CN1830964A - 4-Substituting anilino-3-nitroquinoline compounds, prepn. method and use thereof - Google Patents
4-Substituting anilino-3-nitroquinoline compounds, prepn. method and use thereof Download PDFInfo
- Publication number
- CN1830964A CN1830964A CN 200510024351 CN200510024351A CN1830964A CN 1830964 A CN1830964 A CN 1830964A CN 200510024351 CN200510024351 CN 200510024351 CN 200510024351 A CN200510024351 A CN 200510024351A CN 1830964 A CN1830964 A CN 1830964A
- Authority
- CN
- China
- Prior art keywords
- nitroquinoline
- alkyl
- amino
- methoxyl group
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A 4-substituted phenylmino-3-nitroquinoline compound has the suppression action to the reproduction of tumor cells rich in epidermal growth factor receptor. Its preparing process and usage are also disclosed.
Description
Technical field
The present invention relates to a class 4-substituted benzene amino-3-nitroquinoline compounds, this compounds is inhibited to the cell growth of being rich in EGF-R ELISA (EGFR), can be used for preparing the medicine of the disease that the excessive or undesired hyperplasia of treatment causes, the invention still further relates to the preparation method of this compounds.
Background technology
Cancer is a big persistent ailment of serious harm human health.The annual cancered people in the whole world has 9,000,000, and the patient who dies from cancer is 6,000,000, and China's cancer year number of the infected is about 1,200,000, and the number of dying from cancer every year is up to more than 900,000, and patient to be treated surpasses 1,500,000.Capturing the cancer difficulty is medical worker's great task.
The medicine that people study and use for a long time all is with the effect target of cancer cells as medicine, thus cytotoxic drug be always the treatment cancer main medicine, but indeterminable all the time is the toxic side effect problem of this kind cancer therapy drug.Raising along with biotechnology, and subject development such as combinatorial chemistry, high flux screening, the searching of cancer therapy drug progresses into aims at the specific proteic stage, and wherein, the vital role of protein tyrosine kinase in cancer cell multiplication makes it become the cancer therapy target of very attractive.Protein tyrosine kinase (PTKs) plays crucial effect in the tumour generating process, having known has expression of proto-oncogenes over half to possess the active albumen of PTK.The effect of protein tyrosine kinase is that the phosphate of ATP is transferred on the specific tyrosine residues of functional protein, and the processes such as growth, propagation and differentiation of this tyrosine phosphorylation process energy regulating cell.
Research is EGF-R ELISA (EGFR) the most widely in the protein tyrosine kinase, EGFR is the transmembrane glycoprotein of a 170KDa, and its structure comprises the outer ligand binding domain of film, membrane-spanning domain, cell intracellular domain (possessing the PTK activity) and a C-terminal structural domain.Epidermal Growth Factor Receptor Family comprises four member: EGFR (ErbB-1), ErbB-2 (HER2), ErbB-3 (HER3), ErbB-4 (HER4).
The cancer clinical study shows that this receptor and its part all have important relation with a lot of tumours, the overexpression of EGFR occurs in 60% the cancer.This exception table has a variety of forms now, but every kind all can cause excessive tyrosine phosphorylation signal to import cell into unusually.In cell system, EGF or other ErbB family part often cause uncontrollable cell proliferation, thereby make cell be converted into typical abnormal morphology by normal morphology.Outer part of film and EGFR combination cause the EGFR acceptor to form dimer (homodimer or special-shaped dimerization), activate Tyrosylprotein kinase, import proliferation signal into cell.Utilize drug effect in EGFR, can end the proliferation signal that it mediates, thereby stop the excessive breeding of cancer cells.Have two class medicines can play such effect: a class is a monoclonal antibody, and another kind of is small-molecule drug.The mode of action of monoclonal antibody drug is the outer part of film that occupies EGFR, endogenous ligands such as EGF can't be combined with EGFR, thereby stop signal to import cell into.Small-molecule drug then by Tyrosylprotein kinase catalytic domain in the blocking-up EGFR born of the same parents, stops tyrosine phosphorylation, thereby has blocked the cell proliferation signal.
Small molecules EGFR inhibitor comprises natural product inhibitor and organic synthesis compound.The research of natural product inhibitor mainly be by the natural product structural modification is sought the EGFR inhibitor (Alexander J.Bridges, Chem.Rev.2001,101,2541-2571).The natural product inhibitor has better inhibited activity to EGFR, but because the reason of aspects such as cytotoxicity, enzyme selectivity (especially kinases selectivity) and the mechanism of action does not find the natural product parent nucleus with drug development future at present as yet.
The organic synthesis type small molecular inhibitor can be divided into reversible inhibitor and irreversible inhibitor according to the mode of action with EGFR, can be divided into 4-phenylamino (mixing) ring miazines and 4-phenylamino-3-cyano quinolines class according to the parent nucleus type.4-phenylamino (mixing) ring miazines is to study a class EGFR inhibitor the most widely, comprises 4-phenylamino quinazoline ditosylate salt, 4-phenylamino Pyridopyrimidine class and 4-phenylamino Pyrrolopyrimidine etc., and wherein 4-phenylamino quinazoline ditosylate salt is the most representative.
By the end of the year 2004, there has been the synthetic class inhibitor Iressa of a kind of EGFR to pass through FDA authentication listing as the active drug of treatment non-small cell carcinoma, also have tens kinds of medicines to be in senior clinical experimental stage in addition.
Still there are a lot of problems in the exploitation of EGFR inhibitor, as causes the unknown toxic problem of 4-phenylamino quinazoline compounds that people pay close attention to, the problem of enzyme selectivity etc.Address these problems, the EGFR inhibitor of development of new is the popular research topic of present world the world of medicine.
Kinds of tumors such as squamous cell carcinoma, neurospongioma and former generation the human breast carcinoma kind amplification of EGFR gene is all arranged, wherein, squamous cell carcinoma is A431 and MCF-7 MDA-MB-468, becomes focus (the Shimizu N et al that studies EGF effect and EGFR function now owing to the high-caliber EGFR of its abnormal expression and to the abnormal response of EGF; PNAS, 1983,801:1337).Unusual high-caliber EGFR in the A431 cell is relevant with No. 7 chromosomal transposition, and at No. 7 chromosomal p13, q22 contains in the zone c-erbB/EGFR gene.Also found the amplification of R gene in the MDA-MB-468 human breast cancer cell, and be positioned No. 7 chromosomal zone of unusual apparent generation (7pABR) go up (Filmus J et al.Somat Cell Mol Genet1984,10-45).Therefore, the EGFR inhibitor is that the cell proliferation of A431 and MCF-7 MDA-MB-468 also can play effect for the squamous cell carcinoma that suppresses to be rich in EGFR.
In sum, with EGFR as the cancer target, the EGFR inhibitor that designs and synthesizes, must be inhibited to the growth of cancer cells that is rich in EGF-R ELISA (EGFR), also can be used for preparing the medicine of the disease that the excessive or undesired hyperplasia of treatment causes, the exploitation of cancer therapy drug is had outstanding meaning.
Summary of the invention
The object of the present invention is to provide a class to the inhibited amino 3-nitroquinoline of the novel 4-substituted benzene compounds of the cell growth of being rich in EGFR.
Another object of the present invention provides the preparation method of The compounds of this invention.
A further object of the present invention provides the application of The compounds of this invention in the medicine of the disease that the excessive or undesired hyperplasia of treatment causes.
Compound of the present invention is the amino 3-nitroquinoline of the 4-substituted benzene compounds with following general formula I structure:
Wherein:
R
1, R
2, R
3, R
4, R
6Be selected from hydrogen, C independently of one another
1-5Alkyl, C
1-4Alkoxyl group, aryl, aryloxy, C
1-5Alkylaryl, C
1-5Alkyl-aryloxy, C
3-10Cycloalkyl, sulfydryl, C
1-5Alkane sulfydryl, aromatic thiohydroxy, halogen, trihalogenmethyl, hydroxyl, amino, nitro, carboxyl, oxygen carboxyl, amide group, sulfoamido, O-formamyl and-NR
12R
13, R wherein
1And R
2, R
2And R
4, R
1And R
3Can be in conjunction with forming hexa-atomic aromatic ring, methylene-dioxy or ethylenedioxy;
R
1, R
2Can also be selected from R at the same time or separately
14X
1-, X wherein
1Representative-O-or-CH
2-, R
14Be selected from following arbitrary group: C
1-5Alkyl pyrrolidine-1-base, C
1-5Alkyl imidazole alkane-1-base, C
1-5Alkyl thiomorpholine base, C
1-5Alkyl R
15, R wherein
15For containing one or two heteroatomic 5 yuan of saturated heterocyclyls or 6 yuan of saturated heterocyclyls, when wherein containing two heteroatomss, heteroatoms can be identical or different, and this heterocyclic radical is connected to C by a carbon atom
1-5On the alkyl, and this heterocyclic radical can be by any one or two replacements in the following group: oxygen base, hydroxyl, halogen, C
1-4Alkyl, C
1-4Hydroxyalkyl, C
1-4Alkoxyl group, carbamyl, C
1-4Alkyl formyl radical, N, N-two (C
1-4Alkyl) carbamyl, C
1-4Alkanoyl and C
1-4Alkoxy carbonyl, described heteroatoms refers to O, S or N;
R
5Be selected from hydrogen, C
3-10Cycloalkyl, C
1-5Alkyl, halogen;
R
7, R
8, R
9, R
10, R
11Be selected from hydrogen, C separately
1-5Alkyl, C
1-4Alkoxyl group, aryloxy, C
1-5Alkylaryl, C
1-5Alkyl-aryloxy, three halo C
1-5Alkyl, C
3-10Cycloalkyl, sulfydryl, C
1-5Alkane sulfydryl, aromatic thiohydroxy, halogen, hydroxyl, amino, nitro, carboxyl, oxygen carboxyl, amide group, sulfoamido, O-formamyl and-NR
12R
13
R
12And R
13Independently be selected from hydrogen, C
1-5Alkyl, C
2-5Alkenyl, C
3-10Cycloalkyl, ethanoyl, alkylsulfonyl and trifyl.
