CN1858040B - 5,8-disubstituted quinazoline and its preparing method and use - Google Patents
5,8-disubstituted quinazoline and its preparing method and use Download PDFInfo
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- CN1858040B CN1858040B CN200510025663XA CN200510025663A CN1858040B CN 1858040 B CN1858040 B CN 1858040B CN 200510025663X A CN200510025663X A CN 200510025663XA CN 200510025663 A CN200510025663 A CN 200510025663A CN 1858040 B CN1858040 B CN 1858040B
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Abstract
The present invention discloses 5, 8-disubstituted quinazoline and its preparation process and use, the compound having the following formula 1, wherein R1 represents arylamine, alkylamine or alkoxy, R2 represents nitryl or amino or sulfonamido or alkoxy. The new compound 5, 8-disubstituted quinazoline exhibits very high tumor cell growth inhibiting activity, especially on EGFR or ErbB-2 high expression mammary cancer cell and oophoroma cell, with the half inhibition concentration IC50 up to 0.01[mu]m. The present invention also reveals the preparation process of the compound.
Description
Technical field
The present invention relates to polysubstituted quinazoline new compound, synthetic and inhibition tumor cell growth activity, more particularly for containing 5,8-two replacement-4-hydroxyl quinazoline compounds are as the synthesizing of antitumour drug of targeting epidermal growth factor receptor EGFR and HER2 reaches purposes efficiently.
Background technology
Cuticle of cell growth factor receptors (Epidermal Growth Factor Receptor, EGFR) family belongs to I receptor Tyrosylprotein kinase superfamily, it is the cell growth, the important regulatory factor of differentiation and survival, its member has: erbB-1 (EGFR, HER1), erbB-2 (HER2), erbB-3 (HER3) and erbB-4 (HER4), their structural similitudies, the protein tyrosine kinase district of striding film district and high conservative by the outer ligand binding domain of born of the same parents, strand forms.This structure had both been had a function of acceptor, had the ability that extracellular signal is converted into born of the same parents' internal effect again, be a kind of novelty stride the film transfer mode.In case ligands specific such as EGF or TGF-α be in conjunction with getting on, just can be by the self phosphorylation (autophosphorylation) of corresponding Tyrosylprotein kinase activated receptor, signal conducts chain reaction in the cell thereby excited.These signal transmission comprise: the activation of Ras kinase protein and short cell fission kinase protein MAPK, this the two activation is the multiple protein in the activating cells nuclear again, the crucial circulating protein D1 that comprises cell cycle propagation, thereby cause that DNA is synthetic, (Jorissen, R.N. take place a series of important cell incidents such as cell growth, differentiation and survival; Walker, F.W.; Pouliot, N.; Garrett, T.P.J.; Ward, C.W.; Burgess, A.W.Epidermal growth factor receptor:mechanism of activation and signaling.Exp.Cell Res.2003,284,31-53).The overactivity of growth factor receptors causes the uncontrolled propagation of cell, thereby produces various types of excessively proliferative diseases, as the restenosis of nonsmall-cell lung cancer, leukemia, mammary cancer, the cancer of the brain, atherosclerosis and vascularization postoperative.The inhibition of growth factor receptor tyrosine kinase is proved has the effectiveness of regulating uncontrolled cellular replication, therefore become the target (Ritter of novel antitumour drug treatment, C.A.and Arteaga, C.L.The epidermal growth factorreceptor-tyrosine kinase:a promising therapeutic target in solid tumors.Semin.Oncol.2003,30,3-11).
Present many synthetic compounds have the activity that suppresses Cuticle of cell growth factor receptor tyrosine kinase (EGFR-PTK), especially study the most deeply with quinazoline compounds, wherein ZD1839 was used for the treatment of nonsmall-cell lung cancer (Ranson in 2003 by FDA approval listing, M.Epideraml growth factor receptor tyrosine kinase inhibitors.British J.Cancer2004,90,2250-2255.).But the quinazoline compound as tyrosine kinase inhibitor of bibliographical information mainly concentrates on 4-substituted anilinic-6,7-disubstituted quinazoline structure type (Bridges, A.J.Chemical inhibitors of proteinkinases.Chem.Rev.2001,101,2541-2571.), we calculate by molecular model, 4-hydroxyl-5 has been synthesized in design, the novel series compounds of 8-disubstituted quinazoline by optimizing substituent structure, finds to have the small-molecule drug of anti-tumor activity.
Summary of the invention
The objective of the invention is to seek the quinazoline ditosylate salt new compound that a class has the inhibition Cuticle of cell growth factor receptors signal conduction of anti-tumor activity.
Another object of the present invention provides a class 5, the preparation method of 8-two replacement-4-hydroxyl quinazoline compounds.
A further object of the present invention provides 5, and 8-two replacement-4-hydroxyl quinazoline compounds are in medically purposes.
The present invention's design is based on EGFR tyrosine-kinase zymoprotein and the interactional crystalline structure of micromolecular inhibitor (Wood, E.R.; Truesdale, A.T.; McDonald, O.B.; Yuan, D.; Hassell, A.; Dickerson, S.H.; Ellis, B.; Pennisi, C.; Horne, E.; Lackey, K.; Alligood, K.J.; Rusnak, D.W.; Gilmer; T.M.and Shewchuk; L.Aunique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation; inhibitor off-rate; and receptor activity in tumor cells.Cancer Res.2004; 64; 6652-6659); synthetic method by the focus type compound library; be core texture promptly with pharmacophore quinazoline ring; introduce different substituting groups by the aryl nucleophilic substitution reaction in the 5-position of quinazoline ring; cooperate nitration reaction to introduce different 8-bit substituents with sulfonylation with reduction reaction; synthesize a series of 5; 8-two replacement-4-hydroxyl quinazoline new compounds, the while has been measured the inhibition activity of the growth of tumour cell of each compound pair cell Urogastron overexpression at cell levels.
