CN102532113B - Aryl urea derivative - Google Patents
Aryl urea derivative Download PDFInfo
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- CN102532113B CN102532113B CN201110435847.9A CN201110435847A CN102532113B CN 102532113 B CN102532113 B CN 102532113B CN 201110435847 A CN201110435847 A CN 201110435847A CN 102532113 B CN102532113 B CN 102532113B
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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 pharmaceutical chemistry field, be specifically related to one group of aryl ureas compound being represented by general formula, and their preparation method and as the purposes of raf kinase inhibitor.
Background technology
P21ras oncogene is the one of the main reasons of people's essence carcinogenesis and development, and sudden change (Bolton etc., Ann.Rep.Med.Chem, 1994,29,165-74 have occurred this gene of 30% cancer patients; Bos.Cancer.Res.1989,49,4682-9).Not mutated normal form ras albumen be key element in the signal transduction cascade being pointed to by growth factor receptors in nearly all tissue (Avruch etc., Trends Biochem.Sci.1994,19,279-83).In biological chemistry, ras is a kind of protein of combination guanylic acid, and the circulation that GTP is combined between tranquillization state with GDP in conjunction with activated state is subject to ras endogenous GTP enzymic activity and other regulate the strict control of albumen.The endogenous GTP enzymic activity of sudden change ras in cancer cells improves, so, this protein downstream effect thing, for example raf kinases, sends composition growth signals.Therefore cause cell cancerous growths with these mutant (Magnuson etc., Semin.Cancer Biol.1994,5,247-53).Known, the effect that suppresses active ras by suppressing raf kinase signal pathway, for example, by giving kinase whose antibody or the coexpression dominant raf kinases or as the dominant MEK of raf kinase substrate of deactivating of raf, 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 film Related oncogene, with antisense RNA inhibition raf, express propagation capable of inhibiting cell.Similarly, all find in vitro and in vivo raf kinase inhibition (with antisense oligodeoxyribonucleotide) relevant with the inhibition of various human tumor growth (Monia etc., Nat.Med.1996,2,668-75).
Recently the emphasis of research concentrates on and finds potent raf kinase inhibitor.In clinical data display Signal Transduction Pathways, inhibitor class medicine is compared with traditional chemotherapeutics, and toxicity is lower, has expert to estimate that this type of medicine will become the standard care medicine of cancer therapy and is widely used in clinical after next two decades.Aryl urea compounds usually has other kinase whose inhibition activity in tumor signal Signal Transduction Pathways, and these kinases comprise VEGF R2/3 (VEGFR-2, VEGFR-3), platelet derived growth factor receptor β (PDGFR-β), KIT, FLT-3, RET.Make this type of medicine not only can inhibition tumor cell hyperplasia, can also stop tumor neovasculature generation.This has further strengthened clinical effectiveness and the researching value of this compounds inhibition tumour.
Summary of the invention
The present invention utilizes the Computer-Aided Drug Design means such as Pharmacophore Model to set up structure activity relationship model and the medicaments sifting model of aryl urea compounds, has designed on this basis the aryl ureas compound of a series of brand news.
Aryl ureas compound of the present invention is as raf kinase inhibitor, and the raf kinases path inhibition for people or beast, for example, is used for the treatment of by the kinase mediated tumour of raf or cell cancerous growths.Specifically, these compounds can be used for treating human or animal's cancer, and these cancers are such as being 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, myelodysplastic syndrome, the esophageal carcinoma, gastrointestinal cancer or mesothelioma etc.
Therefore, the present invention relates to compound or its pharmacy acceptable salt of general formula I:
formula I
Wherein, R1 is replacement or the unsubstituted five yuan of fragrant heterocycles that formula a represents, 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, C1-4 alkyl.
Replacement or unsubstituted five yuan of fragrant heterocycles that R1 further represents 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 is further selected from hydrogen, hydroxyl, nitro, amino or methyl.