The 4-substituted benzene amino 3-nitroquinoline compounds of a preferred embodiment of The compounds of this invention for having general formula (I) structure, wherein R
1, R
2Be selected from R at the same time or separately
14X
1-, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
14, X
1Definition with the definition of aforementioned compound.
The 4-substituted benzene amino 3-nitroquinoline compounds of another preferred embodiment of The compounds of this invention for having general formula (I) structure, wherein R
1Be hydrogen, hydroxyl, cyano group, nitro, trifluoromethyl, methyl, ethyl, methoxy or ethoxy, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11Definition with the definition of aforementioned compound.
The 4-substituted benzene amino 3-nitroquinoline compounds of another preferred embodiment of The compounds of this invention for having general formula (I) structure, wherein R
2Be hydrogen, R
1, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11Definition with the definition of aforementioned compound.
The 4-substituted benzene amino 3-nitroquinoline compounds of the 4th preferred embodiment of The compounds of this invention for having general formula (I) structure, wherein R
7Be hydrogen, methyl, fluorine or chlorine; R
9Be hydrogen, methoxyl group, bromine, fluorine or chlorine; R
10Be hydrogen or hydroxyl; R
11Be hydrogen, fluorine or chlorine; R
1, R
2, R
3, R
4, R
5, R
6, R
8Definition with the definition of aforementioned compound.
In the present invention, aryl or the aryl that contains in the group of aryl refer to phenyl, naphthyl or xenyl; Heteroaryl refer to monocycle or thick with the ring (promptly having the ring of adjacency pair atom mutually) group, it has on ring, and 1-3 is individual to be selected from the atom of nitrogen, oxygen and sulphur and to have the π-electronic system that is connected fully in addition, for example pyrroles, furans, thiophene, imidazoles, thiazole, pyrazoles, pyridine, pyrimidine, quinoline, isoquinoline 99.9, purine and carbazole etc.
The preferred compound of the present invention comprises: 6-benzyloxy-7-methoxyl group-4-(3-acetylenylbenzene amino)-3-nitroquinoline; 6-benzyloxy-7-methoxyl group-4-(3-chlorobenzene amino)-3-nitroquinoline; 6-benzyloxy-7-methoxyl group-4-(3-bromobenzene amino)-3-nitroquinoline; 7-benzyloxy-6-methoxyl group-4-(3-acetylenylbenzene amino)-3-nitroquinoline; 7-benzyloxy-6-methoxyl group-4-(4-phenetidino)-3-nitroquinoline; 7-benzyloxy-6-methoxyl group-4-(3-bromobenzene amino)-3-nitroquinoline; 7-hydroxyl-6-methoxyl group-4-(3-bromobenzene amino)-3-nitroquinoline; 6-hydroxyl-7-methoxyl group-4-(3-bromobenzene amino)-3-nitroquinoline; 7-hydroxyl-6-methoxyl group-4-(4-phenetidino)-3-nitroquinoline; 6-benzyloxy-7-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline; 6-hydroxyl-7-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline; 6-benzyloxy-7-methoxyl group-4-(4-phenetidino)-3-nitroquinoline; 6-hydroxyl-7-methoxyl group-4-(4-phenetidino)-3-nitroquinoline; 6-hydroxyl-7-methoxyl group-4-(3-acetylenylbenzene amino)-3-nitroquinoline; 6-benzyloxy-7-methoxyl group-4-(3-fluoroanilino)-3-nitroquinoline; 6-hydroxyl-7-methoxyl group-4-(3-fluoroanilino)-3-nitroquinoline; 6-ethoxycarbonyl methoxy-7-methoxyl group-4-(3-phenetidino)-3-nitroquinoline; 6-benzyloxy-7-methoxyl group-4-(3-phenetidino)-3-nitroquinoline; 6-hydroxyl-7-methoxyl group-4-(3-phenetidino)-3-nitroquinoline; 6-benzyloxy-7-methoxyl group-4-(2-trifluoromethoxy phenylamino)-3-nitroquinoline; 6-hydroxyl-7-methoxyl group-4-(2-trifluoromethoxy phenylamino)-3-nitroquinoline; 6,7-dihydroxyl-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline; 6,7-diethoxy-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline; 7-(N-morpholinyl ethyl-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline; 7-(N-morpholinyl amyl group)-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline; 7-(2-(2-methoxy ethoxy) oxyethyl group-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline; 7-(1-methyl piperidine-3-yl)-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline.
The preparation of The compounds of this invention is implemented through the following steps:
The compounds of this invention (Compound I) is made by compound III and Compound I I condensation: equimolar Compound I I and compound III are carried out condensation reaction in organic solvent, and according to the response situation of particular compound, temperature of reaction is 90 ℃～110 ℃; Reaction times is 14～24 hours, and the general post-treating method that adopts comprised cooling concentration, recrystallization and column chromatography for separation etc. after reaction finished.Final product (I) detects proof with nucleus magnetic resonance or mass spectrum.
Among the present invention, organic solvent refers to protonic solvent or aprotic solvent, and wherein protonic solvent is water or alcohols (as ethanol, methyl alcohol, propyl carbinol); Aprotic solvent is polarity or proton inert non-polar solvent, the feature of aprotic solvent is not contain acidic hydrogen, promptly do not contain can with solute bonded hydrogen, preferred proton inert non-polar solvent is pentane, hexane, benzene, toluene, and preferred polar proton inert solvent is propyl carbinol, dimethyl sulfoxide (DMSO) or dimethyl formamide.
Among the present invention, synthetic method reference method (Alexander R., Surrey, the Royal A.Cutler.J.Chem.Soc.1951:2413-2418 of compound III; Alexander R., Royal A., Cutler.J.Chem.Soc.1949:1367-1374.); Compound IV can be synthesized available from reagent company or referenced patent method (WO465464).
Beneficial effect
The present invention designs and has synthesized the novel amino 3-nitroquinoline of the 4-substituted benzene compounds of a class, A-431 human skin squamous cell carcinoma and MDA-MB-468 human breast cancer cell there are the inhibition effect, can be used for preparing the medicine that the excessive or undesired hyperplasia of treatment causes disease.The The compounds of this invention structure is simple relatively, is easy to preparation.
Embodiment
The present invention is further elaborated below in conjunction with specific embodiment, but do not limit the present invention.
In the following preparation example, the X-4 type fusing point instrument that fusing point adopts Shanghai Precision Scientific Apparatus Co., Ltd to produce is measured, and temperature is not calibrated; Nucleus magnetic resonance is by Bruker AMX-400 type and INVOA-600 type nmr determination, and TMS is interior mark, and chemical shift unit is ppm; Mass spectrum is measured by MAT-711 type and MAT-95 type mass spectrograph; Column chromatography silica gel 200-300 order, Haiyang Chemical Plant, Qingdao produces; The HSGF-254 type thin-layer chromatography precoated plate that the TLC silica-gel plate is produced for the chemical plant, Yantai; The sherwood oil boiling range is 60-90 ℃; Adopt ultraviolet lamp, the colour developing of iodine cylinder.If do not particularly point out working method, described concentrated finger steams with the solvent that Rotary Evaporators will prepare in the compound solution in the preparation example; Described drying refers to will prepare the compound oven dry with the DHG-9240A thermostatic drying chamber at 80 ℃.
