CN103570616A - N'-straight chain alkylacyl o-pyridine hydrazide derivative, its preparation method, medicinal composition and use - Google Patents
N'-straight chain alkylacyl o-pyridine hydrazide derivative, its preparation method, medicinal composition and use Download PDFInfo
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- CN103570616A CN103570616A CN201210249757.5A CN201210249757A CN103570616A CN 103570616 A CN103570616 A CN 103570616A CN 201210249757 A CN201210249757 A CN 201210249757A CN 103570616 A CN103570616 A CN 103570616A
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- 0 C*C*C(NNC(c1cc(Oc(cc2)ccc2NC(Nc(cc2)cc(C(F)(F)F)c2Cl)=O)ccn1)=O)=O Chemical compound C*C*C(NNC(c1cc(Oc(cc2)ccc2NC(Nc(cc2)cc(C(F)(F)F)c2Cl)=O)ccn1)=O)=O 0.000 description 2
- NCALWUZXMGDYJS-UHFFFAOYSA-N NNC(c1cc(Oc(cc2)ccc2NC(Nc(cc2C(F)(F)F)ccc2Cl)=O)ccn1)=O Chemical compound NNC(c1cc(Oc(cc2)ccc2NC(Nc(cc2C(F)(F)F)ccc2Cl)=O)ccn1)=O NCALWUZXMGDYJS-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/86—Hydrazides; Thio or imino analogues thereof
Abstract
The invention relates to an N'-straight chain alkylacyl o-pyridine hydrazide derivative shown as formula I, its pharmaceutically acceptable salts, hydrates and solvates, a preparation method thereof, a composition containing one or more of the compounds, and the use of the compounds in the treatment of protein kinase related diseases like immune disorder and tumor diseases.
Description
Invention field
The present invention relates to the adjacent pyridine hydrazide derivatives of the N ' shown in formula I-straight chain alkyloyl; 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, the composition that contains one or more these compounds, with this compounds in the treatment disease relevant with protein kinase as the purposes aspect immune disorder and tumor disease.
Background of invention
Recent years, due to the raising to the understanding of the biomolecules of enzyme and some other and disease-related, discovery or the development of the new drug for the treatment of disease have greatly been promoted, protein kinase is exactly an a kind of important class of broad research, it is extended familys, relevant with the control of various signal transduction processes in cell.Due to they structure and the conservative property of catalysis they be considered to evolve from a common ancestral gene.Nearly all kinases all contains a similar 250-300 amino acid catalytic domain.These protein kinases are divided into a plurality of families according to the difference of phosphorylated substrate, as protein tyrosine kinase, and albumen serine/threonine kinase, lipoid etc.Generally, protein kinase is transferred to a protein receptor relevant to signal transduction pathway from a ribonucleoside triphosphote and is carried out signal transduction in mediated cell by affecting a phosphoryl.These phosphorylated events regulate the biological function of target protein as molecular switch, be finally excited and reacted in various extracellulars 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, can reduce the vasculogenesis of tumour copying of inhibition tumor cell simultaneously, thereby hinder the growth of tumour.
Raf kinases is the protein product of being encoded by proto-oncogene raf, by 648 amino acid, formed, molecular weight is 70000～74000D, contains 3 conserved regions in its structure, is respectively CR1 (61～194D), CR2 (254～269D), CR3 (335～627D).CR1 is positioned at its molecules of ammonia cardinal extremity, is rich in halfcystine, contains zinc-finger structure, with the ligand binding domain structural similitude of protein kinase C, is the Ras main position of being combined with Raf-1 protein kinase of activation.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 a crucial kinases in Ras/Raf/MEK/ERK path, Raf can bring into play its signal conduction regulating effect by relying on or do not rely on the mode of Ras.As the kinase whose downstream of Raf substrate, the MEK phosphorylation ERK of activation, regulates various cell functions.Once this path generation excessive activation, causes cell proliferation acceleration and the prolongation of cells survival phase, thereby leads oncogenic generation.
Research shows, more than 80% oncogene and proto-oncogene are present in people's cancer proteins encoded Tyrosylprotein kinase (PTK), the generation of the various cancers of the mankind is relevant with the abnormal cells signal conduction that comes from protein tyrosine kinase with development, an increase that principal feature is tyrosine kinase activity of malignant cell.Therefore, suppress the activation of Tyrosylprotein kinase or block its signal conducting path to become the new way of controlling tumour.
