CN104230890A - Pyridine-2-amine derivative as well as preparation method, medicine compositions and application thereof - Google Patents
Pyridine-2-amine derivative as well as preparation method, medicine compositions and application thereof Download PDFInfo
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Abstract
The invention relates to 3-(2,6-dichloro-3-fluorobenzyloxy)-5-(1-piperidine-4-yl)-1H-pyridine-4-yl) pyridine-2-amine as shown in the formula I in the specification, pharmaceutical salts, hydrates, solvates and a preparation method of 3-(2,6-dichloro-3-fluorobenzyloxy)-5-(1-piperidine-4-yl)-1H-pyridine-4-yl) pyridine-2-amine, compositions containing one or more of above compounds, and application of the compounds for treating diseases related to protein kinase, such as tumor diseases.
Description
Invention field
The present invention relates to the 3-(2 shown in formula I, 6-bis-chloro-3-fluorine benzyloxy)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base) pyridine-2-amine, its pharmacologically acceptable salt, its hydrate and solvate, its polycrystalline and eutectic, the precursor of its same biological function or derivative, and preparation method thereof, composition containing this compound one or more, is treating the disease relevant with protein kinase as the purposes in tumor disease with this compounds.
background of invention
Recent years, due to the raising of the understanding of the biomolecules to enzyme and some other and disease-related, greatly facilitate discovery or the development of the new drug of disease therapy, protein kinase is exactly an a kind of important class of extensive research, it is extended familys, relevant with the control of signal transduction process various in cell.Due to their structure and catalysis conservative property they be considered to evolve from a common ancestral gene.Nearly all kinases all contains a 250-300 similar amino acid catalytic domain.These protein kinases are divided into multiple family according to the difference of phosphorylated substrate, as protein tyrosine kinase, and Protein Serine/threonine kinase, lipoid etc.Generally, protein kinase is transferred to a protein receptor relevant to signal transduction pathway from a ribonucleoside triphosphote carry out signal transduction in mediated cell by being affected a phosphoryl.These phosphorylated events regulate the biological function of target protein as molecular switch, are finally excited to react to various extracellular and other stimulation.Kinases is present in multilayer signal transduction path, and receptor tyrosine kinase is positioned at the upstream of tumor-blood-vessel growth Signal transduction pathway and the upstream of tumour cell Signal transduction pathway.Serine/threonine protein kitase is positioned at the downstream of the Signal transduction pathway of tumour and tumor-blood-vessel growth cell.Research shows, by upstream retardance VEGFR and pdgf receptor, at downstream retardance Raf/MEK/ERK, to reduce the vasculogenesis of tumour and copying of inhibition tumor cell simultaneously, thus hinder the growth of tumour.
Raf kinases is the protein product of being encoded by proto-oncogene raf, be made up of 648 amino acid, molecular weight is 70 000 ~ 74 000 D, containing 3 conserved regions in its structure, be respectively CR1 (61 ~ 194D), CR2 (254 ~ 269D), CR3 (335 ~ 627D).CR1 is positioned at its molecule possessing amino, is rich in halfcystine, containing zinc-finger structure, with the ligand binding domain structural similitude of protein kinase C, is the main portions that Ras and the Raf-1 protein kinase of activation combines.CR2, also near aminoterminal, is rich in Serine and Threonine.CR3 is positioned at the carboxyl terminal of its molecule, is the catalysis district of protein kinase.As the Key kinases of in Ras/Raf/MEK/ERK path, Raf plays its intracellular signaling regulating effect by the mode relying on or do not rely on Ras.As the kinase whose stream substrates of Raf, the MEK phosphorylated CREB of activation, regulates various cell function.Once this path generation excessive activation, then cause cell proliferation acceleration and cells survival phase to extend, thus lead oncogenic generation.
Research shows, the oncogene of more than 80% and proto-oncogene are present in the cancer proteins encoded Tyrosylprotein kinase (PTK) of people, the emergence and development of the various cancer of the mankind is relevant with the abnormal cells intracellular signaling coming from protein tyrosine kinase, and a principal feature of malignant cell is the increase of tyrosine kinase activity.Therefore, suppress the activation of Tyrosylprotein kinase or block its intracellular signaling path to become the new way controlling tumour.