The preparation of embodiment 1 6-benzyloxy-7-methoxyl group-4-(3-acetylenylbenzene amino)-3-nitroquinoline (F-1)
(9g 0.059mol) is dissolved in the 40ml ethanol, adds the 8.1g anhydrous sodium carbonate, and (11.4g 0.09mol), is heated to and refluxed 5 hours, and the some plate is to reacting completely to drip distilled Benzyl Chloride with Isovanillin.The filtered while hot reaction solution with the filtrate evaporate to dryness, obtains oily matter, places at normal temperatures and solidifies, and uses ethyl alcohol recrystallization, obtains the 4-benzyloxy-3-methoxybenzaldehyde of 10.3g white solid, productive rate 76%.H
1NMR(CDCl
3)：9.8(s，1H，CHO)，7.3-7.5(m，5H，Ph-H)，7.25-7.28(m，2H，Ph-H)，7.0(s，1H，Ph-H)，5.25(s，2H，PhCH
2O)，4.0(s，3H，CH
3O)。
At 0 ℃ of ice bath, (10g 0.041mol) slowly adds in the 40ml concentrated nitric acid, and 40min is continued to stir at 15 ℃ in the reinforced back that finishes with 4-benzyloxy-3-methoxybenzaldehyde.Mixture is poured in the frozen water, had yellow mercury oxide to generate, filtering-depositing, drying obtains 4-benzyloxy-3-methoxyl group-2-nitrobenzaldehyde of 10.4g, productive rate 93%.H
1NMR(CDCl
3)：10.4(s，1H，CHO)，7.6(s，1H，Ph-H)，7.3-7.5(m，5H，Ph-H)，7.25-7.2(s，1H，Ph-H)，5.25(s，2H，PhCH
2O)，4.0(s，3H，CH
3O)。
With 4-benzyloxy-3-methoxyl group-2-nitrobenzaldehyde (10g 0.047mol) is dissolved in the acetone (120ml), add the KMnO4 hydrothermal solution (10%, 100ml), stirred one hour.Filtration residue boils off the acetone in the filtrate, drips concentrated hydrochloric acid (10ml, 37%), obtains white precipitate, collecting precipitation, and drying obtains 5-benzyloxy-4-methoxyl group-2-nitrobenzoic acid of 10.2g, productive rate 58%.H
1NMR(DMCO)：7.56(d，2H，Ph-H)，7.3-7.41(m，5H，Ph-H)，5.35(s，2H，PhCH
2O)，4.0(s，3H，CH
3O)。
(10g 33.3mmol) is dissolved in the acetic acid (300ml), is heated to 90 ℃ and stirring, adds (3g, 188mmol) iron powder in 20min in batches with 5-benzyloxy-4-methoxyl group-2-nitrobenzoic acid.After continue stirring 45min, the cooling reaction solution, filtration residue, clean filter cake with acetic acid after, with filtrate pour into aqueous hydrochloric acid (10%, 500ml) in.The adularescent precipitation is separated out, filtering-depositing, and it is dissolved in the hot water, aqueous sodium hydroxide solution with 15% is regulated pH value to 12, has precipitation to separate out filtering-depositing after the cooling, after the vacuum-drying, use the Virahol recrystallization, obtain the 5-benzyloxy-4-methoxyl group-2-benzaminic acid of 6.1g white solid, productive rate 70%.H
1NMR(DMCO)：7.3-7.41(m，5H，Ph-H)，6.89(d，2H，Ph-H)，5.35(s，2H，PhCH
2O)，4.0(s，3H，CH
3O)。
In 10ml water, keep surrounding temperature below 30 ℃ the 2.68g dissolution of sodium hydroxide, (1.34g, 2mmol) Nitromethane 99Min. are heated to reaction solution 40 ℃ then, all dissolve up to solid in dropping.(1.34g, 2mmol) Nitromethane 99Min. continue to be heated to 50 ℃, continue to stir 15min, and reaction solution is poured in the frozen water in dropping.Concentrated hydrochloric acid (5ml, 37%) is added dropwise in the above-mentioned solution that obtains, regulates pH value to 2, solution shows red-brown.
The above-mentioned solution that obtains is added 5-benzyloxy-4-methoxyl group-2-benzaminic acid (5.48g, 2mmol) and concentrated hydrochloric acid (1ml, 37%) and in the water (50ml), there is yellow mercury oxide to generate immediately, continuation is in stirring at room after 24 hours, filtering-depositing, vacuum-drying, obtain 2-(2-nitro propenyl the amino)-5-benzyloxy-4-methoxybenzoic acid of 6.3g yellow solid, productive rate 90%.EIMS m/e 358(M
+)。
(3.58g 1mmol) adds in the 10ml aceticanhydride, reacting by heating liquid to 110 ℃ with 2-(2-nitro propenyl amino)-5-benzyloxy-4-methoxybenzoic acid.All dissolve the brown solution of formation up to solid.Remove oil bath, slowly add 400mg sodium hydroxide, the reaction solution very exothermic, treat that temperature stops to rise after, be heated to 100 ℃, continue to stir after 5 hours, be cooled to room temperature.Filter, with acetic acid filter wash cake, and then wash with water, dry cake obtains 6-benzyloxy-7-methoxyl group-4-hydroxyl-3-nitroquinoline of 1.3g, productive rate 40%.EIMS m/e 326(M
+)。
(1g 3mmol) joins in the phosphorus oxychloride (15ml), and reacting by heating liquid continues to stir 18 hours to refluxing with 6-benzyloxy-7-methoxyl group-4-hydroxyl-3-nitroquinoline.The cooling reaction solution, the pressure reducing and steaming phosphorus oxychloride is used the ethyl alcohol recrystallization resistates, obtains 1.1g light brown solid 6-benzyloxy-7-methoxyl group-4-chloro-3-nitroquinoline, productive rate 97%.EIMS344(M
+)。
(1.0g, 2.9mmol) (340mg 2.9mmol) is heated to 100 ℃ in DMF (20ml) with 2-ethynyl aniline with 6-benzyloxy-7-methoxyl group-4-chloro-3-nitroquinoline.Stir pressure reducing and steaming solvent after 24 hours,, obtain 6-benzyloxy-7-methoxyl group-4-(3-acetylenylbenzene the amino)-3-nitroquinoline (F-1) of 1.1g yellow solid, productive rate 89% the residue recrystallizing methanol.EIMS m/e 425(M
+)。H
1NMR(DMSO)：9.87(s，1H，quinoline-2-H)，7.19-7.68(m，9H，Ph-H)，5.20(s，2H，CH
2Ph)，4.0(s，3H，OCH
3)，3.8(s，1H，C≡CH)。
The preparation of embodiment 2 6-benzyloxy-7-methoxyl group-4-(3-chlorobenzene amino)-3-nitroquinoline (F-2)
(1.0g, 2.9mmol) (368mg 2.9mmol) is heated to 100 ℃ in DMF (20ml) with the 3-chloroaniline with 6-benzyloxy-7-methoxyl group-4-chloro-3-nitroquinoline.Stir pressure reducing and steaming solvent after 24 hours,, obtain 6-benzyloxy-7-methoxyl group-4-(3-chlorobenzene the amino)-3-nitroquinoline (F-2) of 1.14g yellow solid, productive rate 90% the residue recrystallizing methanol.H
1NMR(DMSO)：9.89(s，1H，quinoline-2-H)，7.19-7.68(m，9H，Ph-H)，5.20(s，2H，CH
2Ph)，4.0(s，3H，OCH
3)。
The preparation of embodiment 3 6-benzyloxy-7-methoxyl group-4-(3-bromobenzene amino)-3-nitroquinoline (F-3)
(1.0g, 2.9mmol) (500mg 2.9mmol) is heated to 100 ℃ in DMF (20ml) with the 3-bromaniline with 6-benzyloxy-7-methoxyl group-4-chloro-3-nitroquinoline.Stir pressure reducing and steaming solvent after 24 hours,, obtain 6-benzyloxy-7-methoxyl group-4-(3-bromobenzene the amino)-3-nitroquinoline (F-3) of 1.26g yellow solid, productive rate 91% the residue recrystallizing methanol.H
1NMR(DMSO)：9.77(s，1H，quinoline-2-H)，7.19-7.68(m，4H，Ph-H)，5.20(s，2H，CH
2Ph)，4.0(s，3H，OCH
3)。
The preparation of embodiment 4 7-benzyloxy-6-methoxyl group-4-(3-acetylenylbenzene amino)-3-nitroquinoline (F-4)
(9g 0.059mol) is dissolved in the 40ml ethanol, adds the 8.1g anhydrous sodium carbonate, and (11.4g 0.09mol), is heated to backflow, reacts five hours, to reacting completely to drip Benzyl Chloride with vanillin food grade,1000.000000ine mesh.Filtered while hot with the filtrate evaporate to dryness, obtains oily matter, places to solidify, and uses ethyl alcohol recrystallization, obtains 4-benzyloxy-3-methoxybenzaldehyde of 10.3g, productive rate 76%.H
