CN102532113A - Aryl urea derivative - Google Patents
Aryl urea derivative Download PDFInfo
- Publication number
- CN102532113A CN102532113A CN2011104358479A CN201110435847A CN102532113A CN 102532113 A CN102532113 A CN 102532113A CN 2011104358479 A CN2011104358479 A CN 2011104358479A CN 201110435847 A CN201110435847 A CN 201110435847A CN 102532113 A CN102532113 A CN 102532113A
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- Prior art keywords
- phenyl
- compound
- chloro
- formula
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 238000006243 chemical reaction Methods 0.000 claims description 16
- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 claims description 14
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Abstract
The invention discloses aryl urea derivative indicated through a group of general formula structures, which belongs to the field of medicinal chemistry. The invention further discloses a preparation method for the aryl urea derivative indicated by the general formula structures. The compound of the aryl urea derivative has an effect of raf kinase inhibitor and can be used for preparing medicine for curing tumor diseases.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to one group of aryl carbamide compound of representing by general formula, and their preparation method and as the purposes of raf SU11752.
Background technology
The p21ras oncogene is the one of the main reasons of people's essence oncogenesis and development, and sudden change (Bolton etc., Ann.Rep.Med.Chem, 1994,29,165-74 have taken place this gene of 30% cancer patients; Bos.Cancer.Res.1989,49,4682-9).Not mutated normal form ras albumen be in the signal transduction cascade that points to by growth factor receptors in nearly all tissue key element (Avruch etc., Trends Biochem.Sci.1994,19,279-83).On the biological chemistry, ras is a kind of protein that combines guanylic acid, and GTP combines activated state to combine the circulation between the tranquillization attitude to receive ras endogenous GTP enzymic activity and the proteic strict control of other adjustings with GDP.The endogenous GTP enzymic activity of sudden change ras in the cancer cells improves, so, this protein downstream effect thing, for example the raf kinases sends the composition growth signals.Therefore cause the cell cancerous growths that has these two mutants (Magnuson etc., Semin.Cancer Biol.1994,5,247-53).Known; Through suppressing the effect that the raf kinase signal pathway suppresses active ras; For example through giving raf kinase whose antibody or the coexpression dominant raf kinases or of deactivating as the dominant MEK of raf kinase substrate, can make transformant be returned to normal growth phenotype (referring to; Daum etc., Trends Biochem, Sci.1994,19,474-80; Fridman etc., J.Biol.Chem.1994,269,30105-8).Kolch etc., (nature, 1991,349,426-28) further point out, in the relevant oncogene of film, suppress raf with sense-rna and express propagation capable of inhibiting cell.Similarly, all find in vitro and in vivo raf kinase inhibition (using AODN) and various human tumor growth suppress relevant (Monia etc., Nat.Med.1996,2,668-75).
Recently the emphasis of research concentrates on and seeks strong raf SU11752 of imitating.Clinical data shows that suppressor factor class medicine is compared with traditional chemotherapeutics in the signal transduction pathway, and toxicity is lower, has the expert to estimate that this type of medicine will become the standard care medicine of cancer therapy and be widely used in clinical after next two decades.Aryl urea compounds usually has other kinase whose inhibition activity in the tumor signal transduction path, and these kinases comprise vascular endothelial growth factor receptor 2/3 (VEGFR-2, VEGFR-3), platelet derived growth factor receptor β (PDGFR-β), KIT, FLT-3, RET.Make this type of medicine not only can suppress tumor cell proliferation, can also stop tumor neovasculature generation.This has further strengthened the clinical effectiveness and the researching value of this compounds inhibition tumour.
Summary of the invention
The present invention utilizes area of computer aided medicinal design means such as Pharmacophore Model to set up the structure activity relationship model and the medicaments sifting model of aryl urea compounds, has designed the aryl carbamide compound of a series of brand news on this basis.
Aryl carbamide compound of the present invention is used for people or beastly raf kinases path inhibition as the raf SU11752, for example, is used to treat kinase mediated tumour or cell cancerous growths by raf.Specifically; These compounds can be used for treating human or animal's cancer, and these cancers for example are melanoma, liver cancer, kidney, acute leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastisches syndromes, the esophageal carcinoma, gastrointestinal cancer or mesothelioma etc.
Therefore, the present invention relates to compound or its pharmacy acceptable salt of general formula I:
Wherein, Replacement or unsubstituted five yuan of fragrant heterocycles that R1 representes for formula a; Wherein, R4, R5, R6 are selected from carbon atom, nitrogen-atoms, Sauerstoffatom or sulphur atom independently of one another, and substituent R 8, R9, R10 are selected from hydrogen, halogen, C1-4 alkyl or C1-4 alkoxyl group independently of one another;
R2 is selected from hydrogen, hydroxyl, nitro, amino, C1-4 alkyl.
Replacement or unsubstituted five yuan of fragrant heterocycles that R1 further representes for formula a, wherein, R4, R5, R6 are selected from carbon atom, nitrogen-atoms or sulphur atom independently of one another, and substituent R 8, R9, R10 are selected from hydrogen or methyl independently of one another.
R2 further is selected from hydrogen, hydroxyl, nitro, amino or methyl.
R2 further is selected from hydrogen.
R1 further is selected from:
R1 further is selected from:
The inventor is through the structure activity study to lead compound; Introduce new substituting group or functional group to bioactive molecule, synthesized a hundreds of new compound, and then according to " bioactive mensuration " test design; To the capable preliminary screening of all new compounds; According to the result of primary dcreening operation, carry out composition optimizes again, the new compound that primary dcreening operation is obtained is capable to be sieved again.Estimate with the whole animal model, carry out pharmacology, pharmacodynamics, toxicologic study, finally confirmed disclosed most preferred new compound among the present invention.
