CN102234270A - Diarylurea derivatives and treatment application thereof - Google Patents
Diarylurea derivatives and treatment application thereof Download PDFInfo
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- CN102234270A CN102234270A CN 201010165555 CN201010165555A CN102234270A CN 102234270 A CN102234270 A CN 102234270A CN 201010165555 CN201010165555 CN 201010165555 CN 201010165555 A CN201010165555 A CN 201010165555A CN 102234270 A CN102234270 A CN 102234270A
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- phenyl
- trifluoromethyl
- pyridine
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- 0 Cc1cnc(C(C=C(C=C)OC(C=C*=C)=*)=N)[n]1 Chemical compound Cc1cnc(C(C=C(C=C)OC(C=C*=C)=*)=N)[n]1 0.000 description 3
- QGVZDUSZCXCPRY-UHFFFAOYSA-N CC1C(OC(C=C2)=C[I]=C2NC(Nc(cc2C(F)(F)F)ccc2F)=O)=CC(c2ncc(C(F)(F)F)[nH]2)=NC1 Chemical compound CC1C(OC(C=C2)=C[I]=C2NC(Nc(cc2C(F)(F)F)ccc2F)=O)=CC(c2ncc(C(F)(F)F)[nH]2)=NC1 QGVZDUSZCXCPRY-UHFFFAOYSA-N 0.000 description 1
- FGWZWHLXYGBXCW-UHFFFAOYSA-N COc(cc(cc1OC)NC(Nc(c(Cl)c2)ccc2Oc2ccnc(-c3ncc(C(F)(F)F)[nH]3)c2)=O)c1OC Chemical compound COc(cc(cc1OC)NC(Nc(c(Cl)c2)ccc2Oc2ccnc(-c3ncc(C(F)(F)F)[nH]3)c2)=O)c1OC FGWZWHLXYGBXCW-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a diarylurea derivatives and treatment application thereof. The compounds are compounds shown as a formula (I) or pharmaceutically acceptable salts or solvates thereof, and R1, R2, R3 and Ar1 are defined as the specification. Medicines taking the compounds or salts thereof as active ingredients can be used for treating proliferative diseases such as cancers, inflammatory diseases and other diseases related with Raf kinase.
Description
Technical field
The present invention relates to a class substituted bisarylurea derivatives, the salt of this compound with serve as the active medicine that becomes to relate to branch with this compound or its salt class, can be used for treating renal cell carcinoma, prostate cancer and the rectum cancer etc. and Raf kinases diseases associated.
Background technology
The generation of tumour, growth and transfer depend on effective tumor cell proliferation and tumor-blood-vessel growth, Ras (gtp binding protein)/Raf/MAPKs (mitogen-activated proteinkinases) signal transduction pathway is an important channel of tumor cell proliferation and vasculogenesis, this signal transduction pathway is present in the most cells, with the extracellular stimulus signal transduction to cell and nuclear thereof, cause in the process of cytobiology reaction (as cell proliferation, differentiation, conversion and apoptosis etc.) to have crucial effects.All there is this transduction path of Raf/MEK/ERK in known all eukaryotic cells at present, signal imported in the nucleus by the extracellular by kinase whose specificity cascade phosphorylations such as Ras, Raf, MEK and ERK in the path.Raf is a crucial kinases in this path, can bring into play its signal transduction regulating effect by the mode that relies on or do not rely on Ras, Raf is a kind of serine/threonine (Ser/Thr) protein kinase, it has 3 isozymes, be respectively A-Raf, B-Raf and C-Raf, they are all closely related with the adjusting of cell proliferation, differentiation and vasculogenesis.Downstream effect device enzyme as Ras, in case be activated, then activate mitogen activation (MEK) 1 and MEK2 kinases, MEK1 and MEK2 make extracellular signal-regulated kinase (ERK) 1 and ERK2 phosphorylation and activation again in succession, and transposition is to karyon, stimulate transcripting starting and translate activated pathway, cause cell proliferation.The formation and development of this signal transduction pathway direct regulation and control tumour in the various tumor tissues of human body.