1NMR(CDCl
3)：9.8(s，1H，CHO)，7.3-7.5(m，5H，Ph-H)，7.25-7.28(m，2H，Ph-H)，7.0(s，1H，Ph-H)，5.25(s，2H，PhCH
2O)，4.0(s，3H，CH
3O)。
Under 0 ℃ of ice bath, (10g 0.041mol) slowly adds in the 40ml concentrated nitric acid, and 15 ℃ are continued to stir 40min with 4-benzyloxy-3-methoxybenzaldehyde.Mixture is poured in the frozen water, had yellow mercury oxide to generate, filtering-depositing, drying obtains the 4-benzyloxy-3-methoxyl group-2-nitrobenzaldehyde of 10.4g yellow solid, productive rate 93%.H
1NMR(CDCl
3)：10.4(s，1H，CHO)，7.6(s，1H，Ph-H)，7.3-7.5(m，5H，Ph-H)，7.25-7.2(s，1H，Ph-H)，5.25(s，2H，PhCH
2O)，4.0(s，3H，CH
3O)。
(10g 0.047mol) is dissolved in the 120ml acetone, and the 10%KMnO4 hydrothermal solution that adds 100ml stirred one hour with 4-benzyloxy-3-methoxyl group-2-nitrobenzaldehyde.Filtration residue boils off the acetone in the filtrate, and cooling drips concentrated hydrochloric acid (10ml, 37%), white precipitate, collecting precipitation, drying obtains 5-benzyloxy-4-methoxyl group-2-nitrobenzoic acid of 10.2g, productive rate 58%.H
1NMR(DMCO)：7.56(d，2H，Ph-H)，7.3-7.41(m，5H，Ph-H)，5.35(s，2H，PhCH
2O)，4.0(s，3H，CH
3O)。
(10g 33.3mmol) is dissolved in the acetic acid of 300ml, is heated to 90 ℃ and stirring, adds (3g, 188mmol) iron powder in 20min in batches with 5-benzyloxy-4-methoxyl group-2-nitrobenzoic acid.After continuing to stir 45min, cooling reaction solution, filtration residue, behind acetic acid cleaning filter cake, filtrate to be poured in 10% aqueous hydrochloric acid of 500ml, the adularescent precipitation is separated out, filtering-depositing, and it is dissolved in the hot water, the aqueous sodium hydroxide solution with 15% is regulated pH value to 12, there is precipitation to separate out after the cooling, filtering-depositing after the vacuum-drying, is used the Virahol recrystallization, obtain the 5-benzyloxy-4-methoxyl group-2-benzaminic acid of 6.1g white solid, productive rate 70%.H
1NMR(DMCO)：7.3-7.41(m，5H，Ph-H)，6.89(d，2H，Ph-H)，5.35(s，2H，PhCH
2O)，4.0(s，3H，CHH
3O)。
Sodium hydroxide (2.68g) is dissolved in the 10ml water, keeps surrounding temperature below 30 ℃, (1.34g, 2mmol) Nitromethane 99Min. are heated to reaction solution 40 ℃ then in dropping.Solid drips 1.34g (2mmol) Nitromethane 99Min. after all dissolving, and continues to be heated to 50 ℃, continues to stir 15min, and reaction solution is poured in the 20ml frozen water.Concentrated hydrochloric acid (5ml, 37%) is added dropwise in the above-mentioned solution that obtains, regulates pH value to 2, solution shows red-brown.The above-mentioned solution that obtains is added 5-benzyloxy-4-methoxyl group-2-benzaminic acid (5.48g, 2mmol) and in 1ml concentrated hydrochloric acid (37%) and the 50ml water, there is yellow mercury oxide to generate immediately, continuation is in stirring at room after 24 hours, filtering-depositing, vacuum-drying obtains 2-(2-nitro propenyl the amino)-5-benzyloxy-4-methoxybenzoic acid of 6.3g yellow solid, productive rate 90%.EIMS m/e358(M
+)。
(3.58g 1mmol) adds in the 10ml aceticanhydride, and reacting by heating liquid to 110 ℃ all dissolves up to solid and to form brown solution with 2-(2-nitro propenyl amino)-5-benzyloxy-4-methoxybenzoic acid.Remove oil bath, slowly add 400mg sodium hydroxide, the reaction solution very exothermic, treat that temperature stops to rise after, be heated to 100 ℃, continue to stir after 5 hours, be cooled to room temperature.Continue to stir after 5 hours, stop heating, the reaction solution naturally cooling.Filter, with acetic acid filter wash cake, and then wash with water, dry cake obtains 1.3g light brown solid 7-benzyloxy-6-methoxyl group-4-hydroxyl-3-nitroquinoline, productive rate 40%.Mp＞300℃。EIMS m/e 326(M
+)。
(1g 3mmol) joins in the 15ml phosphorus oxychloride, and reacting by heating liquid continues to stir 18 hours to refluxing with 7-benzyloxy-6-methoxyl group-4-hydroxyl-3-nitroquinoline.The cooling reaction solution, the pressure reducing and steaming phosphorus oxychloride is used the ethyl alcohol recrystallization resistates, obtains 1.1g light brown solid 7-benzyloxy-6-methoxyl group-4-chloro-3-nitroquinoline, productive rate 97%.Mp＞300℃。EIMS m/e 344(M
+)。
With 7-benzyloxy-6-methoxyl group-4-chloro-3-nitroquinoline (1.0g, 2.9mmol) and 3-ethynyl aniline (340mg, 2.9mmol) in DMF (20ml), be heated to 100 ℃, stir pressure reducing and steaming solvent after 24 hours, with the residue recrystallizing methanol, obtain 7-benzyloxy-6-methoxyl group-4-(3-acetylenylbenzene the amino)-3-nitroquinoline (F-4) of 1.1g yellow solid, productive rate 87%.H
1NMR(DMSO)：9.87(s，1H，quinoline-2-H)，7.19-7.68(m，11H，Ph-H)，5.20(s，2H，CH
2Ph)，4.0(s，3H，OCH
3)，3.8(s，1H，C≡CH)。
The preparation of embodiment 5 7-benzyloxy-6-methoxyl group-4-(4-phenetidino)-3-nitroquinoline (F-5)
(1.0g, 2.9mmol) (397mg 2.9mmol) is heated to 100 ℃ in DMF (20ml) with the 3-phenetidine with 7-benzyloxy-6-methoxyl group-4-chloro-3-nitroquinoline.Stir pressure reducing and steaming solvent after 24 hours,, obtain 7-benzyloxy-6-methoxyl group-4-(4-the phenetidino)-3-nitroquinoline (F-5) of 1.21g yellow solid, productive rate 93% the residue recrystallizing methanol.H
1NMR(DMSO)：9.77(s，1H，quinoline-2-H)，7.19-7.88(m，11H，Ph-H)，5.20(s，2H，CHH
2Ph)，4.31(q，2H，CO
2CH
2CH
3)，4.0(s，3H，OCH
3)，2.1(t，3H，CO
2CH
2CH
3)。
The preparation of embodiment 6 7-benzyloxy-6-methoxyl group-4-(3-bromobenzene amino)-3-nitroquinoline (F-6)
(500mg 2.9mmol) is heated to 100 ℃ in DMF (20ml) with 1.0g (2.9mmol) 7-benzyloxy-6-methoxyl group-4-chloro-3-nitroquinoline and 3-bromaniline.Stir pressure reducing and steaming solvent after 24 hours,, obtain 7-benzyloxy-6-methoxyl group-4-(3-bromobenzene the amino)-3-nitroquinoline (F-6) of 1.26g yellow solid, productive rate 91% the residue recrystallizing methanol.H
1NMR(DMSO)：9.87(s，1H，quinoline-2-H)，7.19-7.68(m，4H，Ph-H)，5.20(s，2H，CH
2Ph)，4.31(q，2H，CO
2CH
2CH
3)，4.0(s，3H，OCH
3)，2.1(t，3H，CO
2CH
2CH
3)。
The preparation of embodiment 7 7-hydroxyl-6-methoxyl group-4-(3-bromobenzene amino)-3-nitroquinoline (F-7)
(1g 2.08mmol) is heated to backflow 1 hour to 7-benzyloxy-6-methoxyl group-4-(3-bromobenzene amino)-3-nitroquinoline in TFA (15ml).Pressure reducing and steaming TFA with ammoniacal liquor adjusting pH value to 7, pressure reducing and steaming solvent, obtains 7-hydroxyl-6-methoxyl group-4-(3-bromobenzene the amino)-3-nitroquinoline (F-7) of 772mg yellow solid, productive rate 95%.EIMS m/e390(M
++1)。H
1NMR(DMSO)：9.27(s，1H，quinoline-2-H)，7.12-7.42(m，4H，Ph-H)，5.20(s，2H，CH
2Ph)，4.0(s，3H，OCH
3)。
