CN104892530A - Diaryl urea compound containing quinazoline structure as well as preparation method and application thereof - Google Patents
Diaryl urea compound containing quinazoline structure as well as preparation method and application thereof Download PDFInfo
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- CN104892530A CN104892530A CN201510279335.6A CN201510279335A CN104892530A CN 104892530 A CN104892530 A CN 104892530A CN 201510279335 A CN201510279335 A CN 201510279335A CN 104892530 A CN104892530 A CN 104892530A
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- ALEFDSRFZLLWNS-UHFFFAOYSA-N COC1C=CC(C=O)=CC1OC Chemical compound COC1C=CC(C=O)=CC1OC ALEFDSRFZLLWNS-UHFFFAOYSA-N 0.000 description 1
- YWSPWKXREVSQCA-UHFFFAOYSA-N COc(cc(C=O)c([N+]([O-])=O)c1)c1OC Chemical compound COc(cc(C=O)c([N+]([O-])=O)c1)c1OC YWSPWKXREVSQCA-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/93—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
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Abstract
The invention relates to a diaryl urea compound containing a quinazoline structure as well as a preparation method and an application thereof. The diaryl urea compound containing a quinazoline structure comprises a compound with a structure as shown in formula (I) in the description or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, C1-C8 alkyl, halogen, -CF3, -OCF3, -NO2, -CN, R2O-, -SO2NH2, -NHSO2R3, -NR4R5, -CONR6R7, -COOR8, R9CO- and disubstituted or trisubstituted substances of the above groups, R2, R3, R4, R5, R6, R7, R8 and R9 are respectively H or C1-C8 hydrocarbon, and X is selected from O or S. Pharmacological experiments prove that the diaryl urea compound containing a quinazoline structure has inhibiting activity on various tyrosine kinases, and has a good anti-tumor effect on human colon cancer, breast cancer and/or gastric cancer.
Description
Technical field
The present invention relates to a kind of diaryl urea compound containing quinazoline structure and its preparation method and application, belong to biomedicine field.
Background technology
Cancer is one of principal disease of serious harm human health, and capturing cancer is current global research topic.According to the World Health Organization (WHO) report, whole world cancer patients increases by 1,000 ten thousand people every year, death about 7,000,000 people, and to the year two thousand twenty, cancer patients will increase 2,000 ten thousand people every year newly.At present, China is large about more than 1,600,000 people's cancer strickens every year, and 1,300,000 people die from cancer, and cancer is just becoming " second killer " of the serious harm human health being only second to cardiovascular disorder.Although over nearly 20 years, molecular biologically to develop rapidly, the understanding of people to cancer start by outer and in, by cell going deep into molecular level, and the method become by chemistry obtains many cancer therapy drugs, but the anticarcinogen of these chemosynthesis great majority produce more serious toxic side effect to the normal cell of human body.How to avoid the toxic side effect of conventional anti-cancer medicines, thus obtain safer PTS thing, become the new direction of medical personal's research.
Along with the development of the subject such as proteomics and genomics, people for medicine in vivo mechanism of action understanding gradually deeply, modern new drug research has entered the Rational drug design epoch, and many selectively actings are also constantly found in the medicine of special target spot.But for some complex disease as cancer, hypertension, diabetes, virus infection and nervous system disorders etc., the medicine of single target spot is usually difficult to reach expection result for the treatment of and even there will be untoward reaction, then has better curative effect when single for several difference target drug coupling or choice for use being acted on " Mutiple Targets " pharmacological agent complex disease of multiple molecular target.In recent years, FDA successively have approved the listing of multiple Mutiple Targets medicine, as 2005 and 2006 have approved Xarelto and Dasatinib respectively, within 2007, have approved Sutent and lapatinibditosylate etc.
BAY 43-9006 (Sorafenib), trade(brand)name Nexavar Nexavar is the oral multi-kinase inhibitor of kind.It has dual antitumor action, suppress the growth of the direct Tumor suppression of Raf/MEK/ERK signal transduction pathway on the one hand, suppress on the other hand several activity generating the tyrosine kinase receptor relevant with tumor development with new vessel, comprise vascular endothelial growth factor receptor-2 (VEGFR-2) etc., block tumor angiogenesis, the growth of indirect inhibition tumor cell, thus play antitumor action.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of diaryl urea compound containing quinazoline structure and its preparation method and application, present inventor is at research Xarelto and with on the basis of the binding pattern of multiple receptor protein, devise a series of diaryl urea compound containing aromatic amine structure, this series compound and drug targets have good match pattern, have good inhibit activities to tumor cell in vitro strain.