Preclinical study is found, comprise VEGF, PDGF-β, Urogastron (EGF) and transforminggrowthfactor-multiple somatomedins such as (TGF-α) in case, can activate the Raf/MEK/ERK path by the mode of receptor tyrosine kinase autophosphorylation with after its homoreceptor combines.In addition, as the upstream gene of this path, the ras gene is undergone mutation in kinds of tumors, maybe can participate in the activation process of Raf/MEK/ERK path directly.3 isozymes of Raf enzyme comprise A-Raf, B-Raf and C-Raf (Raf-1), with cell proliferation, differentiation, survive, adhere to and the adjusting of vasculogenesis closely related.Wherein, C-Raf expresses in most of tissues, and can not regulate the function of cell by the Raf/MEK/ERK path.Though the concrete regulation mechanism of C-Raf pair cell is not bright and clear fully as yet at present, passes through to regulate apoptotic correlation factor probably with the inhibition apoptosis, thereby prolong the lifetime of cell.This mechanism is the tool significance in tumour forms and develops.Found that so far there is abnormal activation in the Raf kinases in kinds of tumors, and related generally to B-Raf and mainly sudden change or overexpression in malignant melanoma and papillary thyroid carcinoma of C-Raf:B-Raf; C-Raf is mainly at the noumenal tumour of rich blood vessel, as abnormal activation in kidney, hepatocellular carcinoma and the nonsmall-cell lung cancer.Except may participating in tumour forms, B-Raf is also closely related with the generation of C-Raf and new vessel.Experimentation on animals finds that the mouse that lacks B-Raf and C-Raf gene can die from the vascularization obstacle between embryonic stage.In addition, angiogenesis factor such as VEGF and basic fiber mother cell growth factor (basic fibroblast growth factor, bFGF) all can suppress the apoptosis of vascular endothelial cell by phosphorylation for C-Raf, the former needs the participation of MEK/ERK path, and the latter then is directly effect.The kinase whose dependency of metastases and Raf may be owing to the participation of ras gene.There is the sudden change of ras gene in known 50% metastatic tumo(u)r at present, and then plays a role by the Raf/MEK/ERK path.The zooscopy result shows, transfection the tumour cell of sudden change ras gene more easily shift, this process is with the activation of C-Raf, the tumour cell that contains normal ras gene does not then have this phenomenon.Research at malignant melanoma and papillary thyroid carcinoma finds that equally the activation of B-Raf is relevant with the high transitivity of tumour.As everyone knows, the enhancing of the rise of multidrug resistance gene (MDR-1) and anti-apoptosis capacity is that tumour cell to the conventional cell cytotoxic drug drug-fast two big mechanism takes place.Available data confirms that the activation of C-Raf can cause the appearance of above-mentioned two kinds of situations.The ERK path can be activated by several different methods, comprising the sudden change of some kinases in the path (as ras, Raf).All found the ras gene of sudden change in intestinal cancer 50%, 90% carcinoma of the pancreas and 30% the lung cancer.The ras gene of this simple point mutation makes the ras kinases be in the propagation that state of activation finally causes cell always.The sudden change of B-raf gene in recent years also is detected in many human tumors, comprises surpassing 60% malignant melanoma and 40%～70% Tiroidina mastoid process knurl.False phosphorylation variation takes place in modal this activity ring district that can cause strengthening the B-Raf kinase activity of sudden change that sports 600 Xie Ansuan of B-Raf.Except transmitting proliferation signal, a large amount of evidences shows the survival that this kinases can also regulating cell and the generation of blood vessel to the Raf-1 kinases in bioprocess.For example in endotheliocyte; when DNA damage type medicine produces apoptosis effect; vascular endothelial growth factor can be transmitted the signal protection cell by the Raf-1 kinases, and similarly base fiber archeocyte somatomedin also can be transmitted signal by the Raf-1 kinases and prevent the necrocytosis of death receptor inductive.The research of SiRNA has confirmed that further the Raf kinases resists vital role in the apoptosis at tumour cell.The SiRNA of Raf21 can be in vivo and external evoked HUVEC, MDA2MB2435 and C6 apoptosis and suppress the propagation of cell.The activity that the SiRNA of B-Raf can block ERK suppresses synthesizing and cell death inducing of DNA.
Therefore, the Raf kinases has not only participated in the formation and the development of tumour, and closely related with tumor neovasculature generation, therefore, the Raf kinases is suppressed to become one of effective way of targeted therapy.In addition, the Raf kinases produces may exist between resistance mechanism related with tumour cell to chemotherapy, and also the combined utilization for Raf kinase inhibitor and traditional chemotherapy provides theoretical foundation.
At present Onyx company has researched and developed two aryl ureas element class Raf kinase inhibitor Xareltos (sorafenib) with the cooperation of Bayer company, and the medicine Initial Public Offering in December, 2005 as kidney becomes the Raf kinase inhibitor of first clinical application.Xarelto is the oral many kinase inhibitor of the plain class of a kind of pair of aryl urea, it has dual antitumor action, thereby directly suppressing tumour by suppressing Raf kinases blocking-up Ras/Raf/MAPK/ERK signal transduction pathway on the one hand generates, on the other hand by suppressing the activity of several tyrosine kinase receptors relevant with tumor development with the new vessel generation, comprise vascular endothelial growth factor (VEGFR-2), VEGFR-3, platelet-derived growth factor receptors-β (PDGFR-β) and c-KIT proto-oncogene, the blocking-up tumor neogenetic blood vessels generates, suppress the growth of tumour cell indirectly, thereby play antitumor action.Make this type of medicine not only can suppress tumor cell proliferation, can also stop tumor neovasculature generation.