The preparation of embodiment 8 6-hydroxyl-7-methoxyl group-4-(3-bromobenzene amino)-3-nitroquinoline (F-8)
(1g 2.08mmol) is heated to backflow 1 hour to 6-hydroxyl-7-methoxyl group-4-(3-bromobenzene amino)-3-nitroquinoline in TFA (15ml).Pressure reducing and steaming TFA with ammoniacal liquor adjusting pH value to 7, pressure reducing and steaming solvent, obtains 6-hydroxyl-7-methoxyl group-4-(3-bromobenzene the amino)-3-nitroquinoline (F-8) of 772mg yellow solid, productive rate 95%.H
1NMR(DMCO)：9.27(s，1H，quinoline-2-H)，7.12-7.42(m，4H，Ph-H)，5.20(s，2H，CH
2Ph)，4.0(s，3H，OCH
3)。
The preparation of embodiment 9 7-hydroxyl-6-methoxyl group-4-(4-phenetidino)-3-nitroquinoline (F-9)
(1g 1.75mmol) is heated to backflow 1 hour to 7-benzyloxy-6-methoxyl group-4-(4-phenetidino)-3-nitroquinoline in TFA (15ml).Pressure reducing and steaming TFA with ammoniacal liquor adjusting pH value to 7, pressure reducing and steaming solvent, obtains 7-benzyloxy-6-methoxyl group-4-(4-the phenetidino)-3-nitroquinoline (F-9) of 741mg yellow solid, productive rate 94%.H
1NMR(DMCO)：9.17(s，1H，quinoline-2-H)，7.09-7.38(m，4H，Ph-H)，4.43(q，2H，CO
2CH
2CH
3)，4.0(s，3H，OCH
3)，2.1(t，3H，CO
2CH
2CH
3)。
The preparation of embodiment 10 6-benzyloxy-7-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline (F-10)
(1.0g, 2.9mmol) (420mg 2.9mmol) is heated to 100 ℃ in DMF (20ml) with 3-fluoro-4 chloroanilines with 6-benzyloxy-7-methoxyl group-4-chloro-3-nitroquinoline.Stir pressure reducing and steaming solvent after 24 hours,, obtain 6-benzyloxy-7-methoxyl group-4-(3-fluoro-4 chlorobenzene the amino)-3-nitroquinoline (F-10) of 1.48g yellow solid, productive rate 87% the residue recrystallizing methanol.H
1NMR(DMSO)：9.0(s，1H，quinoline-2-H)，6.60-7.62(m，10H，Ph-H)，5.2(s，2H，CH
2Ph)，4.0(s，3H，OCH
3)。
The preparation of embodiment 11 6-hydroxyl-7-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline (F-11)
(1g 2.20mmol) is heated to backflow 1 hour to 6-benzyloxy-7-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline in TFA (15ml).Pressure reducing and steaming TFA with ammoniacal liquor adjusting pH value to 7, pressure reducing and steaming solvent, obtains 6-hydroxyl-7-methoxyl group-4-(4-chloro-3-the fluoroanilino)-3-nitroquinoline (F-11) of 741mg yellow solid, productive rate 95%.H
1NMR(DMCO)：9.17(s，1H，quinoline-2-H)，7.00-7.42(m，5H，Ph-H)，4.0(s，3H，OCH
3)。
The preparation of embodiment 12 6-benzyloxy-7-methoxyl group-4-(4-phenetidino)-3-nitroquinoline (F-12)
(397mg 2.9mmol) is heated to 100 ℃ in DMF (20ml) with 1.0g (2.9mmol) 6-benzyloxy-7-methoxyl group-4-chloro-3-nitroquinoline and 4-phenetidine.Stir pressure reducing and steaming solvent after 24 hours,, obtain 6-benzyloxy-7-methoxyl group-4-(4-the phenetidino)-3-nitroquinoline (F-12) of 1.21g yellow solid, productive rate 94% the residue recrystallizing methanol.H
1NMR(DMSO)：9.77(s，1H，quinoline-2-H)，7.19-7.88(m，11H，Ph-H)，5.20(s，2H，CH
2Ph)，4.31(q，2H，CO
2CH
2CH
3)，4.0(s，3H，OCH
3)，2.1(t，3H，CO
2CH
2CHH
3)。
The preparation of embodiment 13 6-hydroxyl-7-methoxyl group-4-(4-phenetidino)-3-nitroquinoline (F-13)
(1g 2.24mmol) is heated to backflow 1 hour to 6-benzyloxy-7-methoxyl group-4-(4-phenetidino)-3-nitroquinoline in TFA (15ml).Pressure reducing and steaming TFA with ammoniacal liquor adjusting pH value to 7, pressure reducing and steaming solvent, obtains 6-hydroxyl-7-methoxyl group-4-(4-the phenetidino)-3-nitroquinoline (F-13) of 775mg yellow solid, productive rate 95%.H
1NMR(DMCO)：9.17(s，1H，quinoline-2-H)，7.09-7.38(m，4H，Ph-H)，5.20(s，2H，CH
2Ph)，4.31(q，2H，CO
2CH
2CH
3)，4.0(s，3H，OCH
3)，2.1(t，3H，CO
2CH
2CH
3)。
The preparation of embodiment 14 6-hydroxyl-7-methoxyl group-4-(3-acetylenylbenzene amino)-3-nitroquinoline (F-14)
(1g 2.35mmol) is heated to backflow 1 hour to 6-benzyloxy-7-methoxyl group-4-(3-acetylenylbenzene amino)-3-nitroquinoline in 15mlTFA.Pressure reducing and steaming TFA with ammoniacal liquor adjusting pH value to 7, pressure reducing and steaming solvent, obtains 6-hydroxyl-7-methoxyl group-4-(3-acetylenylbenzene the amino)-3-nitroquinoline (F-14) of 725mg yellow solid, productive rate 95%.H
1NMR(DMCO)：9.27(s，1H，quinoline-2-H)，7.19-7.68(m，4H，Ph-H)，5.20(s，2H，CH
2Ph)，4.0(s，3H，OCH
3)，3.8(s，1H，C≡CH)。
The preparation of embodiment 15 6-benzyloxy-7-methoxyl group-4-(3-fluoroanilino)-3-nitroquinoline (F-15)
With 6-benzyloxy-7-methoxyl group-4-chloro-3-nitroquinoline (1.0g, 2.9mmol) and 3-fluoroaniline (321mg, 2.9mmol) in DMF (20ml), be heated to 100 ℃, stir pressure reducing and steaming solvent after 24 hours, with the residue recrystallizing methanol, obtain 6-benzyloxy-7-methoxyl group-4-(3-the fluoroanilino)-3-nitroquinoline (F-15) of 1.10g yellow solid, productive rate 91%.H
1NMR(DMSO)：9.0(s，1H，quinoline-2-H)，6.60-7.62(m，11H，Ph-H)，5.2(s，2H，CH
2Ph)，4.0(s，3H，OCH
3)。
The preparation of embodiment 16 6-hydroxyl-7-methoxyl group-4-(3-fluoroanilino)-3-nitroquinoline (F-16)
(1g 2.38mmol) is heated to backflow 1 hour to 6-benzyloxy-7-methoxyl group-4-(3-fluoroanilino)-3-nitroquinoline in TFA (15ml).Pressure reducing and steaming TFA with ammoniacal liquor adjusting pH value to 7, pressure reducing and steaming solvent, obtains 6-hydroxyl-7-methoxyl group-4-(3-the fluoroanilino)-3-nitroquinoline (F-16) of 743mg yellow solid, productive rate 95%.H
1NMR(DMCO)：9.17(s，1H，quinoline-2-H)，7.00-7.42(m，6H，Ph-H)，4.0(s，3H，OCH
3)。
The preparation of embodiment 17 6-ethoxycarbonyl methoxy-7-methoxyl group-4-(3-phenetidino)-3-nitroquinoline (F-17)
(700mg 1.97mmol) is dissolved among the DMF (10ml), adds K with 6-hydroxyl-7-methoxyl group-4-(3-phenetidino)-3-nitroquinoline
2CO
3(500mg), reacting by heating liquid to 80 ℃ stirred 1 hour.(400mg 2.22mmol), stirred 1 hour the dripping bromine ethyl acetate.The pressure reducing and steaming solvent is used re-crystallizing in ethyl acetate, obtains the orange-yellow solid 6-ethoxycarbonyl methoxy of 825mg-7-methoxyl group-4-(3-phenetidino)-3-nitroquinoline (F-17), productive rate 95%.H
1NMR(DMCO)：9.27(s，1H，quinoline-2-H)，7.19-7.88(m，11H，Ph-H)，5.20(s，2H，CH
2Ph)，4.31(q，2H，CO
2CH
2CH
3)，4.2(q，2H，CO
2CH
2CH
3)，4.0(s，3H，OCH
3)，2.3(t，3H，CO
2CH
2CH
3)，2.0(t，3H，CO
2CH
2CH
3)。
The preparation of embodiment 18 6-benzyloxy-7-methoxyl group-4-(3-phenetidino)-3-nitroquinoline (F-18)
(1g 2.24mmol) is heated to backflow 1 hour to 6-benzyloxy-7-methoxyl group-4-(3-phenetidino)-3-nitroquinoline in TFA (15ml).Pressure reducing and steaming TFA with ammoniacal liquor adjusting pH value to 7, pressure reducing and steaming solvent, obtains 6-benzyloxy-7-methoxyl group-4-(3-the phenetidino)-3-nitroquinoline (F-18) of 755mg yellow solid, productive rate 95%.H
1NMR(DMCO)：9.27(s，1H，quinoline-2-H)，7.10-7.48(m，4H，Ph-H)，4.0(s，3H，OCH
3)。
The preparation of embodiment 19 6-hydroxyl-7-methoxyl group-4-(3-phenetidino)-3-nitroquinoline (F-19)