The technical scheme that the present invention solves the problems of the technologies described above is as follows: a kind of diaryl urea compound containing quinazoline structure, and comprise the compound or its pharmacy acceptable salt with formula I structure, formula I structure is as follows:
Wherein, R
1be selected from H, C
1-C
8alkyl, halogen ,-CF
3,-OCF
3,-NO
2,-CN, R
2o-,-SO
2nH
2,-NHSO
2r
3,-NR
4r
5,-CONR
6r
7,-COOR
8, R
9two replacements of CO-and above-mentioned group or three replacements of above-mentioned group, R
2, R
3, R
4, R
5, R
6, R
7, R
8and R
9be respectively H or C
1-C
8alkyl, X is selected from O or S.
On the basis of technique scheme, the present invention can also do following improvement.
Further, described R
1be selected from H, C
1-C
4alkyl, F, CI, CF
3, OCF
3, CN, R
2o, NHSO
2r
3, NR
4r
5, CONR
6r
7, COOR
8, R
9two replacements of CO and above-mentioned group or three replacements of above-mentioned group, R
2, R
3, R
4, R
5, R
6, R
7, R
8and R
9be respectively H or C
1-C
4alkyl.
Further, described pharmacy acceptable salt is selected from: hydrochloride, hydrobromate, vitriol, phosphoric acid salt, mesylate, fluoroform sulphonate, benzene sulfonate, tosilate, 1-naphthalene sulfonic aicd salt, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, Citrate trianion, lactic acid salt, oxalate, succinate, fumarate, maleate, benzoate, salicylate, the water solubles of phenylacetate, mandelate or above-mentioned salt.
Further, the described diaryl urea compound containing quinazoline structure, is selected from the one in following compounds:
B01 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(the fluoro-3-trifluoromethyl of 4-) urea;
B02 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(3-trifluoromethyl) urea;
B03 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(4-Trifluoromethoxyphen-l) urea;
B04 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(the chloro-4-fluorophenyl of 3-) urea;
B05 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(3,4-difluorophenyl) urea;
B06 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(4-chloro-phenyl-) urea;
B07 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(4-fluorophenyl) urea;
B08 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(4-aminomethyl phenyl) urea;
B09 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(the fluoro-3-trifluoromethyl of 4-) urea;
B10 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(3-trifluoromethyl) urea;
B11 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(4-Trifluoromethoxyphen-l) urea;
B12 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(the chloro-4-fluorophenyl of 3-) urea;
B13 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(3,4-difluorophenyl) urea;
B14 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(4-chloro-phenyl-) urea;
B15 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(4-fluorophenyl) urea;
B16 N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(4-aminomethyl phenyl) urea.
The present invention also provides a kind of above-mentioned application of diaryl urea compound in preparation treatment colorectal carcinoma, mammary cancer and/or gastric cancer medicament containing quinazoline structure.
The present invention also provides a kind of pharmaceutical composition, containing the above-mentioned diaryl urea compound containing quinazoline structure, and acceptable carrier, thinner or vehicle in one or more pharmacy or bromatology.
On the basis of technique scheme, the present invention can also do following improvement.
Further, described pharmaceutical composition is oral preparations or injection.
Further, described oral preparations comprises: tablet, capsule, granule or oral solution.
Further, described injection comprises: injection liquid drugs injection, injection powder pin or primary infusion.
Further, described pharmaceutical composition also comprises in pharmacy or bromatology acceptable: one or more in auxiliary material and weighting agent, tamanori, disintegrating agent, wherein, described auxiliary material and weighting agent comprise one or more the mixture in lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, calcium carbonate, Microcrystalline Cellulose; Described tamanori comprises one or more the mixture in starch, polyvidone, Xylo-Mucine, Walocel MT 20.000PV, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more the mixture in starch, polyvinylpolypyrrolidone, croscarmellose sodium, low replacement sodium cellulose glycolate, hydroxypropylcellulose, gas-producing disintegrant.