Yet at present there are shortcomings such as antitumour activity is low, side effect is big mostly in the Raf kinase inhibitor of listing, therefore be necessary very much to develop antitumous effect strong,, the Raf kinase inhibitor of the novel texture that side effect is little.
Two phenyl ureas derivatives involved in the present invention are to have optionally Raf kinase inhibitor, and their main effect is to bring into play its antitumous effect by suppressing the kinase whose activity of Raf.The main kinases that this compounds suppressed also has VEGFR-2, VEGFR-3, PDGFR-β etc.Certainly, do not get rid of the possibility that this compounds suppresses the protein kinase of other and disease-related yet.
Disclosure of the Invention
First purpose of the present invention provides substituted bisarylurea derivatives and its esters or their solvate.
Substituted bisarylurea derivatives provided by the present invention has formula (I) structure,
Or its pharmacy acceptable salt or solvated compounds
R
1, R
2, R
3Be independently selected from hydrogen, hydroxyl, C respectively
1-6Alkyl, C
1-6Alkoxyl group, halogen, (C
1-6Alkoxyl group) carbonyl, aminocarboxyl, C
1-6Alkyl amino-carbonyl, itrile group, cycloalkyl, Heterocyclylalkyl, Heterocyclylalkyl carbonyl, phenyl or heteroaryl, these groups can be replaced arbitrarily by one or more following groups, and these groups are selected from hydroxyl, halogen, C
1-6Alkyl, halo (C
1-6Alkyl), C
1-6Alkoxyl group or halo (C
1-6Alkoxyl group)
Ar
1Be aryl or heteroaryl, and can be by C
1-4Alkyl, halogenated C
1-4Alkyl or halogen replace;
More specifically, the preferred compound of formula of the present invention (I) structure is:
N-(2-chloro-5-(trifluoromethyl) phenyl)-N '-(4-(2-(5-trifluoromethyl)-1H-imidazoles-2-pyridine-4-oxygen base) phenyl) urea;
N-(3-(trifluoromethyl) phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-(5-trifluoromethyl)-1H-imidazoles-2-pyridine-4-oxygen base) phenyl) urea;
N-(3, the 4-dichlorophenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(3-chloro-4-fluoro-phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(4-bromo-2-fluoro-phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(4-fluoro-phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(2-chloro-6-methyl-phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(4-methoxyl group-phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(benzo [1,3] dioxy furans-5-)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(5-methyl-isoxazole-3-)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(4-fluoro-3-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(2-chloro-5-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(3, the 4-dichlorophenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(4-methyl-3-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(3-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea synthetic; Or
N-(3,4,5-(trimethoxy) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea synthetic.
Or its pharmacy acceptable salt or solvated compounds
The compounds of this invention is as containing basic group, then can with sour salify, adopt method well-known to those skilled in the art can prepare the salt of substituted bisarylurea derivatives.
Common salt has organic acid salt, inorganic acid salt etc.Usually organic acid salt relatively more commonly used has citrate, fumarate, oxalate, malate, lactic acid salt, camsilate, tosilate, mesylate etc.; Inorganic acid salt has halogen acid salt, vitriol, phosphoric acid salt, nitrate etc.
For example, with low alkyl group sulfonic acid, as methylsulfonic acid, trifluoromethanesulfonic acid etc. can form mesylate, fluoroform sulphonate; With aryl sulfonic acid, can form tosilate, benzene sulfonate as Phenylsulfonic acid or tosic acid etc.; With organic carboxyl acid, as acetate, fumaric acid, tartrate, oxalic acid, toxilic acid, oxysuccinic acid, succsinic acid or citric acid etc. can form corresponding salt; With amino acid, can form glutaminate or aspartate as L-glutamic acid or aspartic acid.With mineral acid, as haloid acid (as hydrofluoric acid, Hydrogen bromide, hydroiodic acid HI, spirit of salt), nitric acid, carbonic acid, sulfuric acid or phosphoric acid etc. also can form corresponding salt.
Second purpose of the present invention provides the method for a kind of preparation formula (I) compound.
The 3rd purpose of the present invention provides utilizes substituted bisarylurea derivatives of the present invention, and the salt of this compound is the medicine of activeconstituents, is used for the treatment of proliferative disease such as cancer and inflammation class disease etc. and diseases associated such as Raf kinases.
The inventor confirms by experiment, The compounds of this invention has anti-increment restraining effect to human renal carcinoma cell (KCC-853), and suppress activity and be better than existing medicine, but in the medicine of psoriasis, leukemia or solid tumor that application of treatment human or animal cell proliferative is correlated with.
Can also contain one or more pharmaceutically acceptable carriers in said medicine, described carrier comprises the conventional thinner of pharmaceutical field, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant etc., can also add flavouring agent, sweeting agent etc. in case of necessity.Medicine of the present invention can be made tablet, pulvis, and granula, capsule, various ways such as oral liquid and injecting drug use, the medicine of above-mentioned each formulation all can be according to the ordinary method preparation of pharmaceutical field.