(1g 1.56mmol) is heated to backflow 1 hour to 6-benzyloxy-7-methoxyl group-4-(3-phenetidino)-3-nitroquinoline in TFA (15ml).Pressure reducing and steaming TFA with ammoniacal liquor adjusting pH value to 7, pressure reducing and steaming solvent, obtains 6-hydroxyl-7-methoxyl group-4-(3-the phenetidino)-3-nitroquinoline (F-19) of 621mg yellow solid.Productive rate 95%.Mp189℃。H
1NMR(DMCO)：9.27(s，1H，quinoline-2-H)，7.10-7.48(m，4H，Ph-H)，4.0(s，3H，OCH
3)。EIMS m/e 355(M
+)。
The preparation of embodiment 20 6-benzyloxy-7-methoxyl group-4-(2-trifluoromethoxy phenylamino)-3-nitroquinoline (F-20)
(1.0g, 2.9mmol) (500mg 2.9mmol) is heated to 100 ℃ in DMF (20ml), stirred 24 hours with the 2-trifluoro-methoxyaniline with 6-benzyloxy-7-methoxyl group-4-chloro-3-nitroquinoline.The pressure reducing and steaming solvent with the residue recrystallizing methanol, obtains 6-benzyloxy-7-methoxyl group-4-(2-trifluoromethoxy the phenylamino)-3-nitroquinoline (F-19) of 1.29g yellow solid, productive rate 92%.H
1NMR(DMSO)：9.0(s，1H，quinoline-2-H)，6.60-7.62(m，11H，Ph-H)，5.2(s，2H，CH
2Ph)，4.0(s，3H，OCH
3)。
The preparation of embodiment 21 6-hydroxyl-7-methoxyl group-4-(2-trifluoromethoxy phenylamino)-3-nitroquinoline (F-21)
(1g 2.06mmol) is heated to backflow 1 hour to 6-benzyloxy-7-methoxyl group-4-(2-trifluoromethoxy phenylamino)-3-nitroquinoline in TFA (15ml).Pressure reducing and steaming TFA with ammoniacal liquor adjusting pH value to 7, pressure reducing and steaming solvent, obtains 6-hydroxyl-7-methoxyl group-4-(2-trifluoromethoxy the phenylamino)-3-nitroquinoline (F-21) of 781mg yellow solid, productive rate 96%.H
1NMR(DMCO)：9.17(s，1H，quinoline-2-H)，7.00-7.42(m，6H，Ph-H)，4.0(s，3H，OCH
3)。
Embodiment 22 6, the preparation of 7-dihydroxyl-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline (F-22)
(700mg 1.97mmol) is dissolved in the ethanol (10ml), and (906mg, 7.88mmol), reacting by heating liquid to 75 ℃ stirs half an hour to add pyridine hydrochloride with 7-hydroxyl-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline.Filtering reacting liquid boils off solvent with filtrate decompression, uses ethyl alcohol recrystallization, obtains 6 of 636mg yellow solid, 7-dihydroxyl-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline (F-22), productive rate 96%.H
1NMR(DMCO)：9.54(s，1H，quinoline-2-H)，7.00-7.42(m，5H，Ph-H)。
Embodiment 23 6, the preparation of 7-diethoxy-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline (F-23)
With 6, (600mg 1.76mg) is dissolved among the DMF (10ml) 7-dihydroxyl-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline, adds K
2CO
3(500mg), stirring at room is 1 hour.(550mg 3.52mmol), continues to stir half an hour to add iodoethane.The pressure reducing and steaming solvent is used re-crystallizing in ethyl acetate, obtains the orange-yellow solid 6 of 687mg, 7-diethoxy-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline, productive rate 92%, H
1NMR (DMCO): 9.17 (s, 1H, quinoline-2-H), 7.00-7.42 (m, 6H, Ph-H), 4.0-4.5 (m, 6H, 2CH
3), 2.3-2.8 (m, 4H).
The embodiment 24 7-(preparation of N-morpholinyl ethyl-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline (F-24)
(700mg 1.97mmol) is dissolved among the DMF (10ml), adds K with 7-hydroxyl-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline
2CO
3(500mg), reacting by heating liquid to 80 ℃ stirred 1 hour.(400mg 2.22mmol), stirred 1 hour to drip N-morpholinyl monobromoethane.The pressure reducing and steaming solvent is used re-crystallizing in ethyl acetate, obtains the orange-yellow solid 7-of 825mg (N-morpholinyl ethyl)-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline (F-24), productive rate 95%.H
1NMR(DMCO)：9.27(s，1H，quinoline-2-H)，7.19-7.88(m，11H，Ph-H)，5.20(s，2H，CH
2Ph)，4.31(q，2H，CO
2CH
2CH
3)，4.2(q，2H，CO
2CH
2CH
3)，4.0(s，3H，OCH
3)，2.3(t，3H，CH
2CH
3，2.0(t，8H)。
The preparation of embodiment 25 7-(N-morpholinyl amyl group)-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline (F-25)
(700mg 1.97mmol) is dissolved among the DMF (10ml), adds K with 7-hydroxyl-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline
2CO
3(500mg), reacting by heating liquid to 80 ℃ stirred 1 hour.Amyl group-(400mg 2.22mmol), stirred 1 hour the 5-bromine to drip the N-morpholinyl.The pressure reducing and steaming solvent is used re-crystallizing in ethyl acetate, obtains the orange-yellow solid 7-of 825mg (N-morpholinyl amyl group)-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline (F-25), productive rate 95%.H
1NMR(DMCO)：9.27(s，1H，quinoline-2-H)，7.19-7.88(m，11H，Ph-H)，5.20(s，2H，CH
2Ph)，4.31(q，2H，CO
2CH
2CH
3)，4.2(q，2H，CH
2CH
3)，4.0(s，3H，OCH
3)，2.3(t，3H，CH
2CH
3)，2.0(t，3H，CH
2CH
3)。
The embodiment 26 7-(preparation of 2-(2-methoxy ethoxy) oxyethyl group-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline (F-26)
(700mg 1.97mmol) is dissolved among the DMF (10ml), adds K with 7-hydroxyl-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline
2CO
3(500mg), reacting by heating liquid to 80 ℃ stirred 1 hour.(368mg 2.22mmol), stirred 1 hour to drip 2-(2-methoxy ethoxy) oxyethyl group bromine.The pressure reducing and steaming solvent is used re-crystallizing in ethyl acetate, obtains the orange-yellow solid 7-of 764mg (2-(2-methoxy ethoxy) oxyethyl group-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline (F-26), productive rate 86%.H
1NMR(DMCO)：9.27(s，1H，quinoline-2-H)，7.19-7.88(m，11H，Ph-H)，5.20(s，2H，CH
2Ph)，4.31(q，2H，CO
2CH
2CH
3)，4.2(q，2H，CO
2CH
2CH
3)，4.0(s，3H，OCH
3)，2.8(q，2H)，2.3(t，3H，CH
2CH
3)，2.0(t，3H，CH
3)。
The preparation of embodiment 27 7-(1-methyl piperidine-3-oxyethyl group)-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline (F-27)
(700mg 1.97mmol) is dissolved among the DMF (10ml), adds K with 7-hydroxyl-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline
2CO
3(500mg), reacting by heating liquid to 80 ℃ stirred 1 hour.Methyl piperidine-oxyethyl group-(812mg 2.35mmol), stirred 1 hour the 2-bromine to drip 1-.The pressure reducing and steaming solvent is used re-crystallizing in ethyl acetate, obtains 958mg xanchromatic solid 7-(1-methyl piperidine-3-oxyethyl group)-6-methoxyl group-4-(4-chloro-3-fluoroanilino)-3-nitroquinoline (F-27), productive rate 90%.H
1NMR(DMCO)：9.35(s，1H，quinoline-2-H)，7.19-7.88(m，5H，Ph-H)，3.94(t，2H，CH
2)，3.73(s，3H，OCH
3)，2.23-2.27(m，7H，)，1.45-1.67(m，7H)。
Embodiment 28 The compounds of this invention are to the inhibition effect experiment of A-431 human skin squamous cell carcinoma and MDA-MB-468 human breast cancer cell
1, experiment reagent and material:
RPMII640 is available from Gibco company; The sulphonyl rhodamine B is buied by Sigma company; Tricholroacetic Acid (TCA), acetic acid (HAC) and Tris base unbuffer are homemade analytical pure.
