CN107519175A - A kind of pyrimidine compound or its salt are preparing the application in being used to prevent and/or treat the medicine of the disease related to FLT3 or obstacle - Google Patents

A kind of pyrimidine compound or its salt are preparing the application in being used to prevent and/or treat the medicine of the disease related to FLT3 or obstacle Download PDF

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CN107519175A
CN107519175A CN201610451801.9A CN201610451801A CN107519175A CN 107519175 A CN107519175 A CN 107519175A CN 201610451801 A CN201610451801 A CN 201610451801A CN 107519175 A CN107519175 A CN 107519175A
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cancer
flt3
disease
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salt
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蔡伟惠
金方
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Shanghai Fang Yu Health And Medicine Science And Technology Ltd
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Priority to PCT/CN2017/073657 priority patent/WO2017219690A1/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
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Abstract

The present invention relates to a kind of pyrimidine compound or its salt to prepare the application in being used to prevent and/or treat the medicine of the disease related to FLT3 or obstacle, wherein shown in the structure of pyrimidine compound such as formula (I).

Description

A kind of pyrimidine compound or its salt are being prepared for preventing and/or treating and FLT3 phases Application in the disease of pass or the medicine of obstacle
Technical field
The present invention relates to a kind of pyrimidine compound or its salt to prepare for preventing and/or treating the disease related to FLT3 Or the application in the medicine of obstacle.
Background technology
Malignant tumour is one of major disease for seriously endangering human health, what national tumour Register issued a few days ago 《China's tumour registration annual report in 2013》Display:Chinese annual new cancer cases are up to 3,090,000, are counted within 74 years old according to average life span Calculate, all one's life, cancered probability was up to 22%, and cancer turns into a kind of common disease.Just there is one in every 5 dieds of China extremely In cancer, the 1/4 of whole world number of cancer deaths is accounted for, cancer turns into the second largest killer after angiocardiopathy.It is although near Rapid progress is clinically achieved over year in terms of the treatment means such as the chemotherapy of tumour, radiotherapy, molecular targeted therapy, but tumour is grown Phase survival rate is not improved significantly, and researches and develops the focus that new antineoplastic is still current medicine research and development.
In recent years, kinases inhibitor always is the hot fields of antineoplastic research and development, has many small molecules to swash Enzyme inhibitor such as Imatinib, Sorafenib and Sutent have listed, in addition with substantial amounts of small molecule kinase inhibitors In clinical investigation phase.FMS samples EGFR-TK 3 (Fms-like tyrosine kinase, FLT3) also known as tire liver kinases- 2 (Fetal Liver Kinase-2, FLK2) and stem cell kinases -1 (Stem Cell Kinase-1, STK1), it is a kind of the Three receptoroid EGFR-TKs.FLT3 is receptor type tyrosine kinase, and its native ligand includes platelet derived growth factor (Platelet Derived Growth Factor, PDGF), (the Colony Stimulating Factor of colony stimulating factor 1 1, CSF-1) and Kit kinase ligands (Kit ligand, KL), after part is combined with FLT3, make FLT3 that dimerization, while its occur The tyrosine kinase domain of intracellular occurs phosphorylation and is activated, so as to start the phosphatidylinositols -3- hydroxyl kinases in downstream (Phosphatidyl Inositol3-Kinase, PI3K) path and Ras paths, promote the multiple fission of cell, promote simultaneously Anti-apoptotic proteins BCL2 family proteins BAD (BCL2Associated Death promoter) activation, withers so as to suppress cell Die.