The present invention also provides a kind of preparation method of the diaryl urea compound containing quinazoline structure, comprising:
1) compound 1 veratryl aldehyde is nitrated in nitric acid, obtains 6-nitro veratryl aldehyde, i.e. compound 2;
2) 6-nitro veratryl aldehyde and potassium permanganate react, and obtain 6 nitroveratric acid, i.e. compound 3;
3) 6 nitroveratric acid under the catalysis of palladium carbon with hydrogen reaction, obtain 6-aminoveratric acid, i.e. compound 4;
4) 6-aminoveratric acid and FORMAMIDINE ACETATE are reacted in dimethyl sulfoxide (DMSO) (DMSO), obtain 6,7-dimethoxy-4 ' (3H)-quinazolinone, i.e. compound 5;
5) 6,7-dimethoxy-4 's (3H)-quinazolinone is through sulfur oxychloride chloro, obtains 6,7-dimethoxy-4 '-chloro-quinazoline, i.e. compound 6;
6) 6,7-dimethoxy-4 's-chloro-quinazoline and Metha Amino Phenon or m-aminothiophenol condensation, obtain compound 7;
7) compound 8 reacts with triphosgene in ethylene dichloride, obtains compound 9;
8) compound 7 and compound 9 react in organic solvent, obtain the compound with formula I structure, this compound and acid-respons, obtain its pharmacy acceptable salt of compound of formula I structure, and concrete reaction is as follows:
Wherein, R
1be selected from H, C
1-C
8alkyl, halogen ,-CF
3,-OCF
3,-NO
2,-CN, R
2o-,-SO
2nH
2,-NHSO
2r
3,-NR
4r
5,-CONR
6r
7,-COOR
8, R
9two replacements of CO-and above-mentioned group or three replacements of above-mentioned group, R
2, R
3, R
4, R
5, R
6, R
7, R
8and R
9be respectively H or C
1-C
8alkyl, X is selected from O or S.
Diaryl urea compound difference from prior art containing quinazoline structure provided by the invention is: the present invention containing the diaryl urea compound of quinazoline structure contain described generalformulaⅰcompound or its pharmaceutically acceptable salt there is the restraining effect to various tumor cell strains, can be used as the medicine of effective constituent for the preparation of tumour aspect.The activity of generalformulaⅰcompound of the present invention is by heteroplastic transplantation model checking in extracorporeal anti-tumor model, body.Tumor cell line selected by external activity test comprises: human colon cancer cell strain HCT-15, human colon cancer cell strain HCT-116, MCF-7 cell strainHJ2mm, Human gastric carcinoma cell line BGC-823 etc., but is not limited to above-mentioned tumor cell line.The selected model of activity in vivo test is mouse melanin tumour b16 heteroplastic transplantation model.Tumor cell line selected by the Mechanism Study of compound of Formula I of the present invention is human colon cancer cell strain HCT-116.Generalformulaⅰcompound of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-1000mg/ people, is divided into once or administration for several times.The actual dosage taking generalformulaⅰcompound of the present invention can be determined according to interesting cases by doctor.These situations comprise: the physical state of patient, route of administration, the age, body weight, to the individual reaction of medicine, the severity etc. of symptom.
Embodiment
Be described principle of the present invention and feature below, example, only for explaining the present invention, is not intended to limit scope of the present invention.
Embodiment 1
6-nitro veratryl aldehyde (2)
Nitric acid (100ml, 1.52mol) is joined in the 250ml tri-mouthfuls of round-bottomed flasks with mechanical stirring oar, at 20 DEG C, add veratryl aldehyde (16.6g, 0.1mol) in batches, keep the temperature of system within 25 DEG C.Finish rear continuation and stir 0.5h, TLC detection reaction process.Slowly pour reaction solution in 400ml frozen water stirring and crystallizing after reaction terminates, a large amount of yellow solid is separated out, and suction filtration obtains yellow solid, and weigh after drying to obtain crude product 18g.
Crude product adds 50% (V/V) ethanol water recrystallization, obtains product (2) 16.0g, productive rate 78.2%, m.p.133-135 DEG C.
6 nitroveratric acid (3)
500ml water, sodium hydroxide (12g is added in there-necked flask, 300.0mmol) with compound 2 (33g, 156.3mmol), stir, add the potassium permanganate (control temperature less than 20 DEG C) of 19.75g (125mmol) in batches, can be observed solution and become black from reddish-brown gradually.After reaction 7h, suction filtration, obtains blackish green filtrate.Filtrate adds hydrochloric acid and adjusts PH to 7-8, and have a small amount of brown muddy produce raw, double-layer filter paper suction filtration, obtains yellow filtrate.Filtrate salt adding acid for adjusting pH is to 1-2, and a large amount of solid is separated out, suction filtration, dry yellow powder crystal (3) 29.4g, productive rate 83.0%, m.p.193-195 DEG C.
