CN106632254B - 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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- CN106632254B CN106632254B CN201610942575.4A CN201610942575A CN106632254B CN 106632254 B CN106632254 B CN 106632254B CN 201610942575 A CN201610942575 A CN 201610942575A CN 106632254 B CN106632254 B CN 106632254B
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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 purposes in the drug for preparing antiproliferative disease of preparation method, the pharmaceutical composition comprising the crystal form A and the crystal form A and its pharmaceutical composition of the crystal form A of 3- dihydro-1 h-pyrazole -4- formamide tosilate, the crystal form A.
Description
Technical field
The present invention relates to biomedicine fields, in particular it 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 -2,3- dihydro-1 h-pyrazole -4- formyl
The crystal form of the tosilate of amine, the preparation method of the crystal form, the pharmaceutical composition comprising the crystal form and the crystalline substance
The purposes of type and its pharmaceutical composition in the drug for preparing antiproliferative disease.
Background technique
Traditionally, a kind of mechanism utilized in cancer treatment is regulatory protein kinase activity, because most of tumours are thin
The abnormality proliferation of born of the same parents is related to protein kinase-activated abnormal signal transduction.Wherein, thyroid cancer, gastric cancer, head and neck cancer, lung cancer,
The abnormality proliferation of breast cancer, prostate cancer and colorectal cancer and Tumor cells and protein kinase-activated abnormal signal transduction
It is 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 playing to the healing of inflammatory disease and wound critically important
Effect.It is well known that certain diseases and associated angiogenesis out of control, such as eye neovascularization, retinopathy (including sugar
Urinate characteristic of disease retinopathy), macular degeneration related with the age, fibrosis, psoriasis, hemangioblastoma, hemangioma, artery is hard
Change, inflammatory disease, such as rheumatoid or rheumatic inflammatory disease, especially arthritis (rheumatoid arthritis), Huo Zheqi
Its chronic inflammation, such as chronic asthma, artery or transplanting artery atherosis, mullerianosis and proliferative disease, example
Entity tumor and liquid tumors (such as leukaemia) as generally described.Entity tumor depends particularly on angiogenesis and comes to it
Supply nutrition, nutrient and waste processing.In addition, angiogenesis can equally promote the growth of cell or other positions metastatic tumour.
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 VEGFR.Have three by the VEGFR hypotype that the mankind confirm
Kind: VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4).The VEGF's that VEGFR-2 is mediated is main
Cell response includes mitosis and angiogenesis.The expression of VEGFR-1 by anaerobic environment forward direction adjust, mechanism with
VEGF is adjusted similar by HIF-1；Type and developing stage of its function based on cell and change.(Stuttfeld E,
Ballmer-Hofer K(2009)."Structure and function of VEGF receptors".IUBMB Life
61 (9): 915-22.)
The mitosis and survival of the main mediate vascular endothelial cell (EC) of VEGFR-2, while keeping angiogenesis and micro-
The permeability of blood vessel.Therefore, directly inhibit the activity of kinases VEGFR-2 that will reduce the growth of angiogenesis and tumour, and
Inhibit VEGFR-2 targeting in the activity of host epithelial cells more stable on science of heredity, and the tumor group of non-inhibited mutability
It knits, it will reduce the probability of resistance development.Some drug targetings act on the response of VEGFR signal, are either administered alone, and press down
Or be 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 pernicious barrier of myelofibrosis (MF), chronic idiopathic myelofibrosis (IMF) and polycythemia vera (PV)
Hinder, Leukopenia and preceding pernicious myelodysplastic syndrome.Malignant hematologic disease includes leukaemia, lymthoma (non-Hodgkin's
Lymthoma), it is Hodgkin's disease (being also Hodgkin lymphoma) and myeloma such as acute lymphatic leukemia (ALL), acute
Myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic grain are thin
Born of the same parents' leukaemia (CML), chronic neutrophil leukemia (CNL) (Matthew C.Stubbs and Scott
A.Armstrong,“FLT3 as 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
(Griffin JD, et al., Haematol J., 2004,5:188-190) is overexpressed in leukaemia (ALL) situation of cell.