Endothelial growth factor receptor (EGFR) is a kind of protein tyrosine kinase receptor (RTK), be positioned at karyomit(e) p13～q22 district No. 7, total length 200kb, by 28 exons, formed, 1 186 amino acid of encoding, the about 170kDa of its glycoprotein molecule amount, is distributed widely in all histocytes except ripe Skeletal Muscle Cell, body wall entoderm and hemopoietic tissue.There are the acceptor molecule of 4 structural similitudies: ErbB1 (EGFR), ErbB2 (HER2), ErbB3 (HER3), ErbtM (HER4) in EGFR family, belongs to receptor tyrosine kinase (RTKS).They all contain the outer ligand binding domains of 1 born of the same parents, 1 membrane spaning domain and 1 endochylema structural domain with tyrosine kinase activity.Its intracellular region territory and erbB oncoprotein height homology.The receptor dimerization that the activation of EGFR can be induced by part turns into realizing.In ErbB receptor family, except HER2, other members have its respective ligand, and various parts are to be come through proteolysis by corresponding transmembrane protein precursor, have 1 EGF spline structure territory.Comprise 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. with the part of EGFR specific binding.After the outer ligands, EGF (endothelial cell growth factor (ECGF)) of born of the same parents and ErbB2 specific binding, cause that ErbB2 configuration changes, thereby cause receptor dimerization to activate their endochylema site.After the intracellular region territory tyrosine phosphorylation of ErbB2 and then activation second messenger transduction, by the activation (regulating kinases Erkl and Er1) of MAPK (mitogen protein kinase) approach inducing cell external signal: by PDK (phosphatidyl inositol kinase) pathway activation signal transducer JAK; Further start transcription activating of STAT1, STATS3; On the other hand, thin intracellular signal is by the ERK (extracellular regulated protein kinase) in Grb2 (growth factor receptors is in conjunction with albumen) activation downstream, and then mediation ATF, NF-kB, Ap-1, the transcription activating of 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 amplification of acceptor itself, the shortage of crossing expression, activation sudden change and negativity adjusting approach of receptors ligand, therefore EGFR induction cancer is at least by 3 kinds of mechanism: crossing of EGFR part expressed, the amplification of EGFR or the sudden change of EGFR activation.In these 3 kinds of mechanism, the sudden change of EGFR activation is the main factor that causes the abnormal biological behaviour of tumour cell.Some sudden change of EGFR gene can cause the enhancing of acceptor effect and the prolongation of time length.The proof variation acceptors such as Lynch do not affect the stability of receptor protein, by Tyr1068 phosphorylation assay EGFR activation, find, the activation 15min of wild-type receptor lowers, and variation acceptor shows than the effect of high 2 times of normal EGFR, and surpasses the continuous activation of 3h.
EGFR sudden change does not affect the ability of tumour cell and TKI (tyrosine kinase inhibitor) combination.TKI can explain by oncogeneaddiction model because sudden change causes the reason of EGFR activation those.By Ras.Raf-MEK.ERK1/ERK2, PI3K.Akt, STAT3/STAT5 path, EGFR sudden change highly activates downstream signal, start EGFR and regulate anti-apoptosis and survival signaling, cause cancer cell to become and rely on this signal to maintain its existence--there is the oncogene (feature that the EG of sudden change relies on; After using specificity T KI blocking-up EGFR signal, will eliminate its proliferative impact and output survival signaling, cause death of neoplastic cells.Therefore think, in cancer cell, the variation of signal transduction pathway is to occur the high responsive basis of medicine.On the contrary, the tumour cell (reactionless to Gefitinib, Erlotinib) that normal cell or non-EGFR rely on is unaffected.Because ordered about by other genes for survival, or after suppressing, EGFR can be made up by other RTK.Oncogene, rely in model, the oncogene that cell cancer relies on can produce the output of apoptosis and 2 signals of existence simultaneously.Under general Sui condition, oncogene is activated.Survival signaling is occupied an leading position, and apoptotic signal is in relatively low-level, makes cancer cell maintain growth and propagation.After the acute inactivation of oncogene, at crucial window phase, be first to survive in significantly weakening rapidly.And apoptotic signal slow decreasing.Therefore causing signal uneven (apoptotic signal accounts for leading), there is irreversible apoptosis in active cell.Research is found with tyrosine kinase inhibitor Gefitinib (gefitinib)/Tarceva (Erlotinib) treatment NSCLC patient, about 10% patient shows rapidly and satisfied clinical effectiveness, and further research finds that these patient's overwhelming majority exist EGFR transgenation.In the known transgenation relevant with EGFR-TKI (endothelial