Endothelial growth factor receptor (EGFR) is a kind of protein tyrosine kinase receptor (RTK), be positioned at No. 7 karyomit(e) p13 ~ q22 district, total length 200 kb, be made up of 28 exons, to encode 1 186 amino acid, its glycoprotein molecule amount about 170 kDa, is distributed widely in all histocytes except ripe Skeletal Muscle Cell, parietal endoderm and hemopoietic tissue.There is the acceptor molecule of 4 structural similitudies in EGFR family: ErbB1 (EGFR), ErbB2 (HER2), ErbB3 (HER3), ErbtM (HER4), belong to receptor tyrosine kinase (RTKS).They all contain the outer ligand binding domains of 1 born of the same parents, and 1 membrane spaning domain and 1 have the cytoplasmic domain of tyrosine kinase activity.Its intracellular region and erbB oncoprotein very high homology.The Receptor dimerization effect that the activation of EGFR can be induced by part realizes.In ErbB receptor family, except HER2, other members have its respective ligand, and various part is come through proteolysis by the transmembrane protein precursor of correspondence, has 1 EGF spline structure territory.Urogastron (EGF), transforming growth factor-alpha (TGF α), two-ways regulation albumen (AR), beta cell element (BTC), Heparin-binding EGF like growth factor (HB-EGF), epiregulin (EPR) etc. are comprised with the part of EGFR specific binding.Cause ErbB2 configuration to change after the outer ligands, EGF (endothelial cell growth factor (ECGF)) of born of the same parents and ErbB2 specific binding, cause Receptor dimerization thus activate their cytoplasmic location.After the intracellular region tyrosine phosphorylation of ErbB2 and then activation second messenger transduction, by the activation of MAPK (mitogen protein kinase) approach inducing cell external signal (regulating kinases Erkl and Er1): by PDK (phosphatidyl inositol kinase) pathway activation signal transducer JAK; The further transcription activators starting STAT1, STATS3; On the other hand, Intracellular signals activates the ERK (extracellular regulated protein kinase) in downstream by Grb2 (growth factor receptor binding protein precursor), and then the transcription activating of mediation ATF, NF-kB, Ap-1, C-fos and C-Jun.These are all the growth that mediates of EGFR or carcinogenic basic downstream pathway.Abnormal EGFR activate mechanism comprises the shortage of the amplification of acceptor itself, the process LAN of receptors ligand, Activating mutations and negativity adjustment approach, therefore EGFR induced cancer is at least by 3 kinds of mechanism: the process LAN of EGFR part, the amplification of EGFR or the sudden change activation of EGFR.In these 3 kinds of mechanism, the sudden change activation of EGFR is the main factor causing the behavior of tumour cell aberrant biological.Some sudden change of EGFR gene can cause the enhancing of acceptor effect and the prolongation of time length.Lynch etc. prove that variation acceptor does not affect the stability of receptor protein, activated by Tyr1068 phosphorylation assay EGFR and find, namely activation 15 min of wild-type receptor lowers, and the acceptor that makes a variation shows the effect of higher than normal EGFR 2 times, and more than the continuous activation of 3 h.