Embodiment
Below by embodiment exploitativeness of the present invention is described, it will be understood by those of skill in the art that instruction, the corresponding techniques feature is made amendment or replaced, still belong to the scope of protection of present invention according to prior art
Embodiment 1.N-(2-chloro-5-(trifluoromethyl) phenyl)-N '-(4-(2-(5-trifluoromethyl)-1H-imidazoles-2-pyridine-4-oxygen base) phenyl) urea (compound 1)
Synthesizing of step 1.4-chloro-2-pyridine formyl chloride hydrochloride
5.0g4-chloro-2-pyridine carboxylic acid is added in the 100ml three-necked bottle, add 20ml thionyl chloride and 0.1ml DMF, reflux is after 3 hours, and the pressure reducing and steaming thionyl chloride obtains faint yellow solid, is directly used in next step reaction.
Synthesizing of step 2.4-chloro-2-pyridine carboxamide
The ammonia soln (25%) of 30ml is added in the 100ml three-necked bottle, bathe with cryosel and be cooled to below-5 ℃ the dichloromethane solution of dropping 6.0g step 1 product, control reaction temperature is below 7 ℃, drip half an hour,, drip and finish in reaction below 10 ℃ after 1 hour, there are a large amount of solids to generate, TLC shows that reaction finishes, and filters (3 * 50ml) washings of filter cake water, drying gets faint yellow solid.
Synthesizing of step 3.4-chloro-2-cyano group-pyridine
The product and the 5ml triethylamine of 3.5g step 2 are dissolved in the 30ml exsiccant ethyl acetate, bathe with cryosel and be cooled to below-5 ℃ dropping 7ml trifluoroacetic anhydride, control reaction temperature is below 10 ℃, drip to finish in 40 minutes, react 30 minutes at normal temperatures after, TLC shows that reaction finishes, add 50ml solution of potassium carbonate (10%), (3 * 50ml), the organic layer anhydrous sodium sulfate drying filters with ethyl acetate extraction, concentrating under reduced pressure gets white solid.
Synthesizing of step 4.N-(4-(2-cyanopyridine-4-oxygen base) phenyl) ethanamide
With the product of 3.2g step 3,5.3g paracetamol and 5.5g salt of wormwood are dissolved among the dry DMF of 30ml, and 80 ℃ of reactions are after 5 hours, and TLC shows that reaction finishes, add 50ml water, have solid to separate out, filter, (3 * 50ml) washings, drying gets white solid to the filter cake water.
Step 5.N-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) ethanamide synthetic
The product of 4.1g step 4 is dissolved in the 20ml n-propyl alcohol, add the 1.0g sodium methylate, after 3 hours, add the 3.8g ammonium acetate 50 ℃ of reactions, 70 ℃ the reaction 1 hour after, add 3.5ml 3-bromo-1,1, the 1-trifluoroacetone, be warming up to 85 ℃ of reactions 20 hours, TLC shows that reaction finishes, and adds 50ml water, with ethyl acetate extraction (3 * 50ml), the organic layer anhydrous sodium sulfate drying, filter, evaporate to dryness gets oily matter, oily matter is crossed silicagel column, 2: 1 wash-outs of ethyl acetate/petroleum ether, the elutriant evaporate to dryness gets faint yellow look solid.
Step 6.4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) aniline synthetic
Product and 10ml 2N H with 3.0g step 5
2SO
4In the adding 100ml three-necked bottle, after 5 hours, TLC shows that reaction finishes 85 ℃ of reactions, to alkalescence, has solid to separate out with sodium hydroxide solution (50%) accent solution pH value, filters, and (3 * 20ml) washings, solid drying gets the sorrel solid to water.
Synthesizing of step 7.1-chloro-2-isocyanic ester-4-trifluoromethylbenzene
The triphosgene of 0.55g is joined in the 10ml dry toluene N
2Protection, ice bath drip the dichloromethane solution of 15ml2-chloro-5-5-trifluoromethylaniline (0.5g) down, dropwise, and stirring at room 15min, 80 ℃ were reacted 6 hours then, and TLC shows that reaction finishes, and concentrating under reduced pressure toluene obtains oily matter, solidifies.
Synthesizing of step 8.N-(2-chloro-5-(trifluoromethyl) phenyl)-N '-(4-(2-(5-trifluoromethyl)-1H-imidazoles-2-pyridine-4-oxygen base) phenyl) urea
(the product 0.4g of 2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) aniline 0.3g and step 7 joins the dry DMF of 20ml, drips the 0.3ml triethylamine, places one evening of room temperature reaction, and TLC shows that reaction finishes with 4-; Add 25ml water, with ethyl acetate extraction (3 * 50ml), the organic layer anhydrous sodium sulfate drying filters, evaporate to dryness, oily matter, oily matter is crossed silicagel column, 1: 1 wash-out of ethyl acetate/petroleum ether, the elutriant evaporate to dryness gets white solid.