In initial cell, also it is overexpressed in the smaller hypotype of chronic myelogenous leukemia (CML).The white blood of B pedigree has been displayed in research
The cell of sick ALL and AML is continually overexpressed FL, sets up the autocrine or paracrine signal transduction for causing FLT3 composing type to activate
It recycles (Zheng R, et.al., Blood., 2004,103:267-274).Suffering from Langerhans histocytosis
High-caliber FLT3 is found in the serum of (Langerhans cell histocytosis) and the patient of systemic loupus erythematosus
Ligand, this further prove in those autoimmune diseases in dysregulation FLT3 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.Axl silencing (knockdown) improves body
Sensibility of the outer non-small cell lung cancer cell to chemotherapy agents.Compare the effect discovery of Mer and Axl silencing (knockdown), suppression
The expression of Mer processed can more completely block tumour growth and silencing Axl (knockdown) can more effectively improve chemotherapy simultaneously
Sensibility.Therefore, Axl, Mer or double is inhibited to inhibit a kind of therapeutic strategy for being likely to be target cancer cell.(Rachel et
al.,“Mer or Axl Receptor Tyrosine Kinase inhibition promotes apoptosis,
blocksgrowth,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 WO discloses N- (the fluoro- 4- of 3- ((7- (2- hydroxy-2-methyl propoxyl group) 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 that these compounds have the treatment for the signal transduction for inhibiting, adjusting and/or adjusting protein kinase living
Property.
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.
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 invention proposes 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 A is named as in application.Crystal form A can be effectively used for treatment proliferative diseases.In addition, present invention provides prepare crystal form
The method of A treats mammal, the especially method of human pcna disease, and the drug comprising crystal form A using crystal form A
Composition.Inventor surprisingly has found that it is moist that there is the crystal form A that the application proposes excellent stability, nothing to draw, compared to its nothing
Amorphous form, body absorption is more preferable, and pharmacokinetic property significantly improves.
In the first aspect of the present invention, the invention proposes a kind of crystal form of compound shown in formula (I),
It is characterized by:
1) the corresponding 2 θ value of the characteristic peak of the X-ray powder diffraction collection of the crystal form includes 8.29 ° ± 0.2 °, 9.53 °
± 0.2 °, 11.11 ° ± 0.2 °, 16.99 ° ± 0.2 °, 18.75 ° ± 0.2 ° and 23.66 ° ± 0.2 °；Or
2) crystal form has unit cell parameters below:
Structure cell specification:α=96.689 °, β=95.737 °,
γ=99.649 °；
Space group: P-1；
Unit cell volume:
Asymmetry unit number Z:2 in structure cell；With
Calculate density: 1.377g/cm3。
In some embodiments, the corresponding 2 θ value of the characteristic peak of the X-ray powder diffraction collection of the crystal form includes
8.29°±0.2°,9.53°±0.2°,11.11°±0.2°,15.28°±0.2°,16.99°±0.2°,18.75°±0.2°,
19.14 ° ± 0.2 °, 19.98 ° ± 0.2 °, 20.42 ° ± 0.2 °, 21.77 ° ± 0.2 °, 22.02 ° ± 0.2 ° and 23.66 ° ±
0.2°。
In other embodiments, the corresponding 2 θ value of the characteristic peak of the X-ray powder diffraction collection of the crystal form includes
8.29°±0.2°,9.53°±0.2°,11.11°±0.2°,12.67°±0.2°,14.04°±0.2°,15.28°±0.2°,
15.82°±0.2°,16.99°±0.2°,18.75°±0.2°,19.14°±0.2°,19.98°±0.2°,20.42°±
0.2°,21.77°±0.2°,22.02°±0.2°,22.45°±0.2°,22.65°±0.2°,23.66°±0.2°,26.85°
± 0.2 °, 27.94 ° ± 0.2 ° and 28.34 ° ± 0.2 °.