growth factor receptor tyrosine kinase inhibitor) at present, be confined to several as follows: G719X (18 exon), E746-A450 lacks (19 exon), L858R (21 exon), L861Q (21 exon), T790M (20 exon) and D770-N771 (20 exon).Wherein E746A450 lacks and the sudden change of L858R and the curative effect height correlation of TKI.Mitsudomi T, the analytical results of Yatabe Y to 568 routine Patients with Non-small-cell Lungs: about 90% EGFR transgenation concentrates in 19 or 21 exons in all Patients with Non-small-cell Lungs, wherein the patient of the point mutation 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, the slotting human nature sudden change (D770-N771) of EGFR extron 20 can make acceptor to 100 times of the Reduced susceptibilities of EGFR-TKI, and the patient who also finds clinically to have this sudden change is not obvious to EGFR-TKI therapeutic response.The amplified production of extron 20 is carried out to subcloning analysis discovery, T79OM sudden change is that the change from cytidine(C (C) to thymidine (T) occurs a base pair, the Threonine that at protein level is exactly EGFR Tyrosylprotein kinase functional domain 790 sites is replaced (T790M) by methionine(Met), this sudden change can make EGFR again in the state of being activated, thereby the acquired resistance that causes TKI, the reason of resistance is that sudden change causes EGFR structure to change, and makes TKI and its combination occur steric effect.
Having research prompting KRAS sudden change may be the reason of former resistance of Gefitinib, Erlotinib.The Meta of Helena linardou has summed up 1008 routine NSCLC patients' TKI result for the treatment of in analyzing, in there are 165 patients of K-ras sudden change, 94% patient treats without significant reaction TKI.In general, KRAS and EGFR sudden change NSCLC repel mutually. and in different tumors subtypes, exist notable difference: EGFR sudden change to be mainly seen in non-smoker, and KRAS sudden change is more common in the cancer that smoking is relevant.Because KRAS sudden change always betides in the NSCLC with Wild type EGFR, so be difficult to distinguish insensitive to EGFR-TKI, be because KRAS suddenlys change 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 (also can write Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt 1) simultaneously, in addition, also has 1 and 2 two collaborative acceptor of neural pilin (neuropilin).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 lymph endotheliocyte, can be combined with VEGF-A, VEGF-C, VEGF-D, VEGF-E.The effect that VEGF stimulating endothelial cell propagation, increase vascular permeability and neovascularity generate mainly realizes with activation VEGFR-2 by combination. compares with VEGFR-2, the avidity of VEGFR-1 and VEGF is high 10 times, but regulating the activity of endotheliocyte much lower, may be that VEGFR-2 activity is had to negative regulation effect.VEGFR-3 mainly expresses at lymphatic endothelial cells, can be combined with VEGF-C and VEGF-D, and the growth of regulation and control lymph endotheliocyte.
Research shows: when diameter of tumor is greater than 2mm, need to have new vessel that nutritive substance and excretion metabolism refuse are provided.VEGF/VEGFR signal path plays key effect in tumor vascular generation, can be by blocking or disturb the new life of VEGF/VEGFR signal path inhibition blood vessel, to reach the curative effect of the growth of controlling tumour.Compare with traditional cytotoxic drug, the antitumor drug that the VEGF/VEGFR-2 of take is target has very large advantage. under normal physiological conditions, angiogenesis only works in the physiological activities 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, make medicine be more prone to arrive action site. by the understanding to VEGF/VEGFR signal path mechanism of action at present, can obtain following several possible inhibitor research direction: a. utilizes monoclonal antibody to suppress VEGF or VEGFR, make it can not specific binding, disabling signal conduction.Can certainly utilize gene engineering 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, can be also the particular combination territory that is attached to the upper VEGFR of VEGF, competitive antagonism VEGFR.C. the intracellular kinase territory that suppresses VEGFR, is mainly the binding site of ATP, and antagonism ATP, makes it that phosphate cannot be provided competitively.D. the key albumen that suppresses the VEGFR downstream signal in born of the same parents. consider patient's compliance, can may there is 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 mainly by with pdgf receptor (PDGFR) combination, and then activated protein kinase signal transduction pathway and playing a role.PDGFR consists of α and two kinds of subunits of β, 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 180～190ku, 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 growth, the Metastasis and prognosis of some tumour.So PDGFR-β is a comparatively desirable neoplasm targeted therapy target.