A class 5 of the present invention, 8-disubstituted quinazoline compound has following structure 1
R
2:-NO
2,-NHSO
2R,-NRSO
2R,-NHR,-OR
R
3, R
4: halogens such as F, Cl, Br, I, or CF
3, RO-, RNH-, R
2N-
R, R ' independently are C separately
1-C
12Straight or branched or cyclic alkyl contain saturated and unsaturated hydrocarbon chain, C
6-C
12Aryl or heterocyclic aryl, the alkyl that functional groups such as carboxyl or hydroxyl or aryl or halogen replace, the aryl that functional groups such as carboxyl or hydroxyl or aryl or halogen replace
Shown in the synthetic following reaction formula of this compounds:
Specifically, 5,8-two replacement-4-hydroxyl quinazolines are from 3-chloro-2-aminotoluene, through amido protecting, oxidation, take off the N-protected base, be cyclized into the quinazoline ring, nitrated and synthetic the obtaining of aromatic ring nucleophilic substitution reaction 6 step reaction.At first, the commercial raw material 3-chloro-2-aminotoluene that can sell is at inert solvent such as halogenated alkane, toluene, benzene, tetrahydrofuran (THF), dioxane or ether, acetic acid or N, go up the N-protected base in the dinethylformamide equal solvent, protecting group is formyl radical, the ethanoyl of the protection amino used always or replaces ethanoyl, CBZ, BOC, benzyl or substituted benzyl, FMOC, temperature is 0 a ℃~room temperature, or is heated to solvent refluxing; Phenmethyl reflux in potassium permanganate solution is oxidized to phenylformic acid (oxidising agent can also be dichromic acid acid potassium, chromium trioxide, sodium periodate, IBX then, Dess-Martin reagent, new preparing manganese dioxide, hydrogen peroxide, temperature of reaction is controlled at 50 ℃~120 ℃, and solvent is halohydrocarbon, toluene, acetonitrile, acetate and water).Slough the N-protected base under certain condition (to the formyl radical of N-protected; ethanoyl or replacement ethanoyl; CBZ; BOC sloughs protecting group under acidic conditions; formyl radical to N-protected; benzyl or substituted benzyl are sloughed protecting group with catalytic hydrogenation; FMOC to N-protected sloughs protecting group under alkaline condition; the solvent halohydrocarbon; tetrahydrofuran (THF); 1; the 4-dioxane; methyl alcohol; ethanol; temperature is that room temperature arrives the solvent refluxing temperature); 2-amino-6-chloro-benzoic acid that obtains and methane amide are quinazoline in room temperature-175 a ℃ following cyclisation; it is further nitrated again that (nitrating agent can be that nitrosonitric acid and the vitriol oil are 0 ℃~room temperature; or bismuth subnitrate and thionyl chloride; or saltpetre; lanthanum nitrate and concentrated nitric acid; or SODIUMNITRATE; lanthanum nitrate and concentrated hydrochloric acid; water used in solvent; halohydrocarbon or tetrahydrofuran (THF); temperature is 0 ℃~room temperature) obtain 8-nitro-5-chloro-quinazoline; amine or alcohol carry out the aryl nucleophilic substitution reaction as nucleophilic reagent to the 5-chlorine of quinazoline and obtain different 5-substituting groups-8-nitro-quinazoline compound (reaction solvent is with inert solvent such as tetrahydrofuran (THF); ether; toluene; acetonitrile; 1; 4-dioxane or N; nucleophilic substitution reaction takes place 40 ℃~100 ℃ heating in dinethylformamide); 8-position nitro can further be reduced to amino, and (reductive agent is Pd/C hydrogenation; iron powder and acetic acid; iron powder and ammonium chloride; zinc powder and ammonium chloride; hydrazine hydrate; ammonium formiate; water used in solvent; ethanol; methyl alcohol or acetonitrile, temperature is at 40 ℃~100 ℃) and further be converted into sulphonamide.
EGF-R ELISA (EGFR and HER-2) Tyrosylprotein kinase suppresses active testing
The extraction of EGFR and HER-2 enzyme: use Bab~to-Bac insect baculovirus expression system and express activated tyrosine-kinase zymoprotein, with Ni-NTA post affinity purification albumen.Packing ,-70 ℃ of preservations.With enzyme reaction substrate Poly (Glu, Tyr)
4:1Be diluted to optimum concn with no potassium PBS, coated elisa plate is put 37 ℃ of reactions 12-16 hour.Discard liquid in the hole.Wash plate three times, in 37 ℃ of baking ovens dry enzyme plate 1-2 hour.Every hole adds certain density protein tyrosine kinase 10 μ L, establishes and does not have the enzyme contrast accordingly, and the certain density ATP solution 80 μ L that add then with the reaction buffer dilution start reaction.The testing compound 10 μ L that add different concns simultaneously, and with certain density DMSO solution 10 μ L as corresponding negative control, put 37 ℃ of shaking tables reactions 1 hour.T-PBS washes plate three times, each 15 minutes.Add antibody PY99 (1:1000) 100 μ l/ holes, 37 ℃ of shaking tables reacted 0.5 hour.T-PBS washes plate three times, adds IgG (1:2000) the 100 μ l/ holes of horseradish peroxidase-labeled sheep anti mouse, and 37 ℃ of shaking tables reacted 0.5 hour.T-PBS washes plate three times, adds the OPD colour developing liquid 100 μ l/ holes of 2mg/ml, and 25 ℃ of lucifuges were reacted 1-10 minute.Add 2M H
2SO
450 μ l/ hole stopped reactions, with the wavelengthtunable orifice plate microplate reader VERSAmax reading that declines, wavelength is 490nm.