The compound of general formula of the present invention and pharmacy acceptable salt thereof can be:
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(4-pyrazolyl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(4-imidazolyl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(3-pyrryl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(3-thienyl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(1-methyl-4-imidazolyl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(1 methyl-3-pyrryl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(2-hydroxyl-4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(2-methyl-4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(2-nitro-4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea.
Preferred especially compound of the present invention is:
According to the IUPAC nomenclature, formula IV compound called after of the present invention: 1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea.
Pharmacy acceptable salt of the present invention comprises the acid salt that compound of Formula I and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, Hydrocerol A, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, toxilic acid or phenylformic acid.
The present invention comprises that also compound of Formula I or its pharmacy acceptable salt are used for preventing or the purposes of the medicine of treatment and raf SU11752 diseases associated in preparation.Wherein Raf SU11752 diseases associated is melanoma, liver cancer, kidney, acute leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastisches syndromes, the esophageal carcinoma, gastrointestinal cancer or mesothelioma.
The preparation method of compound of Formula I of the present invention is following; All compounds of the present invention can use this preparation method to obtain: at first; The aminophenols thing under the highly basic effect with 2; 4-dihalo pyridine generation nucleophilic substitution reaction, the Suzuki reaction takes place in products therefrom and five yuan of aromatic heterocyclic boric acid pinacol esters under the catalysis of palladium catalyst, and products therefrom and 3-trifluoromethyl-4-chloro-benzene isocyanate reaction obtains the compound of general formula I.
As further giving an example, the preparation method of preferred formula IV compound of the present invention is following:
Step 1:
Step 2:
Step 3:
As two midbodys in the preparation process of the above-mentioned preferred compound of the present invention, formula II compound and formula III compound also are new compounds.
New intermediate formula II compound: according to the IUPAC nomenclature, formula II compound called after of the present invention: 2-chloro-4-(4-amino-benzene oxygen) pyridine.
New intermediate formula III compound: according to the IUPAC nomenclature, formula III compound called after of the present invention: 4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) aniline.
The preparation method of formula IV compound of the present invention is specific as follows:
Step 1: 4.35g 4-amino-phenol is dissolved in the anhydrous dimethyl sulphoxide, behind the logical nitrogen 10min, adds potassium tert.-butoxide 4.7g, stir 30min under the room temperature after; Add 5g 2-chloro-4-fluorine pyridine, again reaction system slowly is warming up to 80 ℃ and insulation reaction 2h, TLC detects and shows and react completely, be cooled to room temperature after; Add entry and ETHYLE ACETATE, behind the separatory water with ethyl acetate extraction twice, the combined ethyl acetate layer; Washing twice, more once with the saturated common salt washing, anhydrous sodium sulfate drying; Filter, concentrate, get formula II compound behind the gained bullion column chromatography purification;
Step 2: under the nitrogen protection; 5.7g 2-chloro-4-(4-amino-benzene oxygen) pyridine and 6.47g 1-methyl-4-pyrazoles boric acid pinacol ester are dissolved in the THF; Stir and add 10.7g salt of wormwood and 17.1mL water down; Add 1.5g four triphenyl phosphorus palladium catalysts then under the lucifuge, in 70 ℃ of insulated and stirred 24h, the TLC detection reaction is complete.Be cooled to room temperature, reaction system is concentrated, add ETHYLE ACETATE and water then, water is with ethyl acetate extraction twice behind the separatory, and the combined ethyl acetate layer washes twice, and saturated common salt is washed once, and anhydrous sodium sulfate drying filters, and concentrates.Get the formula III compound behind the thick product column chromatography purification;
Step 3: 6.7g 4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) aniline is dissolved in the ETHYLE ACETATE; Nitrogen protection adds 5.6g 3-trifluoromethyl-4-chloro-benzene isocyanic ester down, has a large amount of solids to separate out behind the stirring 12h under the room temperature, concentrates; Suction filtration; The ETHYLE ACETATE washing, oven dry gets formula IV compound.
The method of enantiomorph and non-enantiomer mixture is that those skilled in the art are familiar with.The present invention includes the compound of Formula I any raf of having kinase inhibiting activity, isolating racemization or optical activity form.
The present invention also comprises the pharmaceutical composition that comprises the carrier of approving on compound of Formula I and the physiology.The compounds of this invention can be through injection, suction or sprinkling or rectum, and per os, skin, parenteral give, or gives with the unit formulation formulation." injection gives " comprises vein, intramuscular, subcutaneous and parenteral injection, and uses infusion techn.Percutaneous drug delivery comprises external application or transdermal administration.One or more compounds can with one or more non-toxic carriers of pharmaceutically approving, and other activeconstituentss that depend on the needs coexistence.Oral compsns can be made the known appropriate method preparation in field according to any pharmaceutical composition.In order to improve the preparation mouthfeel, said compsn can contain one or more following reagent: thinner, sweeting agent, spices, tinting material and sanitas.Tablet contains activeconstituents, and they mix with the non-toxic excipients of pharmaceutically approving, be fit to tablet manufacturing.Said vehicle is inert diluent for example, lime carbonate for example, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example W-Gum or alginic acid. tackiness agent, for example Magnesium Stearate, Triple Pressed Stearic Acid or talcum powder.Tablet can not have dressing, can wrap up with known technology yet, to postpone its disintegration and absorption in gi tract, secular continuous action is provided.For example, can adopt time-delay material such as glyceryl monostearate or distearin.Said compound also can be processed solid, releases form soon.Oral prepns can also be a hard gelatin capsule; Activeconstituents wherein mixes with for example inert solid diluent such as lime carbonate, calcium phosphate or kaolin mutually; Or soft gelatin capsule, activeconstituents wherein is with water or for example peanut oil, whiteruss or olive wet goods oil mix.