The Raf/MEK/ERK path of Raf kinases and mediation thereof has remarkable effect in tumour progression and transfer process, and comprises that with many somatomedins Urogastron (EGF), vascular endothelial growth factor (VEGF) and PDGF (PDGF) etc. are closely related.People have thought that multiple way regulates this path, comprising the farnesylation, inhibition Rat " expression of I kinases (also claiming C-RAF kinases), inhibition Raf kinases and the kinase whose activity of MEK that suppress Ras albumen.Above-mentioned method has not only suppressed the signal transduction of ERK but also has successfully suppressed the growth of xenotransplantation tumour.In addition, existing evidence demonstration, most of tumour is not arranged by single signal conduction path, for many target spots, suppresses to obtain larger curative effect.
Numerous disease is that the abnormal cell response causing 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 that hormone is relevant etc.Therefore find and find kinases inhibitor to be very important as medicine.Although many inventions have been made very large contribution to this area, for improving medication effect, research is still being continued in this area.
Summary of the invention
The object of the present invention is to provide the adjacent pyridine hydrazide derivatives of the N ' shown in general formula I-straight chain alkyloyl, its pharmacologically acceptable salt, its solvate, its prodrug, its polycrystalline or eutectic.
Another object of the present invention is to provide the preparation method of the adjacent pyridine hydrazide derivatives of the N ' shown in general formula I-straight chain alkyloyl.
A further object of the present invention is to provide a kind of pharmaceutical composition that contains the adjacent pyridine hydrazide derivatives of the N ' shown in general formula I-straight chain alkyloyl.
Another object of the present invention is to provide this compounds anticancer, and with the medicine of protein kinase related disorder in purposes.
In order to complete the present invention's object, can adopt following technical scheme:
The present invention relates to have the adjacent pyridine hydrazide derivatives of the lower array structure N '-straight chain alkyloyl shown in general formula 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 for 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), take hydrazides 1 as raw material, with common method and acyl chlorides or acid anhydrides or acid-respons, be easy to obtain N '-straight chain alkyloyl hydrazide derivatives 2.
In step (b), under alkaline environment, by the chlorine substituted ether in hydrazides 2, obtain compound 3 with para hydroxybenzene amine.
In step (c), can generate urea derivatives I by CDI and the condensation of the chloro-3-5-trifluoromethylaniline of 4-; Also can by nucleophilic addition, obtain urea derivatives I with the chloro-3-trifluoromethylbenzene of 4-based isocyanate; Also can by nucleophilic substitution reaction, obtain urea derivatives I with the chloro-3-trifluoromethyl of 4-phenylamino formic acid 4-nitro phenyl ester.
Route 2
In step (a), take ester 4 or acyl chlorides 5 is raw material, reacts and obtains bishydrazide derivative 2 with N '-straight chain alkane hydrazides 6.
In step (b), PAP obtains compound 3 by the chlorine substituted ether in bishydrazide derivative 2 under alkaline environment.
In step (c), can generate urea derivatives I by CDI and the condensation of the chloro-3-5-trifluoromethylaniline of 4-; Also can by nucleophilic addition, obtain urea derivatives I with the chloro-3-trifluoromethylbenzene of 4-based isocyanate; Also can by nucleophilic substitution reaction, obtain urea derivatives I with the chloro-3-trifluoromethyl of 4-phenylamino formic acid 4-nitro phenyl ester.
Route 3
In step (a), phenolic compound 7 obtains urea derivatives I by the chlorine substituted ether in bishydrazide derivative 2 under alkaline environment.In step (b), ester cpds 8 reacts and obtains equally urea derivatives I with N '-straight chain alkane hydrazides 6.
Route 4
This route be take hydrazides 9 as raw material, by common method, itself and straight chain fatty acid or acyl chlorides or anhydride reaction is easy to obtain urea derivatives I.
In addition, starting raw material and intermediate in above-mentioned reaction easily obtain, or can by the ordinary method in organic synthesis, be easy to synthesize to those skilled in the art.
The adjacent pyridine hydrazide derivatives of N ' described in formula I-straight chain alkyloyl can solvate or the form of non-solvent compound exist, utilize different solvents to carry out crystallization and may obtain different solvates.Described in formula I, pharmacy acceptable salt 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 preparation.In the preparation process of the adjacent pyridine hydrazide derivatives of described N '-straight chain alkyloyl and solvate and its salt, may there is polycrystalline or eutectic in different crystallization conditions.