R2 is further selected from hydrogen.
R1 is further selected from:
R1 is further selected from:
The inventor is by the structure activity study to lead compound, to bioactive molecule, introduce new substituting group or functional group, 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, then carry out composition optimizes, new compound that primary dcreening operation is obtained is capable to be sieved again.With whole animal model, evaluate, carry out pharmacology, pharmacodynamics, toxicologic study, finally determined disclosed most preferred new compound in the present invention.
The compound of general formula of the present invention and pharmacy acceptable salt thereof can be:
1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea;
1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(4-(2-(4-pyrazolyl)-4-pyridyloxy) phenyl) urea;
1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(4-(2-(4-imidazolyl)-4-pyridyloxy) phenyl) urea;
1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(4-(2-(3-pyrryl)-4-pyridyloxy) phenyl) urea;
1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(4-(2-(3-thienyl)-4-pyridyloxy) phenyl) urea;
1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(4-(2-(1-methyl-4-imidazolyl)-4-pyridyloxy) phenyl) urea;
1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(4-(2-(1 methyl-3-pyrryl)-4-pyridyloxy) phenyl) urea;
1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(2-hydroxyl-4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea;
1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(2-methyl-4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea;
1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(2-nitro-4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea.
Particularly preferred compound of the present invention is:
formula IV
According to IUPAC nomenclature, formula IV compound called after of the present invention: 1-(the chloro-3-of 4-(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, citric acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetic acid, toxilic acid or phenylformic acid.
The present invention also comprises compound of Formula I or its pharmacy acceptable salt purposes in the medicine for the preparation of prevention or the treatment disease relevant with raf kinase inhibitor.Wherein the relevant disease of Raf kinase inhibitor 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, myelodysplastic syndrome, the esophageal carcinoma, gastrointestinal cancer or mesothelioma.
The preparation method of compound of Formula I of the present invention is as follows, all compounds of the present invention can be used this preparation method to obtain: first, aminophenols thing under highly basic effect with 2,4-dihalo pyridine generation nucleophilic substitution reaction, there is Suzuki with five yuan of aromatic heterocyclic pinacol borates and react in products therefrom, products therefrom reacts with the chloro-phenylisocyanate of 3-trifluoromethyl-4-the compound that obtains general formula I under the catalysis of palladium catalyst.
As further giving an example, the preparation method of preferred formula IV compound of the present invention is as follows:
Step 1:
Step 2:
Step 3:
As two intermediates in the preparation process of the above-mentioned preferred compound of the present invention, formula II compound and formula III compound are also new compounds.
New intermediate formula II compound: according to IUPAC nomenclature, formula II compound called after of the present invention: the chloro-4-of 2-(4-amino-benzene oxygen) pyridine.
formula II
New intermediate formula III compound: according to IUPAC nomenclature, formula III compound called after of the present invention: 4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) aniline.
formula III
The preparation method of formula IV compound of the present invention is specific as follows:
Step 1: 4.35g PAP is dissolved in anhydrous dimethyl sulphoxide, after logical nitrogen 10min, add potassium tert.-butoxide 4.7g, under room temperature, stir after 30min, add the chloro-4-fluorine of 5g 2-pyridine, again reaction system is slowly warming up to 80 ℃ and insulation reaction 2h, TLC detection display reacts completely, be cooled to after room temperature, add water and ethyl acetate, after separatory, water is extracted with ethyl acetate twice, combined ethyl acetate layer, wash twice, again with saturated common salt washing once, anhydrous sodium sulfate drying, filter, concentrated, after gained crude product column chromatography purification, obtain formula II compound,
Step 2: under nitrogen protection; the chloro-4-of 5.7g 2-(4-amino-benzene oxygen) pyridine and 6.47g 1-methyl-4-pyrazoles pinacol borate are dissolved in tetrahydrofuran (THF); under stirring, add 10.7g salt of wormwood and 17.1mL water; then under lucifuge, add 1.5g tetra-triphenyl phosphorus palladium catalysts; in 70 ℃ of insulated and stirred 24h, TLC detection reaction is complete.Be cooled to room temperature, reaction system is concentrated, then add ethyl acetate and water, after separatory, water is extracted with ethyl acetate twice, combined ethyl acetate layer, washing twice, saturated common salt is washed once, and anhydrous sodium sulfate drying filters, concentrated.After thick product column chromatography purification, obtain formula III compound;
Step 3: 6.7g 4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) aniline is dissolved in ethyl acetate; under nitrogen protection, add the chloro-phenylisocyanate of 5.6g 3-trifluoromethyl-4-; after stirring 12h under room temperature, there are a large amount of solids to separate out; concentrated; suction filtration; ethyl acetate washing, dries, and obtains 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 racemization any raf of having kinase inhibiting activity, separated or the compound of Formula I of optical activity form.