6-aminoveratric acid (4)
In autoclave, add compound 3 (10g, 44.02mmol), add the industrial methanol of 200ml, 0.5g palladium carbon.Envelope still, air 2 times in hydrogen exchange still.Close vent valve, regulate temperature 45.0 DEG C, rotating speed 300n/s, pressure 0.4MPa reacts.Close intake valve after 2h, still internal pressure is without downtrending, and reaction terminates.Open water coolant, after system temperature is down to 25 DEG C, drives still, as early as possible sucking-off reaction solution, filtering palladium carbon, vacuum desolvation agent.When solvent steams about 85%, a large amount of solid is separated out, suction filtration, 2ml industrial methanol drip washing filter cake.The vacuum-drying of gained filter cake, obtains yellow solid (4) 7.2g, yield 83.7%, m.p.170-172 DEG C.
6,7-dimethoxy-4 ' (3H)-quinazolinone (5)
Compound 4 (5g, 25.38mmol) and FORMAMIDINE ACETATE (4g, 38.83mmol) are joined in 100ml there-necked flask, adds 5ml DMSO, under stirring, be warming up to 140-170 DEG C.System gradually becomes brown turbid solution by dark solution.Be cooled to 50 DEG C after 4h, add 20ml water, a large amount of solid is separated out, and suction filtration, obtains light yellow solid, dries, obtains product (5) 5g, yield 95.7%, m.p.295-297 DEG C.
6,7-dimethoxy-4 '-chloro-quinazoline (6)
Obtained compound 5 (1.7g, 8.2mmol) and 15ml thionyl chloride are added in the round-bottomed flask of 100ml, adds the dimethyl formamide (DMF) of 0.5ml slowly, after back flow reaction 1h, sampling, after reacting completely, evaporate to dryness, add saturated aqueous sodium carbonate, adjust pH to 8-9, suction filtration, dries to obtain light yellow solid powder (6) 1.53g, productive rate 82.2%, m.p.180-182 DEG C.
3-(6,7-dimethoxyquinazoline-4-oxygen base) aniline (7a)
In the round-bottomed flask of 100ml, add Metha Amino Phenon (0.35g, 3.2mmol), potassium tert.-butoxide (0.44g, 3.9mmol) and 20ml DMF, 25 DEG C are stirred 1-1.5h, and solution becomes reddish-brown from sap green.Add salt of wormwood (0.31g, 2.2mmol), after 10min, add the compound 6 (0.72g) dissolved with 20mlDMF, be warming up to 85 DEG C, sample TLC after reaction 2.5h, reaction terminates.Add water 50ml, ethyl acetate (EA) extraction (100ml × 3), merges organic phase, anhydrous sodium sulfate drying after saturated nacl aqueous solution washes twice.Be concentrated into evaporate to dryness, weigh to obtain crystal (7a) 0.74g, productive rate 77.9%, m.p.183-185 DEG C, and it is 98.45% that high performance liquid phase measures content.
1H-NMR(400MHz,DMSO-d
6)δ3.97(s,3H,O-CH
3),3.98(s,3H,O-CH
3),5.28(s,2H,-NH
2),6.98(dd,J＝1.6Hz,9.6Hz,1H,Ph-H-6),7.13(d,J＝7.6Hz,1H,Ph-H-4),7.23(d,J＝1.6Hz,1H,Ph-H-2),7.43(t,J＝7.8Hz,1H,Ph-H-5),7.55(s,1H,quinazolineH-5),7.63(s,1H,quinaz oline H-8),8.56(s,1H,quinazoline H-2).HRMS(AP-ESI)m/z:calcd for C
16H
15N
3O
3[M+H]
+298.1192,found 298.1199。
Compound (7b) be have general formula for (7) compound in one, 3-(6,7-dimethoxyquinazoline-4-sulfydryl) aniline (7b) synthesis is raw material with m-aminothiophenol, method and upper embodiment similar.Experimental result is: productive rate 74.0%, m.p.172-175 DEG C, and it is 97.5% that high performance liquid phase measures content.