The invention still further relates to and using the pharmaceutical composition of the compounds of this invention as active ingredient.This pharmaceutical composition can be according to method preparation well known in the art.Can be suitable for any formulation of human or animal's use by the pharmaceutically acceptable solid of the compounds of this invention and one or more or liquid excipient and/or assistant agent being combined, making.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 that contains it can unit dosage form administrations, route of administration can be enteron aisle or non-enteron aisle, 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.
For the compounds of this invention is made to tablet, can be widely used various vehicle well known in the art, 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 further can also be made to coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
For capsule is made in administration unit, effective constituent the compounds of this invention can be mixed with thinner, glidant, mixture is directly placed in to hard capsule or soft capsule.Also can by effective constituent the compounds of this invention first with thinner, tamanori, disintegrating agent granulation or micropill, then be placed in hard capsule or soft capsule.Also the capsule that can be used for preparing the compounds of this invention for the preparation of each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind of the compounds of this invention tablet.
For the compounds of this invention is made to injection, can water, ethanol, Virahol, propylene glycol or their mixture as solvent and add the conventional solubilizing agent in appropriate this area, solubility promoter, pH to 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 prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.
In addition,, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives or other additive.
For reaching medication object, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.
The dosage of the compounds of this invention pharmaceutical composition is according to character and the severity that will prevent or treat disease, the individual instances of patient or animal, and route of administration and formulation etc. can have large-scale variation.In general, the appropriate dose scope 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 is divided into several dose unit administrations, and this depends on doctor's clinical experience and comprises the dosage regimen of using other treatment means.
Compound of the present invention or composition can be taken separately, or merge and use with other treatment medicine or symptomatic drugs.When compound of the present invention and other medicine existence synergy, should adjust according to practical situation its dosage.
The compounds of this invention is many target point proteins kinase inhibitor or its precursor, and these protein kinases are divided into a plurality of families according to the difference of phosphorylated substrate, as protein tyrosine kinase, and albumen serine/threonine kinase, lipoid etc.Generally, protein kinase is transferred to a protein receptor relevant to signal transduction pathway from a ribonucleoside triphosphote and is carried out signal transduction in mediated cell by affecting a phosphoryl.These phosphorylated events regulate the biological function of target protein as molecular switch, be finally excited and reacted in various extracellulars 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, can reduce the vasculogenesis of tumour copying of inhibition tumor cell simultaneously, thereby hinder the growth of tumour.The compounds of this invention has higher bioavailability, can be used for the treatment of multiple human malignancies, comprises that described tumor disease is liver cancer, 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: Vaariaan Mercury300 or 400 type nuclear magnetic resonance analyser for NMR (Nuclear Magnetic Resonance) spectrum.ZAD-2F and VG300 mass spectrograph for mass spectrum.
Embodiment 1.1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(positive butyryl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
Synthesizing of N '-positive butyryl radicals-4-chloropyridine-2-hydrazides
Butyric acid 0.6g (7.0mmol) is dissolved in 3mLDMF, add raw material 4-chloropyridine-2-hydrazides 2.1g (5.8mmol), HATU2.7g (7.0mmol), triethylamine 1.8g (17.4mmol), stirring at room, TLC monitoring raw material reaction is complete, adds 100mL water, there are a large amount of off-white color solids to separate out, obtain product 1.39g.
1H?NMR(400MHz,DMSO-d
6):10.51(s,1H,-CONH-),9.98(s,1H,-CONH-),8.66(d,1H,Ar-H),8.03(d,1H,Ar-H),7.81(dd,1H,Hz,Ar-H),2.16(t,2H,-COCH
2-),1.56(m,2H,-CH
2-Me),0.92(t,3H,-CH
3).MS(FAB):(M
++1=242).
Synthesizing of N '-positive butyryl radicals-4-(p-aminophenyl oxygen base) pyridine-2-hydrazides
P-aminophenol 295mg (2.7mmol) is dissolved in DMF5mL; under nitrogen protection, add potassium tert.-butoxide 416mg (3.4mmol); after stirring at room 3h; add intermediate N '-positive butyryl radicals-4-chloropyridine-2-hydrazides 0.5g (2.1mmol); salt of wormwood 138mg (1.3mmol); 80 ° of C of outer bath; after TLC monitoring intermediate reaction is complete, add 100mL water, ethyl acetate extraction 3 times; merge organic phase; once, anhydrous sodium sulfate drying, filters afterwards in saturated common salt washing; filtrate is concentrated, obtains black solid 0.47g.