Measure medicine to the proteic relative inhibition of Tyrosylprotein kinase.
According to each concentration inhibiting rate, adopt Logit method calculation of half inhibitory concentration IC
50More than each experiment repeat 2 times, obtain the average IC of 2 experiments
50Value is as the final index of the ability of inhibition.
It is active that the growth of tumour cell of EGF-R ELISA (EGFR and HER-2) Tyrosylprotein kinase high expression level suppresses:
According to cell growth rate, in 96 well culture plates, adherent growth 24 hours is dosing 10 μ l/ holes again with 90 μ l/ hole kinds for the tumour cell that will be in logarithmic phase.Each concentration is established three multiple holes.And the physiological saline solvent of establishing respective concentration contrasts and acellular withered hole.Tumour cell is at 37 ℃, 5%CO
2Cultivated 72 hours under the condition, the nutrient solution that inclines then with 10% cold TCA fixed cell, is placed for 4 ℃ and is used distilled water wash 5 times, seasoning in the air after 1 hour.Add SRB (Sigma) the 4mg/ml solution 100 μ l/ holes by the preparation of 1% Glacial acetic acid then, dyeing is 15 minutes in the room temperature, removes supernatant liquor, with 1% acetic acid washing 5 times, dry air.The Tris solution that adds 150 μ l/ holes at last, microplate reader (VERSAmax) 515nm wavelength are measured the OD value down.Calculate the inhibiting rate of analyte to growth of cancer cells, half amount of suppression IC by following formula
50Value adopts the Logit method to calculate.More than each experiment repeat 2 times, obtain the average IC of 2 experiments
50Value is as the final index of the ability of inhibition.
Inhibiting rate=(control group OD value-administration group OD value)/control group OD value * 100%
The MCF-7 of two kinds of overexpression epidermal growth factor recipient tyrosine kinases is used to the inhibition effect of test compounds to growth of tumour cell.Breast cancer cell line SK-BR-3 overexpression ErbB2 (HER2), breast cancer cell line MDA-MB-468 overexpression EGFR.
Table 1. compound 1a-n is to the inhibition effect of growth of tumour cell
aClone SK-BR-3 (mammary cancer) overexpression erbB2; Clone MDA-MB-468 (mammary cancer) overexpression EGFR.
bDosage relies on curve and records at 5 concentration values; Drug level value IC during cell growth inhibiting 50%
50(μ M) obtains from these curves.
cB17 is as positive control (Wang, S.; Yang, D.; Enyedy, I.US Patent US2004023957-A1,2004.).
Table 2. compound 1a-n is to EGFR and the proteic inhibition effect of ErbB-2 Tyrosylprotein kinase
The pharmacology result of cell levels shows, this class 5, it is the highly active tumor growth inhibitor of a class that 8-two replaces 4-hydroxyl quinazoline compound, tumor cell line for Cuticle of cell growth factor receptors EGFR and ErbB-2 overexpression shows very high inhibition activity, especially the 5-position is that the derivatives active that replaces of aniline is best, and the 3-position of 5-aniline and 4-bit substituent to be halogen and electron-donating group can promote 5 of this compounds greatly, the tumor growth that 8-two replaces 4-hydroxyl quinazoline compounds suppresses active.Best compound, suppresses activity and is higher than positive control compd B-17 less than 0.01 μ M the 503nhibiting concentration IC50 of the tumor cell line MDA-MB-468 of EGFR high expression level growth; 503nhibiting concentration IC to the growth of the tumour cell SK-BR-3 of ErbB-2 high expression level
50Be 7.0 μ M.
Pharmacology result shows, this class 5, it is the highly active tumor growth inhibitor of a class that 8-two replaces 4-hydroxyl quinazoline compound, activity with the growth of very strong inhibition mankind mastopathy cell and ovarian cancer cell, especially the tumor cell line for Cuticle of cell growth factor receptors EGFR and ErbB-2 overexpression shows very high selectivity, and best compound is to the 503nhibiting concentration IC of the tumor cell line MDA-MB-468 growth of EGFR high expression level
50Less than 0.01 μ M, suppress activity and be higher than positive control compd B-17; 503nhibiting concentration IC to the growth of the tumour cell SK-BR-3 of ErbB-2 high expression level
50Be 7.0 μ M.In the enzymic activity test shows of molecular level, our compound has certain restraining effect to EGFR Tyrosylprotein kinase and ErbB-2 Tyrosylprotein kinase.
The enzymic activity test of molecular level shows, these compounds have certain inhibition effect to EGFR and ErbB-2 Tyrosylprotein kinase, this class 5,8-two replaces 4-hydroxyl quinazoline compound the growth of mankind mastopathy cell and ovarian cancer cell is had the restraining effect of highly significant, is the tumor growth inhibitor of the highly active new texture of a class.
Embodiment
Below in conjunction with embodiment the present invention is further described, but does not limit the present invention.
Example 15-aniline-8-nitro-4 hydroxyl quinazoline 1a
Step 1:3-chloro-2-methyl phenylacetamide (compound 2)
3-chloro-2-aminotoluene (2.34 grams, 16.50 mmoles) 6 milliliters of methylene dichloride of dissolving slowly drip acetic anhydride (2.53 grams, 24.75 mmoles) under the violent stirring.The a large amount of grey acetylate precipitations that produce are filtered with B, wash with water.The crude product ethyl acetate: methyl alcohol=10:1 recrystallization obtains white crystals product (2.73 grams, 90.2%).
1HNMR(DMOS-d
6,400MHz)9.70(s,1H),7.40(d,J=8.40,1H),7.37(t,J=8.01,1H),1.99(s,3H);MS(EI)m/z183(M
+);Anal.(C
9H
10ClNO)C,H,N:calcd:58.86,5.49,7.63.