1H-NMR(400MHz,DMSO-d
6)δ3.97(s,3H,O-CH
3),3.98(s,3H,O-CH
3),5.33(s,2H,-NH
2),6.68(dd,J＝1.6Hz,9.6Hz,1H,Ph-H-6),6.73(d,J＝7.6Hz,1H,Ph-H-4),6.80(d,J＝1.6Hz,1H,Ph-H-2),7.13(t,J＝7.8Hz,1H,Ph-H-5),7.31(s,1H,quinazolineH-5),7.33(s,1H,quinazoline H-8),8.70(s,1H,quinazoline H-2)。HRMS(AP-ESI)m/z:calcd for C
16H
15N
3O
2S[M+H]
+314.0963,found314.0958。
The synthesis of target compound
N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(the fluoro-3-trifluoromethyl of 4-) urea (B01)
Fluoro-for 4-3-5-trifluoromethylaniline (8,0.21g, 1.2mmol) is dissolved in 10ml ethylene dichloride, stirs under ice bath, be cooled to 0-5 DEG C.Slowly drip the 10ml dichloroethane solution of BTC (triphosgene, 0.18g, 0.6mmol) under low temperature, system temperature slightly rises, and a large amount of white solid is separated out, and keeps system temperature at 0-5 DEG C to dripping end.Drip and terminate the bath of 0.5h recession deicing, after 25 DEG C of stirring 0.5h, be warming up to back flow reaction.In reflux course, a large amount of sour gas overflows.Steam after back flow reaction 8h and desolventize, obtain pale yellow oily liquid body.Add methylene dichloride 10ml to be dissolved by pale yellow oily liquid body, ice bath drips the 10ml dichloromethane solution of 7a (0.3g, 1.0mmol) under stirring, rise to 25 DEG C of reactions after dropwising.After reaction 2h, a large amount of solid is separated out, and suction filtration, a large amount of washed with dichloromethane of filter cake, obtaining the finished product B01 is white solid, 0.33g, content 97.8%, yield 65.1%, m.p.205-208 DEG C.
1H-NMR(400MHz,DMSO-d
6)δ3.99(s,3H,quinazoline-OCH
3-6),4.00(s,3H,quinazoline-OCH
3-7),6.94(d,J＝7.8Hz,1H,Ph-H-6),7.27(d,J＝7.8Hz,1H,Ph-H-4),7.37-7.46(m,3H,Ph-H-5,Ph’-H-5and quinazoline H-5),7.57-7.58(m,2H,Ph-H-2and quinazoline H-8),7.60-7.64(m,1H,Ph’-H-2),7.99(dd,J＝2.5,6.4Hz,Ph’-H-6),8.56(s,1H,quinazoline H-2),9.01(s,1H,-NHCS-),9.10(s,1H,-NHCS-).HRMS(AP-ESI)m/z:calcd for C
24H
18F
4N
4O
4[M+H]
+503.1342,found 503.1345.
Compound (B01) be have general formula for (I) compound in one, the same embodiment of synthetic method of other compounds (B02-B16).Experimental result is as shown in the table.
Table 1
Table 2 compd B 02 is to the structural characterization data of B16
Embodiment 2
Preparation technology: rear mistake 100 mesh sieve pulverized in advance by activeconstituents B01 embodiment 1 prepared and auxiliary material, takes main ingredient and adds auxiliary material lactose, pregelatinized Starch, Xylo-Mucine and Microcrystalline Cellulose and fully mix, and crosses 60 mesh sieve three times, add the povidone solution of mass concentration 10%, mixing, softwood processed, crosses 20 mesh sieves, obtained wet grain, after 50-60 DEG C of drying, add Magnesium Stearate and talcum powder sieves in advance, fully mix, detect, compressing tablet.
Embodiment 3
Preparation technology: rear mistake 100 mesh sieve pulverized in advance by activeconstituents B04 embodiment 1 prepared and auxiliary material, adds auxiliary material silicon-dioxide and Magnesium Stearate, fully mixes, detects, filling with No. 4 capsules.
Embodiment 4
Preparation technology: rear mistake 100 mesh sieve pulverized in advance by activeconstituents B07 embodiment 1 prepared and auxiliary material, fully mixes, adopts roll squeezer cake of press, then crosses 18 mesh sieves with pelletizing machine, finally add Magnesium Stearate, fully mix, and detects, compressing tablet.
Embodiment 5
Preparation technology: rear mistake 100 mesh sieve pulverized in advance by activeconstituents B08 embodiment 1 prepared and auxiliary material, fully mixes, then add tamanori and obtain softwood, 14 mesh sieves are granulated, 55 DEG C of dryings, the whole grain of 12 mesh sieve, detect, packaging.