FLT3 is with including albumen (SH2-containing sequence proteins, SHCs) including SH2, being tied containing SH2 The inositol monophosphate enzyme (SH2-domain-containing InositolPhosphatase, SHIP) in structure domain, include SH2 structures The tyrosine protein in domain phosphatase (SH2-domain-containing Protein Tyrosine Phosphatase-2, SHP2), the interaction of multiple albumen including Cbl and GRB2 associated proteins 2 (GRB2-associated binder, GAB2) PI3K activity can be adjusted.The PI3K of activation can activate (the 3- of kinases -1 relied on including 3- phosphoinositides Phosphoinositide-Dependent Kinase-1, PDK1), protein kinase B (Protein Kinase B, Akt1/ PKB) and the downstream signal including rapamycin target protein (mammalian Target of Rapamycin, mTOR), and then swash Living ribosome S 6 K protein kinases (S6K), suppress eukaryotic initiating because 4E Binding Protein 1s (4E-Binding Protein 1, 4E-BP1), the transcription and translation of key gene is finally started.FLT3 can mediate Ras paths simultaneously, after FLT3 activation, joint Growth factor receptor binding protein precursor 2 (Growth Factor Receptor Bound 2, GRB2) activates Ras by SHC, and then Activation includes Raf, Mitogen-actived protein kinase (MAPK/ERK Kinases, MEK), p38, extracellular signal-regulated kinase 1/2 (Extracellular Signal-Regulated Kinase 1/2, ERK1/2) and ribosome S 6 protein kinase Downstream signal including (Ribosomal S6Kinase, RSK), and these downstream signal and cans activation CAMP reaction member Part associated proteins (cAMP Response Element Binding protein, CREB), Elk (also known as hematopoietin Produce hepatocyte receptors B1, Erythropoietin-Producing Hepatocellular receptor B1, EPH Receptor B1) and signal transduction and transcription activator (Signal Transducer and Activator of Transcription, STAT), final transcription and translation goes out in cell propagation the albumen needed, promotes multipotential stem cell, early stage ancestral Cell and jejune lymphopoiesis.
FLT3 is related to a variety of diseases, as tumour, cancer and hematologic malignancies (Ansari-Lari, Ali.FLT3mutations in myeloid sarcoma.British Journal of Haematology.126(6): 785-91).The target spot that FLT3 researchs and develops as antineoplastic, the broad interest of academia's particularly industrial quarters is attracted. The FLT3 inhibitor of many configurations is had now found that, wherein 4 inhibitor have been approved to list, more candidate compounds are just In clinical experimental stage.At present, the inhibitor listed is mainly used in the treatment of various tumours.FLT3 inhibitor is as anti-swollen Tumor medicine, clinical efficacy is obvious, and side effect is controllable, thus is obtaining more and more extensive application.In 4 marketed drugs, Sorafenib (listing for 2005) and Sutent (listing for 2006) were respectively in the sales volumes of 2013:1000000000 2,300 ten thousand is beautiful Member and 1,200,000,000 400 ten thousand dollars, in pairs more than 1,000,000,000 dollars.And the pa of 2013 listings is received and just reached for the sales volume of Buddhist nun's First Year 45200000 dollars.Card is rich to be listed for Buddhist nun in 2013, and the sale of First Year reaches 15,000,000 dollars.It can be seen that FLT3 inhibitor conducts Antineoplastic, its sales volume have very promising prospects.
The content of the invention
Applicants have unexpectedly found that 5- amino-N- (4- (azepan -4- epoxides) pyrimidine -5-) -2- (2,6- difluorobenzenes Base) thiazole -4-carboxamide (compound shown in formula (I)) and its pharmaceutically acceptable salt have very strong FLT3 activity, because This, it is an object of the invention to provide compound shown in a kind of formula (I) or its pharmaceutically acceptable salt to prepare for preventing And/or the application in the medicine of the treatment disease related to FLT3 or obstacle.
Technical scheme is as described below:
The invention provides compound shown in a kind of formula (I) or its pharmaceutically acceptable salt prepare be used to prevent and/ Or the application in the medicine of the treatment disease related to FLT3 or obstacle;
Wherein, compound shown in the formula (I) is 5- amino-N- (4- (azepan -4- epoxides) pyrimidine -5-) -2- (2,6- difluorophenyls) thiazole -4-carboxamide.
Wherein, the pharmaceutically acceptable salt refers to the conventional salt form of pharmaceutical field, and they can be and physiology The salt that compatible organic and inorganic acid is formed, these acid form the nontoxicity acid containing pharmaceutically acceptable acid radical anion and added Into salt, it is preferable that the pharmaceutically acceptable salt includes but is not limited to:Hydrochloride, hydrobromate, maleate, phosphorus Hydrochlorate, succinate, sulfate, citrate, benzoate, mesylate, lactate, acetate, to toluene sulphur hydrochloric acid, palm fibre Palmitic acid hydrochlorate, fumarate, tartrate, ascorbate, nitrate, formates, propionate, n-butyric acie salt, isobutyric acid Salt, salicylate, oxalates, succinate, malate, glutamate, aspartate or gluconate;
It is highly preferred that the pharmaceutically acceptable salt be hydrochloride, phosphate, mesylate, lactate, acetate, Sulfate or hydrobromate;
It is further preferred that the pharmaceutically acceptable salt is hydrochloride.
Preferably, the pharmaceutically acceptable salt is crystal.