In other embodiments, the X-ray powder diffraction collection of the crystal form and Fig. 2 are substantially the same.
In some embodiments, the differential scanning calorimetric curve of the crystal form has maximum endothermic peak at 219 DEG C ± 3 DEG C.
In other embodiments, the differential scanning calorimetric curve of the crystal form and Fig. 3 are substantially the same.
In some embodiments, when the crystal form is heated to 150 DEG C, thermal gravimetric analysis curve includes about 0.23%
Weight loss.
In other embodiments, the thermal gravimetric analysis curve of the crystal form and Fig. 4 are substantially the same.
In some embodiments, the crystal form is substantially pure.
In the second aspect of the present invention, the invention proposes a kind of pharmaceutical compositions.According to an embodiment of the invention, it is wrapped
Containing mentioned-above crystal form.
In some embodiments, the pharmaceutical composition further include pharmaceutically acceptable excipient, carrier,
Adjuvant, solvent or their combination.
In other embodiments, the pharmaceutical composition further includes other antiproliferatives, described anti-
Multiplication agent be melphalan (melphalan), cyclophosphamide (cyclophosphamide), ifosfamide (ifosfamide),
Busulfan (busulfan), Carmustine (carmustine), lomustine (lomustine), streptozotocin
(streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacca bar
Piperazine (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 (icotinibhydrochloride), 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 (brivanibalaninate), 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 (bafetinib), multidimensional for Buddhist nun (selumetinib), for pyrrole method Buddhist nun (replacing pyrrole method Buddhist nun), Ba Fei
For Buddhist nun (dovitinib), saracatinib (saracatinib), Telatinib (telatinib), replace Wo Zhani
(tivozanib), alemtuzumab (alemtuzumab), bevacizumab (bevacizumab), the appropriate monoclonal antibody Wei Duoting in Belém
(brentuximab 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.
In the third aspect of the present invention, the invention proposes mentioned-above crystal form A or mentioned-above pharmaceutical compositions
Purposes in medicine preparation, the drug are used to prevent, treat or mitigate the proliferative diseases of patient.
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 includes being selected from VEGFR, Flt3, c-Met, Axl
Or at least one of 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 " 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.
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 A 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 new crystal type
A, the invention further relates to the compositions for containing disclosed new crystal type A.The therapeutical uses of the crystal type A and containing it
Therapeutic combination represents the individual aspect of the disclosure.Technology for characterizing crystal type A describes in the examples below.These skills
Art can be used singly or in combination to characterize crystal type disclosed herein.Crystal type is see also drawing features disclosed herein.
On the one hand the present invention provides the crystal form A of compound shown in formula (I),
It is characterized by:
1) the corresponding 2 θ value of the characteristic peak of the X-ray powder diffraction collection of the crystal form includes 8.29 ° ± 0.2 °, 9.53 °
± 0.2 °, 11.11 ° ± 0.2 °, 16.99 ° ± 0.2 °, 18.75 ° ± 0.2 ° and 23.66 ° ± 0.2 °；Or
2) crystal form has unit cell parameters below:
Structure cell specification:α=96.689 °, β=
95.737 °, γ=99.649 °；
Space group: P-1；
Unit cell volume:
Asymmetry unit number Z:2 in structure cell；With
Calculate density: 1.377g/cm3。
In some embodiments, the corresponding 2 θ value of the characteristic peak of the X-ray powder diffraction collection of the crystal form A includes
8.29°±0.2°,9.53°±0.2°,11.11°±0.2°,15.28°±0.2°,16.99°±0.2°,18.75°±0.2°,
19.14 ° ± 0.2 °, 19.98 ° ± 0.2 °, 20.42 ° ± 0.2 °, 21.77 ° ± 0.2 °, 22.02 ° ± 0.2 ° and 23.66 ° ±
0.2°。
In other embodiments, the corresponding 2 θ value packet of the characteristic peak of the X-ray powder diffraction collection of the crystal form A
Include 8.29 ° ± 0.2 °, 9.53 ° ± 0.2 °, 11.11 ° ± 0.2 °, 12.67 ° ± 0.2 °, 14.04 ° ± 0.2 °, 15.28 ° ±
0.2°,15.82°±0.2°,16.99°±0.2°,18.75°±0.2°,19.14°±0.2°,19.98°±0.2°,20.42°
±0.2°,21.77°±0.2°,22.02°±0.2°,22.45°±0.2°,22.65°±0.2°,23.66°±0.2°,
26.85 ° ± 0.2 °, 27.94 ° ± 0.2 ° and 28.34 ° ± 0.2 °.