The present invention also comprises the pharmaceutical composition that comprises the carrier of approving on compound of Formula I and physiology.The compounds of this invention can be by injection, suction or sprinkling or rectum, and per os, skin, parenteral give, or gives with unit formulation formulation." injection gives " comprises vein, intramuscular, subcutaneous and parenteral injection, and application infusion techn.Percutaneous drug delivery comprises that external application or transdermal give.The non-toxic carrier that one or more compounds can pharmaceutically be approved with one or more, and other activeconstituentss that depend on the needs coexist.Oral compositions can be manufactured the known appropriate method preparation in field according to any pharmaceutical composition.In order to improve preparation mouthfeel, described composition 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 applicable to tablet manufacturing.Described vehicle is inert diluent for example, calcium carbonate for example, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example W-Gum or alginic acid. tackiness agent, for example Magnesium Stearate, 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, provides long-term continuous action.For example, can adopt time delay material such as glyceryl monostearate or distearin.Described compound also can be made solid, releases soon form.Oral preparations can also be hard gelatin capsule, activeconstituents wherein mixes mutually with inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsule, activeconstituents is wherein with water or for example peanut oil, whiteruss or olive wet goods oil mix.
Also can use and contain active substance and the waterborne suspension that is applicable to the mixed with excipients of manufacture waterborne suspension.Described vehicle is suspension agent, Xylo-Mucine for example, methylcellulose gum, hydroxypropyl-methylcellulose gum, sodiun alginate, Polyvinylpyrolidone (PVP), tragcanth and Sudan Gum-arabic; Dispersion agent or wetting agent can be natural phospholipids, Yelkin TTS for example, or the condensation product of oxyethane and lipid acid, polyoxyethylene stearic acid ester for example, 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 ethyl p-hydroxybenzoate or n-propyl, one or more tinting materials, one or more spices, and one or more sweeting agents, for example sucrose or asccharin.Being applicable to adding water becomes dispersibling in powder or particle of waterborne suspension, activeconstituents and dispersion agent or wetting agent, and suspension agent and one or more sanitass mix.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 by being suspended in activeconstituents peanut oil, sweet oil, sesame oil or peanut wet goods vegetables oil or such as preparing in the mineral oil such as whiteruss.This oily suspensions can contain thickening material, for example beeswax, paraffinum durum or hexadecanol.In order to improve mouthfeel, can add above-mentioned sweeting agent and spices.Described composition can be guaranteed the quality such as antioxidants such as xitix by adding.
The form of pharmaceutical composition of the present invention can also be O/w emulsion.Oil phase can be such as sweet oil or peanut wet goods vegetables oil or such as mineral oil such as liquid beeswaxs, or their mixture.Suitable emulsifying agent can be the 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 described partial ester and oxyethane, for example single oleic acid Sorbitan ethoxylate.Described emulsion also can contain sweeting agent and spices.