1H?NMR(400MHz,DMSO-d
6):8.66(d,1H,Ar-H),8.03(s,1H,Ar-NH),7.81(dd,1H,Ar-H),7.71(d,2H,Ar-H),6.90(d,2H,Ar-H),2.16(t,2H,-CO-CH
2-),1.57(m,2H,-CH
2-Me),0.92(t,3H,-CH
3).MS(FAB):(M
++1=315).
.
1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(positive butyryl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
By 1.12g(6.9mmol) CDI is dissolved in the methylene dichloride that 7mL is dry; beginning solution is white opacity; to be dissolved with 1.2g(6.2mmol) the 10mL dichloromethane solution of the chloro-3-5-trifluoromethylaniline of 4-; splash in above-mentioned solution, solution becomes clarification gradually, after stirring at room 8h; add and be dissolved with 0.66g(2.1mmol) the dichloromethane solution 5mL of N '-positive butyryl radicals-4-(p-aminophenyl oxygen base) pyridine-2-hydrazides; after reflux 10h, stopped reaction, column chromatography separates target compound 0.26g.
1H?NMR(300MHz,DMSO-d
6):δ(ppm):10.38(s,1H,-NHCO),9.94(s,1H,-NHCO-),9.27(s,1H,-NHCO-),9.05(s,1H,-NHCO-),8.55(d,1H,ArH),8.12(s,1H,ArH),7.68~7.63(m,2H,ArH),7.60(d,2H,ArH),7.37(d,1H,ArH),7.21~7.19(m,3H,ArH),2.13(t,2H,-CH
2),1.59~1.49(m,2H,-CH
2),0.90(q,3H,-CH
3).MS(FAB):(M
++1=536).
Or by 200mg(0.43mmol) compound 1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea is dissolved in 7mlTHF, add 0.09mL(0.64mmol) TEA, be added dropwise to 2ml and be dissolved with 0.05ml(0.52mmol) the THF solution of butyryl chloride, after backflow 4h, adularescent solid generates, stopped reaction, filter, a small amount of tetrahydrofuran (THF) is washed, washing, dry, obtain equally 1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(positive butyryl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea, white solid 80mg.
Embodiment 2.1-(4-(2-(2-acethydrazide carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize acetic acid to replace butanic acid, with reference to the operation of embodiment 1, carry out, obtaining target compound is white solid 175mg.
1HNMR(300MHz,DMSO-d
6):δ(ppm):10.38(s,1H,-NHCO-CH
3),9.99(s,1H,-NHCO-),9.21(s,1H,-NHCO-),9.00(s,1H,-NHCO-),8.53(d,1H,ArH),8.11(s,1H,ArH),7.67~7.62(m,2H,ArH),7.59(d,2H,ArH),7.36(d,1H,ArH),7.20~7.17(m,3H,ArH),1.88(s,3H,-CH
3).MS(FAB)（M
++1=508）
Embodiment 3.1-(4-(2-(2-propionyl hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize n Propanoic acid to replace butanic acid, with reference to the operation of embodiment 1, carry out, obtaining target compound is white solid 135mg.
1H?NMR(400MHz,DMSO-d
6):δ(ppm):10.37(s,1H,-NHCO-CH
2-),9.94(s,1H,-NHCO-),9.22(s,1H,-NHCO-),9.01(s,1H,-NHCO-),8.55(d,1H,ArH),8.12(s,1H,ArH),7.68~7.63(m,2H,ArH),7.60(d,2H,ArH),7.37(d,1H,ArH),7.20~7.18(m,3H,ArH),2.16(q,2H,-CH
2-),1.04(t,3H,-CH
3).MS(FAB)（M
++1=522）
Embodiment 4.1-(4-(2-(2-valeryl hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize positive valeric acid to replace butanic acid, with reference to the operation of embodiment 1, carry out, obtaining target compound is white solid 145mg.