Also can use and contain active substance and the suitable waterborne suspension of making the mixed with excipients of waterborne suspension.Said vehicle is a suspension agent, Xylo-Mucine for example, methylcellulose gum, hydroxypropyl-methylcellulose gum, sodiun alginate, PVP K120, tragcanth and Sudan Gum-arabic; Dispersion agent or wetting agent can be natural phospholipids; The condensation product of for example Yelkin TTS, or oxyethane and lipid acid, for example polyoxyethylene stearic acid ester; Or the condensation product of oxyethane and long chain aliphatic alcohol; For example 17 oxygen ethene cetyl alcohols, or oxyethane and the condensation product of lipid acid with partial ester that hexitol becomes, for example single oleic acid polyoxyethylene sorbitan ester.Waterborne suspension also can contain one or more sanitass, for example ethylparaben or n-propyl, one or more tinting materials, one or more spices and one or more sweeting agents, for example sucrose or asccharin.Become in the dispersed powders or particle of waterborne suspension but be fit to add water, activeconstituents and dispersion agent or wetting agent, suspension agent mixes with one or more sanitass.Suitable dispersion agent or wetting agent and suspension agent can mentioned abovely be example.Can also contain other vehicle, for example sweeting agent, spices and tinting material.
The form of pharmaceutical composition of the present invention can also be non-aqueous liquid preparation, oily suspensions for example, and this can be through being suspended in activeconstituents peanut oil, sweet oil, til or peanut wet goods vegetables oil or such as preparing in the MO such as whiteruss.This oily suspensions can contain thickening material, for example beeswax, paraffinum durum or Tego Alkanol 16.In order to improve mouthfeel, can add above-mentioned sweeting agent and spices.Said compsn can be guaranteed the quality such as inhibitors such as xitix through adding.
The form of pharmaceutical composition of the present invention can also be an O/w emulsion.Oil phase can be such as sweet oil or peanut wet goods vegetables oil or MO such as liquid beeswax for example, or their mixture.Suitable emulsifying agent can be natural gums such as tragcanth and Sudan Gum-arabic, or natural phospholipid, for example soybean lecithin or Yelkin TTS: the partial ester that lipid acid and dewatering hexitol form, for example but oleic acid anhydro sorbitol vinegar; The condensation product of said partial ester and oxyethane, for example single oleic acid Sorbitan ethoxylate.Said emulsion also can contain sweeting agent and spices.
Sweeting agent obtain syrup agent such as also available for example glycerine, W 166, sorbyl alcohol or sucrose.This type preparation also can contain demulcen, sanitas and spices and tinting material.
Said compound can also suppository form be used for rectum or vagina administration.This based composition can be solid-state under the said vehicle normal temperature through medicine and suitable non-stimulated mixed with excipients are prepared, but is liquid in rectal temperature or vagina temperature, and therefore, its can melt and discharge medicine at rectum or intravaginal.Such material comprises theobroma oil and polyoxyethylene glycol.
In specification sheets of the present invention and claim, the name of compound all is according to chemical structural formula, if the name and the chemical structural formula of compound is not inconsistent when representing same compound, is as the criterion with chemical structural formula or reaction formula.
Combine embodiment at present, the present invention further described:
Embodiment
Embodiment 1:1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea
Synthesizing of 1a:2-chloro-4-(4-amino-benzene oxygen) pyridine:
4.35g (39.8mmol) 4-amino-phenol is dissolved in the 40mL anhydrous dimethyl sulphoxide; Behind the logical nitrogen 10min; Add potassium tert.-butoxide 4.7g (41.8mmol), behind the stirring 30min, add 5g (38.0mmol) 2-chloro-4-fluorine pyridine under the room temperature; Again reaction system slowly is warming up to 80 ℃ and insulation reaction 2h, TLC detects demonstration and reacts completely.After being cooled to room temperature, add 100mL water and 100mL ETHYLE ACETATE, water is with twice of 100mL ethyl acetate extraction behind the separatory; The combined ethyl acetate layer is washed twice (100mL/ time), washes once (100mL/ time) with saturated common salt again; Anhydrous sodium sulfate drying filters, and concentrates; Get 7.26g faint yellow solid, productive rate 86.8% behind the gained bullion column chromatography purification.
1H?NMR(300MHz，CDCl
3)：δ4.07(br?s，2H)，6.72(d，J＝8.7Hz，2H)，6.75-6.77(m，2H)，6.88(d，J＝8.7Hz，2H)，8.19(d，J＝5.4Hz，1H).MS(ESI+)：221.1[M+H]
+
Synthesizing of 1b:4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) aniline:
Under the nitrogen protection; 5.7g (25.9mmol) 2-chloro-4-(4-amino-benzene oxygen) pyridine and 6.47g (31.1mmol) 1-methyl-4-pyrazoles boric acid pinacol ester are dissolved in (THF) in the 70mL THF; Stir and add 10.7g (77.5mmol) salt of wormwood and 17.1mL water down; Add 1.5g (1.29mmol) four triphenyl phosphorus palladium catalysts then under the lucifuge, in 70 ℃ of insulated and stirred 24h, the TLC detection reaction is complete.
Be cooled to room temperature, reaction system is concentrated, add each 50mL of ETHYLE ACETATE and water then, water is with twice of 50mL ethyl acetate extraction behind the separatory; The combined ethyl acetate layer is washed twice (50mL/ time), and the saturated common salt washing is (50mL/ time) once; Anhydrous sodium sulfate drying filters, and concentrates.Get the 5.85g faint yellow solid, yield 85% behind the thick product column chromatography purification.