Embodiment 6
Preparation technology: get water for injection 50.0ml, takes the stirring of the SODIUM PHOSPHATE, MONOBASIC of recipe quantity, citric acid and sodium-chlor and makes it dissolve, add main ingredient B13 prepared by embodiment 1, stirring and dissolving.Adjust pH to be 4.0-7.0 with the hydrochloric acid of 0.1mol/L or sodium hydroxide, add the charcoal absorption 20min accounting for main ingredient quality 0.1%.First filter with the filter membrane of 0.45 μm, then filter by the filter membrane essence of 0.22 μm.Filling by every bottle of 1ml, 105 DEG C of high-temperature sterilization 30min, obtain injection liquid.
Embodiment 7
Preparation technology: get water for injection 100.0ml, adds main ingredient B09, N.F,USP MANNITOL, lactose and poloxamer stirring and dissolving prepared by embodiment 1.Adjust pH to be 7.0-9.0 with the Citric Acid of 1mol/L, mend and add water to 150ml.Add the gac of 0.5g, stir 30min at 30 DEG C, de-charcoal.Employing filtering with microporous membrane is degerming, and filtrate is by often propping up 1ml packing, and after pre-freeze 2h, freezing lower drying under reduced pressure 12h, dry 5h again after sample temperature to 25 DEG C, obtained white loose block, seals and get final product.
Embodiment 8
Take water for injection 2000.0ml, add main ingredient B12, Tutofusin tris, low molecular dextran and EDTA-2Na stirring and dissolving prepared by embodiment 1.Adjust pH to be 7.0-9.0 with sodium bicarbonate, add 10g gac at 20-50 DEG C of whip attachment 30min, carbon removal, mend and add water to 5000.0ml.Essence filter, embedding every bottle 50ml, sterilizing and get final product.
Embodiment 9
In this experiment, B01-B16 sample used is the sample of preparation in embodiment 1.
(1) material
HTC-15 cell strain, HTC-116 cell strain, MCF-7 cell strain and BGC-823 cell strain provided by greenery pharmaceutical development center non-clinical research and development department laboratory, and adopt cellar culture, experimentation all adopts logarithmic phase cell.RPMI1640 substratum is purchased from GIBCO, and foetal calf serum is Tian Hang bio tech ltd, Zhejiang product, and MTT is green skies biotech company product, and DMSO is Sai Ersi Products.
Instrument: CO
2incubator (SANYO MCO-20AIC, Japan), Bechtop (Shandong three is auspicious), microplate reader (Molecular Devices SpectraMax M5), inverted microscope (OLYMPUS CKX41), Tissue Culture Dish (Costar, USA), 96 porocyte culture plates (Costar, USA).
Software: Microsoft Excel statistical analysis software
(2) method
Respectively by the HTC-15 cell of logarithmic phase, HTC-116 cell, MCF-7 cell, BGC-823 cell, after 0.25% pancreas enzyme-EDTA digestion, be mixed with certain density single cell suspension, according to the difference of vitro growth rates, be inoculated in 96 orifice plates by 1000-2000/hole, every hole adds cell suspension 100 μ L.After 24h, add the fresh culture containing different concns compound and coordinative solvent contrast, every hole adds 100 μ L (DMSO final concentration <0.1%), often kind of test-compound establishes 5 ~ 7 dosage groups, often organize and at least establish 3 parallel holes, after continuing to cultivate 72h in 37 DEG C, abandon supernatant, every hole adds the freshly prepared serum free medium containing 0.5mg/mL MTT of 100 μ L, continue to cultivate 2h, after abandoning supernatant, every hole adds 200 μ L DMSO and dissolves MTT first hairpin precipitation, after microoscillator vibration mixing, microplate reader is at reference wavelength 450nm, optical density value (OD) is measured under determined wavelength 570nm condition, with the tumour cell of solvent control process for control group, with the inhibiting rate of following formulae discovery compound on tumor cell, and by middle effect Equation for Calculating IC
50:
(3) result
Table 3 sample is to the half-inhibition concentration IC of tumor cell in vitro