Preferably, when the pharmaceutically acceptable salt is hydrochloride, in the X ray diffracting spectrum of the hydrochloric acid salt crystal The diffraction maximum represented including following 2 θ angles:5.5±0.2°、8.5±0.2°、9.8±0.2°、17.2±0.2°、23.1±0.2°、 25.5±0.2°、27.8±0.2°;
It is highly preferred that also include the diffraction maximum that following 2 θ angles represent in the X ray diffracting spectrum of the hydrochloric acid salt crystal: 13.6±0.2°、20.9±0.2°、26.7±0.2°、30.0±0.2°、34.2±0.2°;
It is further preferred that the X ray diffracting spectrum of the hydrochloric acid salt crystal is as shown in Figure 3.
Preferably, formula (I) compound or its pharmaceutically acceptable salt can be by oral, quiet as active ingredient Arteries and veins injection, intramuscular injection, hypodermic injection or the mode that is locally administered are applied to mammal (such as people).
Preferably, the medicine is solid pharmaceutical preparation or liquid preparation, i.e., compound shown in described formula (I) or its pharmaceutically may be used The salt of receiving can be prepared into solid pharmaceutical preparation or liquid preparation;
Preferably, the solid pharmaceutical preparation is selected from capsule, tablet, pill, powder, granule, sugar-pill and freeze-dried;
Preferably, the liquid preparation is selected from solution, injection, suspension, oral liquid, syrup, tincture and emulsion agent.
The disease related to FLT3 or obstacle include the disease related with FLT3 acceptors, are related to the disease of FLT3 activity Or the illness with above-mentioned disease.
Preferably, the disease related to FLT3 or obstacle refer to as caused by abnormal or uncontrolled cell growth Tumour, including but not limited to hematopoietic disorder, specifically there are myeloproliferative disorder, such as thrombocythemia, essential thrombocythemia Increase (ET), agnogenic myeloid metaplasia, myelofibrosis (MF), the myelofibrosis (MMM) with the outer metaplasia of marrow, chronic spy Hair property myelofibrosis (IMF), polycythemia vera (PV), cytopenia and pernicious preceding myelodysplasia synthesis Sign.
Preferably, the disease related to FLT3 or obstacle are selected from glioma, lung cancer, breast cancer, colorectal cancer, preceding Row gland cancer, stomach cancer, cancer of the esophagus, colon cancer, cancer of pancreas, oophoroma, kidney, thyroid cancer, neuron cancer and uterine cancer.
Preferably, the disease related to FLT3 or obstacle are selected from leukaemia, lymthoma and myeloma;
Preferably, the leukaemia is selected from acute myelocytic leukemia (AML), ALL (ALL), urgency It is property progranulocyte leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), chronic thermophilic Neutrophil leucocyte leukaemia (CNL), acute undifferentiated cell leukemia (AUL), prolymphocytic leukemia (PML), juvenile form Myelomonocytic leukemia (JMML), human adult T cell's ALL, acute myeloid leukemia are with three systems morbid state Hematopoiesis (AML/TMDS), mixing blood system's leukaemia (MLL);
Preferably, the lymthoma is NHL or Hodgkin lymphoma, such as anaplastic maxicell Property lymthoma;
Preferably, the plasma cell dyscrasias includes Huppert's disease, macroglobulinemia or heavy chain disease;
Preferably, the myeloma is selected from myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), multiple Myeloma (MM) and spinal cord sarcoma.
Brief description of the drawings
Hereinafter, embodiment of the present invention is described in detail with reference to accompanying drawing, wherein:
Fig. 1 is formula (I) compound hydrochloride that embodiment 2 obtains1HNMR collection of illustrative plates;
Fig. 2 is the mass spectrogram of formula (I) compound hydrochloride that embodiment 2 obtains;
Fig. 3 is the X-ray powder diffraction pattern of formula (I) compound hydrochloride that embodiment 2 obtains.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip Part or according to the condition proposed by manufacturer.
Unless otherwise defined, anticipated known to all specialties used in text and scientific words and one skilled in the art Justice is identical.In addition, any method similar or impartial to described content and material all can be applied in the inventive method.Wen Zhong Described preferable implementation only presents a demonstration with material to be used.