Also available sweeting agent obtain syrup agent such as glycerine, polypropylene glycol, sorbyl alcohol or sucrose.This class preparation also can contain demulcen, sanitas and spices and tinting material.
The form of all right suppository of described compound is for rectum or vagina administration.This based composition can be solid-state under described vehicle normal temperature, but be liquid in rectal temperature or vagina temperature by prepared by medicine and suitable non-stimulated mixed with excipients, 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 is all according to chemical structural formula, if the name of compound and chemical structural formula are not inconsistent while representing same compound, with chemical structural formula or chemical equation, is as the criterion.
Now in conjunction with the embodiments, the invention will be further described:
Embodiment
Embodiment 1:1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea
Synthesizing of the chloro-4-of 1a:2-(4-amino-benzene oxygen) pyridine:
4.35g (39.8mmol) PAP is dissolved in 40mL anhydrous dimethyl sulphoxide, after logical nitrogen 10min, add potassium tert.-butoxide 4.7g (41.8mmol), under room temperature, stir after 30min, add the chloro-4-fluorine of 5g (38.0mmol) 2-pyridine, reaction system is slowly warming up to 80 ℃ and insulation reaction 2h, TLC detection display reacts completely again.Be cooled to after room temperature, add 100mL water and 100mL ethyl acetate, 100mL ethyl acetate extracting twice for water after separatory, combined ethyl acetate layer, washes twice (100mL/ time), with saturated common salt, wash once (100mL/ time) again, anhydrous sodium sulfate drying, filters, concentrated, after gained crude product column chromatography purification, obtain 7.26g faint yellow solid, productive rate 86.8%.
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 nitrogen protection; the chloro-4-of 5.7g (25.9mmol) 2-(4-amino-benzene oxygen) pyridine and 6.47g (31.1mmol) 1-methyl-4-pyrazoles pinacol borate are dissolved in to (THF) in 70mL tetrahydrofuran (THF); under stirring, add 10.7g (77.5mmol) salt of wormwood and 17.1mL water; then under lucifuge, add 1.5g (1.29mmol) four triphenyl phosphorus palladium catalysts; in 70 ℃ of insulated and stirred 24h, TLC detection reaction is complete.
Be cooled to room temperature, reaction system is concentrated, then add each 50mL of ethyl acetate and water, 50mL ethyl acetate extracting twice for water after separatory, combined ethyl acetate layer, washes twice (50mL/ time), saturated common salt washing is (50mL/ time) once, anhydrous sodium sulfate drying, filters, concentrated.After thick product column chromatography purification, obtain 5.85g faint yellow solid, yield 85%.
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-(the chloro-3-of 4-(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 80mL ethyl acetate; under nitrogen protection, add the chloro-phenylisocyanate of 5.6g (25.1mmol) 3-trifluoromethyl-4-; after stirring 12h under room temperature, there are a large amount of solids to separate out; system is concentrated into solvent residue 40mL; suction filtration, ethyl acetate is washed, and dries; obtain 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-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(4-(2-(4-pyrazolyl)-4-pyridyloxy) phenyl) urea
Preparation method is with embodiment 1, and wherein methyl-the 4-of the 1-in 1b pyrazoles pinacol borate replaces with 4-pyrazoles pinacol borate, and the methylene dichloride in 1c replaces with ethyl 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-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(4-(2-(4-imidazolyl)-4-pyridyloxy) phenyl) urea
Preparation method is with embodiment 1, and wherein methyl-the 4-of the 1-in 1b pyrazoles pinacol borate replaces with 4-imidazoles pinacol borate.
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-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(4-(2-(3-pyrryl)-4-pyridyloxy) phenyl) urea
Preparation method is with embodiment 1, and wherein methyl-the 4-of the 1-in 1b pyrazoles pinacol borate replaces with 3-pyrroles's pinacol borate.