Step 2:2-(ethanamide)-6-chloro-benzoic acid (compound 3)
Compound 2 (3.3 grams, 18.0 mmoles), six Magnesium sulfate heptahydrates (4.3 grams, 38.8 mmoles) and ℃ backflow of water Hybrid Heating to 135.The aqueous solution (100 milliliters) of potassium permanganate (11.4 grams, 72.2 mmoles) slowly is added drop-wise to (about 3 hours) in the above-mentioned solution.Behind reinforced the finishing, being warmed up to 160 ℃ refluxed 2 hours, stop heating, filter with B after cooling, filtrate is transferred PH=1.0 with the aqueous hydrochloric acid of 6M, and a large amount of white solid product are separated out the solid collected by filtration product, get white crystals purified product (2.5 grams, 65.7%) with recrystallizing methanol after the vacuum-drying.
1H?NMR(DMSO-d
6,400MHz),δ9.70(s,1H),7.40(d,J=8.04,1H),7.37(t,J=8.01,1H),7.31(d,J=8.06,1H),1.99(s,3H);MS(EI)m/z213(M
+);Anal.(C
9H
8ClNO
3)C,H,N,calcd:50.60,3.77,6.56,found:50.42,3.54,6.45.
Step 3:5-chloro-4-hydroxyl quinazoline (compound 5)
Compound 3 (250 milligrams, 1.17 mmoles) adds 4 milliliters of concentrated hydrochloric acids, is heated to 80-90 ℃ and stirs 1.5 hours, and temperature should not be higher than 90 ℃.Stop heating, the adularescent xln is separated out after cooling, and the solid collected by filtration product with getting 2-amido-6 chloro-benzoic acid (4) after the recrystallizing methanol, is directly used in next step reaction.Add 1.5 milliliters of methane amides in compound 4 (1.2 grams, 5.8 mmoles), heating was stirred 45 minutes down at 130 ℃, stirred 75 minutes down at 175 ℃.Stop heating, the translucent solid that obtains after cooling stirs with 1.5 milliliters of methylcellulose gum dissolvings, resultant soup compound pours in 5 milliliters of frozen water, the solid collected by filtration crude product, separate purified product with column chromatography and get 0.75 gram white solid product 5, developping agent ethyl acetate: sherwood oil=1:1, yield 67.6%.
1H?NMR(DMSO-d
6,400MHz),δ12.09(br,1H),8.07(s,1H),7.71(t,J=8.25,7.7,1H),7.59(d,J=8.0,1H),7.51(d,J=7.43,1H);MS(EI)m/z180(M
+);Anal.(C
8H
5ClN
2O)C,H,N,calcd:53.21,2.79,15.51,found:53.14,2.72,15,36.
Step 4:5-chloro-8-nitro-4-hydroxyl quinazoline (compound 6)
In compound 5 (155 milligrams, 0.86 mmole), add 3 milliliters of vitriol oils, and, slowly dripped nitrosonitric acid (3 milliliters) about 10 minutes with the ice bath cooling.Dropwise the back and keep 0 ℃ to continue to stir 10 minutes, stopped reaction pours into reaction soln in the trash ice, and with in 20% the aqueous sodium hydroxide solution and transfer pH=7, the solid collected by filtration product is with washing twice on a small quantity.Get faint yellow solid product (193.5 milligrams) with the ethanol-water system recrystallization.
1HNMR(DMSO-d
6,400MHz)δ12.68(br,1H),8.27(d,J=8.86,1H),8.22(s,1H),7.75(d,J=8.85,1H);MS(EI)m/z225(M
+);Anal(C
8H
4ClN
3O
3)C,H,N,calcd:42.59,1.79,18.63,found:42.47,1.68,18.60.
Step 5:5-aniline-8-nitro-4-hydroxyl quinazoline (compound 1a)
Compound 6 (100 milligrams, 0.44 mmole) is dissolved in 18 milliliters of tetrahydrofuran (THF)s, adds 82 milligrams of aniline (0.88 mmole).Mixed system reflux 24 hours (80-90 ℃), stopped reaction removes most of tetrahydrofuran (THF) under reduced pressure, add entry dilution (15 milliliters), dissolving with hydrochloric acid with 20% is transferred pH=7, with twice of ethyl acetate extraction (2 * 20 milliliters), merges organic phase, use anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, with silica gel column chromatography separate (90 milligrams of pure product of brown solid, 72.5%), the developping agent system is ethyl acetate: sherwood oil=1:1.Mp:233-235℃;
1H?NMR(DMSO-d
6,300MHz)δ9.88(br,1H),8.81(s,1H),8.80(d,J=9.08,1H),7.34(d,J=8.9,1H),7.0-7.2(m,5H);MS(EI)m/z282(M
+);Anal.(C
14H
10N
4O
3)C,H,N,calcd:59.57,3.57,19.85,found:59.45,3.44,19.98.
Target compound 1b-1t makes with similar approach.
Embodiment 2:5-benzylamine-8-nitro-4 hydroxyl quinazoline 1b
Starting raw material obtains orange solid product (100 milligrams, 76.9%) with benzylamine (94 milligrams, 0.88 mmole).Mp:182-184℃;
1H?NMR(DMSO-d
6,300MHz).10.00(br,1H),8.68(d,J=9.1,1H),7.2-7.3(m,5H),6.77(d,J=8.99,1H),4.25(s,2H);MS(EI)m/z296(M
+);Anal.(C
15H
12N
4O
3),C,H,N,calcd:60.81,4.08,18.91,found:60.72,4.11,18.87.