1HNMR(DMSO-d
6)(ppm)：δ7.08-7.09(dd，1H)，δ7.22-7.25(d，2H)，δ7.38-7.40(d，2H)，δ7.62-7.75(m，3H)，δ7.875(s，1H)，δ8.54-8.68(m，3H)，δ9.75(s，1H)，δ13.58(s，1H)；MS(FAB)：543(M+1).
Embodiment 2.N-(3-(trifluoromethyl) phenyl-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl)-3-) urea (compound 2)
Synthesis step reference example 1.
1HNMR(DMSO-d6)(ppm)：δ7.07-7.09(dd，1H)，δ7.21-7.23(d，2H)，δ7.32-7.34(d，1H)，δ7.39-7.40(dd，1H)，δ7.51-7.53(t，1H)，δ7.59-7.63(m，3H)，δ7.88(s，1H)，δ8.05(s，1H)，δ8.54-8.56(d，1H)，δ8.98(s，1H)，δ9.13(s，1H)，δ13.58(s，1H)；MS(FAB)：508(M+1).
Embodiment 3.N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-(5-trifluoromethyl)-1H-imidazoles-2-pyridine-4-oxygen base) phenyl) urea (compound 3)
Synthesis step reference example 1.
1HNMR(DMSO-d6)(ppm)：δ7.07-7.09(dd，1H)，δ7.21-7.23(d，2H)，δ7.39-7.40(d，1H)，δ7.60-7.66(m，4H)，δ7.87(s，1H)，δ8.13-8.14(d，1H)，δ8.54-8.55(d，1H)，δ9.03(s，1H)，δ9.25(s，1H)，δ13.57(s，1H)；MS(FAB)：543(M+1).
Embodiment 4.N-(3, the 4-dichlorophenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea (compound 4)
Synthesis step reference example 1.
1HNMR(DMSO-d6)(ppm)：δ7.07-7.40(m，5H)，δ7.53-7.62(m，3H)，δ7.88-7.91(m，2H)，δ8.54-8.55(d，1H)，δ8.99(s，1H)，δ9.09(s，1H)，δ13.58(s，1H)；MS(FAB)：509(M+1).
Embodiment 5.N-(3-chloro-4-fluoro-phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea (compound 5)
Synthesis step reference example 1.
1HNMR(DMSO-d6)(ppm)：δ7.06-7.07(dd，1H)，δ7.19-7.21(d，2H)，δ7.33-7.41(m，3H)，δ7.59-7.61(d，2H)，δ7.81-7.85(m，2H)，δ8.53-8.55(d，1H)，δ8.92-8.93(d，2H)，δ13.53(s，1H)；MS(FAB)：493(M+1).
Embodiment 6.N-(4-bromo-2-fluoro-phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea (compound 6)
Synthesis step reference example 1.
1HNMR(DMSO-d6)(ppm)：δ7.05-7.07(dd，1H)，δ7.20-7.22(d，2H)，δ7.36-7.40(m，2H)，δ7.57-7.60(m，3H)，δ7.85(s，1H)，δ8.12-8.17(t，1H)，δ8.53-8.55(d，1H)，δ8.70(d，1H)，δ9.23(s，1H)，δ13.53(s，1H)；MS(FAB)：537(M+1)
Embodiment 7.N-(4-fluoro-phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea (compound 7)
Synthesis step reference example 1.
1HNMR(DMSO-d6)(ppm)：δ7.07-7.21(m，5H)，δ7.39(s，2H)，δ7.59-7.61(d，2H)，δ7.67-7.73(m，1H)，δ7.88(s，1H)，δ8.54-8.55(d，1H)，δ8.78(s，1H)，δ8.85(s，1H)，δ13.57(s，1H)；MS(FAB)：458(M+1)
Embodiment 8.N-(2-chloro-6-methyl-phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea (compound 8)
Synthesis step reference example 1.
1HNMR(DMSO-d6)(ppm)：δ2.28(s，3H)，δ7.03-7.41(m，7H)，δ7.58-7.61(d，2H)，δ7.85(s，1H)，δ8.01(s，1H)，δ8.52-8.54(d，1H)，δ9.06(s，1H)，δ13.52(s，1H)；MS(FAB)：489(M+1)
Embodiment 9.N-(4-methoxyl group-phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea (compound 9)
Synthesis step reference example 1.
1HNMR(DMSO-d6)(ppm)：δ3.91(s，3H)，δ7.03-7.43(m，8H)，δ7.58-7.62(d，2H)，δ7.86(s，1H)，δ8.03(s，1H)，δ8.52-8.53(d，1H)，δ9.06(s，1H)，δ13.54(s，1H)；MS(FAB)：489(M+1)
Embodiment 10.N-(benzo [1,3] dioxy furans-5-)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea (compound 10)
Synthesis step reference example 1.