The synthesis of the formula of embodiment 1 (I) compound
1) preparation of 4- (5- amidino-pyridine -4- hydroxyls)-azepan -1- t-butyl formates (SM-3)
Under the conditions of room temperature (25 DEG C), NaH (71mg, 2.94mmol) is added into the tertiary fourth of 4- hydroxy-azepane -1- formic acid THF (tetrahydrofuran) (10mL) solution & stir of ester (SM-2) (574mg, 2.67mmol) 1 hour, it is phonetic then to add 4- bromines Pyridine -5- amine (SM-1) (348mg, 2.67mmol).Reactant is heated to 100 DEG C under nitrogen protection, in room temperature after stirring 4 hours Vacuum rotating concentrates under (20-30 DEG C).Residue by silica gel chromatography post purifies (eluent after concentration:10-30% ethyl acetate/ Petroleum ether) obtain product 4- (5- amidino-pyridine -4- hydroxyls)-azepan -1- t-butyl formates (SM-3) (370mg, 1.2mmol)。
2) 4- (5- (5- amino -2- (2,6- difluorophenyls) thiazole -4-carboxamide) pyrimidine -4- epoxides) azepan - The preparation of 1- t-butyl formates (SM-5)
Compound (SM-3) (52mg, 0.169mmol), compound 5- amino -2- (2,6- difluorophenyl)-thiazole -4- first Sour (1E) (SM-4) (40mg, 0.169mmol), HATU (77mg, 0.203mmol) and DIEA (93 μ L, 0.507mmol) are in DMF Mixture in (5mL) stirs 1 hour at 50 DEG C.Diluted with ethyl acetate (50mL) after cooling, then washed with saturated common salt Wash.Organic phase is through Na2SO4Vacuum rotating concentrates under room temperature (20-30 DEG C) after drying.Residue by silica gel chromatography post after concentration (eluent after purification:10-30% ethyl acetate/petroleum ethers) obtain product 4- (5- (5- amino -2- (2,6- difluorophenyls) thiophenes Azoles -4- formamides) pyrimidine -4- epoxides) azepan -1- t-butyl formates (SM-5) (32mg, 0.0585mmol).
3) 5- amino-N- (4- (azepan -4- epoxides) pyrimidine -5-) -2- (2,6- difluorophenyls) thiazole -4- formyls The preparation of amine (structural formula I)
Under the conditions of room temperature (25 DEG C), by TFA (trifluoracetic acid) (0.5mL) add compound (SM-5) (21mg, CH 0.0384mmol)2Cl2(1mL) solution, stir 10 minutes, under room temperature (25 DEG C) after vacuum rotating concentration, by residue It is dissolved in CH2Cl2(10mL), solution are washed with the sodium hydroxide (5mL) and saturated aqueous common salt (5mL) of 1 equivalent respectively, organic phase warp Na2SO4Product 5- amino-N- (4- (azepan -4- epoxides) are made in vacuum rotating concentration under room temperature (25 DEG C) after drying Pyrimidine -5-) -2- (2,6- difluorophenyl) thiazole -4-carboxamide (structural formula I) (11mg, 0.0246mmol).
1H NMR (400MHz, CD3OD):δ ppm 1.55-1.65 (m, 1H), 1.83-1.96 (m, 1H), 2.03-2.13 (m, 4H), 2.76-2.79 (m, 1H), 2.81-2.85 (m, 2H), 2.90-2.96 (m, 1H), 5.44-5.50 (m, 1H), 7.02- 7.06 (m, 2H), 7.31-7.38 (m, 1H), 8.31 (s, 1H), 9.36 (s, 1H).
MS(ESI)447m/z(M+H)+
The synthesis of the formula of embodiment 2 (I) compound hydrochloride
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 is added to anti- Answer in bottle, 20~30 DEG C of stirring clarifications, disposable to add 165ul1N hydrogen chloride methanol solutions (0.165mmol), solution slowly becomes Muddiness, 20~30 DEG C of insulated and stirred half an hour, filtering, 50 DEG C of filter cake are dried in vacuo to obtain 38mg off-white powders, yield: 52.7%, mp:232.3~235.4 DEG C.
Wherein1HNMR (400MHz, DMSO-d6) spectrogram as shown in figure 1, mass spectrogram as shown in Fig. 2 wherein, m/z:447.9 [(M-HCl)+H]+, 446.9 [M-HCl]+.
Formula (I) compound hydrochloride being prepared is crystal, and the X ray diffracting spectrum of its crystal is as shown in figure 3, specific Testing conditions are as follows, and testing result refers to table 1:
Detecting instrument:Bruker D8 AdvanceX light ray diffractometers
Testing conditions:Target=Cu copper, start 2 θ scannings=3.000, terminate 2 θ and scan=40.000, voltage 40KV, electricity Flow 40mA, Ka1=1.54060, Ka2=1.54439, Ka2/Ka1 ratios=0.5, Ka=1.54186.