Embodiment 3:5-(3-chloroaniline)-8-nitro-4 hydroxyl quinazoline 1c
Starting raw material obtains yellow solid (110 milligrams, 79.5%) with 3-chloroaniline (211 milligrams, 0.88 mmole).Mp:235-237℃;
1H?NMR(DMSO-d
6,300MHz):δ12.90(br,1H),11.45(s,1H),8.27(s,1H),8.23(d,J=9.07,1H),7.32(t,J=7.93,1H),7.16(d,J=9.07,1H),7.16-7.07(m,2H),6.95(d,J=7.96,1H);MS(EI)m/e316(M
+);Anal.(C
14H
9ClN
4O
3)C,H,N,Calcd:53.09,2.86,17.69.Found:53.24,2.97,17.57.
Embodiment 3:5-(4-chloroaniline)-8-nitro-4 hydroxyl quinazoline 1d
Starting raw material obtains yellow solid (106 milligrams, 76.8%) with 4-chloroaniline (112 milligrams, 0.88 mmole).Mp:241-243℃;
1H?NMR(DMSO-d
6,300MHz):δ11.48(br,1H),8.28(s,1H),8.20(d,J=9.08,1H),7.32(d,J=8.51,2H),7.10(d,J=9.06,1H),6.99(d,J=8.52,2H);MS(EI):317(M
++1);Anal.(C
14H
9ClN
4O
3),C,H,N,Calcd:53.09,2.86,17.69,Found:52.86,3.21,17.35.
Embodiment 5:5-(3-monomethylaniline)-8-nitro-4-hydroxyl quinazoline 1e
Starting raw material obtains brownish black solid (185 milligrams, 71.2%) with 4-monomethylaniline (95 milligrams, 0.88 mmole).Mp:215-217℃;
1H?NMR(DMSO-d
6,300MHz):δ12.85(br,1H),11.42(s,1H),8.26(s,1H),8.18(d,J=9.89,1H),7.15(t,J=7.69,1H),7.08(d,J=8.79,1H),6.93(d,J=9.89,1H),6.78(s,1H),6.76(d,J=8.79,1H),2.23(s,3H);MS(EI)m/e=296(M
+);Anal.(C
15H
12N
4O
3)C,H,NCalcd:60.81,4.08,18.91;Found:60.92,4.11,18.76.
Embodiment 6:5-methoxyl group-8-nitro-4-hydroxyl quinazoline 1f
In compound 6 (100 milligrams, 0.44 mmole), add 10 ml methanol and 100 milligrams of sodium methylates (1.85 mmole) solid.Mixed system was 70 ℃ of following reflux 24 hours.Stopped reaction, steam and remove most of methanol solvate, add entry dilution (15 milliliters), the hydrochloric acid soln with 20% is transferred pH=7, with twice of ethyl acetate extraction (2*20 milliliter), merge organic phase, use anhydrous sodium sulfate drying, steaming desolventizes, and separates obtaining (65 milligrams of white solid product with silica gel column chromatography, 66.8%), developping agent is ethyl acetate: sherwood oil=1:1.MP:209-210℃,
1H?MNR(DMSO-d
6,300MHz)δ11.28(br,1H),9.13(s,1H),8.67(d,J=8.79,1H),6.83(d,J=8.66,1H),3.90(s,3H);MS(EI)m/z221(M
+);Anal.(C
9H
7N
3O
4)C,H,N,calcd:48.87,3.19,19.00,found:48.77,3.23,18.89.
Embodiment 7:5-oxyethyl group-8-nitro-4 hydroxyl quinazoline 1g
The preparation method of compound 1g is identical with the preparation method of compound 1f.Starting raw material sodium ethylate (125 milligrams, 1.85 mmoles), 10 milliliters of ethanol are made solvent, obtain 80 milligrams of white solids, productive rate 77.6%.Mp:195-198℃;
1H?NMR(DMSO-d
6,300MHz)δ11.28(br,1H),9.14(s,1H),8.63(d,J=8.20,1H),6.81(d,J=8.40,1H),4.12(m,J=6.9,2H),1.48(t,J=6.9,3H);MS(EI)m/z235(M
+);Anal.(C
10H
9N
3O
4)C,H,N,calcd:51.07,3.86,17.87,found:51.13,3.68,17.74.
Embodiment 8:5-(4-anisidine)-8-nitro-4-hydroxyl quinazoline 1h:
The preparation method of compound 1h is with the preparation method of compound 1a.Starting raw material obtains blackish green solid (81 milligrams, 58.9%) with 4-anisidine (108 milligrams, 0.88 mmole).Mp:200-203℃;
1H?NMR(DMSO-d
6,300MHz):δ12.65(br,1H),δ11.40(s,1H),8.24(s,1H),8.14(d,J=9.07,1H),7.02(d,J=9.07,1H),6.95(d,J=9.06,2H),6.85(d,J=9.06,2H),3.73(s,3H);MS(EI)m/e312(M
+);Anal.(C
15H
12N
4O
4)C,H,N,Calcd:57.69,3.87,17.94;Found:57.79,3.98,17.67.
Embodiment 9:5-(4-amido aniline)-8-nitro-4-hydroxyl quinazoline 1i
The preparation method of compound 1i is with the preparation method of compound 1a.Starting raw material obtains brownish black solid (68 milligrams, 51.4%) with 4-amido aniline (48 milligrams, 0.44 mmole).Mp:223-226℃;
1HNMR(DMSO-d
6,300MHz):δ11.28(br,1H),8.21(s,1H),8.08(d,J=9.06,1H),6.90(d,J=9.07,1H),6.68(d,J=8.52,2H),6.47(d,J=8.79,2H);MS(EI)m/z?M
+=297;Anal.(C
14H
11N
5O
3)C,H,N,Calcd:56.56,3.73,23.56,Found:56.70,3.46,23.44.
