CN102153508B - 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone and application of the 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone in preparing antitumour drugs - Google Patents
3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone and application of the 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone in preparing antitumour drugs Download PDFInfo
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Abstract
The invention discloses 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone and application of the 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone in preparing antitumor drugs. The 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compound can be obtained by Claisen-Schimidt reaction of aromatic aldehyde and N-cyclopropyl-4-piperidine ketone. The 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compound can obviously restrain the proliferation of various tumor cells and can be used for preparing drugs for treating leukocythemia, colorectal cancer, lover cancer, skin cancer, gastric cancer, breast cancer, prostatic cancer or other malignant tumor.
Description
Technical field:
The present invention relates to synthesizing antineoplastic medicament and preparation method, be specifically related to synthetic 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compounds and for the preparation of the application of antitumor drug.
Background technology:
Take the 4-piperidone as intermediate and the aromatic aldehyde condensation obtain a series of compounds and have antitumor, anti-inflammatory, antibiotic isoreactivity, wherein representation compound EF-24 (structural formula is as follows) inside and outside has preferably anti-tumor activity [document
1,2].But bibliographical information 3 is not arranged at present, the synthetic and application in preparation treatment antitumor drug of 5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compounds.
The chemical structural formula of EF-24
Reference
1.Subramaniam D，May R，Sureban SM，et al.Diphenyl difluoroketone：a curcumin derivative with potent in vivo anticancer activity.[J].Cancer Res.，2008，68(6)：1962-1969.
2.Adams BK，Ferstl EM，Davis MC，etal.Synthesis and biological evaluation ofnovel curcumin analogs as anti-cancer and anti-angiogenesis agents[J].Bioorg Med Chem，2004，12(14)：3871-3883.
Summary of the invention:
It is a kind of 3 that one of purpose of the present invention is to provide, 5-(E)-dibenzylidene-N-cyclopropyl piperidine 4-ketone compound.
Of the present invention 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compound general formula is as follows:
The present invention also can adopt and contain 3 for the treatment of significant quantity, and 5-(E)-dibenzylidene-N-cyclopropyl piperidine 4-ketone compounds and pharmaceutically acceptable carrier form composition.The group of the Ar representative in the formula (I) is: substituted-phenyl or heterocycle, the substituting group on the phenyl can be R
1, R
2, R
3, R
4, R
5In at least one non-hydrogen substituting group, if entirely be hydrogen, substituted-phenyl is phenyl (seeing embodiment 7), and two substituting groups such as R are perhaps arranged
1, R
3, also can three substituting group such as R
3, R
4, R
5, five substituent R can be arranged at most
1, R
2, R
3, R
4, R
5, R
1, R
2, R
3, R
4, R
5Can be that identical group also can be different group, as can R
1=R
2, also can, R
1≠ R
2, described substituting group preferred alkyl, alkoxyl group, halogen, haloalkyl or nitro, methoxyl group most preferably, the alkyl of 1-4 carbon, fluorine, trifluoromethyl or nitro; Substituting group on the most preferred phenyl is 2-methoxyl group (seeing embodiment 5); 2,5-dimethoxy (seeing embodiment 4); 3,4-dimethoxy (seeing embodiment 3); 2,4,5-trimethoxy (seeing embodiment 1); 2-fluorine (seeing embodiment 2); 2-chlorine (seeing embodiment 9); 2-bromine (seeing embodiment 8); 4-methyl (seeing embodiment 12); 2-trifluoromethyl (seeing embodiment 6); 3,4-methylene dioxy base (seeing embodiment 10); Substituted-phenyl Ar is 2-naphthylidene (seeing embodiment 11).The preferred pyridyl of described heterocycle, pyrryl or furyl, most preferably 3-pyridyl.
Two of the object of the invention is to provide the preparation method of 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compounds.Compound 3 of the present invention, 5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compound can carry out the Claisen-Schimidt reaction by aromatic aldehyde and N-cyclopropyl-4-piperidone and obtain.Reaction equation is schematically as follows:
Three of the object of the invention is to provide the application of composition in the preparation antitumor drug of 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compounds and composition thereof.
Of the present invention 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compounds can be used for but is not limited to medicine as preparation treatment leukemia, colorectal carcinoma, skin carcinoma, cancer of the stomach, liver cancer, mammary cancer or prostate cancer.