1H?NMR(400MHz,DMSO-d
6):δ(ppm):10.37(s,1H,-NHCO-CH
2-),9.94(s,1H,-NHCO-),9.34(s,1H,-NHCO-),9.10(s,1H,-NHCO-),8.54(d,1H,ArH),8.12(s,1H,ArH),7.68~7.63(m,2H,ArH),7.61(d,2H,ArH),7.37(d,1H,ArH),7.20~7.18(m,3H,ArH),2.16(t,2H,-CH
2-),1.51(m,2H,-CH
2-),1.32(m,2H,-CH
2-),0.89(t,3H,-CH
3).MS(FAB)（M
++1=550）
Embodiment 5.1-(4-(2-(the pungent formyl hydrazine carbonyl of 2-) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize n-caprylic acid to replace butanic acid, with reference to the operation of embodiment 1, carry out, obtaining target compound is white solid 115mg.
1H?NMR(400MHz,DMSO-d
6):δ(ppm):10.37(s,1H,-NHCO-CH
2-),9.94(s,1H,-NHCO-),9.22(s,1H,-NHCO-),9.00(s,1H,-NHCO-),8.54(d,1H,ArH),8.12(s,1H,ArH),7.67~7.63(m,2H,ArH),7.60(d,2H,ArH),7.37(d,1H,ArH),7.20~7.18(m,3H,ArH),2.14(t,2H,-CH
2-),1.54~1.51(m,2H,-CH
2-),1.26(brs,8H,4×-CH
2-),0.86(t,3H,-CH
3).MS(FAB)（M
++1=592）
Embodiment 6.1-(4-(2-(the own formyl hydrazine carbonyl of 2-) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize n-caproic acid to replace butanic acid, with reference to the operation of embodiment 1, carry out, obtaining target compound is white solid 155mg.
1H?NMR(400MHz,DMSO-d
6):δ(ppm):10.37(s,1H,-NHCO-CH
2-),9.94(s,1H,-NHCO-),9.24(s,1H,-NHCO-),9.02(s,1H,-NHCO-),8.54(d,1H,ArH),8.12(s,1H,ArH),7.67~7.63(m,2H,ArH),7.60(d,2H,ArH),7.37(d,1H,ArH),7.20~7.18(m,3H,ArH),2.15(t,2H,-CH
2-),1.54~1.51(m,2H,-CH
2-),1.26(brs,4H,2×-CH
2-),0.86(t,3H,-CH
3).MS(FAB)（M
++1=564）
Pharmacologically active
External activity is evaluated:
Mtt assay is measured tumour cell survival rate
By the cell of logarithmic phase, with being mixed with concentration after trysinization, be 0.8 ~ 2 * 10
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%), every medicine is established 5～7 dosage groups, at least establish three parallel holes for every group, in 37 ℃, continue to cultivate after 120hr, abandon supernatant, every hole adds the freshly prepared serum free medium containing 0.5mg/ml MTT of 100 μ l, continue to cultivate 4hr, abandon culture supernatant, every hole adds 200 μ l DMSO and dissolves MTT first hairpin precipitation, with microoscillator vibration, mix, by MK3 type microplate reader at reference wavelength 450nm, detect under wavelength 570nm condition and measure optical density value (OD), the tumour cell that the solvent control of take is processed is control group, inhibiting rate with the medicine of formula calculating below to tumour cell, and by middle effect Equation for Calculating IC
50:
MTT the selection result
Activity in vivo is evaluated:
Impact on Renca tumor-bearing mice tumor growth
Laboratory animal entered in SPF level environment breeding observing after 24 hours, without the experiment of being extremely allowed for access.By in advance, at the Renca knurl liquid of Balb/c kind mouse peritoneal recovery, with aseptic physiological saline, press 1:3 dilution proportion.Diluent is inoculated in to experiment mice left fore subcutaneous, every injection dilution posterior tuberosity liquid 0.2mL.After all animal injections, by requirement of experiment random packet, 8 every group.
In inoculation, after 24 hours, start administration, once a day, gavage, administration is 12 times altogether, and after last administration, animal is put to death in dislocation, strips tumor tissues, and weighs.
Growth-inhibiting effect to mice-transplanted tumor Renca
* P<005; * P<001; * * P<0001, with negative control group comparison.
Claims (13)
1. the adjacent pyridine hydrazide derivatives of the N ' shown in formula I-straight chain alkyloyl, its pharmacologically acceptable salt, its hydrate and solvate,
In formula: n can be selected from 0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16.
2. according to the compound of claim 1, it is characterized in that, described pharmacologically acceptable salt comprises: hydrochloride, hydrobromate, phosphoric acid salt, vitriol, mesylate, tosilate, acetate, trifluoroacetate, salicylate, amino acid salts, matrimony vine hydrochlorate, maleate, tartrate, fumarate, Citrate trianion, lactic acid salt.