Embodiment 10:5-(4-benzyloxy-aniline)-8-nitro-4-hydroxyl quinazoline 1j
The preparation method of compound 1j is with the preparation method of compound 1a.Starting raw material obtains pale brown look solid (110 milligrams, 64.7%) with 4-benzyloxy-aniline (175 milligrams, 0.88 mmole).Mp:220-222℃;
1H?NMR(DMSO-d
6,300MHz):δ11.40(br,1H),8.25(s,1H),8.15(d,J=9.07,1H),7.46-7.35(m,5H),7.02(d,J=9.07,1H),6.94(s,4H),5.05(s,1H);MS(EI)m/e388(M
+).Anal.(C
21H
16N
4O
4)C,H,N,Calcd.:64.94,4.15,14.43,Found:64.82,4.45,14.56.
Embodiment 11:5-pyrroline-8-nitro-4-hydroxyl quinazoline 1k
The preparation method of compound 1k is with the preparation method of compound 1a.Starting raw material obtains brown solid (90 milligrams, 78.5%) with pyrroline (63 milligrams, 0.88 mmole).Mp:208-210℃;
1H?NMR(DMSO-d
6,300MHz):δ12.30(br,1H),8.12(s,1H),8.09(d,J=9.07,1H),6.72(d,J=9.07,1H),3.29(dt,4H),1.89(dt,4H);MS(EI)m/e260(M
+);Anal.(C
12H
12N
4O
3)C,H,N,Calcd:55.38,4.65,21.53,Found:55.41,4.35,21.78.
Embodiment 12:5-(2H-pyrroles)-8-nitro-4-hydroxyl quinazoline 11
The preparation method of compound 11 is with the preparation method of compound 1a.Starting raw material obtains brownish black solid (79 milligrams, 69.8%) with 2H-pyrroles's (61 milligrams, 0.88 mmole).Mp:154-160℃;
1H?NMR(DMSO-d
6,300MHz):δ12.41(br,1H),8.11(s,1H),7.99(d,J=8.99,1H),6.79(d,J=8.99,1H),6.79(d,J=9.06,1H),5.91(s,2H),3.98(s,4H);MS(EI)m/e257(M
+-1);Anal.(C
12H
10N
4O
3)C,H,N,Calcd:55.81,3.90,21.70,Found:55.79,3.86,21.92.
Embodiment 13:5-N-(methionine(Met))-8-nitro-4-hydroxyl quinazoline 1m
The preparation method of compound 1m is with the preparation method of compound 1a.Starting raw material obtains brown solid (76 milligrams, 51.2%) with methionine(Met) (131 milligrams, 0.88 mmole), and the developping agent system is chloroform: methyl alcohol=2:1.Mp:214-217℃;
1H?NMR(DMSO-d
6,300MHz):δ12.78(br,1H),10.34(br,1H),8.23(s,1H),8.11(d,1H,J=9.07),6.91(d,1H,J=9.06),4.01(s,1H),2.37(s,2H),2.2-1.8(m,5H);MS(EI)m/e338(M
+);Anal.(C
13H
14N
4O
5S)C,H,N,Calcd:46.15,4.17,16.56.Found:46.23,4.25,16.43.
Embodiment 14:5-N-(phenylalanine)-8-nitro-4-hydroxyl quinazoline 1n
The preparation method of compound 1n is with the preparation method of compound 1a.Starting raw material obtains brown solid (74 milligrams, 49.7%) with phenylalanine (133 milligrams, 0.88 mmole), and the developping agent system is chloroform: methyl alcohol=2:1.Mp:>250℃;
1HNMR(DMSO-d
6,300MHz):δ12.80(br,1H),11.25(br,1H),8.22(s,1H),7.91(d,J=9.34,1H),7.25-7.12(d,5H),5.12(s,1H);MS(EI)m/e340(M
+);Anal.(C
16H
12N
4O
5)C,H,N?Calcd:56.47,3.55,16.46,Found:56.22,3.31,16.28.
Embodiment 15:5-(4-(4-hydroxyl-8-nitro-quinazoline-5-amino) aniline)-8-nitro-4-hydroxyl quinazoline 1o
The preparation method of compound 1o is with compound 1a.Starting raw material is with 1, and 4-two amido aniline (24 milligrams, 0.22 mmole) obtain pale brown look solid (67 milligram 62.6%).Mp:>250℃;
1H?NMR(DMSO-d
6,300MHz):δ14.06(br,2H),8.17(s,2H),7.94(d,J=9.3,2H),6.74(d,J=9.3,2H),6.71(s,4H);MS(EI)m/e486(M
+);Anal.(C
22H
14N
8O
6)C,H,N?Calcd:54.33,2.90,23.04.
Embodiment 16:5-(3-chloro-4-anisidine)-8-nitro-4-hydroxyl quinazoline 1p
Preparation method with compound 1a.Starting raw material obtains orange solid (62 milligrams, 81.0%) with 3-chlorine 4-anisidine (100 milligrams, 0.68 mmole).Mp:=216℃;
1H?NMR(CD
3OD,300MHz):δ8.14(s,1H),7.03(d,J=5.4,2H),7.01(s,1H),6.98(d,J=9.1,2H),6.91(d,J=9.1,2H),3.84(s,3H);MS(EI)m/e346(M
+);Anal.(C
15H
11ClN
4O
4)C,H,N?Calcd:51.96,3.20,16.16.
Embodiment 17:5-(4-carboxyl aniline)-8-nitro-4-hydroxyl quinazoline 1q
Preparation method with compound 1a.Starting raw material obtains glassy yellow solid (63 milligrams, 44.0%) with 4-carboxyl aniline (301 milligrams, 2.2 mmoles).Mp:>250℃;
1H?NMR(DMSO-d
6,300MHz):δ13.8(br,1H),8.22(s,1H),8.03(d,J=9.3,2H),7.80(d,J=8.2,2H),6.90(d,J=9.1,2H),6.84(d,J=8.2,2H);Anal.(C
15H
10N
4O
5)C,H,N?Calcd:55.22,3.09,17.17.