The invention provides and be used for the treatment of antitumor medicine composition, wherein contain compound and the pharmaceutically acceptable carrier of any one in the claim 1～5 for the treatment of significant quantity.Described treatment significant quantity is the minimum dose that result for the treatment of is arranged on the pharmacology clinically.
The invention provides the pharmaceutical composition that is used for the treatment of from blood disease, colorectal carcinoma, skin carcinoma, cancer of the stomach, liver cancer, mammary cancer, prostate cancer, wherein contain compound and the pharmaceutically acceptable carrier of any one in the claim 1～5 for the treatment of significant quantity.Described treatment significant quantity is the minimum dose that result for the treatment of is arranged on the pharmacology clinically.
According to embodiment of the present invention, 3 for the treatment of cancer of the present invention, medicine or the composition of 5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compounds, the example of treatable cancer is including, but not limited to from blood disease, colorectal carcinoma, skin carcinoma, cancer of the stomach, liver cancer, mammary cancer, prostate cancer.
Beneficial effect of the present invention is: of the present invention 3, the external propagation that can significantly suppress the various human tumour cell of 5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone one compounds sees Table 1; Oral administration adds 100mgKg as an example of compound 2 example
-1D
-1Amount can be to H22 transplanted human hepatocellular carcinoma mouse inhibitory rate 48.4%, see Table 2, Fig. 1, illustrate of the present inventionly 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compounds can be used for as the medicine of preparation treatment from blood disease, colorectal carcinoma, liver cancer, skin carcinoma, cancer of the stomach, mammary cancer or prostate cancer etc.
And preparation method of the present invention is different from the EF-24 compounds process for production thereof in the background technology, the EF-24 compounds process for production thereof can not be used for preparation of the present invention, EF-24 is synthetic to be to make catalyzer and reaction solvent with the Glacial acetic acid of saturated HCl etc., and the reaction times is generally 2d.Target compound 3 of the present invention, 5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone is to use base catalysis, and ethanol is solvent, and the reaction times obviously shortens, and generally at 30min-1d, separation and purification is simple, and the solvent non-corrosiveness, green safety.The time of the present invention's preparation is short, and usefulness is high, and preparation technology is simple, and yield is high, reaches more than 60%, can reach 88%.
Description of drawings:
Fig. 1 is the restraining effect figure of 2 couples of mouse H22 of compound of the present invention ascitic type liver cancer transplanted tumor,
That upper row is the transplanted human hepatocellular carcinoma shape figure that does not add compound 2 among the figure, among the figure with the lower row of upper row contrast for adding the inhibition shape figure of compound 2 rear transplanted human hepatocellular carcinomas, upper figure below is compared and is added as can be known compound 2 rear mouse H22 ascitic type liver cancer transplanted tumors and be subject to obvious inhibition.
Embodiment:
The present invention is described in detail below in conjunction with embodiment:
Fusing point is used the Nereid X-4 of close instrument plant type micro-meldometer and is measured, and temperature is not calibrated.
1H,
13C NMR spectrum adopts Bruker Avance III type nuclear magnetic resonance analyser (400MHz) to measure, and TMS is interior mark.Mass spectrum adopts Agilent 1100LC/MSD Trap ion trap LC-MS instrument to measure.Raw materials used 1-cyclopropyl 4-piperidone, aromatic aldehyde are available from the chemical company limited of A Faaisha (Tianjin), and sodium hydroxide, dehydrated alcohol, concentrated hydrochloric acid, acetic acid are available from traditional Chinese medicines chemical reagents corporation.