1H?NMR(300MHz，CDCl
3)：δ3.84(br?s，2H)，3.92(s，3H)，6.60(dd，J＝2.4，5.7Hz，1H)，6.71(d，J＝8.7Hz，2H)，6.91(d，J＝8.7Hz，2H)，6.94(d，J＝2.1Hz，1H)，7.86(s，2H，)，8.34(d，J＝5.7Hz，1H).MS(ESI+)：221.1[M+H]
+
Synthesizing of 1c:1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea:
6.7g (25.1mmol) 4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) aniline is dissolved in the 80mL ETHYLE ACETATE, and nitrogen protection adds 5.6g (25.1mmol) 3-trifluoromethyl-4-chloro-benzene isocyanic ester down, has a large amount of solids to separate out behind the stirring 12h under the room temperature; System is concentrated into solvent residue 40mL; Suction filtration, ETHYLE ACETATE is washed, oven dry; Get white solid 7.5g, yield 60.9%.
1H?NMR(300MHz，DMSO-d
6)：δ3.88(s，3H)，6.63(d，J＝3.9Hz，1H)，7.15(d，J＝8.4Hz，2H)，7.21(s，1H)，7.57-7.69(m，4H)，7.96(s，1H)，8.12(s，1H)，8.24(s，1H)，8.37(d，J＝5.4Hz，1H)，8.93(s，1H)，9.17(s，1H).MS(ESI+)：488.1[M+H]
+
Embodiment 2:1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(4-pyrazolyl)-4-pyridyloxy) phenyl) urea
The preparation method is with embodiment 1, and wherein the methyl of the 1-among the 1b-4-pyrazoles boric acid pinacol ester replaces with 4-pyrazoles boric acid pinacol ester, and the methylene dichloride among the 1c replaces with ETHYLE ACETATE.
1H?NMR(300MHz，DMSO-d
6)：δ6.40(br?s，1H)，6.63(d，J＝3.9Hz，1H)，7.15(d，J＝8.4Hz，2H)，7.21(s，1H)，7.57-7.69(m，4H)，7.96(s，1H)，8.12(s，1H)，8.24(s，1H)，8.37(d，J＝5.4Hz，1H)，8.93(s，1H)，9.17(s，1H).MS(ESI+)：474.1[M+H]
+
Embodiment 3:1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(4-imidazolyl)-4-pyridyloxy) phenyl) urea
The preparation method is with embodiment 1, and wherein the methyl of the 1-among the 1b-4-pyrazoles boric acid pinacol ester replaces with 4-imidazoles boric acid pinacol ester.
1H?NMR(300MHz，DMSO-d
6)：δ6.30(br?s，1H)，6.63(d，J＝3.9Hz，1H)，7.15(d，J＝8.4Hz，2H)，7.21(s，1H)，7.57-7.69(m，4H)，7.96(s，1H)，8.17(s，1H)，8.24(s，1H)，8.37(d，J＝5.4Hz，1H)，8.93(s，1H)，9.17(s，1H).MS(ESI+)：474.1[M+H]
+
Embodiment 4:1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(3-pyrryl)-4-pyridyloxy) phenyl) urea
The preparation method is with embodiment 1, and wherein the methyl of the 1-among the 1b-4-pyrazoles boric acid pinacol ester replaces with 3-pyrroles's boric acid pinacol ester.
1H?NMR(300MHz，DMSO-d
6)：δ6.35(br?s，1H)，6.63(d，J＝3.9Hz，1H)，7.15(d，J＝8.4Hz，2H)，7.21(s，1H)，7.57-7.69(m，5H)，7.96(s，1H)，8.17(s，1H)，8.24(s，1H)，8.37(d，J＝5.4Hz，1H)，8.93(s，1H)，9.17(s，1H).MS(ESI+)：473.1[M+H]
+
Embodiment 5:1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(3-thienyl)-4-pyridyloxy) phenyl) urea
The preparation method is with embodiment 1, and wherein the methyl of the 1-among the 1b-4-pyrazoles boric acid pinacol ester replaces with the 3 thienylboronic acid pinacol ester.
1H?NMR(300MHz，DMSO-d
6)：δ6.52(s，1H)，6.63(d，J＝3.9Hz，1H)，7.15(d，J＝8.4Hz，2H)，7.21(s，1H)，7.57-7.69(m，4H)，7.96(s，1H)，8.17(s，1H)，8.24(s，1H)，8.37(d，J＝5.4Hz，1H)，8.93(s，1H)，9.17(s，1H).MS(ESI+)：490.1[M+H]
+
Embodiment 6:1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(1-methyl-4-imidazolyl)-4-pyridyloxy) phenyl) urea
The preparation method is with embodiment 1, and wherein the methyl of the 1-among the 1b-4-pyrazoles boric acid pinacol ester replaces with 1-methyl-4-imidazoles boric acid pinacol ester.
1H?NMR(300MHz，DMSO-d
6)：δ3.75(s，3H)，6.63(d，J＝3.9Hz，1H)，7.15(d，J＝8.4Hz，2H)，7.28(s，1H)，7.57-7.69(m，4H)，7.91(s，1H)，8.15(s，1H)，8.24(s，1H)，8.32(d，J＝5.4Hz，1H)，8.99(s，1H)，9.17(s，1H).MS(ESI+)：488.1[M+H]
+
Embodiment 7:1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(1-methyl-3-pyrryl)-4-pyridyloxy) phenyl) urea
The preparation method is with embodiment 1, and wherein the methyl of the 1-among the 1b-4-pyrazoles boric acid pinacol ester replaces with 1-methyl-3-pyrroles's boric acid pinacol ester.
1H?NMR(300MHz，DMSO-d
6)：δ3.67(s，3H)，6.63(d，J＝3.9Hz，1H)，6.82(s，1H)，7.15(d，J＝8.4Hz，2H)，7.28(s，1H)，7.57-7.69(m，4H)，7.91(s，1H)，8.15(s，1H)，8.24(s，1H)，8.32(d，J＝5.4Hz，1H)，8.99(s，1H)，9.17(s，1H).MS(ESI+)：487.1[M+H]
+
Embodiment 8:1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(2-hydroxyl-4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea
The preparation method is with embodiment 1, and wherein the 4-amino-phenol among the 1a replaces with 4-amino-1, the 3-dihydroxy-benzene.
