CN101270060B - 2,6-(amino-benzene methylene)naphthenone compounds, preparation method and application thereof - Google Patents
2,6-(amino-benzene methylene)naphthenone compounds, preparation method and application thereof Download PDFInfo
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- CN101270060B CN101270060B CN2008100696313A CN200810069631A CN101270060B CN 101270060 B CN101270060 B CN 101270060B CN 2008100696313 A CN2008100696313 A CN 2008100696313A CN 200810069631 A CN200810069631 A CN 200810069631A CN 101270060 B CN101270060 B CN 101270060B
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Abstract
The present invention relates to a compound of 2, 6- bi (amino benzylidene) naphthenone. The compound has a structure as shown in the general formula I. The present invention also relates to a preparation method of the compound. Aromatic aldehydes and naphthenone are condensed to prepare 2, 6 - bi (dinitrophenyl) naphthenone that is reduced to prepare a series of compounds of the 2, 6- bi (amino benzylidene) naphthenone. Preliminary tests on pharmacological activity have proven that the compounds have anti-tumor activity and certain selectivity. The preparation method has the advantages of easy operation, mild conditions and high yield of the products.
Description
Technical field
The present invention relates to organic compound and synthetic, be specifically related to 2,6-two (amino-benzene methylene radical) cycloalkanones compound and preparation method thereof, and the application in preparation antitumor action medicine.
Background technology
Kind surplus the present clinical in the world common antitumor drug about 80, generally according to its source and mechanism of action classification, the medicine that can be divided into antimetabolite, radiosensitizer, hormone medicine, immunomodulator, spindle body mitotic inhibitor (mitotic spindle inhibitor) and act on DNA.The medicine that acts on DNA generally is divided into alkylating agent, DNA ditch district's wedding agent and intercalator (CurrMed.Chem.2001,8 (5): 476-505) again.The main mechanism of DNA intercalator is to cause the gene phase shift mutation, because their structure and a purine-pyrimidine are to quite similar, cause double-helical part to untie (two original 0.34nm apart of base pairs between two adjacent DNA base pairs so can embed, after embedding other molecules, promptly become 0.68nm, thereby in the dna replication dna process, make to increase on the chain or lack a base, whole genetic codes of this back, position are transcribed and translation error.The DNA intercalator suppresses transcribing of RNA and duplicating of DNA, thereby shows antineoplastic activity by inserting the DNA base pair.
Anthracene nucleus medicament is typical DNA intercalator.Anthracene nucleus medicament comprises Zorubicin, daunorubicin, aclacinomycin, carminomycin etc., effective to 70% solid tumor, as mammary cancer, malignant lymphoma, lung cancer, acute leukemia etc., main pharmacological mechanism is to insert the dna double spirane structure, drawing up relies on the RNA building-up process of DNA, makes and transcribes and translation error.In addition, the nitrogen heterocyclic derivative of anthracene---acridine (Acridine) class medicine, 10 carbon atoms that are equivalent to anthracene are replaced by nitrogen-atoms, so this compounds also belongs to the DNA intercalator.In the derivative of acridine 9-aminoacridine, as amsacrine (N-[4-(9-acridine amino) aminomethyl phenyl] Toluidrin), 4-(9-acridine amido) monomethylaniline, 9-aniline-2,3-methylene radical dioxy acridine etc. all demonstrates better antitumor activity, and part of compounds has been applied to clinical.Have recently the derivative 1 of research report proflavin ', 1 " (acridine-3; 6-dialkyl)-3 '; 3 "-dialkyl group allophanamide, has cytotoxic activity, its main mechanism also is by inserting the DNA base pair in conjunction with aromatic ring behind the DNA, causing transcribing and translation error (Bioorg.Med.Chem.2008.Jan.19).
Has 2 of similar configuration to proflavin, 6-two (amino-benzene methylene radical) cycloalkanones compound, be mainly used in synthetic photosensitive polymer at present, be applied to high-performance fiber, microelectronic device and special electronic material (Polym.Int.48:421 ± 425 (1999)), its biology and pharmacologically active also do not have relevant report.