The synthetic logical method of 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine 4-ketone
N-cyclopropyl-4-piperidone 348mg (2.5mmol), sodium hydroxide 20mg (0.5mmol), dehydrated alcohol 20mL, stirring at room after mixing wait clarifying rear adding aromatic aldehyde (5mmol), is reacted 0.5h～24h under the room temperature, has solid to separate out.Suction filtration, filter cake absolute ethanol washing, vacuum-drying.The various aromatic aldehydes that adopt in this example (its mole number is 5mmol), referring to as follows: the chemical structural formula of 1～12 compound that embodiment one～12 are synthesized is as follows:
Be 1-12 kind 3, the chemical structural formula of 5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compounds is:
1-12 kind 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compounds is measured through melting point apparatus, nuclear magnetic resonance analyser and mass spectrograph, and its measured value is as follows:
Embodiment one, when aromatic aldehyde be 2,4, during the 5-TMB, make 3,5-(E)-two (2,4,5-trimethoxy benzylidene)-and N-cyclopropyl piperidine-4-ketone (compound 1), be the orange powder, yield 60%, mp150～153 ℃, ESI-MS:496.3 (M+1);
1H-NMR (CDCl
3, ppm) δ: 8.02 (2H, s ,-CH=), 6.82 (2H, s, Ar-H), 6.55 (2H, s, Ar-H), 4.63 (4H, s ,-CH
2-), 3.86 (18H, s ,-OCH
3), 1.93 (s, 1H ,-N-CH (CH
2)
2), 0.44-0.39 (m, 4H ,-CH (CH
2)
2). δ: 87.99,154.18,151.13,142.54,131.93,116.36,114.32,109.17,97.27,56.86,56.35,56.21,55.19,37.42,6.67
Embodiment two, when aromatic aldehyde is the 2-fluorobenzaldehyde, make 3,5-(E)-two (2-fluorine benzylidene)-N-cyclopropyl piperidine-4-ketone (compound 2), be pale yellow powder, yield 88%, mp169～172 ℃, ESI-MS:352.3 (M+1);
1H-NMR (CDCl
3, ppm) δ: 7.88 (2H, s ,-CH=), 7.39～7.31 (4H, m, Ph-H), 7.22～7.11 (4H, m, Ph-H), 3.86 (s, 4H ,-CH
2-), 1.90 (s, 1H ,-N-CH (CH
2)
2), 0.47-0.40 (m, 4H ,-CH (CH
2)
2).
13C-NMR (100MHz, CDCl
3, ppm) δ: 186.71,162.22,159.72,135.09,130.76,129.25,123.99,123.25,115.82,54.98,37.70,6.77.
Embodiment three, when aromatic aldehyde is Veratraldehyde, make 3,5-(E)-two (3,4-dimethoxybenzylidenegroup group)-N-cyclopropyl piperidine-4-ketone (compound 3) is yellow powder, yield 66%, mp195～198 ℃, ESI-MS:436.3 (M+1);
1H-NMR (CDCl
3, ppm) δ: 7.75 (2H, s ,-CH=), 7.06 (2H, d, J=8Hz, Ar-H), 6.97 (2H, s, Ar-H), 6.93 (2H, d, J=8Hz, Ar-H), 4.01 (4H, s ,-CH
2-), 3.92 (12H, s ,-OCH
3), 1.97 (s, 1H ,-N-CH (CH
2)
2), 0.53-0.48 (m, 4H ,-CH (CH
2)
2).
13C-NMR (100MHz, CDCl
3, ppm) δ: 187.16,150.01,148.86,136.26,128.40,124.04,123.89,114.04,111.13,55.99,55.75,55.12,37.90,6.73
Embodiment four, when aromatic aldehyde is 2,5-dimethoxy benzaldehyde, make 3,5-(E)-two (2,5-dimethoxybenzylidenegroup group)-N-cyclopropyl piperidine-4-ketone (compound 4) is golden yellow powder, yield 77%, mp138～141 ℃, ESI-MS:436.3 (M+1);
1H-NMR (CDCl
3, ppm) δ: 7.99 (2H, s ,-CH=), 6.91-6.84 (4H, m, Ar-H), 6.81 (2H, s, Ar-H), 3.89 (4H, s ,-CH
2-), 3.80 (12H, s ,-OCH
3), 1.89 (s, 1H ,-N-CH (CH
2)
2), 0.43-0.37 (m, 4H ,-CH (CH2) 2).
13C-NMR (100MHz, CDCl
3, ppm) δ: 187.43,152.99,152.96,133.70,132.14,125.38,116.34,114.88,111.89,56.17,55.87,55.05,37.59,6.77
Embodiment five, when aromatic aldehyde is the 2-dimethoxy benzaldehyde, make 3,5-(E)-two (2-methoxyl group benzylidene)-N-cyclopropyl piperidine-4-ketone (compound 5), be faint yellow needle-like crystal, yield 80%, mp178～181 ℃, ESI-MS:476.3 (M+1);
1H NMR (CDCl
3, ppm) δ: 8.05 (2H, s ,-CH=), 7.36 (2H, t, J=8Hz, Ar-H), (7.25 2H, d, J=8Hz, Ar-H), 6.99 (2H, t, J=8Hz, Ar-H), (6.92 2H, d, J=8Hz, Ar-H), 3.88 (4H, s ,-CH
2-), 3.85 (6H, s ,-OCH
3), 1.88 (s, 1H ,-N-CH (CH
2)
2), 0.42-0.35 (m, 4H ,-CH (CH
2)
2).