1H?NMR(300MHz，DMSO-d
6)：δ3.88(s，3H)，6.21(br?s，1H)，6.63(d，J＝5.4Hz，1H)，7.15(d，J＝8.4Hz，2H)，7.57-7.69(m，4H)，7.96(s，1H)，8.12(s，1H)，8.24(d，J＝2.4Hz，1H)，8.37(d，J＝5.4Hz，1H)，8.93(s，1H)，9.17(s，1H).MS(ESI+)：504.1[M+H]
+
Embodiment 9:1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(2-nitro-4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea
The preparation method is with embodiment 1, and wherein the 4-amino-phenol among the 1a replaces with 3-nitro-4-amino-phenol.
1H?NMR(300MHz，DMSO-d
6)：δ3.81(s，3H)，6.61(dd，J＝2.1，5.4Hz，1H)，6.82(d，J＝8.4Hz，1H)，7.05(dd，J＝2.4，8.4Hz，1H)，7.25(d，J＝2.4Hz，1H)，7.51-7.64(m，3H)，7.96(s，1H)，8.16(s，1H)，8.29(d，J＝2.4Hz，1H)，8.37(d，J＝5.4Hz，1H)，8.93(s，1H)，9.17(s，1H).MS(ESI+)：533.1[M+H]
+
Embodiment 10:1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(2-methyl-4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea
The preparation method is with embodiment 1, and wherein the 4-amino-phenol among the 1a replaces with 3-methyl-4-amino-phenol.
1H?NMR(300MHz，DMSO-d
6)：δ2.23(s，3H)，3.81(s，3H)，6.61(d，J＝5.4Hz，1H)，6.72(d，J＝2.4Hz，1H)，6.87(dd，J＝2.4，5.4Hz，1H)，6.95(d，J＝8.4Hz，1H)，7.51-7.64(m，3H)，7.96(s，1H)，8.16(s，1H)，8.29(d，J＝8.1Hz，1H)，8.37(d，J＝5.4Hz，1H)，8.93(s，1H)，9.17(s，1H).MS(ESI+)：502.1[M+H]
+
Experimental example 1: external raf screening
Through ATP, MEK substrate are provided, and measure the phosphoric acid part can be measured activity from the various isotypes of raf serine/threonine kinase to the transfer of MEK residue.Sf9 insect cell through infecting from people raf recombination rhabdovirus expression vector carries out purifying, obtains raf reorganization isotype body.The kinases inactivation MEK of reorganization uses biotin labeling at expression in escherichia coli behind the purifying.For each mensuration, test compound is diluted in DMSO continuously, in reaction buffer and ATP (1uM), mix then with raf (0.50nM) and kinases inactivation vitamin H-MEK (50nM).At room temperature, reactant continues to cultivate 2 hours, and stops through adding 0.5M EDTA.The reaction mixture that will stop to be transferred to coating neutradavin plate (pierce), and cultivates 1 hour.Use rabbit anti--p-MEK (Cell Signaling) as anti--rabbit of first antibody and europium mark as SA, through DELFIA time-resolutions fluorescing system (Wallac) measurement phosphorylation product.Time resolved fluorescence is read on Wallac 1232 DELFIA photofluorometers.Use XL fitting data analysis software to calculate each compound 50% and suppress concentrating of (IC50) through non-linear regression.
Use above-mentioned steps, the compound exhibits of embodiment 1 has the raf kinase inhibiting activity, and IC50 is less than 5 μ M.
Experimental example 2: The compounds of this invention suppresses ACHN kidney Study on Growth
1 materials and methods
1.1 experiment material
Female BALB/c-nu/nu nude mouse, 4 ages in week, mean body weight 14.2g (12.6-15.8) g.The ACHN renal cancer cell line is available from U.S. typical case species preservation centers (ATCC).
1.2 experimental technique
It is subcutaneous that ACHN kidney cancer cell 2.0 * 106/0.2ml is inoculated in back, every nude mice right side, by the body weight numbering 16 nude mouses is divided into medication group and control group at random.Two groups of body weight do not have significant difference.Rose on the 3rd day the inoculation back, the administration next day of beginning, and the medication group gives embodiment 1 compound (60mg/kg; Solvent: 3% absolute ethyl alcohol+97% saline water), control group gives solvent (3% absolute ethyl alcohol+97% saline water).Away from the tumour subcutaneous injection, each every 0.2ml.Observe the mouse generalized case during the administration, the next day measure the mouse body weight, the tumour size, gross tumor volume is used formula: V=1/2 * a * b2, (a is a major diameter, and b is a minor axis).Inoculate the 31st day, disconnected neck is put to death mouse, measures gross tumor volume before dissecting, claims that mouse is heavy.The dissection Subcutaneous tumor is also weighed, and cuts mouse lung.FAA (Glacial acetic acid min. 99.5+Superlysoform+ethanol) is Subcutaneous tumor and mouse lung fixedly, paraffin embedding.Calculate mouse heavy (mouse weight=band knurl mouse weight-knurl is heavy) once more.The maximum tangent plane HE dyeing of two lung coronal-planes, microscopically (100 times of visuals field) counting lung shifts tubercle.
1.3 statistical procedures
Knurl weight, volume, mouse are reused the t check between two groups, and the gross tumor volume growth curve is used the SAS covariance analysis, and the lung metastatic nodules is checked with accurate stochastic method.
2 results
2.1 heavily reaching gross tumor volume, subcutaneous tumors changes
When inoculating the 31st day, two groups of subcutaneous tumors heavily are respectively 628.42 ± 149.87mg and 262.25 ± 61.82mg, and medication group knurl heavily is starkly lower than control group (p＜0.01).During 31d, two groups of subcutaneous tumors volumes are respectively 326.85 ± 58.21mm3 and 110.85 ± 47.66mm3 (p＜0.01).Two groups of knurl volume-times change sees table 1:
Table 1: gross tumor volume-time changes
Table 1 is the result show, the growth of medication group gross tumor volume significantly is lower than control group.