The X-ray diffractogram modal data of the formula of table 1 (I) compound hydrochloride crystal
The phosphatic preparation of the formula of embodiment 3 (I) compound
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 is added to anti- Answer in bottle, 20~30 DEG C of stirring clarifications, the disposable mixed solution for adding 5mg phosphoric acid (0.051mmol) and 0.5ml methanol is molten Liquid slowly becomes cloudy, 20~30 DEG C of insulated and stirred half an hour, and filtering, 50 DEG C of filter cake is dried in vacuo to obtain 45mg off-white powders, receives Rate:85.4%, mp:218.3~220.8 DEG C.m/z:447.9[(M-H3PO4)+H]+, 446.9 [M-H3PO4]+。
The preparation of the formula of embodiment 4 (I) compound methanesulfonic acid salt
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 is added to anti- Answer in bottle, 20~30 DEG C of stirring clarifications, the disposable mixed solution for adding 16mg methanesulfonic acids (0.166mmol) and 0.5ml methanol, Solution is clarified, 20~30 DEG C of insulated and stirred half an hour, 50 DEG C of evaporated under reduced pressure solvents, adds 20~30 DEG C of stirrings of 10ml dichloromethane Half an hour, filtering, 50 DEG C of filter cake are dried in vacuo to obtain 41mg off-white powders, yield:68.7%, mp:238.1~241.7 DEG C.m/ z:447.9[(M-CH4O3S)+H]+, 446.9 [M-CH4O3S]+。
The preparation of the formula of embodiment 5 (I) compound lactate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 is added to anti- Answer in bottle, 20~30 DEG C of stirring clarifications, the disposable mixed solution for adding 15mg lactic acid (0.167mmol) and 0.5ml methanol is molten Liquid is clarified, 20~30 DEG C of insulated and stirred half an hour, 50 DEG C of evaporated under reduced pressure solvents, adds 20~30 DEG C of stirrings of 10ml dichloromethane half Hour, filtering, 50 DEG C of filter cake is dried in vacuo to obtain 40mg off-white powders, yield:67.8%, mp:208.2~211.5 DEG C.m/z: 447.9[(M-C3H6O3)+H]+, 446.9 [M-C3H6O3]+。
The preparation of the formula of embodiment 6 (I) compound acetate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 is added to anti- Answer in bottle, 20~30 DEG C of stirring clarifications, the disposable mixed solution for adding 10mg acetic acid (0.167mmol) and 0.5ml methanol is molten Liquid is clarified, 20~30 DEG C of insulated and stirred half an hour, 50 DEG C of evaporated under reduced pressure solvents, adds 20~30 DEG C of stirrings of 10ml dichloromethane half Hour, filtering, 50 DEG C of filter cake is dried in vacuo to obtain 35mg off-white powders, yield:62.8%, mp:230.2~235.7 DEG C.m/z: 447.9[(M-CH3COOH)+H]+, 446.9 [M-CH3COOH]+。
The preparation of the formula of embodiment 7 (I) compound sulfate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 is added to anti- Answer in bottle, 20~30 DEG C of stirring clarifications, the disposable mixed solution for adding 8mg sulfuric acid (0.081mmol) and 0.5ml methanol is molten Liquid slowly becomes cloudy, 20~30 DEG C of insulated and stirred half an hour, and filtering, 50 DEG C of filter cake is dried in vacuo to obtain 55mg off-white powders, receives Rate:91.8%, mp:228.5~231.7 DEG C.m/z:447.9[(M-H2SO4)+H]+, 446.9 [M-H2SO4]+。
The preparation of the formula of embodiment 8 (I) compound hydrobromate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 is added to anti- Answer in bottle, 20~30 DEG C of stirring clarifications, the disposable mixing for adding 30%44mg hydrobromic acids (0.163mmol) and 0.5ml methanol Solution, solution slowly become cloudy, 20~30 DEG C of insulated and stirred half an hour, and filtering, 50 DEG C of filter cake is dried in vacuo to obtain 28mg off-white colors Solid, yield:48.2%, mp:221.2~223.5 DEG C.m/z:447.9 [(M-HBr)+H]+, 446.9 [M-HBr]+.