According to the literature, relevant 2, the preparation method of 6-two (4-amino-benzene methylene radical) cycloalkanones compound (Ia) is as follows: nitrobenzaldehyde is after cyclization becomes (IVa) compound with cyclopentanone, and the branch two lines are reduced and made compound (Ia).Route one: with ethanol is solvent, the Pd/C-hydrazine hydrate is a reductive agent, filtered while hot after reacting completely, the solid that the filtrate rotary evaporation obtains obtains compound (Ia) (Eur.Polym.J.Vol.28.No.4.pp 439-448,1992) with the mixing solutions recrystallization of tetrahydrofuran (THF)/ether (1: 2).Route two: with ethanol as solvent; iron powder, ammonium chloride and Resorcinol are made reductive agent; need the nitrogen protection back flow reaction; after reacting completely reaction solution was placed 5 hours down at 0-5 ℃; after the filtration filtrate is poured in the 2000ml distilled water; filter the solid chloroform recrystallization that obtains once more, promptly get compound (Ia) (Polym.Int.48:421 ± 425 (1999)).These route weak points are: selectivity is low, produces to be difficult to control, and by product is many, and yield is low, the highlyest is no more than 90%.
Summary of the invention
Purpose of the present invention for provide a class novel 2,6-two (amino-benzene methylene radical) cycloalkanones compound, preparation method and the application of preparation in the antitumor drug thereof.
Provided by the invention 2,6-two (amino-benzene methylene radical) cycloalkanones compound has following structure:
Wherein:
R
1Be hydrogen atom, n=0 or 1; Or R
1Be methyl or alkyl, n=1;
R
2Position chlorine atom or other halogen atom.
This 2, the constructional feature of 6-two (amino-benzene methylene radical) cycloalkanones compound is: (1) has five rings; (2) has the unsaturated ketonic bond of α ' α; (3) amino on the Ben Yajiaji ring.
Provided by the invention 2,6-two (amino-benzene methylene radical) naphthenone compound can prepare according to the following steps:
(1) be starting raw material with nitrobenzaldehyde II and naphthenone III, at ionic liquid [bmim] [BF
4] in the Indium-111 chloride for the catalyzer condensation obtains 2,6-two (oil of mirbane methylene radical) naphthenone IV, its temperature of reaction is 50～70 ℃, the reaction times is 6～12h: its structure and reaction formula are as follows:
(2) the compound IV obtains 2 by reduction reaction, 6-two (amino-benzene methylene radical) naphthenone I, and reflux, the reaction times is 1～6h, its structure and reaction formula are as follows:
Compound IV in the step (2) is 1～3: 10～30 with the ratio of iron powder, ammonium chloride amount of substance: 1, and the solution of reduction reaction is alcoholic solution.Alcoholic solution is the aqueous solution of the alcoholic acid aqueous solution, methanol in water or Virahol, and the concentration of described alcoholic solution is 80～98%.
Synthetic 2 of the present invention, 6-two (amino-benzene methylene radical) naphthenone is easy to operate, mild condition, yield is higher, can surpass 90%, and Compound I has stronger physiology and pharmacologically active, can be used for anti-tumor drug.
Embodiment
Will be further understood that the present invention by following embodiment, but do not limit content of the present invention.
Embodiment 1: the preparation of this example explanation compound IV
Synthesizing of (1) 2,6-two (4-oil of mirbane methylene radical) pimelinketone (IVa);
In a round-bottomed flask, add InCL
3-4H
2O (0.30g, 2mmol), paranitrobenzaldehyde (1.511g, 10mmol) with ionic liquid 8ml, in temperature adding pimelinketone (0.51ml when stirring the 30min postcooling to 50-70 ℃ under 100 ℃ the condition, 5mmol) and TMSCl (0.75ml, 5mmol), under 50-70 ℃ of condition, react 6-12h (TLC shows obviously progress of reaction nothing) then, with reacting liquid filtering, filtrate ice washing with alcohol, use the DMF recrystallization, solid places the vacuum drying oven drying, obtains the good yellow needle-like solid 1.6692g of crystal formation, and yield is 92%.Recording this product, to get fusing point be 206-208 ℃.
(2) other 2, the preparation method of 6-two (oil of mirbane methylene radical) naphthenone compound is the same.