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-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(4-(2-(3-thienyl)-4-pyridyloxy) phenyl) urea
Preparation method is with embodiment 1, and wherein methyl-the 4-of the 1-in 1b pyrazoles pinacol borate replaces with 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-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(4-(2-(1-methyl-4-imidazolyl)-4-pyridyloxy) phenyl) urea
Preparation method is with embodiment 1, and wherein methyl-the 4-of the 1-in 1b pyrazoles pinacol borate replaces with 1-methyl-4-imidazoles pinacol borate.
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-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(4-(2-(1-methyl-3-pyrryl)-4-pyridyloxy) phenyl) urea
Preparation method is with embodiment 1, and wherein methyl-the 4-of the 1-in 1b pyrazoles pinacol borate replaces with 1-methyl-3-pyrroles pinacol borate.
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-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(2-hydroxyl-4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea
Preparation method is with embodiment 1, and wherein the PAP in 1a replaces with 4-amino-Resorcinol.
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-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(2-nitro-4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea
Preparation method is with embodiment 1, and wherein the PAP in 1a replaces with 3-nitro-PAP.
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-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(2-methyl-4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) phenyl) urea
Preparation method is with embodiment 1, and wherein the PAP in 1a replaces with 3-methyl-PAP.
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
By ATP, MEK substrate are provided, and measure phosphoric acid part and can measure the activity of the various isotypes of raf serine/threonine kinase to the transfer of MEK residue.By the sf9 insect cell infecting from people raf recombination rhabdovirus expression vector, carry out purifying, obtain raf restructuring isotype body.The kinases inactivation MEK of restructuring, at expression in escherichia coli, uses biotin labeling after purifying.For each, measure, test compound is diluted continuously in DMSO, then in reaction buffer and ATP (1uM), mix with raf (0.50nM) and kinases inactivation vitamin H-MEK (50nM).At room temperature, reactant continues to cultivate 2 hours, and by adding 0.5M EDTA to stop.The reaction mixture stopping is transferred to coating neutradavin plate (pierce), and cultivate 1 hour.Use the anti-p-MEK of rabbit (Cell Signaling) as the anti-rabbit of first antibody and europium mark as second antibody, during by DELFIA, m-resolution fluorescing system (Wallac) is measured phosphorylation product.Time resolved fluorescence is read on Wallac 1232 DELFIA photofluorometers.Use XL fitting data analysis software to calculate each compound 50% by non-linear regression and suppress the concentrated of (IC50).
Use above-mentioned steps, the compound of embodiment 1 shows to have raf kinase inhibiting activity, and IC50 is less than 5 μ M.
Experimental example 2: the compounds of this invention suppresses the research of ACHN kidney growth
1 materials and methods
1.1 experiment material
Female BALB/c-nu/nu nude mouse, 4 week age, mean body weight 14.2g (12.6-15.8) g.ACHN renal cancer cell line is purchased from U.S. typical case species preservation center (ATCC).
1.2 experimental technique
ACHN kidney cancer cell 2.0 * 106/0.2ml is inoculated in to back, every nude mice right side subcutaneous, by body weight numbering, 16 nude mouses is divided into medication group and control group at random.Two groups of body weight are without significant difference.After inoculation, within the 3rd day, rise, the administration next day of beginning, medication group gives embodiment 1 compound (60mg/kg; Solvent: 3% dehydrated alcohol+97% physiological saline), control group gives solvent (3% dehydrated alcohol+97% physiological saline).Away from tumour subcutaneous injection, each every 0.2ml.During administration, observe mouse generalized case, the next day measure Mouse Weight, tumor size, gross tumor volume formula: V=1/2 * a * b2, (a is major diameter, and b is minor axis).Inoculate the 31st day, disconnected neck is put to death mouse, dissects pre-test gross tumor volume, claims mouse heavy.Dissect Subcutaneous tumor and weigh, cutting mouse lung.FAA (Glacial acetic acid+formalin+ethanol) is Subcutaneous tumor and mouse lung fixedly, paraffin embedding.Again calculate mouse heavy (weigh=band of mouse knurl mouse weight-knurl weight).The maximum tangent plane HE dyeing of two lung coronal-planes, (100 times of visuals field) counting lung Nodules under microscope.