EGFR sudden change does not affect the ability that tumour cell and TKI (tyrosine kinase inhibitor) combine.TKI can be explained by oncogeneaddiction model those reasons causing EGFR to activate because of sudden change.By Ras.Raf-MEK.ERK1/ERK2, PI3K.Akt, STAT3/STAT5 path, EGFR discontinuity height activates downstream signal, start EGFR and regulate anti-apoptotic and survival signaling, cause cancer cell to become and rely on this signal to maintain its existence--namely there is the oncogene (feature of the EG dependence of sudden change; After use specificity T KI blocks EGFR signal, its proliferative effects will be eliminated and export survival signaling, causing death of neoplastic cells.Therefore think, in cancer cell, the variation of signal transduction pathway occurs the high responsive basis of medicine.On the contrary, the tumour cell (reactionless to Gefitinib, Erlotinib) of normal cell or non-EGFR dependence is unaffected.Because also ordering about by other genes for survival, or after EGFR suppression can make up by other RTK.Rely in model oncogene, the oncogene that cell carcinomas relies on can produce the output of apoptosis and existence 2 signals simultaneously.Under general Sui condition, oncogene is activated.Survival signaling is occupied an leading position, and apoptotic signal is in low relative levels, makes cancer cell maintain growth and propagation.When after the acute inactivation of oncogene, at the window phase of key, be first that existence significantly weakens rapidly.And apoptotic signal slowly declines.Therefore causing signal imbalance (apoptotic signal accounts for leading), there is irreversible apoptosis in active cell.Research discovery tyrosine kinase inhibitor Gefitinib (gefitinib)/Tarceva (Erlotinib) treats NSCLC patient, about 10% patients goes out satisfied clinical effectiveness rapidly, and research finds that these patient's overwhelming majority exist EGFR genetic mutation further.Be confined to several as follows in the known transgenation relevant with EGFR-TKI (endothelial growth factor receptor tyrosine kinase inhibitor) at present: G719X (18 exon), E746-A450 lacks (19 exon), L858R (21 exon), L861Q (21 exon), T790M (20 exon) and D770-N771 (20 exon).Wherein E746-A450 disappearance and the sudden change of L858R and the curative effect height correlation of TKI.Mitsudomi T, Yatabe Y is to the analytical results of 568 routine Patients with Non-small-cell Lungs: in all Patients with Non-small-cell Lungs, the EGFR genetic mutation of about 90% concentrates in 19 or 21 exons, and the patient of the point mutation wherein in the deletion mutantion of 19 exons and 21 exons takes the efficient of EGFR-TKI and all reaches more than 70%.Recent research prompting, slotting human nature sudden change (D770-N771) of EGFR extron 20 can make the susceptibility of acceptor to EGFR-TKI reduce by 100 times, also finds that the patient with this sudden change is not obvious to EGFR-TKI therapeutic response clinically.Subcloning analysis discovery is carried out to the amplified production of extron 20, T79OM sudden change is the change that a base pair occurs from cytidine(C (C) to thymidine (T), the Threonine at protein level being exactly EGFR tyrosine kinase domain 790 site is replaced (T790M) by methionine(Met), this sudden change can make EGFR again be in the state of being activated, thus cause the acquired resistance of TKI, the reason of resistance is that sudden change causes EGFR structure to change, and makes TKI and its combination occur steric effect.
Have and study the reason that prompting KRAS may be Gefitinib, Erlotinib initial drug-resistant.Summarize the TKI result for the treatment of of 1 008 routine NSCLC patients in the Meta analysis of Helena linardou, in 165 patients that K-ras sudden change occurs, the patient of 94% treats without significant reaction TKI.In general, KRAS and EGFR sudden change NSCLC repels mutually. in different tumors subtypes, there is notable difference: EGFR sudden change is mainly seen in non-smoker, and KRAS is more common in the relevant cancer of smoking.Have in the NSCLC of Wild type EGFR because KRAS always betides, so being difficult to distinguish insensitive to EGFR-TKI is because KRAS on earth, or because suddenly change without EGFR.
Vascular endothelial growth factor receptor (vascular endothelial growth factor receptor, VEGFR) family includes 3 kinds of hypotypes, that is: VEGFR-1 (simultaneously also can write Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt 1), in addition, neuropilin (neuropilin) l and 2 two cooperative expert systems is also had.Wherein VEGFR-1 is mainly distributed in vascular endothelial cell, hemopoietic stem cell, scavenger cell and monocyte, can be combined with VEGF-A, VEGF-B and P1GF, main relevant with the growth regulating of hemopoietic stem cell.VEGFR-2 is mainly distributed in vascular endothelial cell and lymphatic endothelium, can be combined with VEGF-A, VEGF-C, VEGF-D, VEGF-E.VEGF stimulating endothelial cell propagation, increase vascular permeability realize with activation VEGFR-2 mainly through combining with the effect of new vascular generation. compared with VEGFR-2, the avidity of VEGFR-l and VEGF is high 10 times, but regulating the activity of endotheliocyte much lower, may be have negative regulation effect to VEGFR-2 activity.VEGFR-3 mainly expresses at lymphatic endothelial cells, can be combined with VEGF-C and VEGF-D, the growth of regulation and control lymphatic endothelium.