Embodiment 2: the preparation of this example explanation Compound I
Synthesizing of (1) 2,6-two (4-amino-benzene methylene radical) pimelinketone (Ia)
Adding Fe powder in round-bottomed flask (0.1344g, 2.4mmol), NH
4Cl (0.006g, 0.12mmol), 95% ethanol of 25ml and 2ml distilled water behind the reflux 30min, add 2,6-two (4-oil of mirbane methylene radical) pimelinketone (0.1092g, 0.3mmol).Reaction 2h (TLC show react completely) back filtered while hot, cooling obtains yellow solid, filter, drying, yellow solid 0.083g, yield is 90.5%, the fusing point that records this product is 140-142 ℃.
(2) other 2, the preparation method of 6-two (amino-benzene methylene radical) naphthenone compound is the same.
The present invention adopts the Fe/NH among the embodiment two
4The Cl method has obtained nine 2,6-two (amino-benzene methylene radical) x cycloalkanones compound, be respectively 2,6-two (4-amino-benzene methylene radical) pimelinketone (Ia), 2,6-two (3-amino-benzene methylene radical) pimelinketone (Ib), 2,6-two (2-chloro-5-amino-benzene methylene radical) pimelinketone (Ic), 2,6-two (4-amino-benzene methylene radical) cyclopentanone (Id), 2,6-two (3-amino-benzene methylene radical) cyclopentanone (Ie), 2,6-two (2-chloro-5-amino-benzene methylene radical) pimelinketone (If), 2,6-two (4-amino-benzene methylene radical) is to methylcyclohexanone (Ig), 2,6-two (3-amino-benzene methylene radical) is to methylcyclohexanone (Ih), and 2,6-two (2-chloro-5-amino-benzene methylene radical) is to methylcyclohexanone (Ii).The yield of Compound I a-Ii, fusing point, LC/MS data see Table 1.
Table 1:2, results such as the yield of 6-two (amino-benzene methylene radical) naphthenone compound, fusing point
Table 1 result shows, and is provided by the invention 2, and 6-two (amino-benzene methylene radical) cycloalkanones compounds process for production thereof is easy to operate, mild condition, and product yield is higher, and has avoided severe condition such as nitrogen protection.
Embodiment 3: the anti-tumor activity testing method
(1) experiment material:
RPMI-1640 (U.S. Hyclone); Trypsin U.S. Hyclone); Calf serum (Hangzhou folium ilicis chinensis company); MTT (tetramethyl-azo azoles salt) (north is with positive biological products company); Methyl-sulphoxide (Chongqing Chuan Dong chemical industry company limited)
Tumor cell line and substratum: human leukemia cell line k562, human lung carcinoma cell line A549 are provided by Medical University Of Chongqing group embryo laboratory; Human hepatoma cell strain QGY-7701 is provided by the second hepatopathy institute of clinical institute of Medical University Of Chongqing.With the RPMI-1640 nutrient solution that contains 10% calf serum, put 37 ℃, 5%CO
2Cultivate in the saturated humidity incubator.
Laboratory apparatus: YJ-1450 type Bechtop (Suzhou Decontamination Equipment Plant); SHEL.LAB 2300 type CO2gas incubator (U.S.); Nikon inverted phase contrast microscope (Japan); Low speed centrifuge (Beijing Medical Centrifugal Machine Factory)
(2) test method:
Take the logarithm the vegetative period cell cultures in 96 well culture plates, and every hole 200ul (contains 10
4Individual tumour cell), simultaneously the administration group adds the test-compound that contains different concns, and every kind of medicine is established 5 dosage groups (40,20,10,5,2.5ug/ml), establishes 5 parallel holes for every group, and control group adds and the isopyknic solvent of administration group, puts 37 ℃, 5%CO
2Cultivate 72h in the incubator, every hole adds the 0.5mg/mlMTT solution of 20ul.Hatch 4h for 37 ℃, abandoning supernatant, every hole adds 200ulDMSO dissolving first meals particle, under reference wavelength 450nm, detection wavelength 570nm condition, measure absorbance (A) with microplate reader behind the mixing, the tumour cell of handling with solvent control is a control group, calculate inhibiting rate=(control group average A value-administration group average A value)/(control group average A value) * 100% of medicine, and calculate IC tumour cell
50Value.