50(μM)
| Numbering | HCT-15 | HCT-116 | MCF-7 | BGC-823 |
| B01 | 12.87±1.32 | 5.87±0.95 | 15.32±2.79 | 10.91±0.99 |
| B02 | 24.11±0.49 | 10.08±0.33 | 20.96±4.20 | 16.71±1.26 |
| B03 | 15.39±0.82 | 11.94±0.85 | 18.42±0.77 | 12.38±1.57 |
| B04 | 25.36±2.63 | 16.81±0.73 | 29.29±1.51 | 33.45±4.36 |
| B05 | 32.82±3.53 | 17.68±0.96 | 26.97±2.23 | 29.24±3.38 |
| B06 | 19.73±1.14 | 13.87±1.33 | 24.79±0.82 | 19.92±1.76 |
| B07 | 30.64±2.76 | 20.31±1.46 | 36.94±5.13 | 42.56±5.49 |
| B08 | >100 | 43.68±3.44 | 47.62±5.91 | 69.49±0.46 |
| B09 | 10.42±1.00 | 6.97±0.15 | 23.09±0.19 | 12.97±1.08 |
| B10 | 10.78±0.53 | 8.44±0.62 | 21.98±1.54 | 11.87±0.30 |
| B11 | 12.14±1.15 | 13.68±0.53 | 22.06±1.03 | 14.50±1.60 |
| B12 | 13.28±0.65 | 12.17±0.69 | 22.10±0.99 | 12.42±2.48 |
| B13 | 11.18±0.80 | 13.65±0.91 | 14.40±2.72 | 14.30±0.63 |
| B14 | 20.54±7.27 | 16.34±1.32 | 29.87±1.77 | 21.82±1.91 |
| B15 | 45.74±16.90 | 39.80±6.42 | 21.15±1.29 | 14.97±1.07 |
| B16 | >100 | >100 | 73.89±24.51 | 39.09±12.25 |
| Sorafenib | 11.81±0.37 | 10.55±14.07 | 18.55±1.87 | 14.65±2.96 |
(4) conclusion
Diaryl urea compound B 01 containing quinazoline structure and the B09 of logical formula I of the present invention have proliferation inhibition activity to human colon cancer cell strain HCT-15, human colon cancer cell strain HCT-116, human colon cancer cell strain SW-480, MCF-7 cell strainHJ2mm, Human gastric carcinoma cell line BGC-823
Embodiment 10
(1) material
C57BL/6 mouse is provided by Fukang bio tech ltd of China, Beijing, adopts conventional raising.
Software: Microsoft Excel statistical analysis software
This is tested B01 and B09 used and is embodiment 1 and prepares.
(2) method
Select male C57/BL6 mouse, 18-22g.Experimentation is summarized as follows: get well-grown tumor-bearing mice, cervical dislocation is put to death, the melanin tumour b16 knurl block grown fine is stripped under aseptic condition, homogenate, give every mouse oxter subcutaneous vaccination 0.1mL knurl liquid after releasing with the ratio of every gram of tumor tissue 4mL physiological saline, next day is by animal random packet and start administration.Compd B 01, B09 under 90mg/kg dosage in inoculation 24h after gastric infusion, administration volume is 0.2mL/10g; Sorafenib is with 90mg/kg dosage gastric infusion, and administration volume is 0.2mL/10g.Every day is administered once, and after successive administration 14 times, cervical dislocation is put to death, and weighs in respectively, knurl weight.Calculate inhibition rate of tumor growth (%), and result is carried out statistical procedures.
(3) result
Table 4 sample is to the inhibiting rate of B16 xenograft tumor in body
(4) conclusion
As can be seen from above-mentioned experiment in vivo result, diaryl urea compound B01 and B09 containing quinazoline structure of logical formula I of the present invention has growth inhibitory activity to mouse melanin B16 transplanted tumor.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (8)
1., containing a diaryl urea compound for quinazoline structure, it is characterized in that, comprise the compound or its pharmacy acceptable salt with formula I structure, formula I structure is as follows:
Wherein, R
1be selected from H, C
1-C
8alkyl, halogen ,-CF
3,-OCF
3,-NO
2,-CN, R
2o-,-SO
2nH
2,-NHSO
2r
3,-NR
4r
5,-CONR
6r
7,-COOR
8, R
9two replacements of CO-and above-mentioned group or three replacements of above-mentioned group, X is selected from O or S.
2. the diaryl urea compound containing quinazoline structure according to claim 1, is characterized in that, described R
1be selected from H, C
1-C
4alkyl, F, CI, CF
3, OCF
3, CN, R
2o, NHSO
2r
3, NR
4r
5, CONR
6r
7, COOR
8, R
9two replacements of CO and above-mentioned group or three replacements of above-mentioned group, R
2, R
3, R
4, R
5, R
6, R
7, R
8and R
9be respectively H or C
1-C
4alkyl.