In other embodiments, the X-ray powder diffraction collection of the crystal form A and Fig. 2 are substantially the same.
In some embodiments, the differential scanning calorimetric curve of the crystal form A has maximum endothermic peak at 219 DEG C ± 3 DEG C.
In other embodiments, the differential scanning calorimetric curve of the crystal form A and Fig. 3 are substantially the same.
In some embodiments, when the crystal form A is heated to 150 DEG C, thermal gravimetric analysis curve includes about 0.23%
Weight loss.
In other embodiments, the thermal gravimetric analysis curve of the crystal form A and Fig. 4 are substantially the same.
In some embodiments, the crystal form A is substantially pure.
On the other hand, the present invention provides a kind of pharmaceutical composition, and it includes crystal form A shown in the formula (I) compound.
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 (icotinibhydrochloride), 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 (brivanibalaninate), 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 (bafetinib), multidimensional for Buddhist nun (selumetinib), for pyrrole method Buddhist nun (replacing pyrrole method Buddhist nun), Ba Fei
For Buddhist nun (dovitinib), saracatinib (saracatinib), Telatinib (telatinib), replace Wo Zhani
(tivozanib), alemtuzumab (alemtuzumab), bevacizumab (bevacizumab), the appropriate monoclonal antibody Wei Duoting in Belém
(brentuximab 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 present invention provides the medicine groups of the crystal form A of formula (I) compound or crystal form A comprising (I) compound
The purposes of object in medicine preparation is closed, 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 includes being selected from VEGFR, Flt3, c-Met, Axl
Or at least one of Mer.
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.
Detailed description of the invention
Fig. 1 is that the conformation of the crystal form A of formula (I) compound of based single crystal x-ray analysis according to an embodiment of the present invention is shone
Piece；
Fig. 2 is X-ray powder diffraction (XRPD) figure of the crystal form A of formula according to an embodiment of the present invention (I) compound；
Fig. 3 is differential scanning calorimetry (DSC) curve of the crystal form A of formula according to an embodiment of the present invention (I) compound；
Fig. 4 is thermogravimetric analysis (TGA) curve of the crystal form A of formula according to an embodiment of the present invention (I) compound；And
Fig. 5 is the solid-state of the crystal form A of formula according to an embodiment of the present invention (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.
It is realApply 1 N- of example (the fluoro- 4- of 3- ((7- (2- hydroxy-2-methyl propoxyl group) quinolyl-4) oxygroup) phenyl) -1,5- The preparation of the crystal form A of dimethyl -3- oxo -2- phenyl -2,3- dihydro-1 h-pyrazole -4- formamide tosilate
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 (10g, 17.97mmol) is suspended in ethyl alcohol (36mL), room temperature
After stirring 30 minutes, it is slowly added to water (15mL) solution of 4- toluenesulfonic acid hydrate (4.44g, 23.36mmol) thereto.