1HNMR(DMSO-d6)(ppm)：δ5.96-5.98(d，2H)，δ7.06-7.07(dd，1H)，δ7.20-7.22(d，2H)，δ7.36-7.41(m，2H)，δ7.56-7.60(m，3H)，δ7.83(s，1H)，δ8.11-8.15(t，1H)，δ8.52-8.54(d，1H)，δ8.71(d，1H)，δ9.21(s，1H)，δ13.49(s，1H)；MS(FAB)：484(M+1).
Embodiment 11.N-(5-methyl-isoxazole-3-)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea (compound 11)
Synthesis step reference example 1.
1HNMR(DMSO-d6)(ppm)：δ2.33-2.37(s，3H)，δ6.55(s，1H)，δ7.05-7.07(dd，1H)，δ7.20-7.22(d，2H)，δ7.39-7.40(d，1H)，δ7.58-7.60(d，2H)，δ7.85(s，1H)，δ8.53-8.55(d，1H)，δ8.97(s，1H)，δ9.50(s，1H)，δ13.53(s，1H)；MS(FAB)：445(M+1).
Embodiment 12.N-(4-fluoro-3-(trifluoromethyl) phenyl-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea (compound 12)
Synthesizing of step 1.N-(2-chloro-4-(2-cyanopyridine-4-oxygen base) phenyl) ethanamide
With 3.0g 4-chloro-2-cyano group-pyridine, 5.0g 3-chloro-4 acetyl aminophenols and 5.5g salt of wormwood are dissolved among the dry DMF of 30ml, and 80 ℃ of reactions are after 5 hours, and TLC shows that reaction finishes, add 50ml water, have solid to separate out, filter, (3 * 50ml) washings, drying gets white solid to the filter cake water.Step 2.N-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) ethanamide synthetic
The product of 4.1g step 1 is dissolved in the 20ml n-propyl alcohol, add the 1.2g sodium methylate, after 3 hours, add the 3.6g ammonium acetate 50 ℃ of reactions, 70 ℃ the reaction 1 hour after, add 3.5ml 3-bromo-1,1, the 1-trifluoroacetone, be warming up to 85 ℃ of reactions 20 hours, TLC shows that reaction finishes, and adds 50ml water, with ethyl acetate extraction (3 * 50ml), the organic layer anhydrous sodium sulfate drying, filter, evaporate to dryness gets oily matter, oily matter is crossed silicagel column, 2: 1 wash-outs of ethyl acetate/petroleum ether, the elutriant evaporate to dryness gets faint yellow look solid.
Step 3.2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) aniline synthetic
Product and 10ml 2N H with 3.0g step 2
2SO
4In the adding 100ml three-necked bottle, after 5 hours, TLC shows that reaction finishes 85 ℃ of reactions, to alkalescence, has solid to separate out with sodium hydroxide solution (50%) accent solution pH value, filters, and (3 * 20ml) washings, solid drying gets the sorrel solid to water.
Synthesizing of step 4.1-fluoro-4-isocyanic ester-2-trifluoromethylbenzene
The triphosgene of 0.55g is joined in the 10ml anhydrous methylene chloride N
2Protection, ice bath drip the dichloromethane solution of 15ml 4-fluoro-5-5-trifluoromethylaniline (0.5g) down, dropwise, and stirring at room 15min, 80 ℃ were reacted 6 hours then, and TLC shows that reaction finishes, and concentrating under reduced pressure toluene obtains oily matter, solidifies.
Step 5.N-(4-fluoro-3-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea synthetic
(the product 0.4g of 2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) aniline 0.3g and step 4 joins the dry DMF of 20ml, drips the 0.3ml triethylamine, places one evening of room temperature reaction, and TLC shows that reaction finishes with 2-chloro-4-; Add 25ml water, with ethyl acetate extraction (3 * 50ml), the organic layer anhydrous sodium sulfate drying filters, evaporate to dryness, oily matter, oily matter is crossed silicagel column, 1: 1 wash-out of ethyl acetate/petroleum ether, the elutriant evaporate to dryness gets white solid.
1HNMR(DMSO-d
6)(ppm)：δ7.08-7.10(dd，1H)，δ7.25-7.28(dd，1H)，δ7.44-7.65(m，4H)，δ7.87(s，1H)，δ8.02-8.04(dd，1H)，δ8.22-8.24(d，1H)，δ8.48-8.57(t，2H)，δ9.79(s，1H)，δ13.56(s，1H)；MS(FAB)：560(M+1).
Embodiment 13.N-(2-chloro-5-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea (compound 13)
Synthesis step reference example 12.