(3) test-results:
Adopt mtt assay, measured 8 target compounds under five concentration (40,20,10,5,2.5ug/ml) at external inhibiting rate to human leukemia cell (k562), human lung carcinoma cell (A549), human liver cancer cell (QGY) cell strain, and calculation of half inhibitory concentration IC
50, the result is as shown in table 2:
Table 2: target compound is to the IC of different tumor cell lines
50Value
Table 2 result shows that target compound Ia-Ii all has anti-tumor activity in various degree, and wherein the effect of Compound I g is stronger, to the IC of k562, A549 and QGY-7701 cell
50Value is respectively 2.76,6.34,5.78ug/ml.
(1) for the effect of human leukemia cell K562, except the effect of Compound I c was more weak, other compound all demonstrated stronger restraining effect, IC
50All below 10ug/ml, wherein the restraining effect of Ig is the strongest.
(2) for human lung cancer cell A549's effect, Compound I e, Ig, Ih are stronger to the restraining effect of A549, three's IC
50Below 10ug/ml, the restraining effect of remaining several compound a little less than, IC
50＞10ug/ml.
(3) for the effect of human liver cancer cell QGY-7701, Compound I a and Ic are more weak to the restraining effect of QGY-7701, and the restraining effect of all the other compounds is more intense, and IC
50Between 5.78～6.69ug/ml.
Claims (5)
1.2,6-two (amino-benzene methylene radical) cycloalkanones compound, its general structure is:
Wherein
R
1Be hydrogen atom, n=0 or 1; Or R
1Be alkyl, n=1;
R
2Be chlorine atom or other halogen atom.
2. one kind prepares as claimed in claim 1ly 2, and the method for 6-two (amino-benzene methylene radical) cycloalkanones compound is characterized in that synthesizing as follows:
(1) be starting raw material with nitrobenzaldehyde II and naphthenone III, at ionic liquid [bmim] [BF
4] in the Indium-111 chloride for the catalyzer condensation obtains 2,6-two (oil of mirbane methylene radical) naphthenone IV, its temperature of reaction is 50～70 ℃, the reaction times is 6～12h, its structure and reaction formula are as follows:
(2) the compound IV is carried out reduction reaction and obtain 2,6-two (amino-benzene methylene radical) naphthenone I, reflux, the reaction times is 1～6h, its structure and reaction formula are as follows:
3. preparation 2 according to claim 2, the method of 6-two (amino-benzene methylene radical) cycloalkanones compound, it is characterized in that: the compound IV is 1～3: 10～30 with the ratio of iron powder, ammonium chloride amount of substance in the step (2): 1, and the solution of reduction reaction is alcoholic solution.
4. according to claim 32, the preparation of 6-two (amino-benzene methylene radical) naphthenone compound is characterized in that alcoholic solution is the aqueous solution of the alcoholic acid aqueous solution, methanol in water or Virahol, and the concentration of described alcoholic solution is 80～98%.
5. claim 1 is described 2, the application of 6-two (amino-benzene methylene radical) cycloalkanones compound in the preparation antitumor drug.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1019572B (en) * | 1987-02-17 | 1992-12-23 | 沃德·布林金索普及其合伙人有限公司 | Benzophenone derivatives |
| US6310249B1 (en) * | 1998-07-23 | 2001-10-30 | Nissan Chemical Industries, Ltd. | Process for producing 2-aminobenzophenone compound |
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2008
- 2008-05-07 CN CN2008100696313A patent/CN101270060B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1019572B (en) * | 1987-02-17 | 1992-12-23 | 沃德·布林金索普及其合伙人有限公司 | Benzophenone derivatives |
| US6310249B1 (en) * | 1998-07-23 | 2001-10-30 | Nissan Chemical Industries, Ltd. | Process for producing 2-aminobenzophenone compound |
Non-Patent Citations (4)
| Title |
|---|
| Hou, Haoqing.Main-chain photosensitive polyamic acids usingalkalineaqueous solution as developer..Polymer International48 5.1999,48(5),421-425. |
| Hou, Haoqing.Main-chain photosensitive polyamic acids usingalkalineaqueous solution as developer.Polymer International48 5.1999,48(5),421-425. * |
| 胡雪原等.离子液体中a a ‘ -双亚苄基环烷酮的绿色合成.河南师范大学学报（自然科学版）32 1.2004 |
| 胡雪原等.离子液体中a,a‘-双亚苄基环烷酮的绿色合成.河南师范大学学报(自然科学版)32 1.2004,32(1),52-55. * |
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