Embodiment 18:5-pyrroles-8-nitro-4-hydroxyl quinazoline 1r
Preparation method with compound 1a.Starting raw material obtains brownish black solid (75 milligrams, 66.9%) with pyrroles's (147 milligrams, 2.2 mmoles).Mp:>250℃;
1H?NMR(DMSO-d
6,400MHz):δ10.8(br,1H),8.00(s,1H),7.88(d,J=9.6,2H),6.68(s,2H),6.08(d,J=9.6,2H),5.99(s,2H);Anal.(C
12H
8N
4O
3)C,H,NCalcd:56.25,3.15,21.87.
Embodiment 19:5-(3-chloro-4-encircles oxygen base aniline)-8-nitro-4-hydroxyl quinazoline 1s
Preparation method with compound 1a.Starting raw material encircles oxygen base aniline (100 milligrams, 0.45 mmole) with 3-chlorine 4-, obtains khaki color solid (72 milligrams, 79.1%).Mp:=190℃;
1H?NMR(CD
3OD,300MHz):δ8.17(s,1H),8.13(d,J=9.0,1H),7.42(d,J=2.7,1H),7.27(dd,J=2.7,9.0,1H),7.22(d,J=8.9,1H),6.98(d,J=9.0,1H),4.47(m,1H),1.93-1.23(m,10H);;MS(EI)m/e414(M
+);Anal.(C
20H
19ClN
4O
4)C,H,N?Calcd:57.90,4.62,13.51.
Embodiment 20:5-(3-chloro-4-hydroxyanilines)-8-nitro-4-hydroxyl quinazoline 1t
Preparation method with compound 1a.Starting raw material obtains khaki color solid (185 milligrams, 99.4%) with 3-chloro-4-hydroxyanilines (100 milligrams, 0.53 mmole).Mp:>250℃;
1H?NMR(DMSO-d
6,300MHz):δ11.34(br,1H),10.13(br,1H),8.27(s,1H),8.13(d,J=8.9,1H),7.03(m,2H),6.85(m,2H);MS(EI)m/e332(M
+);Anal.(C
14H
9ClN
4O
4)C,H,N?Calcd:50.54,2.73,16.84.
Embodiment 21:5-(4-anisidine)-8-amino-4-hydroxy quinazoline 1u
(10 milligrams of 5-(4-anisidine)-8-nitro-4 hydroxyl quinazoline, 0.032 mmole) be dissolved in 5 ml methanol, the palladium-carbon catalyst that adds 1 milligram 5%, normal pressure and temperature hydrogenation, stopped reaction after 12 hours, filter, drain after the filtrate solid crude product, recrystallizing methanol gets 8 milligrams of blackish green solid products (productive rate is 92%).Mp:>250℃;
1H?NMR(DMSO-d
6,300MHz):δ7.76(s,1H),7.18(s,2H),6.76(d,J=9.0,2H),6.59(d,J=9.0,2H),?3.65(s,3H);MS(EI)m/e282(M
+);Anal.(C
15H
14N
4O
2)C,H,N?Calcd:63.82,5.00,19.85.
Embodiment 22:5-(3-chloroaniline)-8-amino-4-hydroxy quinazoline 1v
(10 milligrams of 5-(3-chloroaniline)-8-nitro-4 hydroxyl quinazoline, 0.032 mmole) be dissolved in 5 ml methanol, the palladium-carbon catalyst that adds 1 milligram 5%, normal pressure and temperature hydrogenation, stopped reaction after 12 hours, filter, drain after the filtrate solid crude product, recrystallizing methanol gets 9 milligrams of blackish green solid products (productive rate is 98%).Mp:>250℃;
1H?NMR(CD
3OD,300MHz):δ8.01(s,1H),7.34(d,J=9.6,2H),7.16(d,J=9.0,1H),6.86(m,1H),6.74(d,J=9.0,1H),6.62(s,1H);MS(EI)m/e286(M
+);Anal.(C
14H
11ClN
4O)C,H,N?Calcd:58.65,3.87,19.54.
Embodiment 23:5-(3-chloro-4-benzyloxy-aniline)-8-amino-4-hydroxy quinazoline 1w
Preparation method with compound 1a.Starting raw material obtains orange solid (47 milligrams, 60.0%) with 3-chloro-4-benzyloxy-aniline (40 milligrams, 0.207 mmole).Mp:=247℃;
1H?NMR(DMSO-d
6,300MHz):δ8.24(s,1H),8.17(d,J=9.0,1H),7.68(d,J=9.0,1H),7.45(m,5H);7.16(s,1H),7.05(d,J=9.1,1H),6.95(d,J=9.1,1H),5.16(s,2H);Anal.(C
21H
16N
4O
4)C,H,N?Calcd:64.94,4.15,14.43.
Claims (11)
1. a class has 5 of following general formula, 8-disubstituted quinazoline compound,
R
2:-NO
2;
R
3, R
4: be halogen independently, or RO-;
R is independently selected from C
1-C
12Straight or branched or cyclic alkyl, C
6-C
12Aryl, wherein cyclic alkyl does not comprise C
1-C
2Cyclic alkyl.
2. according to claim 15,8-disubstituted quinazoline compound is characterized in that:
Work as R
1During for RO-,
R
2For-NO
2,
R is selected from methyl, ethyl.