1HNMR(DMSO-d
6)(ppm)：δ7.11-7.12(dd，1H)，δ7.26-7.55(m，4H)，δ7.74-7.76(d，1H)，δ7.90(s，1H)，δ8.18-8.20(d，1H)，δ8.57-8.58(t，2H)，δ9.35-9.37(d，2H)，δ13.61(s，1H)；MS(FAB)：577(M+1).
Embodiment 14.N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea (compound 14)
Synthesis step reference example 12.
1HNMR(DMSO-d6)(ppm)：δ7.10-7.12(dd，1H)，δ7.25-7.56(m，4H)，δ7.73-7.76(d，1H)，δ7.91(s，1H)，δ8.18-8.21(d，1H)，δ8.56-8.58(t，2H)，δ9.35-9.38(d，2H)，δ13.60(s，1H)；MS(FAB)：577(M+1)
Embodiment 15.N-(3, the 4-dichlorophenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea (compound 15)
Synthesis step reference example 12.
1HNMR(DMSO-d6)(ppm)：δ7.08-7.10(dd，1H)，δ7.22-7.55(m，4H)，δ7.71-7.74(d，1H)，δ7.81(s，1H)，δ8.16-8.20(d，1H)，δ8.54-8.56(t，2H)，δ9.33-9.37(d，2H)，δ13.58(s，1H)；MS(FAB)：544(M+1)
Embodiment 16.N-(4-methyl-3-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea (compound 16)
Synthesis step reference example 12.
1HNMR(DMSO-d6)(ppm)：δ2.50(s，3H)，δ7.09-7.11(dd，1H)，δ7.25-7.28(dd，1H)，δ7.36-7.39(d，1H)，δ7.43-7.44(dd，1H)，δ7.49-7.54(m，2H)，δ7.88(s，1H)，δ7.96-7.97(d，1H)，δ8.25-8.27(d，1H)，δ8.44(s，1H)，δ8.56-8.57(d，1H)，δ9.67(s，1H)，δ13.56(s，1H)；MS(FAB)：555(M+1)
Embodiment 17.N-(3-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(5-(Trifluoromethyl-1 H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea (compound 17)
Synthesis step reference example 12.
1HNMR(DMSO-d6)(ppm)：δ7.07-7.09(dd，1H)，δ7.21-7.23(dd，2H)，δ7.32-7.34(d，1H)，δ7.39-7.40(d，1H)，δ7.51-7.55(t，1H)，δ7.59-7.63(m，3H)，δ7.88(d，1H)，δ8.04(d，1H)δ8.54-8.55(d，1H)，δ9.13(s，1H)δ13.58(s，1H)；MS(FAB)：541(M+1).
Embodiment 18.N-(3,4,5-(trimethoxy) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea (compound 18)
Synthesis step reference example 12.
1HNMR(DMSO-d6)(ppm)：δ3.73-3.78(s，9H)，δ6.66(s，2H)δ7.06-7.08(dd，1H)，δ7.19-7.22(dd，1H)，δ7.44-7.45(m，3H)，δ7.87-7.88(d，1H)，δ8.22-8.27(t，2H)，δ8.54-8.56(d，1H)，δ13.59(s，1H)；MS(FAB)：563(M+1)
Embodiment 19. compounds are to the restraining effect of KCC-853
The KCC-853 cell inoculation (replenishes penicillin, each 100ku/L of Streptomycin sulphate) in the RPMI1640 cell culture fluid that contains 10% foetal calf serum, cultivate vessel and place 37 ℃ to contain 5%CO
2Cell culture incubator in, every 2-3 days centrifugal changes liquid once, goes down to posterity and collecting cell.With the logarithmic phase cell, be mixed with the cell suspension of desired concn with the RPMI1640 nutrient solution that contains 10% foetal calf serum, (100 μ l) joins in the 96 porocyte culture plates by every hole 3000 cells, every hole adds the different storing solutions of measuring after cultivating 12h, the final concentration of sample effect is respectively 100 μ g/ml, 10 μ g/ml, 1 μ g/ml, 0.10 μ g/ml, 0.01 μ g/ml, and each concentration has 3 parallel holes.Cultivate and abandon supernatant after 3-5 days, every hole adds the serum-free medium of 20 μ l freshly prepared 5mg/ml tetrazole indigo plants (MTT), and MTT is made into 5mg/ml solution with physiological saline behind 37 ℃ of 4h, and every hole adds 20 μ l, cultivates 4 hours, and makes MTT be reduced to the Jia Za for 37 ℃.The sucking-off supernatant liquor adds the dissolving of 200 μ l DMSO Shi Jia Za, and (plate shaker) shakes up with dull and stereotyped shaking table.Under 570 wavelength, measure absorbance value (OD-value) with microplate reader.Inhibiting rate=(control group OD value-administration group OD value)/control group OD value * 100%;
Target compound is to the restraining effect of human renal carcinoma cell KCC-853
| Target compound | IC 50Value (μ M) |
| Compound 1 | 12.9 |
| Compound 2 | 7.7 |
| Compound 3 | 9.8 |
| Compound 4 | 7.8 |
| Compound 5 | 10.2 |
| SORAFENIB | 16.9 |
Conclusion: target compound has higher restraining effect to KCC-853, is better than positive drug Xarelto (SORAFENIB).