Gained system is heated to 60~70 DEG C, and stirring to solid is all dissolved, and after continuing stirring 30 minutes, cooled to room temperature has
Solid is precipitated.The suspension obtained again is stirred at room temperature 1 hour, and is slowly added to 129mL water thereto.It is small to continue stirring 3
Shi Hou, filtering, obtained solid 55 DEG C dry 24 hours to constant weight, obtain title compound be white solid (12.50g,
95.4%).
Solid phase13C NMR (101MHz) δ (ppm): 167.83,165.36,162.39,156.94,152.86,146.62,
144.28,141.33,134.26,131.79,128.33,126.21,124.21,120.71,115.77,113.98,108.33,
102.58,101.68,98.69,73.39,71.77,33.94,28.13,25.54,21.59,12.66。
Characterize embodiment
1. single crystal X-ray is studied
Cu K α radiation is used on Agilent Technologies Gemini A Ultra diffractometer
Data are collected, being indexed and handle using CrysAlis PRO program for the intensity data of measurement is determined brilliant by preliminary experiment
Born of the same parents' parameter formulates data collection strategy according to cell parameter to carry out data collection.
Structure elucidation and refine use SHELX-97 (Sheldrick, G.M.SHELXTL-97, Program for
Crystal Structure Solution and Refinement；University of Gottingen:Gottingen,
Germany, 1997) program progress, it is parsed by direct method.Derived atomic parameter (coordinate and temperature factor) has passed through
Complete matrix least square method amendment.The function ∑ minimized in amendmentw(|Fo|-|Fc|)2.R is defined as ∑ | | Fo|-|Fc||/
∑|Fo|, and Rw=[∑w(|Fo|-|Fc|)2/∑w|Fo|2]1/2, wherein w is that the suitable of the error in the intensity based on observation adds
Weight function.Difference plot checks in modified all stages.In addition to the position of hydrogen atom H1N and H2N are true using difference Fourier figure
Fixed outer, the position of remaining hydrogen atom is obtained by theoretical calculation.Simulation powder X-ray pattern is calculated using Mercury software
It arrives.
Select be tested to be 0.15 × 0.15 × 0.10 millimeter monocrystalline carry out single crystal diffraction analysis.The crystal of selection is used
A small amount of vaseline is fixed on thin glass fiber, and is installed to Agilent Technologies Gemini A Ultra diffraction
It is measured on instrument.
The crystal form A of formula (I) compound, which has, is approximately equal to cell parameter characterization listed in table 1.Cell parameter is in about 150K
Temperature measurement.
Table 1: the cell parameter of the crystal form A of formula (I) compound
The result of structure elucidation is that for tool there are two formula unit (formula unit), structure is three oblique spaces in structure cell
Group P-1.The structure contains N- (the fluoro- 4- of 3- ((7- (2- hydroxy-2-methyl propoxyl group) quinoline-in the protonation of quinoline nitrogen-atoms
4- yl) oxygroup) phenyl) and -1,5- dimethyl -3- oxo -2- phenyl -2,3- dihydro-1 h-pyrazole -4- formamide cation and
The p-methyl benzenesulfonic acid anion of single ion, ratio 1:1.The fractional atomic coordinates of the crystal form A of formula (I) compound such as 2 institute of table
Show.
Table 2: the fractional atomic coordinates of the crystal form A of formula (I) compound
2. 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 be (Cu, k α,1.540598；1.544426；1 intensity of K α 2/K α: 0.50), wherein voltage is set in 45KV, electricity
Stream is set in 40mA, the divergence of X-ray, i.e., the effective dimensions that X-ray constrains on sample is 10mm, continuous using θ-θ
Scan pattern 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
At specimen holder circular groove, is gently pressed with clean glass slide, obtain a smooth plane, and zero Background Samples frame is fixed.
Sample (usually 1~2mg) is generated within the scope of 3~40 ° of 2 θ ± 0.2 ° to traditional XRPD figure with 0.0167 ° of scanning step
Case (as shown in Figure 2).Software for data collection is Data Collector, data Data Viewer and HighScore
Plus analysis and displaying, such as table 3.