Research shows: when diameter of tumor is greater than 2mm, needs new vessel to provide nutritive substance and excretion metabolism refuse.VEGF/VEGFR signal path plays key effect in tumor vascular generation, can suppress the new life of blood vessel, to reach the curative effect of the growth controlling tumour by blocking or disturb VEGF/VEGFR signal path.Compared with traditional cytotoxic drug, be that the antitumor drug of target has very large advantage with VEGF/VEGFR-2. under normal physiological conditions, angiogenesis only works in the physiological activity such as wound healing and menstrual cycle, so use anti-angiogenic medicaments treatment tumour, little to human toxicity effect, vascular endothelial cell directly contacts with blood, medicine is made to be more prone to arrive action site. by the current understanding to VEGF/VEGFR signal path mechanism of action, following several possible inhibitor research direction can be obtained: a. utilizes monoclonal antibody to suppress VEGF or VEGFR, make it can not specific binding, disabling signal conducts.Gene engineering can certainly be utilized to suppress their expression, weaken its activity.B. design specific micromolecular inhibitor, be attached to the outer VEGF calmodulin binding domain CaM of VEGFR born of the same parents, competitive antagonism VEGF in like manner, also can be the particular combination territory being attached to VEGFR on VEGF, competitive antagonism VEGFR.C. suppress the intracellular kinase territory of VEGFR, mainly the binding site of ATP, competitively antagonism ATP, make it provide phosphate.D. the critical proteins of the VEGFR downstream signal in born of the same parents is suppressed. consider the compliance of patient, can may have good prospect by oral micromolecular inhibitor.
Thr6 PDGF BB (platelet.derived growth factor, PDGF) be induction and promote vascularization effect the most by force, one of the most single-minded angiogenesis factor.PDGF is mainly through combining with pdgf receptor (PDGFR), and then activated protein kinase signal transduction pathway and playing a role.PDGFR is made up of α and β two kinds of subunits, have 3 kinds of dimers (PDGFR-α α, α β, β β), wherein β β dimer acceptor (PDGFR-β) is the most important, its molecular weight is about 180 ~ 190 ku, belong to tyrosine kinase receptor (receptor tyrosine kinase, RTK) family.PDGFR also plays an important role in tumour formation and development process.The overexpression of PDGFR-β or overactivity all can stimulate intratumoral vasculature to generate, and promote tumor growth.PDGFR-β is one of molecular marker of tumor vascular endothelial cell, high expression level in endothelial cells in tumor neogenetic blood vessels, and closely related with the growth of some tumour, Metastasis and prognosis.So PDGFR-β is an ideal neoplasm targeted therapy target.PHGF (HGF) acceptor (C-MET, or HGFR) Tyrosylprotein kinase participates in tumour and generates in many human cancers.
The Raf/MEK/ERK path of Raf kinases and mediation thereof has remarkable effect in tumour progression and transfer process, and to comprise Urogastron (EGF), vascular endothelial growth factor (VEGF) and PDGF (PDGF) etc. closely related with many somatomedins.People have thought that multiple way is to regulate this path, comprising suppressing the farnesylation of Ras albumen, suppressing Rat " expression of-I kinases (also claiming C-RAF kinases), suppresses Raf kinases and the kinase whose activity of MEK.Above-mentioned method not only inhibits the signal transduction of ERK but also successfully inhibits the growth of xenograft tumours.In addition, existing evidence shows, and most of tumour not arranged by single signal conduction path, carries out suppression may obtain larger curative effect for Mutiple Targets.
Numerous disease is that the abnormal cell response caused with protein kinase mediated event is associated.These diseases include, but not limited to tumour, inflammatory disease, Immunological diseases, osteopathia, metabolic trouble, sacred disease, cardiovascular and cerebrovascular diseases, the disease etc. that hormone is relevant.Therefore find and find kinases inhibitor to be very important as medicine.Although many inventions have made very large contribution to this area, for improving medication effect, this area is still in continuation research.
Summary of the invention
The object of the present invention is to provide the 3-(2 shown in general formula I, 6-bis-chloro-3-fluorine benzyloxy)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base) pyridine-2-amine, its pharmacologically acceptable salt, its solvate, its prodrug, its polycrystalline or eutectic.
Another object of the present invention is to the 3-(2 provided shown in general formula I, 6-bis-chloro-3-fluorine benzyloxy)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base) preparation method of pyridine-2-amine.