3. the diaryl urea compound containing quinazoline structure according to claim 2, it is characterized in that, described pharmacy acceptable salt is selected from: hydrochloride, hydrobromate, vitriol, phosphoric acid salt, mesylate, fluoroform sulphonate, benzene sulfonate, tosilate, 1-naphthalene sulfonic aicd salt, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, Citrate trianion, lactic acid salt, oxalate, succinate, fumarate, maleate, benzoate, salicylate, the water solubles of phenylacetate, mandelate or above-mentioned salt.
4. the diaryl urea compound containing quinazoline structure according to claim 3, is characterized in that, the described diaryl urea compound containing quinazoline structure is selected from the one in following compounds:
B01N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(the fluoro-3-trifluoromethyl of 4-) urea;
B02N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(3-trifluoromethyl) urea;
B03N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(4-Trifluoromethoxyphen-l) urea;
B04N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(the chloro-4-fluorophenyl of 3-) urea;
B05N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(3,4-difluorophenyl) urea;
B06N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(4-chloro-phenyl-) urea;
B07N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(4-fluorophenyl) urea;
B08N-{3-[(6,7-dimethoxy-4 '-quinazolyl) oxygen base] phenyl }-N'-(4-aminomethyl phenyl) urea;
B09N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(the fluoro-3-trifluoromethyl of 4-) urea;
B10N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(3-trifluoromethyl) urea;
B11N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(4-Trifluoromethoxyphen-l) urea;
B12N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(the chloro-4-fluorophenyl of 3-) urea;
B13N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(3,4-difluorophenyl) urea;
B14N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(4-chloro-phenyl-) urea;
B15N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(4-fluorophenyl) urea;
B16N-{3-[(6,7-dimethoxy-4 '-quinazolyl) sulfenyl] phenyl }-N'-(4-aminomethyl phenyl) urea.
5. according to the arbitrary described application of diaryl urea compound in preparation treatment colorectal carcinoma, mammary cancer and/or gastric cancer medicament containing quinazoline structure of claim 1-4.
6. a pharmaceutical composition, is characterized in that, containing the described diaryl urea compound containing quinazoline structure arbitrary in claim 1-4, and acceptable carrier, thinner or vehicle in one or more pharmacy or bromatology.
7. pharmaceutical composition according to claim 6, is characterized in that: described pharmaceutical composition is oral preparations or injection.
8., containing a preparation method for the diaryl urea compound of quinazoline structure, it is characterized in that: comprising:
1) compound 1 veratryl aldehyde is nitrated in nitric acid, obtains 6-nitro veratryl aldehyde, i.e. compound 2;
2) 6-nitro veratryl aldehyde and potassium permanganate react, and obtain 6 nitroveratric acid, i.e. compound 3;
3) 6 nitroveratric acid under the catalysis of palladium carbon with hydrogen reaction, obtain 6-aminoveratric acid, i.e. compound 4;
4) 6-aminoveratric acid and FORMAMIDINE ACETATE are reacted in DMSO, obtain 6,7-dimethoxy-4 ' (3H)-quinazolinone, i.e. compound 5;
5) 6,7-dimethoxy-4 's (3H)-quinazolinone is through sulfur oxychloride chloro, obtains 6,7-dimethoxy-4 '-chloro-quinazoline, i.e. compound 6;
6) 6,7-dimethoxy-4 's-chloro-quinazoline and Metha Amino Phenon or m-aminothiophenol condensation, obtain compound 7;
7) compound 8 reacts with triphosgene in ethylene dichloride, obtains compound 9;
8) compound 7 and compound 9 react in organic solvent, obtain the compound with formula I structure, this compound and acid-respons, obtain its pharmacy acceptable salt of compound of formula I structure, and concrete reaction is as follows:
Wherein, R
1be selected from H, C
1-C
8alkyl, halogen ,-CF
3,-OCF
3,-NO
2,-CN, R
2o-,-SO
2nH
2,-NHSO
2r
3,-NR
4r
5,-CONR
6r
7,-COOR
8, R
9two replacements of CO-and above-mentioned group or three replacements of above-mentioned group, R
2, R
3, R
4, R
5, R
6, R
7, R
8and R
9be respectively H or C
1-C
8alkyl, X is selected from O or S.
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