1.3 statistical procedures
Between two groups, knurl weight, volume, mouse are reused t check, the SAS covariance analysis of gross tumor volume growth curve, and lung metastatic nodules is checked by accurate stochastic method.
2 results
2.1 subcutaneous tumors weigh and gross tumor volume changes
While inoculating the 31st day, two groups of subcutaneous tumors are heavily respectively 628.42 ± 149.87mg and 262.25 ± 61.82mg, and medication group knurl is heavily 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 in Table 1:
Table 1: gross tumor volume-time changes
Table 1 result shows, medication group gross tumor volume increases significantly lower than control group.
2.2 lung Nodules
In 8 mouse of control group, 7 there is lung transfer, and 3 is 1 Nodules, and all the other are 3-5 Nodules, and medication group is not found lung Nodules.Through accurate stochastic method, check two groups of differences to have significant (p < 0.05).The control group not only rate of transform is high, and metastatic nodules is also more.
During 2.3 medications, side effect is observed
During medication, each mouse is movable good, has no the untoward reactions such as diarrhoea.
3 experiment conclusion
The compounds of this invention medication group knurl is heavily starkly lower than control group, there is statistical significance (p < 0.01), medication group gross tumor volume increases significantly lower than control group, the compounds of this invention has the effect of obvious tumor growth, 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 therapeutic evaluation of the compounds of this invention to 786-O transplanted tumor in nude mice
1. test objective
The restraining effect of investigationization the compounds of this invention to people 786-O nude mice transplantation tumor tumor growth, and the toxicity of preliminary observation compound.
2. test materials
Test-compound: the embodiment of the present 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): China Patent Publication No. CN101801383A, open day: 2010-08-11, the 11st page of capable disclosed compound of inverse 3-4 of specification sheets " 1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(the fluoro-4-of 2-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) phenyl) urea ", preparation method: with the embodiment of the present invention 1, wherein raw material PAP is replaced with to the fluoro-PAP of 3-.
Control compounds 2 (numbering B2): China Patent Publication No. CN101801383A, open day: 2010-08-11, disclosed compound during the 11st page of [0120] section of 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 ", preparation method, with the embodiment of the present invention 1, wherein replaces with 3-trifluoromethyl-phenylisocyanate by the chloro-phenylisocyanate of raw material 3-trifluoromethyl-4-.
Solvent material:
Dehydrated alcohol
Shanghai Run Jie chemical reagent company limited
Lot identification mark: 20100525
Cremophor EL: polyoxyethylenated castor oil
Beijing Feng Lijingqiu commerce and trade limited liability company
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 company limited
Production licence number: SCXK (Shanghai) 2007-0005
Occupancy permit number: SYXK (Shanghai) 2009-0075
Sex: male.
Age in week: 6 week age
The strain of transplanted tumor knurl
Title: human body kidney 786-O
Source: this laboratory conservation, BALB/C nude mice by subcutaneous is transplanted to go down to posterity and maintained
3. test method
Drug-delivery preparation and collocation method:
The solvent 1:0.5%HPMC-K4M & 0.2%SLS aqueous solution.
Compound method: take appropriate HPMC-K4M and SLS and pack the blue lid bottle of 250mL into, add appropriate ultrapure water, more than magnetic stirrer 4hrs; After solid matter is all dispersed, the static 2～3hrs of this liquid is used.
Solvent 2:50% ethanol & 50% polyoxyethylenated castor oil
Compound method: take appropriate polyoxyethylenated castor oil, pack the blue lid bottle of 250ml into, add same volume dehydrated alcohol, vibration is rocked, and both are mixed.