Another object of the present invention is to provide a kind of containing the 3-(2 shown in general formula I, 6-bis-chloro-3-fluorine benzyloxy)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base) pharmaceutical composition of pyridine-2-amine.
Another object of the present invention is to provide this compounds anticancer, and with the purposes in the medicine of protein kinase related disorder.
In order to complete the object of the present invention, following technical scheme can be adopted:
The present invention relates to the structure had shown in formula I:
I
Or its pharmacologically acceptable salt, its hydrate and solvate, its polycrystalline and eutectic, the precursor of its same biological function or derivative.
The invention also discloses the method preparing the compounds of this invention, comprise following route steps:
The method of the described compound of preparation claim 1, comprises the steps:
Route 1
In step (a) with benzylalcohol 1 for raw material, dewatered under organo phosphorous compounds catalysis and between phenolic compound 2 by DEAD and form ether compound 3.
In step (b) by conventional nitroreduction agent as compound 3 is reduced to compound 4 by iron powder or zinc powder.
In step (c), compound 4 is by generating bromide 5 with bromizating agent as NBS reacts.
In step (d), bromide 5 generates compound 7 with boron compound 6 by palladium catalyst catalysis generation coupling.
In step (e), compound 7 is removed protecting group by acidolysis and is obtained target compound I.
Route 2
In step (a) with amine compound 5 for raw material, by with the protective material that can be hydrolyzed under acidic conditions as two tert.-butoxy formic anhydrides are obtained by reacting the compound 8 of amido protecting.
In step (b), compound 8, reacts with two (tetramethyl ethylene ketone base) boron 9 and generates boron ester cpds 10 under palladium catalyst exists.
Compound 10 is hydrolyzed in acid condition and deviates from tertiary fourth oxygen formyl protecting group and obtain compound 11 in step (c).
In step (d), bromide 12 generates compound 6 with boron compound 11 by palladium catalyst catalysis generation coupling, can remove protecting group obtain target compound I further by acidolysis.
In addition, the starting raw material in above-mentioned reaction and intermediate easily obtain, or can be easy to synthesis to those skilled in the art by the ordinary method in organic synthesis.
3-(2,6-bis-chloro-3-fluorine benzyloxy described in formula I)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base) pyridine-2-amine the form of solvate or non-solvent compound can exist, utilizes different solvents to carry out crystallization and may obtain different solvates.Pharmacy acceptable salt described in formula I comprises different acid salt, as following mineral acid or organic acid acid salt: hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid, methylsulfonic acid, tosic acid, trifluoroacetic acid, matrimony vine acid, toxilic acid, tartrate, fumaric acid, citric acid, lactic acid.All these salt within the scope of the present invention all can adopt ordinary method to prepare.At described 3-(2,6-bis-chloro-3-fluorine benzyloxy)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base) pyridine-2-amine: and in the preparation process of solvate and its salt, may there is polycrystalline or eutectic in different crystallization condition.
The invention still further relates to the pharmaceutical composition using the compounds of this invention as active ingredient.This pharmaceutical composition can be prepared according to method well known in the art.By pharmaceutically acceptable to the compounds of this invention and one or more solid or liquid excipient and/or assistant agent being combined, make any formulation being suitable for human or animal and using.The content of the compounds of this invention in its pharmaceutical composition is generally 0.1-95 % by weight.
The compounds of this invention or the pharmaceutical composition containing it can administrations in a unit, route of administration can be enteron aisle or non-bowel, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
In order to the compounds of this invention is made tablet, various vehicle well known in the art can be widely used, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet can also be made coating tablet further, such as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
In order to administration unit is made capsule, effective constituent the compounds of this invention can be mixed with thinner, glidant, mixture is directly placed in hard capsule or soft capsule.Also effective constituent the compounds of this invention first particle or micropill be can be made with thinner, tamanori, disintegrating agent, then hard capsule or soft capsule are placed in.Also the capsule preparing the compounds of this invention is can be used for for the preparation of each thinner of the compounds of this invention tablet, tamanori, wetting agent, disintegrating agent, glidant kind.
For the compounds of this invention is made injection, can with water, ethanol, Virahol, propylene glycol or their mixture as solvent and add the conventional solubilizing agent in appropriate this area, solubility promoter, pH adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepared lyophilized injectable powder, N.F,USP MANNITOL, glucose etc. also can be added as propping agent.