The FLT3 kinase inhibiting activities of embodiment 9
Representative implication of being abridged in following experiments is as follows:
HEPES:Hydroxyethyl piperazine second thiosulfonic acid;
Brij-35:Brij-35;
DTT:Dithiothreitol (DTT);
EDTA:Ethylenediamine tetra-acetic acid;
EGFR:Human epidermal growth factor acceptor;
HER2:Human epidermal growth factor receptor 2;
EGFRT790M:Human epidermal growth factor acceptor T790M mutant;
Peptide FAM-P22:FAM-labeled peptide 22;
ATP:Triphosphoric acid adenosine monophosphate;
DMSO:Dimethyl sulfoxide (DMSO);
Staurosporine:Staurosporine;
Coating Reagent#3:#3 fruit glaze agents
1st, the preparation of 1 × kinase buffer liquid and termination test buffer:
(1) 1 × be free of MnCl2Kinase buffer liquid:50mM HEPES, pH 7.5,0.0015%Brij-35,10mM MgCl2, 2mMDTT;
(2) test buffer is terminated:100mM HEPES, pH 7.5,0.015%Brij-35,0.2%Coating Reagent#3,50mM EDTA.
2nd, the compound of test kinase prepares:Compound serial dilution
(1) using 100%DMSO by 50 times of diluted chemical compound to highest final concentration.By the compound of the 100mL concentration Solution is transferred to a hole of 96 orifice plates.
(2) ratio diluted in 20mL original solutions with 60mL DMSO 10 concentration of diluted compounds successively.
(3) 100mL100%DMSO solution is added in two emptying apertures, compareed as without compound control and without enzyme.
(4) prepare an intermediate plate, each concentration compounds of 10mL are transferred to intermediate plate from raw sheet respectively, and add 1 × kinase buffer liquids of 90mL, vibration mix 10 minutes.
(5) preparing experiment plate:Corresponding aperture transferase 45 mL compound solutions are to corresponding 384 hole from the intermediate plate of 96 orifice plates In plate.
3rd, kinase reaction
(1) 2.5 × enzyme solutions are prepared:Enzyme is added in 1 × kinase buffer liquid.
(2) 2.5 × peptide solution is prepared:FAM-labeled peptide and ATP are added in 1 × kinase buffer liquid.
(3) 10mL2.5 × enzyme solutions are added to the 384 holes reality containing the compound solution that 5mL DMSO contents are 10% Test in plate, be incubated at room temperature 10 minutes.
(4) 10mL2.5 × peptide solution is added in 384 hole brassboards.
(5) kinase reaction and termination:28 DEG C are incubated the corresponding time, add 25mL stop buffer terminating reactions.
4th, DATA REASONING
Read data and collect.
5th, curve matching
(1) data of copy and converted measurement
(2) inhibiting rate is converted to
Inhibiting rate=(maximum-sample value)/(maximum-minimum value) * 100;
Wherein, " maximum " is DMSO control values;" minimum value " is without kinase control hole count value.
(3) enter data into corresponding analysis software and draw IC50 values.
Experimental result is as shown in table 2:
The FLT3 kinase inhibiting activities of the compounds of this invention of table 2
As a result show, the compounds of this invention has preferably external FLT3 inhibitory activity.
Influence of the embodiment 10 to tumor cell proliferation
The present embodiment test present invention compound (formula (I) compound and its hydrochloride that embodiment 1-8 is prepared, Phosphate, mesylate, lactate, acetate, sulfate, hydrobromate) influence to growth of cancer cells, further assess text The inhibitory action of middle compound on tumor cell propagation, and its to suppressing the selectivity of tumor cell proliferation.
Wherein, the present embodiment has selected following cell:
(1) people's acute monocytic leukemia cell line MV4-11 (expression FLT3/ITD mutated genes);
(2) human muscle creatine kinase cell line MOLM-13 (expression FLT3/ITD mutated genes and wild type FLT3 bases Cause);
(3) human muscle creatine kinase cell line MOLM-14 (expression FLT3/ITD mutated genes and wild type FLT3 bases Cause);
(4) human muscle creatine kinase cell line OCI-AML-3 (expression FLT3A680V mutated genes);
(5) human muscle creatine kinase cell line U937 (expression wild type FLT3 genes);
(6) mouse TEL-BaF3-FLT3/ITD (activated protein kinase of stable expression FLT3/ITD mutation);
(7) mouse TEL-BaF3-FLT3-D835Y (activated protein kinase of stable expression FLT3D835Y mutation);
(8) mouse TEL-FLT3-BaF3 (stable expression FLT3 kinases);
(9) mouse BaF3-FLT3-ITD-D835Y (activated protein kinase of stable expression FLT3/ITD D835Y mutation);
(10) mouse BaF3-FLT3-ITD-F691L (activated protein kinase of stable expression FLT3/ITD F691L mutation).