A-431 human skin squamous cell carcinoma, MDA-MB-468 human breast cancer cell reference literature method make up (EuropeanJournal of Pharmacology, 2004,494:101-109);
Testing compound: according to compound F 17-hydroxy-corticosterone-1, F-2, F-3, F-4, F-5, F-6, F-7, F-8, F-9, F-10, F-11, F-12, F-13, F-14, F-15, F-16, F-17, F-18, F-19, F-20, the F-21 of embodiment 1-21 preparation.
Testing compound dilutes with DMSO, and concentration gradient is 10
-4M, 10
-5M, 10
-6M, 10
-7M, 10
-8M.
2, experimental implementation (sulphonyl rhodamine B (SRB) protein staining method)
According to cell growth rate, the A-431 human skin squamous cell carcinoma and the MDA-MB-468 human breast cancer cell that will be in logarithmic phase respectively are inoculated in 96 well culture plates with 90 μ l/ holes, and adherent growth 24 hours is dosing 10 μ l/ holes again.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 adds the Tris solution in 150 μ l/ holes at last, and microplate reader (VERSAmax) 540nm wavelength is measured the A value down.
3, method of calculation:
Calculate the inhibiting rate of growth of tumour cell with following formula:
Inhibiting rate=(A540 control wells-A540 dosing holes)/A540 control wells * 100%
4, experimental result:
Experimental result sees Table 1-2.
Table 1 The compounds of this invention is to the inhibiting rate (%) of A-431 human skin squamous cell carcinoma growth
| Compound | 10 -4M | 10 -5M | 10 -6M | 10 -7M | 10 -8M |
| F-1 F-2 F-3 F-4 F-5 F-6 F-7 F-8 F-9 F-10 F-11 F-12 F-13 F-14 F-15 F-16 F-17 F-18 F-19 F-20 F-21 | 43.3 45.6 25.0 67.5 89.3 85.7 51.3 70.9 24.2 73.1 72.5 74.6 85.4 91.6 72.6 31.7 51.7 64.0 93.7 76.7 80.7 | 34.0 7.0 11.7 87.3 61.0 47.6 22.7 0 0 82.8 26.5 0 89.0 0 0 30 24.0 14.6 29.0 12.7 4.8 | 4.7 1.7 0 78.9 0 0 0 0 0 81.4 7.9 0 69.2 0 0 0 16.4 9.0 8.5 0 0 | 0 0 1.6 0 0 0 0 0 0 78.7 5.3 11.6 21.1 0 0 2.9 0 17.8 31.4 8.4 1.9 | 2.2 1.6 8.8 0 0 0 0 0 0 56.9 1.9 30.1 24.8 19.4 26.7 19.1 17.3 21.8 29.9 14.9 8.2 |
Table 2 The compounds of this invention is to the inhibiting rate (%) of MDA-MB-468 human breast cancer cell growth
| Numbering | 10 -4M | 10 -5M | 10 -6M | 10 -7M | 10 -8M |
| F-1 F-2 F-3 F-4 F-5 F-6 F-7 F-8 F-9 F-10 F-11 F-12 F-13 F-14 F-15 F-16 F-17 F-18 F-19 F-20 F-21 | 60.8 55.1 70.3 70.2 30.6 40.8 17.6 47.8 24.1 36.4 79.4 80.9 90.2 94.7 86.0 84.2 82.2 0 90.7 79.9 81.3 | 3.4 17.8 31.4 0 0 0 0 14.7 11.7 17.9 27.5 18.8 88.8 28.8 44.3 12.7 9.9 50.0 14.5 33.9 41.2 | 0 6.7 0 0 0 0 0 11.0 1.5 0 11.8 6.3 75.1 4.8 17.2 42.8 1.6 0 0 6.3 22.0 | 0 0 0 0 0 0 0 4.3 4.0 7.5 11.6 34.9 34.9 14.1 22.2 0 0 0 0 0 23.5 | 0 0 0 0 0 0 0 4.0 0 0 3.8 13.7 13.7 0 21.9 0 11.4 0 0 0 11.0 |
From the table 1-2 as can be seen, The compounds of this invention has certain inhibition activity to the cell growth that A-431 human skin squamous cell carcinoma, MDA-MB-468 human breast cancer cell etc. are rich in EGFR, and wherein compound F 17-hydroxy-corticosterone-4, F-10 and F-13 show as potent inhibition to A-431 human skin squamous cell carcinoma; Compound F 17-hydroxy-corticosterone-13 can the potent growth that suppresses the MDA-MB-468 human breast cancer cell.
Claims (9)
1, the amino 3-nitroquinoline of the 4-substituted benzene compounds that has following general formula (I) structure
Wherein:
R
1, R
2, R
3, R
4, R
6Be selected from hydrogen, C independently of one another
1-5Alkyl, C
1-4Alkoxyl group, aryl, aryloxy, C
1-5Alkylaryl, C
1-5Alkyl-aryloxy, C
3-10Cycloalkyl, sulfydryl, C
1-5Alkane sulfydryl, aromatic thiohydroxy, halogen, trihalogenmethyl, hydroxyl, amino, nitro, carboxyl, oxygen carboxyl, amide group, sulfoamido, O-formamyl and-NR
12R
13, R wherein
1And R
2, R
2And R
4, R
1And R
3Can be in conjunction with forming hexa-atomic aromatic ring, methylene-dioxy or ethylenedioxy;
R
1, R
2Can also be selected from R at the same time or separately
14X
1-, X wherein
1Representative-O-or-CH
2-, R
14Be selected from following arbitrary group: C
1-5Alkyl pyrrolidine-1-base, C
1-5Alkyl imidazole alkane-1-base, C
1-5Alkyl thiomorpholine base, C
1-5Alkyl R
15, R wherein
15For containing one or two heteroatomic 5 yuan of saturated heterocyclyls or 6 yuan of saturated heterocyclyls, when wherein containing two heteroatomss, heteroatoms can be identical or different, and this heterocyclic radical is connected to C by a carbon atom
1-5On the alkyl, and this heterocyclic radical can be by any one or two replacements in the following group: oxygen base, hydroxyl, halogen, C
1-4Alkyl, C
1-4Hydroxyalkyl, C
1-4Alkoxyl group, carbamyl, C
1-4Alkyl formyl radical, N, N-two (C
1-4Alkyl) carbamyl, C
1-4Alkanoyl and C
1-4Alkoxy carbonyl, described heteroatoms refers to O, S or N;
R
5Be selected from hydrogen, C
3-10Cycloalkyl, C
1-5Alkyl, halogen;
R
7, R
8, R
9, R
10, R
11Be selected from hydrogen, C separately
1-5Alkyl, C
1-4Alkoxyl group, aryloxy, C
1-5Alkylaryl, C
1-5Alkyl-aryloxy, three halo C
1-5Alkyl, C
3-10Cycloalkyl, sulfydryl, C
1-5Alkane sulfydryl, aromatic thiohydroxy, halogen, hydroxyl, amino, nitro, carboxyl, oxygen carboxyl, amide group, sulfoamido, O-formamyl and-NR
12R
13
R
12And R
13Independently be selected from hydrogen, C
1-5Alkyl, C
2-5Alkenyl, C
3-10Cycloalkyl, ethanoyl, alkylsulfonyl, trifyl.
2, the amino 3-nitroquinoline of 4-substituted benzene according to claim 1 compounds is characterized in that wherein R
1, R
2Be selected from R at the same time or separately
14X
1
3,4-substituted benzene amino according to claim 1-3-nitroquinoline compounds is characterized in that wherein R
1Be hydrogen, hydroxyl, cyano group, nitro, trifluoromethyl, methyl, ethyl, methoxy or ethoxy.
4,4-substituted benzene amino according to claim 1-3-nitroquinoline compounds is characterized in that wherein R
2Be hydrogen.
5,4-substituted benzene amino according to claim 1-3-nitroquinoline compounds is characterized in that wherein R
7Be hydrogen, methyl, fluorine or chlorine; R
9Be hydrogen, methoxyl group, bromine, fluorine or chlorine; R
10Be hydrogen or hydroxyl; R
11Be hydrogen, fluorine or chlorine.
6, the preparation method of the amino 3-nitroquinoline of the described 4-substituted benzene of claim 1 compounds is characterized in that compound (I) carries out condensation reaction by equimolar compound (II) and compound (III) and makes in organic solvent:
7, the preparation method of the amino 3-nitroquinoline of 4-substituted benzene according to claim 6 compounds is characterized in that temperature of reaction is 90 ℃～110 ℃; Reaction times is 14～24 hours.