In addition, as needs, also tinting material, sanitas, spices, correctives or other additive can be added in pharmaceutical preparation.
For reaching medication object, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can with any known medication administrations.
The dosage of the compounds of this invention pharmaceutical composition is according to preventing or the character of disease therapy and severity, and the individual instances of patient or animal, route of administration and formulation etc. can have large-scale change.In general, the Suitable dosage ranges of the every day of the compounds of this invention is 0.001-150mg/Kg body weight, is preferably 0.01-100mg/Kg body weight.Above-mentioned dosage can a dose unit or be divided into several dosage unit administration, and this depends on the clinical experience of doctor and comprises the dosage regimen using other treatment means.
Compound of the present invention or composition can be taken separately, or merge with other treatment medicine or symptomatic drugs and use.When compound of the present invention and other medicine exist act synergistically time, its dosage should be adjusted according to practical situation.
The compounds of this invention is Mutiple Targets kinases inhibitor or its precursor, and these protein kinases are divided into multiple family according to the difference of phosphorylated substrate, as protein tyrosine kinase, and Protein Serine/threonine kinase, lipoid etc.Generally, protein kinase is transferred to a protein receptor relevant to signal transduction pathway from a ribonucleoside triphosphote carry out signal transduction in mediated cell by being affected a phosphoryl.These phosphorylated events regulate the biological function of target protein as molecular switch, are finally excited to react to various extracellular and other stimulation.Kinases is present in multilayer signal transduction path, and receptor tyrosine kinase is positioned at the upstream of tumor-blood-vessel growth Signal transduction pathway and the upstream of tumour cell Signal transduction pathway.Serine/threonine protein kitase is positioned at the downstream of the Signal transduction pathway of tumour and tumor-blood-vessel growth cell.Research shows, by upstream retardance VEGFR and pdgf receptor, at downstream retardance Raf/MEK/ERK, to reduce the vasculogenesis of tumour and copying of inhibition tumor cell simultaneously, thus hinder the growth of tumour.The compounds of this invention has higher bioavailability, can be used for the treatment of multiple human malignancies, comprising described tumor disease is liver cancer, cancer of the stomach, kidney, lung cancer, carcinoma of the pancreas, colorectal cancer, bladder cancer and mammary cancer, ovarian cancer, squamous cell carcinoma, neurospongioma, leukemia, incidence cancer.
Embodiment
Below with reference to embodiment, invention is described further, but does not limit the scope of the invention.
Determining instrument: NMR (Nuclear Magnetic Resonance) spectrum Vaariaan Mercury 300 or 400 type nuclear magnetic resonance analyser.Mass spectrum ZAD-2F and VG300 mass spectrograph.
Embodiment. 3-(2,6-bis-chloro-3-fluorine benzyloxy)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base) pyridine-2-amine
Toluene solution by 8 grams of triphenylphosphines and DEAD(13 milliliter 40%) be placed in THF solution; add containing 3.9 gram 2 under stirring at 0 DEG C; 150 milliliters of THF solution of the chloro-3-fluoro benzyl alcohol of 6-bis-and 2.8 grams of 3-hydroxyl-2-nitropyridines, under nitrogen protection, stirring at room temperature disappears to raw material.Desolventizing is revolved in decompression, and column chromatography for separation obtains 5.1 grams of pink solid 3-(2,6-bis-chloro-3-fluorine benzyloxy)-2-nitropyridine.Then under agitation, by chloro-for the 3-(2 obtained, 6-bis-3-fluorine benzyloxy)-2-nitropyridine 4.5 grams and iron powder 7 grams be suspended in the mixed solvent of 300 milliliters of acetic acid and 250 milliliters of ethanol, be heated to backflow, be stirred to raw material and disappear, be chilled to room temperature, add water, with sodium carbonate solution neutralization, add extracted with diethyl ether, organic layer saturated sodium bicarbonate solution is washed, washing, saturated salt is washed, dry, concentrate and obtain light pink solid 3-(2,6-bis-chloro-3-fluorine benzyloxy) pyridine-2-amine.