By various concentrations (0.000508 μM, 0.00152 μM, 0.00457 μM, 0.0137 μM, 0.0411 μM, 0.123 μM, 0.370 μM, 1.11 μM, 3.33 μM, 10 μM in DMSO) compound be added separately in above-mentioned cell, and be incubated 72 hours, With CellTiter-Glo (Promega, the U.S.) chemical self-luminous method cell viability detection kit, by living cells ATP is quantitative determined to detect number of viable cells, and experimental result is as shown in table 3.
The influence of the formula of table 3 (I) compound and its salt form (embodiment 1-8 is prepared) cell proliferation
The effect of embodiment 11 is to people's MV-4-11 nude mouse subcutaneous transplantation knurls
Test sample is prepared:With 5% absolute ethyl alcohol+5%Cremophor EL+90% normal salines.
Experimental animal:BALB/cA-nude nude mouses, 6-7 weeks, female ♀, purchased from the limited public affairs of the smooth biotechnology of Shanghai spirit Department.Production licence number:SCXK (Shanghai) 2013-0018;Animal quality certification number 2013001810589.Feeding environment:SPF levels.
Experimental procedure:Nude mouse subcutaneous vaccination people's acute monocytic leukemia MV-4-11 cells, treat tumour growth extremely 80-150mm3Afterwards, animal is grouped at random, every group 6.Dosage 15mg/kg, intraperitoneal injection, 3 times a day, it is administered 21 days. Knurl volume is surveyed, claims mouse weight, record data.
Gross tumor volume (V) calculation formula is:
V=1/2 × a × b2
Wherein, a, b represent length and width respectively.
T/C (%)=(T-T0)/(C-C0)×100
Wherein, T, C are the gross tumor volume at the end of experiment;T0、C0Gross tumor volume when starting for experiment.
Tumour inhibiting rate is calculated, experimental result is as shown in table 4.
The effect of table 4 is to MV-4-11 nude mouse subcutaneous transplantation knurls
The preparation of the tablet of embodiment 12
Take formula (I) compound hydrochloride (embodiment 2 is prepared) 20g, microcrystalline cellulose 60g, lactose 80g, 1g crosslinking PVP crosses 80 mesh sieves respectively, is well mixed, and by the use of 2%HPMC solution as adhesive, crosses the granulation of 18 mesh sieves, dries, cross 20 mesh Whole grain is sieved, adds 1g PVPPs, 1g superfine silica gel powders, 1g magnesium stearates, 10min is mixed, tabletting (0.16g/ pieces), produces.
The preparation of the capsule of embodiment 13
Take formula (I) compound (embodiment 1 is prepared) 5g, microcrystalline cellulose 60g, lactose 80g to cross 80 mesh sieves respectively, mix Close uniformly, addition 1g CMSs are received, 1g magnesium stearates, mix 10min, fill No. 3 capsules, produce.
The preparation of the parenteral solution of embodiment 14
Formula (I) compound acetate (embodiment 6 is prepared) 25g, glucose 50g are taken, adds to 900ml waters for injection In, it is stirred to dissolve, injects water to 1000ml, stir, filtered through 0.22 micron membrane filter, 1ml/ branch is filling to peace Small jar, sealing, 121 DEG C sterilize 20 minutes, produce.
The preparation of the lyophilized formulations of embodiment 15
Formula (I) compound hydrochloride (embodiment 2 is prepared) 10g, mannitol 50g are taken, adds to 900ml waters for injection In, it is stirred to dissolve, injects water to 1000ml, stir, filtered through 0.22 micron membrane filter, 1ml/ branch is filling to XiLin Bottle, it is freeze-dried, sealing, produces.
The preparation of the oral liquid of embodiment 16
Formula (I) compound methanesulfonic acid salt (embodiment 4 is prepared) 30g, sucrose 200g are taken, essence 1g, adds to 900ml water In, it is stirred to dissolve, adds water to 1000ml, stir, is filtered through 0.22 micron membrane filter, 1ml/ branch is filling to oral liquid bottle, Produce.

Claims (7)

1. compound shown in formula (I) or its pharmaceutically acceptable salt are being prepared for preventing and/or treating related to FLT3 Application in the medicine of disease or obstacle:
2. application according to claim 1, it is characterised in that the pharmaceutically acceptable salt is hydrochloride, hydrobromic acid Salt, maleate, phosphate, succinate, sulfate, citrate, benzoate, mesylate, lactate, acetic acid Salt, to toluene sulphur hydrochloric acid, palmitate, fumarate, tartrate, ascorbate, nitrate, formates, propionic acid Salt, n-butyric acie salt, isobutyrate, salicylate, oxalates, succinate, malate, glutamate, aspartate or Gluconate;
Preferably, the pharmaceutically acceptable salt is hydrochloride, phosphate, mesylate, lactate, acetate, sulfate Or hydrobromate;
It is highly preferred that the pharmaceutically acceptable salt is hydrochloride.