Table 3: the X-ray powder diffraction of the crystal form A of formula (I) compound analyzes result
3. 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 A of formula (I) compound, can as shown in figure 3, it includes 219 DEG C of endothermic peak
In the presence of ± 3 DEG C of error margin.
4. thermogravimetric 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 A of formula (I) compound as shown in figure 4, when being heated to 150 DEG C, it includes
0.23% weight loss.
5. 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 (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 4, data result
It is shown in Table 5.
Table 4:
Table 5:
NT: undetermined.
Conclusion: 5 data of table can be seen that the crystal form A 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 A of formula (I) compound and amorphous in high temperature, high humidity and normal
It is stable under the conditions of temperature.
Under illumination condition, the crystal form A of formula (I) compound: compared with 0 day, main peak decline 0.13%；Formula (I) compound
It is amorphous: main peak decline 0.42%；Illustrate under illumination condition, the crystal form A of formula (I) compound is than amorphous stabilization.
6. hygroscopicity test
Empty weighing bottle jump a queue son weight be denoted as m1, crystal form A 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% relative humidity (RH)), place 10 days under the conditions of 25 DEG C ± 1 DEG C, taken respectively in the 5th, the 10th day
One bottle of detection, the weight of weighing bottle are denoted as m3, draw and moist calculated according to following formula, wherein judge hygroscopic foundation such as table 6
It is shown, the crystal form A of formula (I) compound and unbodied draw wet test the results are shown in Table 7.
Table 6:2015 version " Chinese Pharmacopoeia " is to drawing the description of moist feature 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 | Moisture absorption weight gain is 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% |
Table 7: the crystal form A of formula (I) compound and unbodied draw wet test result
Conclusion: consolidated statement 6 and table 7 are it is found that the crystal form A of compound shown in formula (I) is moist without drawing；Compound shown in formula (I)
It is amorphous have draw it is moist.
7. 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: 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.
The crystal form A 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 8.
Table 8: the crystal form A and the amorphous pharmacokinetic data in beasle dog of formula (I) compound
Conclusion: from upper table result as it can be seen that the C of crystal form Amax、AUC0-24hAnd AUC0-∞It is more much larger than amorphous, show this
Crystal form A 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 (12)
1. the crystal form of compound shown in formula (I),
It is characterized by:
1) the corresponding 2 θ value of the characteristic peak of the X-ray powder diffraction collection of the crystal form include 8.29 ° ± 0.2 °, 9.53 ° ±
0.2 °, 11.11 ° ± 0.2 °, 16.99 ° ± 0.2 °, 18.75 ° ± 0.2 ° and 23.66 ° ± 0.2 °；Or
2) crystal form has unit cell parameters below:
Structure cell specification:α=96.689 °, β=95.737 °, γ=
99.649°；
Space group: P-1；
Unit cell volume:
Asymmetry unit number Z:2 in structure cell；With
Calculate density: 1.377g/cm3。
2. crystal form according to claim 1, the corresponding 2 θ value of the characteristic peak of X-ray powder diffraction collection includes 8.29 °
±0.2°,9.53°±0.2°,11.11°±0.2°,15.28°±0.2°,16.99°±0.2°,18.75°±0.2°,19.14°
± 0.2 °, 19.98 ° ± 0.2 °, 20.42 ° ± 0.2 °, 21.77 ° ± 0.2 °, 22.02 ° ± 0.2 ° and 23.66 ° ± 0.2 °.
3. crystal form according to claim 1, the corresponding 2 θ value of the characteristic peak of X-ray powder diffraction collection includes 8.29 °
±0.2°,9.53°±0.2°,11.11°±0.2°,12.67°±0.2°,14.04°±0.2°,15.28°±0.2°,15.82°
±0.2°,16.99°±0.2°,18.75°±0.2°,19.14°±0.2°,19.98°±0.2°,20.42°±0.2°,
21.77°±0.2°,22.02°±0.2°,22.45°±0.2°,22.65°±0.2°,23.66°±0.2°,26.85°±
0.2 °, 27.94 ° ± 0.2 ° and 28.34 ° ± 0.2 °.