By obtain 2.87 grams of 3-(2,6-bis-chloro-3-fluorine benzyloxies) pyridine-2-amine is dissolved in 80 milliliters of acetonitriles, and ice bath adds 1.8 grams of NBS under stirring in batches, and lucifuge is stirred to raw material and disappears.Removal of solvent under reduced pressure, column chromatography obtains the chloro-3-fluorine benzyloxy of white solid 5-bromo-3-(2,6-bis-) pyridine-2-amine.
By 3.77 grams of 4-(4, 4, 5, 5) tetramethyl--(1, 3, 2)-dioxaborolan alkane-2-base)-1H-pyrazol-1-yl) piperidines-1-carboxylic acid tert-butyl ester and 3.66 grams of bromo-3-(2 of 5-, 6-bis-chloro-3-fluorine benzyloxy) pyridine-2-amine is dissolved in 50 milliliters of DME, 10 ml water solution of 3 grams of sodium carbonate are added under stirring, and with nitrogen washings solution 3 times, add 0.4 gram of dichloro two (triphen is seen) palladium, again use nitrogen washings solution 3 times, under nitrogen protection, 85 DEG C of stirrings are spent the night to raw material and are disappeared, be cooled to room temperature, with diluted ethyl acetate, and with diatomite filtration, ethyl acetate is washed, merging filtrate washing lotion, dry, concentrated, column chromatography purification obtains 3-(2, 6-bis-chloro-3-fluorine benzyloxy)-5-(1-(1-tertiary fourth oxygen formyl piperidine-4-base)-1H-pyrazoles-4-base) pyridine-2-amine 1.4 grams.Be dissolved in 50 milliliters of methylene dichloride; add 22 milliliters of 4N HCl dioxane solution, stirring at room temperature, to sloughing protection completely, revolves desolventizing; column chromatography purification obtains 3-(2,6-bis-chloro-3-fluorine benzyloxy)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base) pyridine-2-amine 0.7 gram.
1H?NMR?(400?MHz,?DMSO-
d 6):?9.41(br,?1H,?-NH
2-),?9.31(br,?1H,?-NH
2-),?8.42(s,?1H,?Ar-H),?8.05(s,?1H,?Ar-H),?8.03(s,?1H,?NH),?7.94(s,?1H,?Ar-H),?7.83(s,?1H,?Ar-H),?7.65(m,?3H,?Ar-H),?5.48(s,?2H,?-OCH
2-),?4.50(m,?1H,?-NCH-),?3.37?(m,?2H,?-NCH
2-),?3.10?(m,?2H,?-NCH
2-),?2.22?(m,?4H,?2XCH
2-).?MS(FAB):?(M
++1=436).
?1H?NMR?(400?MHz,?DMSO-
d 6+D
2O):?8.31(s,?1H,?Ar-H),?7.99(s,?1H,?Ar-H),?7.91(s,?1H,?Ar-H),?7.78(s,?1H,?Ar-H),?7.57(m,?3H,?Ar-H),?5.44(s,?2H,?-OCH
2-),?4.50(m,?1H,?-NCH-),?3.38?(m,?2H,?-NCH
2-),?3.07?(m,?2H,?-NCH
2-),?2.18?(m,?4H,?2XCH
2-).
Pharmacologically active
external activity is evaluated:
mtt assay measures tumor cell survival
Be 0.8 ~ 2 × 10 by being mixed with concentration after the cell trysinization of logarithmic phase
4the enchylema of cell/ml, is inoculated in 96 orifice plates by 1000/hole, and every hole adds 100 μ l.Add the fresh culture containing different concns medicine and coordinative solvent contrast next day, every hole adds 100 μ l(DMSO final concentration <0.5%), 5 ~ 7 dosage groups established by every medicine, often organize and at least establish three parallel holes, after continuing cultivation 120 hr in 37 DEG C, abandon supernatant, every hole adds the freshly prepared serum free medium containing 0.5mg/ml MTT of 100 μ l, continue cultivation 4 hr, abandon culture supernatant, every hole adds 200 μ l DMSO and dissolves MTT first hairpin precipitation, with microoscillator vibration mixing, by MK3 type microplate reader at reference wavelength 450nm, optical density value (OD) is measured under determined wavelength 570nm condition, with the tumour cell of solvent control process for control group, with the inhibiting rate of formulae discovery drug on tumor cell the following, and by middle effect Equation for Calculating IC
50:
Inhibiting rate=
Claims (9)
1. the 3-(2 shown in formula I, 6-bis-chloro-3-fluorine benzyloxy)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base) pyridine-2-amine, its pharmacologically acceptable salt, its hydrate and solvate.