3. the method for the described compound of preparation claim 1, comprises the steps:
1) route 1
2) route 2
3) route 3
4) route 4
4. according to the preparation method of claim 3 route 1, it is characterized in that, in step (a), take hydrazides 1 as raw material, with common method and acyl chlorides or acid anhydrides or acid-respons, be easy to obtain N '-straight chain alkyloyl hydrazide derivatives 2; In step (b), under alkaline environment, by the chlorine substituted ether in hydrazides 2, obtain compound 3 with para hydroxybenzene amine; In step (c), can generate urea derivatives I by CDI and the condensation of the chloro-3-5-trifluoromethylaniline of 4-; Also can by nucleophilic addition, obtain urea derivatives I with the chloro-3-trifluoromethylbenzene of 4-based isocyanate; Also can by nucleophilic substitution reaction, obtain urea derivatives I with the chloro-3-trifluoromethyl of 4-phenylamino formic acid 4-nitro phenyl ester.
5. according to the preparation method of claim 3 route 2, it is characterized in that, in step (a), take ester 4 or acyl chlorides 5 is raw material, reacts and obtains bishydrazide derivative 2 with N '-straight chain alkane hydrazides 6; In step (b), PAP obtains compound 3 by the chlorine substituted ether in bishydrazide derivative 2 under alkaline environment; In step (c), can generate urea derivatives I by CDI and the condensation of the chloro-3-5-trifluoromethylaniline of 4-; Also can by nucleophilic addition, obtain urea derivatives I with the chloro-3-trifluoromethylbenzene of 4-based isocyanate; Also can by nucleophilic substitution reaction, obtain urea derivatives I with the chloro-3-trifluoromethyl of 4-phenylamino formic acid 4-nitro phenyl ester.
6. according to the preparation method of claim 3 route 3, it is characterized in that, in step (a), phenolic compound 7 obtains urea derivatives I by the chlorine substituted ether in bishydrazide derivative 2 under alkaline environment; In step (b), ester cpds 8 reacts and obtains equally urea derivatives I with N '-straight chain alkane hydrazides 6.
7. according to the preparation method of claim 3 route 4, it is characterized in that, take hydrazides 9 as raw material, by common method, itself and straight chain fatty acid or acyl chlorides or anhydride reaction are easy to obtain urea derivatives I.
8. a composition for medicine, is characterized in that, the compound that contains claim 1 and technology of pharmaceutics acceptable carrier.
9. the application of the compound of claim 1 in the medicine of the preparation prevention disease relevant with protein kinase with treatment.
10. the application of the compound of claim 1 in the medicine of the preparation prevention disease relevant with Tyrosylprotein kinase with treatment.
The application of the compound of 11. claims 1 in the medicine of the preparation prevention disease relevant with Raf kinases with treatment.
12. according to the application of claim 11, it is characterized in that, the described disease relevant with Raf kinases is tumour, immune disorder, sacred disease.
13. according to the application of claim 12, it 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 and mammary cancer, ovarian cancer, squamous cell carcinoma, neurospongioma, incidence cancer.
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|---|---|---|---|---|
| WO2004078128A2 (en) * | 2003-02-28 | 2004-09-16 | Bayer Pharmaceuticals Corporation | Substituted pyridine derivatives useful in the treatment of cancer and other disorders |
| CN101674833A (en) * | 2007-03-20 | 2010-03-17 | 柯瑞斯公司 | Raf kinase inhibitors containing a zinc binding moiety |
| WO2010066684A2 (en) * | 2008-12-09 | 2010-06-17 | Novartis Ag | Pyridyloxyindoles Inhibitors of VEGF-R2 and Use Thereof for Treatment of Disease |
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|---|---|---|---|---|
| WO2004078128A2 (en) * | 2003-02-28 | 2004-09-16 | Bayer Pharmaceuticals Corporation | Substituted pyridine derivatives useful in the treatment of cancer and other disorders |
| CN101674833A (en) * | 2007-03-20 | 2010-03-17 | 柯瑞斯公司 | Raf kinase inhibitors containing a zinc binding moiety |
| WO2010066684A2 (en) * | 2008-12-09 | 2010-06-17 | Novartis Ag | Pyridyloxyindoles Inhibitors of VEGF-R2 and Use Thereof for Treatment of Disease |
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