draws moist；Formula (I) compound it is amorphous
Have draw it is moist.
6. pharmacokinetic studies
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
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: 100x4.6mm 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.
The crystal form C of formula (I) compound and it is amorphous mixed respectively with pharmaceutical adjunct after pour into capsule, respectively with about
It is 0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0,12 at time point after beasle dog is given in 7mg/kg or 10mg/kg stomach-filling
Blood (0.3mL) was taken with 24 hours, prepares plasma containing drug, and is centrifuged 2~10 minutes at 3,000 or 4,000rpm.Use LC-MS/
(analysis is using Agilent 1200 or Agilent G6430 series the ceremony of LC/MS/MS spectrum (I) compound in blood plasma by MS
Concentration calculates pharmacokinetic parameters using the non-compartment model method of WinNonlin software.Design parameter is shown in Table 6.
The crystal form C and the amorphous pharmacokinetic data in beasle dog of 6 formula of table (I) compound
Conclusion: from upper table result as it can be seen that and the C of crystal form Cmax、AUC0-24hAnd AUC0-∞It is more much larger than amorphous, show this
Crystal form drug is big in the intracorporal exposed amount of beasle dog, absorbs well, pharmacokinetic property is significantly better than amorphous.
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 (10)
1. the crystal form of compound shown in formula (I),
Its X-ray powder diffraction collection be included in 2 θ values be 7.20 ° ± 0.2 °, 10.06 ° ± 0.2 °, 17.40 ° ± 0.2 °,
17.75 ° ± 0.2 °, 18.65 ° ± 0.2 °, 19.48 ° ± 0.2 ° and 20.13 ° ± 0.2 ° of peak.
2. crystal form according to claim 1, X-ray powder diffraction collection be included in 2 θ values be 7.20 ° ± 0.2 °,
10.06°±0.2°、14.96±0.2°、16.76±0.2°、17.40°±0.2°、17.75°±0.2°、18.65°±0.2°、
19.48°±0.2°、20.13°±0.2°、20.90°±0.2°、21.71°±0.2°、22.69°±0.2°、23.37°±
0.2 °, 24.40 ° ± 0.2 °, 25.52 ° ± 0.2 °, 26.29 ° ± 0.2 ° and 28.41 ° ± 0.2 ° of peak.
3. crystal form according to claim 1, X-ray powder diffraction collection are substantially the same with Fig. 1.
4. crystal form according to claim 1, wherein the crystal form is substantially pure.
5. a kind of pharmaceutical composition, it includes crystal forms described in claim 1-4 any one.
6. pharmaceutical composition according to claim 5 further includes pharmaceutically acceptable excipient, carrier, assistant
Agent, solvent or their combination.
7. pharmaceutical composition according to claim 5 or 6, wherein further including antiproliferative, the antiproliferative
Agent be melphalan, cyclophosphamide, ifosfamide, busulfan, Carmustine, lomustine, streptozotocin, cis-platinum, carboplatin,
Oxaliplatin, Dacarbazine, Temozolomide, procarbazine, methotrexate (MTX), fluorouracil, cytarabine, gemcitabine, sulfydryl
Purine, fludarabine, vincaleukoblastinum, vincristine, vinorelbine, taxol, Docetaxel, topotecan, Irinotecan, according to
Support pool glycosides, tributidine, dactinomycin D, Doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitogen are mould
Plain C, Ipsapirone, tamoxifen, Flutamide, Gonadorelin analog, megestrol acetate, prednisone, dexamethasone, first sprinkle Buddhist nun
Dragon, Thalidomide, interferon-' alpha ', Calciumlevofolinate, sirolimus, tesirolimus, everolimus, Afatinib, Axitinib,
Bosutinib, card it is rich for Buddhist nun, Ceritinib, gram Zhuo for Buddhist nun, dabrafenib, Dasatinib, Tarceva, Gefitinib, according to Shandong
It is more for Buddhist nun, hydrochloric acid Conmana, Imatinib, Lapatinib, nilotinib, pazopanib, piperazine Jia Tani, Ponatinib, drawing
Buddhist nun, Sorafenib, Sutent, tropsch imatinib, Trimetinib, Vande Thani, Wei Luofei are replaced for Buddhist nun, Rui Gefeini, Luso benefit
Buddhist nun, methanesulfonic acid Ah pa for Buddhist nun, Masitinib, alanine Bu Linibu, Si Dinibu, up to can for Buddhist nun, good fortune he for Buddhist nun, diphosphonic acid not
For husky Buddhist nun, linatinib, department's beauty for Buddhist nun, for pyrrole method Buddhist nun, Ba Fei for Buddhist nun, multidimensional for Buddhist nun, saracatinib, Telatinib, prick for fertile
Buddhist nun, alemtuzumab, bevacizumab, the appropriate monoclonal antibody Wei Duoting in Belém, catumaxomab, Cetuximab, promise monoclonal antibody, lucky appropriate pearl it is single
Anti-, her monoclonal antibody, Buddhist nun's trastuzumab, difficult to understand, Victibix, Rituximab, tositumomab, Herceptin,
idelalisib、duvelisib、gilteritinib、buparlisib、taselisib、copanlisib、voxtalisib、
pilaralisib、sonolisib、perifosine、alectinib、ibrutinib、pertuzumab、nintedanib、
Cobimetinib, temsirolimus, sirolimus, pixantrone or their any combination.
8. prepared by pharmaceutical composition described in crystal form described in claim 1-4 any one or claim 5-7 any one
Purposes in drug, the drug are used to prevent, handle, treat or mitigate the proliferative diseases of patient.
9. purposes according to claim 8, wherein the proliferative diseases are colon and rectum carcinoma, gastric cancer, gastric gland
Cancer, cancer of pancreas, bladder cancer, gallbladder cancer, breast cancer, kidney, liver cancer, lung cancer, cutaneum carcinoma, melanoma, thyroid cancer, bone and flesh
Tumor, soft tissue sarcoma, head and neck cancer, central nerve neuroma, glioma, glioblastoma, oophoroma, uterine cancer,
Carcinoma of endometrium, prostate cancer, acute myelogenous leukemia or acute lymphoblastic leukemia or their metastatic carcinoma.
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, the drug is for inhibiting receptor tyrosine kinase activity, wherein the receptor tyrosine kinase is
VEGFR, Flt3, c-Met, Axl, Mer or their combination.
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| WO2012118632A1 (en) * | 2011-02-28 | 2012-09-07 | Ning Xi | Substituted quinoline compounds and methods of use |
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| WO2012118632A1 (en) * | 2011-02-28 | 2012-09-07 | Ning Xi | Substituted quinoline compounds and methods of use |
| CN102675282A (en) * | 2011-03-15 | 2012-09-19 | 广东东阳光药业有限公司 | Substitutive quinoline compound and application method and uses thereof |
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