13C-NMR (100MHz, CDCl
3, ppm) δ: 187.56,158.52,133.40,132.19,130.39,130.31,124.63,120.09,110.82,55.52,55.15,37.67,6.72
Embodiment six, when aromatic aldehyde is the 2-trifluoromethylated benzaldehyde, make 3,5-(E)-two (2-trifluoromethyl benzylidene)-N-cyclopropyl piperidine-4-ketone (compound 6), be yellow needle, yield 60%, mp152～154 ℃, ESI-MS:452.3 (M+1);
1H-NMR (400MHz, CDCl
3, ppm) δ: 8.04 (2H, s ,-CH=), 7.75 (2H, d, Ph-H, J=7.6Hz), (7.59 2H, t, Ph-H, J=7.6Hz), 7.48 (2H, t, Ph-H, J=7.6Hz), (7.30 2H, d, Ph-H, J=7.6Hz), 3.73 (s, 4H ,-CH
2-), 1.86 (s, 1H ,-N CH (CH
2)
2), 0.39-0.33 (m, 4H ,-CH (CH
2)
2).
13C-NMR (100MHz, CDCl
3, ppm) δ: 186.11,162.22,159.72,135.09,130.76,129.25,123.99,123.25,115.82,54.05,36.65,6.62.
Embodiment seven, when aromatic aldehyde is phenyl aldehyde, make 3,5-(E)-two (2-benzylidene)-N-cyclopropyl piperidine-4-ketone (compound 7), pale yellow powder, yield 80%, 156～159 ℃ of mp, ESI-MS:316.3 (M+1);
1H-NMR (400MHz, CDCl
3, ppm) δ 7.80 (2H, s ,-CH=), 7.46～7.35 (10H, m, Ph-H), 3.99 (s, 4H ,-CH
2-), 1.97～1.92 (m, 1H ,-N-CH (CH
2)
2), 0.50-0.38 (m, 4H ,-CH (CH
2)
2).
13C-NMR (100MHz, CDCl
3, ppm) δ: 187.54,136.26,135.37,133.50,13 0.49,128.97,128.59,128.23,127.25,55.18,38.03,6.81
Embodiment eight, when aromatic aldehyde is the 2-bromobenzaldehyde, make 3,5-(E)-two (2-bromine benzylidene)-N-cyclopropyl piperidine 4-ketone (compound 8), yellow powder, yield 77%, mp130～135 ℃, ESI-MS:492.3 (M+1);
1H-NMR (400MHz, CDCl
3, ppm) δ: 7.94 (2H, s ,-CH=), 7.66 (2H, d, Ph-H, J=8Hz), 7.37 (2H, t, Ph-H, J=7.6Hz), 7.27～7.21 (4H, q, Ph-H, J=7.2Hz), 3.82 (s, 4H ,-CH
2-), 1.88 (s, 1H ,-N-CH (CH
2)
2), 0.44-0.37 (m, 4H ,-CH (CH
2)
2).
13C-NMR (100MHz, CDCl
3, ppm) δ: 186.81,136.30,135.52,134.25,133.19,130.32,130.09,127.10,125.24,54.51,37.49,6.74
Embodiment nine, when aromatic aldehyde is the 2-chlorobenzaldehyde, make 3,5-(E)-two (2-chlorine benzylidene)-N-cyclopropyl piperidine 4-ketone (compound 9), pale yellow powder, yield 74%, 152～155 ℃ of mp, ESI-MS:384.3 (M+1);
1H-NMR (400MHz, CDCl
3, ppm) δ: 7.99 (2H, s ,-CH=), 7.34～7.26 (8H, m, Ph-H), 3.83 (s, 4H ,-CH
2-), 1.88 (m, 1H ,-N-CH (CH
2)
2), 0.45-0.35 (m, 4H ,-CH (CH
2)
2).