Claims (4)
1. general formula (I) compound:
Or its pharmacy acceptable salt or solvated compounds
R
1, R
2, R
3Be independently selected from hydrogen, hydroxyl, C respectively
1-6Alkyl, C
1-6Alkoxyl group, halogen, (C
1-6Alkoxyl group) carbonyl, aminocarboxyl, C
1-6Alkyl amino-carbonyl, itrile group, cycloalkyl, Heterocyclylalkyl, Heterocyclylalkyl carbonyl, phenyl or heteroaryl, these groups can be replaced arbitrarily by one or more following groups, and these groups are selected from hydroxyl, halogen, C
1-6Alkyl, halo (C
1-6Alkyl), C
1-6Alkoxyl group or halo (C
1-6Alkoxyl group)
Ar
1Be aryl or heteroaryl, and can be by C
1-4Alkyl, halogenated C
1-4Alkyl or halogen replace arbitrarily;
2. formula according to claim 1 (I) compound is characterized in that described compound is:
N-(2-chloro-5-(trifluoromethyl) phenyl)-N '-(4-(2-(5-trifluoromethyl)-1H-imidazoles-2-pyridine-4-oxygen base) phenyl) urea;
N-(3-(trifluoromethyl) phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-(5-trifluoromethyl)-1H-imidazoles-2-pyridine-4-oxygen base) phenyl) urea;
N-(3, the 4-dichlorophenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(3-chloro-4-fluoro-phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(4-bromo-2-fluoro-phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(4-fluoro-phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(2-chloro-6-methyl-phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(4-methoxyl group-phenyl)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(benzo [1,3] dioxy furans-5-)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(5-methyl-isoxazole-3-)-N '-(4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(4-fluoro-3-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(2-chloro-5-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(3, the 4-dichlorophenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(4-methyl-3-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea;
N-(3-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea synthetic; Or
N-(3,4,5-(trimethoxy) phenyl)-N '-(2-chloro-4-(2-(5-(trifluoromethyl)-1H-imidazoles-2-) pyridine-4-oxygen base) phenyl) urea synthetic.
Or its pharmacy acceptable salt or solvated compounds
3. a pharmaceutical composition contains the described compound of arbitrary claim or its pharmacy acceptable salt and pharmaceutically acceptable carrier among the claim 1-2.
4. the described compound of arbitrary claim or its pharmacy acceptable salt application in the medicine of relevant psoriasis, leukemia or solid tumor of preparation treatment human or animal cell proliferative in the claim 1-2 item.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974132A (en) * | 2014-04-08 | 2015-10-14 | 北大方正集团有限公司 | Polysubstituted pyridine compound and preparation method and application thereof as well as pharmaceutical composition |
| CN105924390A (en) * | 2016-05-19 | 2016-09-07 | 广州南新制药有限公司 | Synthesis method of metafenib |
| CN107935935A (en) * | 2017-11-13 | 2018-04-20 | 镇江斯格派医疗器械有限公司 | A kind of carboxyl imidazoles histone deacetylases inhibitor |
-
2010
- 2010-05-07 CN CN 201010165555 patent/CN102234270A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974132A (en) * | 2014-04-08 | 2015-10-14 | 北大方正集团有限公司 | Polysubstituted pyridine compound and preparation method and application thereof as well as pharmaceutical composition |
| WO2015154535A1 (en) * | 2014-04-08 | 2015-10-15 | 北大方正集团有限公司 | Polysubstituted pyridine compound, preparation method, use and pharmaceutical composition |
| CN104974132B (en) * | 2014-04-08 | 2017-05-17 | 北大方正集团有限公司 | Polysubstituted pyridine compound and preparation method and application thereof as well as pharmaceutical composition |
| EP3130588A4 (en) * | 2014-04-08 | 2017-09-06 | Peking University Founder Group Co., Ltd | Polysubstituted pyridine compound, preparation method, use and pharmaceutical composition |
| US9902709B2 (en) | 2014-04-08 | 2018-02-27 | Peking University Founder Group Co., Ltd. | Polysubstituted pyridine compound, preparation method, use and pharmaceutical composition |
| CN105924390A (en) * | 2016-05-19 | 2016-09-07 | 广州南新制药有限公司 | Synthesis method of metafenib |
| CN107935935A (en) * | 2017-11-13 | 2018-04-20 | 镇江斯格派医疗器械有限公司 | A kind of carboxyl imidazoles histone deacetylases inhibitor |
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