2.2 lung shifts tubercle
7 lung metastasis in 8 mouse of control group, 3 is 1 transfer tubercle, all the other are 3-5 and shift tubercle that the medication group does not find that lung shifts tubercle.Check two groups of differences that significance meaning (p＜0.05) is arranged through accurate stochastic method.The control group not only rate of transform is high, and metastatic nodules is also more.
2.3 spinoff is observed during the medication
During the medication, each mouse is movable good, does not see untoward reactions such as diarrhoea.
3 experiment conclusion
The compounds of this invention medication group knurl heavily is starkly lower than control group; Has statistical significance (p＜0.01); The growth of medication group gross tumor volume significantly is lower than control group, and The compounds of this invention has the effect of tangible tumor growth, and The compounds of this invention obviously suppresses the incidence of metastases; And The compounds of this invention has lower toxic side effect.
Experimental example 3: The compounds of this invention is to the therapeutic evaluation of 786-O transplanted tumor in nude mice
1. test objective
The restraining effect of investigationization The compounds of this invention to growing in the people 786-O nude mice transplantation tumor body, and the toxicity of preliminary observation compound.
2. test materials
Test-compound: the embodiment of the invention 1 compound (numbering A1); The production unit of providing: Fangzheng Medicinal Research Institute Co., Ltd
Positive control drug: Xarelto (Sorafenib); The production unit of providing: Fangzheng Medicinal Research Institute Co., Ltd
Control compounds:
Control compounds 1 (numbering B1): Chinese patent publication number CN101801383A; Open day: 2010-08-11; The 11st page of capable disclosed compound of inverse 3-4 of specification sheets " 1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(2-fluoro-4-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) phenyl) urea "; Preparing method:, wherein raw material 4-amino-phenol is replaced with 3-fluoro-4-amino-phenol with the embodiment of the invention 1.
Control compounds 2 (numbering B2): Chinese patent publication number CN101801383A; Open day: 2010-08-11; Disclosed compound during the 11st page of [0120] section 7-8 of specification sheets is capable " 1-(4-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) phenyl)-3-(3-(trifluoromethyl) phenyl) urea "; The preparation method wherein replaces with 3-trifluoromethyl-benzene isocyanic ester with raw material 3-trifluoromethyl-4-chloro-benzene isocyanic ester with the embodiment of the invention 1.
The solvent material:
Absolute ethyl alcohol
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Cremophor EL: Witconol 5909
Beijing phoenix gift essence is asked commerce and trade Ltd
Lot identification mark: 57219156PO
HPMC-K4M: hypromellose
Production unit: Shanghai Colorcon Coating Technology Co., Ltd
Lot number: PD224587
Proterties: white powder
SLS: sodium lauryl sulphate
Production unit: the mountains and rivers, Anhui pharmaceutical excipient limited-liability company
Lot number: 080602
Proterties: white powder
Experimental animal:
Strain: BALB/C nude mice (SPF level)
Source: Shanghai Si Laike laboratory animal responsibility ltd
Production licence number: SCXK (Shanghai) 2007-0005
Occupancy permit number: SYXK (Shanghai) 2009-0075
Sex: male.
Age in week: 6 ages in week
The strain of transplanted tumor knurl
Title: human body kidney 786-O
The source: this laboratory is protected and is planted, and BALB/C nude mice subcutaneous transplantation goes down to posterity and keeps
3. TP
Drug-delivery preparation and collocation method:
The solvent 1:0.5%HPMC-K4M&0.2%SLS aqueous solution.
Compound method: take by weighing an amount of HPMC-K4M and the SLS blue lid bottle of 250mL of packing into, add an amount of ultrapure water, more than the magnetic stirrer 4hrs; Treat behind the whole homodisperse of solid matter the static 2～3hrs of this liquid to be used.
Solvent 2:50% Yi Chun &50% Witconol 5909
Compound method: take by weighing an amount of Witconol 5909, the blue lid bottle of the 250ml that packs into adds with the volume absolute ethyl alcohol, and vibration is rocked, and both are mixed.
Sorafenib compound method: take by weighing in an amount of Sorafenib and the 50ml centrifuge tube, in centrifuge tube, add the solvent 2 of suitable weight; After vibration mixes about 1min on the turbine mixer, put into the ice bath supersound process more than 20 minutes; Treat that compound all dissolves the ultrapure water that (homodisperse) back adds an amount of volume, centrifuge tube is rocked in vibration, and suspension is mixed, and the concentration of alcohol and Witconol 5909 is 12.5% in the suspension; Be stored in 4 ℃ subsequent use.
Embodiment 1 compound compound method: take by weighing an amount of sample in the 50ml centrifuge tube; The solvent 2 that in centrifuge tube, adds suitable weight; After vibration mixes about 1min on the turbine mixer, put into the ice bath supersound process more than 20 minutes; Treat that compound all dissolves the ultrapure water that (homodisperse) back adds an amount of volume, centrifuge tube is rocked in vibration, and suspension is mixed, and the concentration of alcohol and Witconol 5909 is 12.5% in the suspension; Be stored in 4 ℃ subsequent use.
Solvent contrast: the 12.5% Yi Chun &12.5% Witconol 5909 aqueous solution
Compound method: take by weighing an amount of Witconol 5909, the blue lid bottle of the 250ml that packs into adds with the volume absolute ethyl alcohol, and vibration is rocked, and both are mixed.Add the ultrapure water of proper volume, make the final concentration of ethanol and Witconol 5909 be 12.5%.