4. crystal form according to claim 1, X-ray powder diffraction collection are substantially the same with Fig. 2.
5. crystal form according to claim 1, wherein the crystal form is substantially pure.
6. a kind of pharmaceutical composition, it includes crystal forms described in claim 1-5 any one.
7. pharmaceutical composition according to claim 6 further includes pharmaceutically acceptable excipient, carrier, assistant
Agent, solvent or their combination.
8. pharmaceutical composition according to claim 6 or 7, wherein further include other antiproliferatives, it is described anti-
Multiplication agent be melphalan, cyclophosphamide, ifosfamide, busulfan, Carmustine, lomustine, streptozotocin, cis-platinum,
Carboplatin, oxaliplatin, Dacarbazine, Temozolomide, procarbazine, methotrexate (MTX), fluorouracil, cytarabine, gemcitabine,
Purinethol, fludarabine, vincaleukoblastinum, vincristine, vinorelbine, taxol, Docetaxel, topotecan, Yi Li are replaced
Health, Etoposide, tributidine, dactinomycin D, Doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, silk
Rimocidin C, Ipsapirone, tamoxifen, Flutamide, Gonadorelin analog, megestrol acetate, prednisone, dexamethasone, first are sprinkled
Nylon, Thalidomide, interferon-' alpha ', Calciumlevofolinate, sirolimus, tesirolimus, everolimus, Afatinib, A Xi are replaced
Buddhist nun, bosutinib, card it is rich for Buddhist nun, Ceritinib, gram Zhuo for Buddhist nun, dabrafenib, Dasatinib, Tarceva, Gefitinib, according to
Replace Buddhist nun, hydrochloric acid Conmana, Imatinib, Lapatinib, nilotinib, pazopanib, piperazine Jia Tani, Ponatinib, drawing in Shandong
Mostly Buddhist nun, Sorafenib, Sutent, tropsch imatinib, Trimetinib, Vande Thani, prestige sieve are replaced for Buddhist nun, Rui Gefeini, Luso benefit
Fei Ni, methanesulfonic acid Ah pa for Buddhist nun, Masitinib, alanine Bu Linibu, Si Dinibu, up to can for Buddhist nun, good fortune he replace Buddhist nun, diphosphonic acid
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, for fertile
Zha Ni, alemtuzumab, bevacizumab, the appropriate monoclonal antibody Wei Duoting in Belém, catumaxomab, Cetuximab, promise monoclonal antibody, lucky appropriate pearl
Monoclonal antibody, her monoclonal antibody, Buddhist nun's trastuzumab, difficult to understand, Victibix, Rituximab, tositumomab, toltrazuril list
Anti-, idelalisib, duvelisib, gilteritinib, buparlisib, taselisib, copanlisib,
voxtalisib、pilaralisib、sonolisib、perifosine、alectinib、ibrutinib、pertuzumab、
Nintedanib, cobimetinib, temsirolimus, sirolimus, pixantrone or their any combination.
9. prepared by pharmaceutical composition described in crystal form described in claim 1-5 any one or claim 6-8 any one
Purposes in drug, the drug are used to prevent, treat or mitigate the proliferative diseases of patient.
10. purposes according to claim 9, wherein the proliferative diseases include colon and rectum carcinoma, gastric cancer, stomach
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.
11. pharmaceutical composition described in crystal form described in claim 1-5 any one or claim 6-8 any one is being made
Purposes in standby drug, the drug is for inhibiting receptor tyrosine kinase activity.
12. purposes according to claim 11, wherein the receptor tyrosine kinase includes being selected from VEGFR, Flt3, c-
At least one of Met, Axl or Mer.
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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 |
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