8, the preparation method of the amino 3-nitroquinoline of 4-substituted benzene according to claim 6 compounds, it is characterized in that described organic solvent is protonic solvent or aprotic solvent, wherein protonic solvent is water or alcohols, and does not contain acidic hydrogen, promptly do not contain can with solute bonded hydrogen; Aprotic solvent is polarity or proton inert non-polar solvent, and wherein proton inert non-polar solvent can adopt pentane, hexane, benzene or toluene; Polar proton inert solvent can adopt propyl carbinol, dimethyl sulfoxide (DMSO) or dimethyl formamide.
9, the amino 3-nitroquinoline of the described 4-substituted benzene of claim 1 compounds causes application in the medicine of disease in the excessive or undesired hyperplasia of preparation treatment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2005100243517A CN1830964B (en) | 2005-03-11 | 2005-03-11 | 4-Substituting anilino-3-nitroquinoline compounds, prepn. method and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2005100243517A CN1830964B (en) | 2005-03-11 | 2005-03-11 | 4-Substituting anilino-3-nitroquinoline compounds, prepn. method and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1830964A true CN1830964A (en) | 2006-09-13 |
| CN1830964B CN1830964B (en) | 2011-06-15 |
Family
ID=36993484
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005100243517A Expired - Fee Related CN1830964B (en) | 2005-03-11 | 2005-03-11 | 4-Substituting anilino-3-nitroquinoline compounds, prepn. method and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1830964B (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102633719A (en) * | 2012-04-19 | 2012-08-15 | 广东工业大学 | Anilino-substituted-methylbenzofuryl quinoline derivatives, and preparation method and application thereof |
| JP2013536256A (en) * | 2010-08-28 | 2013-09-19 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | Imidazo [4,5-c] quinoline as a DNA-PK inhibitor |
| CN109232417A (en) * | 2018-11-08 | 2019-01-18 | 浙江工业大学 | The preparation method of 4- phenoxyquinolines |
| CN111135171A (en) * | 2013-01-23 | 2020-05-12 | 奥尔德拉医疗公司 | Diseases and treatments associated with toxic aldehydes |
| CN114805201A (en) * | 2021-01-21 | 2022-07-29 | 天津理工大学 | Preparation method and application of 2-N-morpholinyl ethoxy group substituted quinoline derivatives |
| US12006298B2 (en) | 2018-08-06 | 2024-06-11 | Aldeyra Therapeutics, Inc. | Polymorphic compounds and uses thereof |
| US12029735B2 (en) | 2019-05-02 | 2024-07-09 | Aldeyra Therapeutics, Inc. | Polymorphic compounds and uses thereof |
| US12064516B2 (en) | 2020-05-13 | 2024-08-20 | Aldeyra Therapeutics, Inc. | Pharmaceutical formulations and uses thereof |
| US12097188B2 (en) | 2009-12-11 | 2024-09-24 | Aldeyra Therapeutics, Inc. | Compositions and methods for the treatment of macular degeneration |
| US12098132B2 (en) | 2019-05-02 | 2024-09-24 | Aldeyra Therapeutics, Inc. | Process for preparation of aldehyde scavenger and intermediates |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR035851A1 (en) * | 2000-03-28 | 2004-07-21 | Wyeth Corp | 3-CIANOQUINOLINS, 3-CIANO-1,6-NAFTIRIDINES AND 3-CIANO-1,7-NAFTIRIDINS AS INHIBITORS OF PROTEIN KINASES |
| DE10035928A1 (en) * | 2000-07-21 | 2002-03-07 | Asta Medica Ag | New heteroaryl derivatives and their use as medicines |
-
2005
- 2005-03-11 CN CN2005100243517A patent/CN1830964B/en not_active Expired - Fee Related
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12097188B2 (en) | 2009-12-11 | 2024-09-24 | Aldeyra Therapeutics, Inc. | Compositions and methods for the treatment of macular degeneration |
| JP2013536256A (en) * | 2010-08-28 | 2013-09-19 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | Imidazo [4,5-c] quinoline as a DNA-PK inhibitor |
| US9598408B2 (en) | 2010-08-28 | 2017-03-21 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Imidazo[4,5-C]quinolines as DNA-PK inhibitors |
| CN102633719A (en) * | 2012-04-19 | 2012-08-15 | 广东工业大学 | Anilino-substituted-methylbenzofuryl quinoline derivatives, and preparation method and application thereof |
| CN102633719B (en) * | 2012-04-19 | 2014-08-13 | 广东工业大学 | Anilino-substituted-methylbenzofuryl quinoline derivatives, and preparation method and application thereof |
| CN111135171A (en) * | 2013-01-23 | 2020-05-12 | 奥尔德拉医疗公司 | Diseases and treatments associated with toxic aldehydes |
| CN111135171B (en) * | 2013-01-23 | 2023-09-08 | 奥尔德拉医疗公司 | Diseases and treatments associated with toxic aldehydes |
| US12006298B2 (en) | 2018-08-06 | 2024-06-11 | Aldeyra Therapeutics, Inc. | Polymorphic compounds and uses thereof |
| CN109232417A (en) * | 2018-11-08 | 2019-01-18 | 浙江工业大学 | The preparation method of 4- phenoxyquinolines |
| US12029735B2 (en) | 2019-05-02 | 2024-07-09 | Aldeyra Therapeutics, Inc. | Polymorphic compounds and uses thereof |
| US12098132B2 (en) | 2019-05-02 | 2024-09-24 | Aldeyra Therapeutics, Inc. | Process for preparation of aldehyde scavenger and intermediates |
| US12064516B2 (en) | 2020-05-13 | 2024-08-20 | Aldeyra Therapeutics, Inc. | Pharmaceutical formulations and uses thereof |
| CN114805201B (en) * | 2021-01-21 | 2024-09-13 | 陕西蒲城万德科技有限公司 | Preparation method and application of 2-N-morpholinoethoxy group substituted quinoline derivative |
| CN114805201A (en) * | 2021-01-21 | 2022-07-29 | 天津理工大学 | Preparation method and application of 2-N-morpholinyl ethoxy group substituted quinoline derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1830964B (en) | 2011-06-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1830964A (en) | 4-Substituting anilino-3-nitroquinoline compounds, prepn. method and use thereof | |
| JP5897590B2 (en) | Quinazoline carboxamidoazetidine | |
| CN1807413B (en) | Carbazole sulfonamide derivative and its preparation method | |
| RU2494103C2 (en) | Thienopyridazine compounds, preparing them, pharmaceutical compositions containing them, and using them | |
| AU2018228541A1 (en) | Novel isoindoline derivative, and pharmaceutical composition and application thereof | |
| JP2015110649A (en) | Hydrochloric acid icotinib, composite, crystallographic form, combined medicine and its application | |
| JP2019527699A (en) | IDO1 inhibitor and its production method and application | |
| CN109293657B (en) | Alpha-carboline ketone compound and preparation method and application thereof | |
| CN1365972A (en) | Indole derivatives and its anticancer usage | |
| CA2958741C (en) | Quinazoline derivatives | |
| CN105153026B (en) | Sorafenib derivative of the amide structure containing biaryl and its preparation method and application | |
| CN102887904A (en) | 2,3-dioxyethyl-5-methyl-8,9-dimethoxy benzophenanthridine derivative, and preparation method and application thereof | |
| CN114920704B (en) | Phenyl piperazine quinazoline compound or pharmaceutically acceptable salt thereof, preparation method and application | |
| EP3253750A1 (en) | Novel flavone based egfr inhibitors and process for preparation thereof | |
| CN109970717A (en) | 4- (cycloaliphatic ring and pyrimidine/pyridine replaces) amino -1H-3- pyrazole carboxamides FLT3 inhibitor and application thereof | |
| CN103864680B (en) | There is the 7-chloro-4-oxo-quinoline derivative of anti-tumor activity | |
| CN109776551A (en) | Dioxanes and quinazoline derivant preparation method | |
| CN1177843C (en) | Novel chalcones | |
| CN108026076B (en) | 4- (3-pyrazolyl amino) -benzimidazole compounds and their use as JAK1 inhibitors | |
| CA3090829C (en) | Urea-substituted aromatic ring-linked dioxinoquinoline compounds, preparation method and uses thereof | |
| CN1958572A (en) | Compound in category of dihydro quinolines, preparation method, and composition of medication | |
| CN115368362A (en) | Quinoxalinone derivatives as BTK inhibitors and application thereof | |
| CN106866642A (en) | The quinazoline compounds of the structure of acylhydrazone containing aryl and its application | |
| US20160102095A1 (en) | Pyrazolo[1,5-a]pyrimidine derivative and use of anti-tumor thereof | |
| CN106008480A (en) | Quinazoline compound containing cinnamamide structure and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110615 Termination date: 20130311 |