The animal model preparation:
Get well-grown 786-O solid tumor, cut into about 1mm under the aseptic condition
3Fritter of uniform size, it is subcutaneous to be inoculated in nude mice right fore armpit with trochar.Routine observation tumor growth situation grows to 250～550mm until gross tumor volume
3.
Divide into groups and administration:
Eliminate excessive or too small, the irregular animal of tumor shape of knurl volume, selection mode is good, gross tumor volume 250～550mm
3Mice with tumor, totally 72, animal is divided into 9 groups, receive test product group and 4 control compound groups as solvent control group, 2 positive controls, 2 respectively.Positive control, receive test product and control compound group, all adopt gastric infusion, every day 1 time; The solvent control group gives 12.5% Yi Chun &12.5% Witconol 5909 ultrapure water solution, every day 1 time; Irritate gastric capacity and be 10ml/kg.
Measure the knurl footpath during the administration weekly 2 times, and calculate gross tumor volume, write down the weight of animals simultaneously.Observe the animal state during each administration, and ERST is carried out record.
Collect blood plasma:
Off-test rises animal fasting (can't help water) 5: 30 noon before that day.Each administration group is divided into 4 groups, gathers 0hr, 2hr, 4hr, 8hr time point blood (heparin sodium anti-freezing) behind the gastric infusion respectively, 2000g 10min centrifugal separation plasma.Keep in Dark Place and treat further test in-80 ℃ of refrigerators.
Put to death animal:
CO
2Put to death animal, strip the knurl piece and weigh, and take pictures.Animal is carried out gross anatomy, and the visual inspection internal organs have no abnormal.
Observation index:
1) gross tumor volume (tumor volume, TV), calculation formula is:
TV＝1/2×a×b
2
Wherein a is the tumour major diameter, and b is a minor axis,
2) relative tumour volume (relative tumor volume, RTV), calculation formula is:
RTV＝Vt/V
0，
V
0(d0) measures the gained gross tumor volume when dividing into groups, the gross tumor volume of Vt when measuring each time.
3) relative tumor proliferation rate T/C (%):
T/C(％)＝(T
RTV/C
RTV)×100％
T
RTV: treatment group relative tumour volume;
C
RTV: solvent control group relative tumour volume.
4) inhibition rate of tumor growth (GI):
GI＝100×{1-[(T
Vt-T
V0)/(C
Vt-C
V0)]}
T
Vt: the treatment group is measured the knurl volume at every turn;
T
V0: initial knurl volume is organized in treatment;
C
Vt: the solvent control group is measured the knurl volume at every turn;
C
V0: the initial knurl volume of solvent control group;
5) the heavy tumour inhibiting rate (IR) of knurl
IR＝(W
C-W
T)/WC
W wherein
C, W
TRepresent that respectively the average knurl of solvent control group is heavy and the average knurl of administration group is heavy.
Statistical method:
Testing data is calculated with ASSOCIATE STATISTICS with Microsoft Office Excel 2003 softwares and is learned processing.Data are except that specifying, (Mean ± S.E) expression relatively adopts the t-check between two groups all to use mean ± standard error.
4. test-results
4.1 respectively organize compound to the 786-O growth of nude mice transplantation tumor
786-O knurl piece was transplanted after 31 days, and the knurl piece grows to about 380mm
3, begin the administration of dividing into groups, oral administration, one day 1 time, totally 14 days.
Concrete outcome is seen table 2:
4.2 respectively organize the compound influence heavy to 786-O transplanted tumor in nude mice knurl
Concrete outcome is seen table 3:
Table 3 is respectively organized the compound influence heavy to human body kidney 786-O transplanted tumor in nude mice knurl
Annotate: 1. compare * P＜0.05, * * P＜0.01 with Vehicle Control group;
2./animal is all dead, does not have corresponding data.
Experiment conclusion:
It is active that embodiment 1 compound oral administration goes out obvious anti-tumor in vivo in people 786-O transplanted tumor in nude mice models show, and its drug effect obviously is superior to a line medicine Xarelto (Sorafenib) of the treatment kidney in late period of Beyer Co., Ltd.
In addition, embodiment 1 compound obviously is superior to control compound B1 and B2, and control compound B1 and B2 toxicity are big, and drug effect is low, does not become the property of medicine basically.
Experimental example 4: external raf screening
Through ATP, MEK substrate are provided, and measure the phosphoric acid part can be measured activity from the various isotypes of raf serine/threonine kinase to the transfer of MEK residue.Sf9 insect cell through infecting from people raf recombination rhabdovirus expression vector carries out purifying, obtains raf reorganization isotype body.The kinases inactivation MEK of reorganization uses biotin labeling at expression in escherichia coli behind the purifying.For each mensuration, test compound is diluted in DMSO continuously, in reaction buffer and ATP (1uM), mix then with raf (0.50nM) and kinases inactivation vitamin H-MEK (50nM).At room temperature, reactant continues to cultivate 2 hours, and stops through adding 0.5M EDTA.The reaction mixture that will stop to be transferred to coating neutradavin plate (pierce), and cultivates 1 hour.Use rabbit anti--p-MEK (Cell Signaling) as anti--rabbit of first antibody and europium mark as SA, through DELFIA time-resolutions fluorescing system (Wallac) measurement phosphorylation product.Time resolved fluorescence is read on Wallac 1232 DELFIA photofluorometers.Use XL fitting data analysis software to calculate each compound 50% and suppress concentrating of (IC50) through non-linear regression.
Use above-mentioned steps, the compound exhibits of embodiment 2-10 has the raf kinase inhibiting activity, and IC50 is all less than 5 μ M.
Claims (19)
1. the compound of general formula I or its pharmacy acceptable salt:
Wherein, Replacement or unsubstituted five yuan of fragrant heterocycles that R1 representes for formula a; Wherein, R4, R5, R6 are selected from carbon atom, nitrogen-atoms, Sauerstoffatom or sulphur atom independently of one another, and substituent R 8, R9, R10 are selected from hydrogen, halogen, C1-4 alkyl or C1-4 alkoxyl group independently of one another;
formula a
R2 is selected from hydrogen, hydroxyl, nitro, amino or C1-4 alkyl.