Sorafenib compound method: take in appropriate Sorafenib and 50ml centrifuge tube, add the solvent 2 of suitable weight in centrifuge tube; On turbine mixer, vibration mixes behind 1min left and right, puts into ice bath supersound process more than 20 minutes; The ultrapure water that adds appropriate volume after compound all dissolves (dispersed), centrifuge tube is rocked in vibration, and suspension is mixed, and in suspension, the concentration of alcohol and polyoxyethylenated castor oil is 12.5%; Be stored in 4 ℃ standby.
Embodiment 1 compound compound method: take appropriate sample in 50ml centrifuge tube; The solvent 2 that adds suitable weight in centrifuge tube; On turbine mixer, vibration mixes behind 1min left and right, puts into ice bath supersound process more than 20 minutes; The ultrapure water that adds appropriate volume after compound all dissolves (dispersed), centrifuge tube is rocked in vibration, and suspension is mixed, and in suspension, the concentration of alcohol and polyoxyethylenated castor oil is 12.5%; Be stored in 4 ℃ standby.
Solvent contrast: the 12.5% ethanol & 12.5% polyoxyethylenated castor oil aqueous solution
Compound method: take appropriate polyoxyethylenated castor oil, pack the blue lid bottle of 250ml into, add same volume dehydrated alcohol, vibration is rocked, and both are mixed.The ultrapure water that adds proper volume, makes the final concentration of ethanol and polyoxyethylenated castor oil be 12.5%.
Animal model preparation:
Get well-grown 786-O solid tumor, under aseptic condition, cut into about 1mm
3fritter of uniform size, is inoculated in nude mice right fore armpit with trochar subcutaneous.Routine observation tumor growth situation, until gross tumor volume grows to 250～550mm
3.
Grouping and administration:
Superseded knurl volume is excessive or too small, the irregular animal of tumor shape, and selection mode is good, gross tumor volume 250～550mm
3mice with tumor, totally 72, animal is divided into 9 groups, as solvent control group, 2 positive controls, 2, be subject to test product group and 4 control compound groups respectively.Positive control, be subject to test product and control compound group, all adopt gastric infusion, every day 1 time; Solvent control group gives 12.5% ethanol & 12.5% polyoxyethylenated castor oil ultrapure water solution, every day 1 time; Gavage capacity is 10ml/kg.
During administration, measure weekly knurl footpath 2 times, and calculate gross tumor volume, record the weight of animals simultaneously.During each administration, observe animal state, and error state (ERST) is carried out to 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 respectively 0hr, 2hr, 4hr, 8hr time point blood (heparin sodium anti-freezing), 2000g 10min centrifugal separation plasma after gastric infusion.Keep in Dark Place and treat further test in-80 ℃ of refrigerators.
Put to death animal:
CO
2put to death animal, strip knurl piece and weigh, and take pictures.Animal is carried out to gross anatomy, and visual inspection internal organs have or not extremely.
Observation index:
1) gross tumor volume (tumor volume, TV), calculation formula is:
TV＝1/2×a×b
2
Wherein a is tumour major diameter, and b is minor axis,
2) relative tumour volume (relative tumor volume, RTV), calculation formula is:
RTV＝Vt/V
0，
V
0for when grouping (d0) measured gained gross tumor volume, 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: treatment group is measured knurl volume at every turn;
T
v0: the initial knurl volume for the treatment of group;
C
vt: solvent control group is measured 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 weighs and the average knurl weight of administration group.
Statistical method:
Testing data is calculated with Microsoft Office Excel 2003 softwares and ASSOCIATE STATISTICS is learned processing.Data, except special instruction, all use mean ± standard error (Mean ± S.E) to represent, relatively adopt t-check between two groups.
4. test-results
4.1 respectively organize the impact of compound on the growth of 786-O transplanted tumor in nude mice
786-O knurl piece was transplanted after 31 days, and knurl piece grows to about 380mm
3, start the administration of dividing into groups, oral administration, one day 1 time, totally 14 days.