13C-NMR (100MHz, CDCl
3, ppm) δ: 186.81,135.21,134.63,133.89,133.74,130.34,129.97,129.95,126.47,54.67,37.58,6.76
Embodiment ten, when aromatic aldehyde is piperonylaldehyde, make 3,5-(E)-two (3,4-methylene dioxy base benzylidene)-and N-cyclopropyl piperidine-4-ketone (compound 10), yellow powder, yield 68%, mp215～218 ℃, ESI-MS:404.3 (M+1);
1H-NMR (400MHz, CDCl
3, ppm) δ: 7.68 (2H, s ,-CH=), 6.97 (2H, d, Ph-H, J=8Hz), 6.93 (2H, s, Ph-H), 6.88 (2H, d, Ph-H, J=8Hz), 6.03 (4H, s, O-CH2-O), 3.94 (s, 4H ,-CH
2-), 1.95 (m, 1H ,-N-CH (CH
2)
2), 0.54-0.40 (m, 4H ,-CH (CH
2)
2).
13C-NMR(100MHz，CDCl
3，ppm)δ：187.24，148.38，147.91，135.93，132.02，129.62，126.09，110.06，108.61，101.48，55.26，38.14，6.87
Embodiment 11, when aromatic aldehyde is the 2-naphthaldehyde, make 3,5-(E)-two (2-naphthylidene)-N-cyclopropyl piperidine 4-ketone (compound 11), pale yellow powder, yield 82%, 199～202 ℃ of mp, ESI-MS:416.3 (M+1);
1H-NMR (400MHz, CDCl
3, ppm) δ: 7.99 (2H, s ,-CH=), 7.92～7.98 (4H, m, Ph-H), 7.88～7.85 (4H, m, Ph-H), 7.56～7.51 (6H, m, Ph-H), 4.14 (s, 4H ,-CH
2-), 2.02 (m, 1H ,-N-CH (CH
2)
2), 0.50-0.40 (m, 4H ,-CH (CH
2)
2).
13C-NMR (100MHz, CDCl
3, ppm) δ: 136.61,133.76,133.26,133.14,132.93,130.58,128.58,128.23,127.72,127.50,127.13,126.58,55.19,37.91,6.85
Embodiment 12, when aromatic aldehyde is the 4-tolyl aldehyde, make 3,5-(E)-two (4-methyl benzylidene)-N-cyclopropyl piperidine-4-ketone (compound 12), pale yellow powder, yield 88%, 196～199 ℃ of mp, ESI-MS:344.3 (M+1);
1H-NMR (400MHz, CDCl
3, ppm) δ: 7.76 (2H, s ,-CH=), 7.33 (4H, d, Ph-H, J=8Hz), 7.24 (4H, d, Ph-H, J=8Hz), 3.99 (s, 4H ,-CH
2-), 2.40 (s, 6H, Ph-CH
3) 1.95 (m, 1H ,-N-CH (CH
2)
2), 0.45-0.35 (m, 4H ,-CH (CH
2)
2).
13C-NMR (100MHz, CDCl
3, ppm) δ: 187.49,139.27,136.22,132.78,132.62,130.60,129.36,55.22,38.01,21.45,6.78
Embodiment 13
The detection of anti tumor activity in vitro:
The tumor cell line that uses has: human acute transformation of chronic myelocytic leukemia cell K562, and people's promyelocytic leukemia cell HL60, human colon cancer cell SW480, human colon cancer cell SW1116, above cell all derive from Chinese Academy of Sciences's Shanghai cell bank.
Cell cultures in the RPMI1640 that adds 10% calf serum cultivates, at 37 ℃, 5%CO
2Cultivate in the incubator, the vegetative period cell of taking the logarithm is used for experiment.
Some amount is in the cell of logarithmic phase, be inoculated in (attached cell is until adherent rear) in 96 orifice plates by certain density, experimental group adds respectively the tested medicine of different concns, control group adds with the concentration solvent, other establishes blank group and (only adds substratum, acellular), establish three parallel holes for every group, cultivate 48h for 37 ℃, add the MTT solution 20ul/ hole of 5mg/ml, after continuing to cultivate 4h, the centrifugal supernatant of abandoning adds DMSO 150ul, vibration 10min, fully after the cracking, detect absorbancy (OD570) value at 570nm place with full-automatic microplate reader (production of U.S. BIO-RAD company).Calculate inhibitory rate of cell growth according to absorbancy.Inhibitory rate of cell growth=[OD contrast-OD experiment]/[OD contrast-OD is blank] * 100%.