2. replacement or unsubstituted five yuan of fragrant heterocycles that compound according to claim 1 or its pharmacy acceptable salt: R1 represent for formula a; Wherein, R4, R5, R6 are selected from carbon atom, nitrogen-atoms or sulphur atom independently of one another, and substituent R 8, R9, R10 are selected from hydrogen or methyl independently of one another.
3. compound according to claim 1 or its pharmacy acceptable salt: R2 are selected from hydrogen, hydroxyl, nitro, amino or methyl.
4. compound according to claim 3 or its pharmacy acceptable salt: wherein, R2 is selected from hydrogen.
5. according to any described compound or its pharmacy acceptable salt among the claim 1-4: wherein, R1 is selected from:
6. compound according to claim 5 or its pharmacy acceptable salt: wherein, R1 is selected from:
7. compound according to claim 1 or its pharmacy acceptable salt are selected from:
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(4-pyrazolyl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(4-imidazolyl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(3-pyrryl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(3-thienyl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(1-methyl-4-imidazolyl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(2-(1-methyl-3-pyrryl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(2-hydroxyl-4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(2-methyl-4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea;
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(2-nitro-4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea.
8. compound according to claim 1 or its pharmacy acceptable salt, it is:
9. the preparation method of formula IV compound or its pharmacy acceptable salt:
10. preparation method according to claim 9 is characterized in that: 6.7 weight part 4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) aniline is dissolved in the ETHYLE ACETATE, and nitrogen protection adds 5.6 weight part 3-trifluoromethyls-4-chloro-benzene isocyanic ester down; There are a large amount of solids to separate out after stirring 12h under the room temperature; Concentrate suction filtration, ETHYLE ACETATE washing; Oven dry gets formula IV compound.
11. the compound of general formula I or the preparation method of its pharmacy acceptable salt; It is characterized in that: the aminophenols thing under the highly basic effect with 2; 4-dihalo pyridine generation nucleophilic substitution reaction; The Suzuki reaction takes place in products therefrom and five yuan of aromatic heterocyclic boric acid pinacol esters under the catalysis of palladium catalyst, products therefrom and 3-trifluoromethyl-4-chloro-benzene isocyanate reaction obtains the compound of general formula I.
12. formula II compound or its pharmacy acceptable salt:
13. the preparation method of formula II compound or its pharmacy acceptable salt:
14. preparation method according to claim 13 is characterized in that: 4.35 weight part 4-amino-phenols are dissolved in the anhydrous dimethyl sulphoxide, behind the logical nitrogen 10min, add potassium tert.-butoxide 4.7 weight parts; After stirring 30min under the room temperature, add 5 weight part 2-chloro-4-fluorine pyridines, again reaction system slowly is warming up to 80 ℃ and insulation reaction 2h, TLC detects demonstration and reacts completely; After being cooled to room temperature, add entry and ETHYLE ACETATE, behind the separatory water with ethyl acetate extraction twice, the combined ethyl acetate layer; Washing twice, more once with the saturated common salt washing, anhydrous sodium sulfate drying; Filter, concentrate, get formula II compound behind the gained bullion column chromatography purification.
15. formula III compound or its pharmacy acceptable salt:
16. the preparation method of formula III compound or its pharmacy acceptable salt:
17. preparation method according to claim 16; It is characterized in that: under the nitrogen protection; 5.7 weight part 2-chloro-4-(4-amino-benzene oxygen) pyridines and 6.47 weight part 1-methyl-4-pyrazoles boric acid pinacol ester are dissolved in the THF, stir adding 10.7 weight part salt of wormwood and 17.1 parts by volume water down, add 1.5 weight parts, four triphenyl phosphorus palladium catalysts then under the lucifuge; In 70 ℃ of insulated and stirred 24h, the TLC detection reaction is complete; Be cooled to room temperature, reaction system is concentrated, add ETHYLE ACETATE and water then, water is with ethyl acetate extraction twice behind the separatory, and the combined ethyl acetate layer washes twice, and saturated common salt is washed once, and anhydrous sodium sulfate drying filters, and concentrates; Get the formula III compound behind the thick product column chromatography purification.
18. the said compound of claim 1 or its pharmacy acceptable salt are used for preventing or the purposes of the medicine of treatment and raf SU11752 diseases associated in preparation.
19. purposes according to claim 18, wherein raf SU11752 diseases associated is melanoma, liver cancer, kidney, acute leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastisches syndromes, the esophageal carcinoma, gastrointestinal cancer or mesothelioma.
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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 |
| US20170029404A1 (en) * | 2014-04-08 | 2017-02-02 | Peking University Founder Group Co., Ltd. | 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 |
| CN106866623A (en) * | 2014-04-08 | 2017-06-20 | 北大方正集团有限公司 | Polysubstituted pyridine compounds, preparation method, purposes and pharmaceutical composition |
| KR101821516B1 (en) | 2014-04-08 | 2018-01-23 | 피킹 유니버시티 파운더 그룹 컴퍼니, 리미티드 | 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 |
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Address after: 100871, Beijing, Haidian District, Cheng Fu Road, No. 298, Zhongguancun Fangzheng building, 5 floor Patentee after: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee after: PKUCARE PHARMACEUTICAL R&D CENTER Patentee after: PKU HEALTHCARE INDUSTRY Group Address before: 100871, Beijing, Haidian District, Cheng Fu Road, No. 298, Zhongguancun Fangzheng building, 5 floor Patentee before: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee before: PKUCARE PHARMACEUTICAL R&D CENTER Patentee before: Pku Healthcare Industry Group Co.,Ltd. |
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