3. a class 5,8-disubstituted quinazoline compound is characterized in that:
Described compound is selected from 5-aniline-8-nitro-4-hydroxyl quinazoline, 5-benzylamine-8-nitro-4-hydroxyl quinazoline, 5-(3-chloroaniline)-8-nitro-4-hydroxyl quinazoline, 5-(4-chloroaniline)-8-nitro-4-hydroxyl quinazoline, 5-(3-monomethylaniline)-8-nitro-4-hydroxyl quinazoline, 5-methoxyl group-8-nitro-4-hydroxyl quinazoline, 5-oxyethyl group-8-nitro-4-hydroxyl quinazoline, 5-(4-anisidine)-8-nitro-4-hydroxyl quinazoline, 5-(4-amido aniline)-8-nitro-4-hydroxyl quinazoline, 5-(4-benzyloxy-aniline)-8-nitro-4-hydroxyl quinazoline, 5-pyrroline-8-nitro-4-hydroxyl quinazoline, 5-(2H-pyrroles)-8-nitro-4-hydroxyl quinazoline, 5-N-(methionine(Met))-8-nitro-4-hydroxyl quinazoline, 5-N-(phenylalanine)-8-nitro-4-hydroxyl quinazoline, 5-(4-(4-hydroxyl-8-nitro-quinazoline-5-amino) aniline)-8-nitro-4-hydroxyl quinazoline, 5-(3-chloro-4-anisidine)-8-nitro-4-hydroxyl quinazoline, 5-(4-carboxyl aniline)-8-nitro-4-hydroxyl quinazoline, 5-pyrroles-8-nitro-4-hydroxyl quinazoline, 5-(3-chloro-4-cyclohexyloxy aniline)-8-nitro-4-hydroxyl quinazoline, 5-(3-chloro-4-hydroxyanilines)-8-nitro-4-hydroxyl quinazoline, 5-(4-anisidine)-8-amino-4-hydroxy quinazoline, 5-(3-chloroaniline)-8-amino-4-hydroxy quinazoline, or 5-(3-chloro-4-benzyloxy-aniline)-8-amino-4-hydroxy quinazoline.
4. as claimed in claim 15, the preparation method of 8-disubstituted quinazoline compound comprises the steps:
3-chloro-2-aminotoluene sets out, through amido protecting, oxidation, take off the N-protected base, become the quinazoline ring, nitrated and aromatic ring nucleophilic substitution reaction gets target compound, reaction formula is as follows:
5. according to claim 45, the preparation method of 8-disubstituted quinazoline compound is characterized in that the N-protected base is formyl radical, ethanoyl, CBZ, BOC, benzyl, FMOC; The inert solvent is halogenated alkane, toluene, benzene, tetrahydrofuran (THF), dioxane or ether, acetic acid or N, dinethylformamide, and temperature of reaction is 0 a ℃~room temperature, or is heated to solvent refluxing.
6. according to claim 45, the preparation method of 8-disubstituted quinazoline compound is characterized in that:
Oxygenant is dichromic acid acid potassium, chromium trioxide, sodium periodate, potassium permanganate solution, IBX, Dess-Martin reagent, and new preparing manganese dioxide, hydrogen peroxide, temperature of reaction is controlled at 50 ℃~120 ℃, and solvent is halohydrocarbon, toluene, acetonitrile, acetate and water.
7. according to claim 45, the preparation method of 8-disubstituted quinazoline compound is characterized in that the N-protected base is that FMOC sloughs protecting group under alkaline condition; solvent halohydrocarbon, tetrahydrofuran (THF), 1; the 4-dioxane, methyl alcohol, ethanol, temperature is that room temperature arrives the solvent refluxing temperature.
8. according to claim 45, the preparation method of 8-disubstituted quinazoline compound is characterized in that:
Cyclization is a quinazoline at 2-amino-6-chloro-benzoic acid and methane amide cyclisation, and the cyclisation temperature is a room temperature to 175 ℃, gradient-heated.
9. according to claim 45, the preparation method of 8-disubstituted quinazoline compound is characterized in that:
Nitrating agent be nitrosonitric acid and the vitriol oil 0 ℃~room temperature, or bismuth subnitrate and thionyl chloride, or saltpetre, lanthanum nitrate and concentrated nitric acid, or SODIUMNITRATE, lanthanum nitrate and concentrated hydrochloric acid, water used in solvent, halohydrocarbon or tetrahydrofuran (THF), temperature is 0 ℃~room temperature.
10. according to claim 45, the preparation method of 8-disubstituted quinazoline compound is characterized in that:
Amine or alcohol carry out the aryl nucleophilic substitution reaction as nucleophilic reagent to the 5-chlorine of quinazoline and obtain different 5-substituting groups-8-position nitro-quinazoline compound, reaction solvent is inert solvent tetrahydrofuran (THF), ether, toluene, acetonitrile, 1,4-dioxane or N, nucleophilic substitution reaction takes place 40 ℃~100 ℃ heating in dinethylformamide.
11. claim 1 or 3 described 5, the application of 8-disubstituted quinazoline compound in preparation treatment human breast cancer and oophoroma tumor medicine.
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CN1211239A (en) * | 1996-02-13 | 1999-03-17 | 曾尼卡有限公司 | Quinazoline derivatives as VEGF inhibitors |
CN1212684A (en) * | 1996-03-05 | 1999-03-31 | 曾尼卡有限公司 | 4-anilinoquinazoline derivatives |
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CN1212684A (en) * | 1996-03-05 | 1999-03-31 | 曾尼卡有限公司 | 4-anilinoquinazoline derivatives |
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Robert O.Dempcy.Rational design of quinazoline-basedirreversibleinhibitorsofhumanerythrocytepurinenucleosidephosphorylase.Biochemistry30 34.1991,30(34),8480-8487 尤其是8480页第一段,8481页第2栏第9段,8482页第2栏第5段,表1. |
Robert O.Dempcy.Rational design of quinazoline-basedirreversibleinhibitorsofhumanerythrocytepurinenucleosidephosphorylase.Biochemistry30 34.1991,30(34),8480-8487 尤其是8480页第一段,8481页第2栏第9段,8482页第2栏第5段,表1. * |
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