Concrete outcome is in Table 2:
4.2 respectively organize the impact that compound is heavy on 786-O transplanted tumor in nude mice knurl
Concrete outcome is in Table 3:
Table 3 is respectively organized the impact that compound is heavy on human body kidney 786-O transplanted tumor in nude mice knurl
Note: 1. compare * P < 0.05, * * P < 0.01 with Vehicle Control group;
2./animal is all dead, there is no corresponding data.
Experiment conclusion:
It is active that embodiment 1 compound oral administration demonstrates obvious anti-tumor in vivo at people 786-O Nude Mouse Model, and its drug effect is obviously better than the first-line drug Xarelto (Sorafenib) of the treatment advanced renal cell cancer of Beyer Co., Ltd.
In addition, embodiment 1 compound is obviously better than control compound B1 and B2, and control compound B1 and B2 toxicity are large, and drug effect is low, does not substantially become the property of medicine.
Experimental example 4: external raf screening
By ATP, MEK substrate are provided, and measure phosphoric acid part and can measure the activity of the various isotypes of raf serine/threonine kinase to the transfer of MEK residue.By the sf9 insect cell infecting from people raf recombination rhabdovirus expression vector, carry out purifying, obtain raf restructuring isotype body.The kinases inactivation MEK of restructuring, at expression in escherichia coli, uses biotin labeling after purifying.For each, measure, test compound is diluted continuously in DMSO, then in reaction buffer and ATP (1uM), mix with raf (0.50nM) and kinases inactivation vitamin H-MEK (50nM).At room temperature, reactant continues to cultivate 2 hours, and by adding 0.5M EDTA to stop.The reaction mixture stopping is transferred to coating neutradavin plate (pierce), and cultivate 1 hour.Use the anti-p-MEK of rabbit (Cell Signaling) as the anti-rabbit of first antibody and europium mark as second antibody, during by DELFIA, m-resolution fluorescing system (Wallac) is measured phosphorylation product.Time resolved fluorescence is read on Wallac 1232 DELFIA photofluorometers.Use XL fitting data analysis software to calculate each compound 50% by non-linear regression and suppress the concentrated of (IC50).
Use above-mentioned steps, the compound of embodiment 2-10 shows to have raf kinase inhibiting activity, and IC50 is all less than 5 μ M.
Claims (6)
1. the compound shown in formula IV or its pharmacy acceptable salt, it is:
2. according to the formula IV compound shown in claim 1 or the preparation method of its pharmacy acceptable salt:
3. preparation method according to claim 2; it is characterized in that: 6.7 weight part 4-(2-(1-methyl-4-pyrazolyl)-4-pyridyloxy) aniline is dissolved in ethyl acetate; under nitrogen protection, add the chloro-phenylisocyanate of 5.6 weight part 3-trifluoromethyl-4-; after stirring 12h under room temperature, there are a large amount of solids to separate out; concentrated, suction filtration, ethyl acetate washing; dry, obtain formula IV compound.
4. the compound shown in formula IV according to claim 1 or the preparation method of its pharmacy acceptable salt, it is characterized in that: aminophenols under highly basic effect with 2,4-dihalo pyridine generation nucleophilic substitution reaction, there is Suzuki with five yuan of aromatic heterocyclic pinacol borates and react in products therefrom, products therefrom reacts and obtains the compound shown in formula IV with the chloro-phenylisocyanate of 3-trifluoromethyl-4-under the catalysis of palladium catalyst.
5. compound or its pharmacy acceptable salt purposes in the medicine for the preparation of prevention or the treatment disease relevant with raf kinase inhibitor described in claim 1.
6. purposes according to claim 5, wherein the relevant disease of raf kinase inhibitor 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, myelodysplastic syndrome, the esophageal carcinoma, gastrointestinal cancer or mesothelioma.
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