3. application according to claim 1 or 2, it is characterised in that the pharmaceutically acceptable salt is crystal;
Preferably, when the pharmaceutically acceptable salt is hydrochloride, the X ray diffracting spectrum of the hydrochloric acid salt crystal includes The diffraction maximum that following 2 θ angles represent:5.5±0.2°、8.5±0.2°、9.8±0.2°、17.2±0.2°、23.1±0.2°、25.5 ±0.2°、27.8±0.2°;
It is highly preferred that also include the diffraction maximum that following 2 θ angles represent in the X ray diffracting spectrum of the hydrochloric acid salt crystal:13.6± 0.2°、20.9±0.2°、26.7±0.2°、30.0±0.2°、34.2±0.2°;
It is further preferred that the X ray diffracting spectrum of the hydrochloric acid salt crystal is as shown in Figure 3.
4. application according to any one of claim 1 to 3, it is characterised in that the medicine is solid pharmaceutical preparation or liquid Preparation;
Preferably, the solid pharmaceutical preparation is selected from capsule, tablet, pill, powder, granule, sugar-pill and freeze-dried;
Preferably, the liquid preparation is selected from solution, injection, suspension, oral liquid, syrup, tincture and emulsion agent.
5. application according to any one of claim 1 to 4, it is characterised in that the disease related to FLT3 or barrier Hinder for myeloproliferative disorder, for example, thrombocythemia, idiopathic thrombocythemia, agnogenic myeloid metaplasia, myelofibrosis, With myelofibrosis, chronic idiopathic myelofibrosis, polycythemia vera, cytopenia and the evil of the outer metaplasia of marrow Myelodysplastic syndrome before property.
6. application according to any one of claim 1 to 5, it is characterised in that the disease related to FLT3 or barrier Hinder selected from glioma, lung cancer, breast cancer, colorectal cancer, prostate cancer, stomach cancer, cancer of the esophagus, colon cancer, cancer of pancreas, ovary Cancer, kidney, thyroid cancer, neuron cancer and uterine cancer.
7. application according to any one of claim 1 to 6, it is characterised in that the disease related to FLT3 or barrier Hinder and be selected from leukaemia, lymthoma and myeloma;
Preferably, it is white to be selected from acute myelocytic leukemia, ALL, acute progranulocyte for the leukaemia It is blood disease, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic neutrophilic granulocytic leukemia, acute undifferentiated thin Born of the same parents' leukaemia, prolymphocytic leukemia, juvenile myelomonocytic leukaemia, the white blood of human adult T cell's acute lymphoblastic Disease, acute myeloid leukemia are morbid hematopoiesis, mixing blood system leukaemia with three;
Preferably, the lymthoma is NHL or Hodgkin lymphoma, such as the leaching of anaplastic macrocytic Bar knurl;
Preferably, the plasma cell dyscrasias includes Huppert's disease, macroglobulinemia or heavy chain disease;
Preferably, the myeloma is selected from myelodysplastic syndrome, myeloproliferative disorder, Huppert's disease and spinal cord meat Knurl.
CN201610451801.9A 2016-06-21 2016-06-21 A kind of pyrimidine compound or its salt are preparing the application in being used to prevent and/or treat the medicine of the disease related to FLT3 or obstacle Pending CN107519175A (en)

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CN202011038578.8A CN112043712B (en) 2016-06-21 2016-06-21 Use of a hydrochloride salt of a pyrimidine compound for the manufacture of a medicament for the treatment of a disease or disorder associated with FLT3
PCT/CN2017/073657 WO2017219690A1 (en) 2016-06-21 2017-02-15 Application of pyrimidine compound or salt thereof for manufacturing pharmaceutical product for preventing and/or treating flt3-related disease or disorder

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WO2010026124A1 (en) * 2008-09-02 2010-03-11 Novartis Ag Picolinamide derivatives as kinase inhibitors
CN102924446A (en) * 2011-08-11 2013-02-13 上海吉铠医药科技有限公司 PIM kinase inhibitor, preparation method thereof, and application thereof in pharmacy
WO2014033631A1 (en) * 2012-08-31 2014-03-06 Novartis Ag N-(3-pyridyl) biarylamides as kinase inhibitors

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