2. prepare the method for the described compound of claim 1, comprise the steps:
?
3., according to the preparation method of claim 2 route 1, it is characterized in that, in step (a) with benzylalcohol 1 for raw material, dewatered under organo phosphorous compounds catalysis and between phenolic compound 2 by DEAD and form ether compound 3.In step (b) by conventional nitroreduction agent as compound 3 is reduced to compound 4 by iron powder or zinc powder.In step (c), compound 4 is by generating bromide 5 with bromizating agent as NBS reacts.In step (d), bromide 5 generates compound 7 with boron compound 6 by palladium catalyst catalysis generation coupling.In step (e), compound 7 is removed protecting group by acidolysis and is obtained target compound I.
4., according to the preparation method of claim 2 route 2, it is characterized in that, in step (a) with amine compound 5 for raw material, by with the protective material that can be hydrolyzed under acidic conditions as two tert.-butoxy formic anhydrides are obtained by reacting the compound 8 of amido protecting.In step (b), compound 8, reacts with two (tetramethyl ethylene ketone base) boron 9 and generates boron ester cpds 10 under palladium catalyst exists.Compound 10 is hydrolyzed in acid condition and deviates from tertiary fourth oxygen formyl protecting group and obtain compound 11 in step (c).In step (d), bromide 12 generates compound 6 with boron compound 11 by palladium catalyst catalysis generation coupling, can remove protecting group obtain target compound I further by acidolysis.
5. a composition for medicine, is characterized in that, the compound containing claim 1 and technology of pharmaceutics acceptable carrier.
6. the application of compound in the medicine preparing the prevention and therapy disease relevant with protein kinase of claim 1.
7. the application of compound in the medicine preparing the prevention and therapy disease relevant with Tyrosylprotein kinase of claim 1.
8. application according to claim 7, is characterized in that, the described disease relevant with Tyrosylprotein kinase is tumour.
9. application according to claim 8, is characterized in that, described tumor disease is liver cancer, kidney, lung cancer, carcinoma of the pancreas, cancer of the stomach, colorectal cancer, bladder cancer, mammary cancer, ovarian cancer, squamous cell carcinoma, neurospongioma, incidence cancer.
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| WO2019196937A1 (en) * | 2018-04-13 | 2019-10-17 | 华东理工大学 | Selective jak2 inhibitor and application thereof |
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| CN101018780A (en) * | 2004-08-26 | 2007-08-15 | 辉瑞大药厂 | Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors |
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| CN102850328A (en) * | 2011-07-01 | 2013-01-02 | 中国科学院上海药物研究所 | Pyridine chemical, its preparation method, and pharmaceutical composition containing the chemical and application thereof |
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| CN101018780A (en) * | 2004-08-26 | 2007-08-15 | 辉瑞大药厂 | Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors |
| CN101166733A (en) * | 2004-10-15 | 2008-04-23 | 记忆药物公司 | Pyrazole derivatives as phosphodiesterase 4 inhibitors |
| CN102850328A (en) * | 2011-07-01 | 2013-01-02 | 中国科学院上海药物研究所 | Pyridine chemical, its preparation method, and pharmaceutical composition containing the chemical and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019196937A1 (en) * | 2018-04-13 | 2019-10-17 | 华东理工大学 | Selective jak2 inhibitor and application thereof |
| CN110372664A (en) * | 2018-04-13 | 2019-10-25 | 华东理工大学 | Selective JAK2 inhibitor and its application |
| CN112119070A (en) * | 2018-04-13 | 2020-12-22 | 华东理工大学 | Selective JAK2 inhibitor and application thereof |
| EP3782993A4 (en) * | 2018-04-13 | 2022-06-08 | East China University of Science and Technology | Selective jak2 inhibitor and application thereof |
| CN112119070B (en) * | 2018-04-13 | 2023-02-17 | 华东理工大学 | Selective JAK2 inhibitors and uses thereof |
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