To the mapping of growth of tumour cell inhibiting rate, can obtain dose response curve with the different concns of same medicine, obtaining this medicine cell growth inhibiting rate according to equation of linear regression is that 50% concentration is half-inhibition concentration IC
50The results are shown in Table 1, the compound number 1～12 in the table 1 represents embodiment one～12 compounds that synthesized, and EF-24 is as contrast.As can be seen from Table 1,2 pairs of HL60 cell inhibitory activities of compound are stronger than EF-24,7 pairs of K562 cell inhibitory activities of compound are stronger than EF-24, compound 3,9 pairs of SW1116 cell inhibitory activities of compound are stronger than EF-24, illustrate that 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compounds can significantly suppress the propagation of various human tumour cell.Protection scope of the present invention is not limited only to above-described embodiment.
Table 13,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compounds is to the IC of cultured tumor cells in vitro
50(μ molL
-1)
| Compound number | K562 | HL60 | SW480 | SW1116 |
| 1 | 12.5 | 33.6 | 134 | 49.5 |
| 2 | 4.22 | 5.13 | 25.8 | 17.25 |
| 3 | 8.90 | 2.60 | ||
| 4 | 18.6 | 19.7 | 32.3 | 14.9 |
| 5 | 17.8 | 44.0 | 49.1 | 35.6 |
| 6 | 24.0 | 38.6 | ||
| 7 | 0.559 | 74.0 | ||
| 8 | 6.86 | 14.1 | ||
| 9 | 14.2 | 10.4 | ||
| 10 | 37.2 | 61.0 | ||
| 11 | 412 | 89.6 | ||
| 12 | 417 | 37.9 | ||
| EF-24 | 1.58 | 11.2 | 10.0 | 11.7 |
* the space is that compound is not done this cell strain
2 couples of mouse H22 of embodiment ten Four Modernizations compounds ascites hepatoma cells affects on the growth
Inoculated tumour cell according to a conventional method: get the abdominal cavity well-grown oyster white ascites of 6～8d that goes down to posterity, with normal saline dilution to 1 * 10
7Individual/mL, be inoculated in the right armpit of mouse with 0.2mL subcutaneous, animal random packet after the inoculation.Experiment is divided into 2 groups, and 10 every group, negative control group (giving the equivalent solvent), compound 2100mg/kg organize (compound 2 usefulness poloxamers are prepared into solid dispersion).Gastric infusion behind inoculation 24h, once a day, continuous 7d.Weigh in 8d, animal is put to death in the cervical vertebra dislocation.Peel off tumor tissues, weigh after blotting with filter paper.Calculate tumor control rate.
Tumour inhibiting rate=(1-experimental group knurl weight/negative control group knurl is heavy) * 100%
The restraining effect of 2 couples of mouse H22 of compound ascitic type subcutaneous transplantation knurl is obvious, and the inhibiting rate of 100mg/kg/d gavage is 48.4%, and difference has significance (P＜0.01) (the results are shown in Table 2, Fig. 1).
The restraining effect of 2 couples of mouse H22 of table 2 compound ascitic type liver cancer transplanted tumor
**：p＜0.01，*：p＜0.05 vs control.t test
Claims (8)
1. the compound of following general formula (I):
Wherein:
Substituent R on the phenyl in the following formula
1, R
2, R
3, R
4, R
5In have one at least for non-hydrogen substituting group; Described non-hydrogen substituting group is selected from alkyl, fluorine, chlorine, bromine substituent, the trifluoromethyl of methoxyl group, a 1-4 carbon independently of one another.
2. compound according to claim 1 is characterized in that the substituting group on the phenyl is the 2-methoxyl group; 2,5-dimethoxy; 3,4-dimethoxy; 2,4,5-trimethoxy; The 2-fluorine; 2-chlorine; The 2-bromine; The 4-methyl; The 2-trifluoromethyl.
3. following compounds:
4. be used for the treatment of antitumor medicine composition, wherein contain compound and the pharmaceutically acceptable carrier of any one in the claim 1～3 for the treatment of significant quantity.
5. the pharmaceutical composition that is used for the treatment of leukemia, colorectal carcinoma, skin carcinoma, cancer of the stomach, liver cancer, mammary cancer or prostate cancer wherein contains compound and the pharmaceutically acceptable carrier of any one in the claim 1～3 for the treatment of significant quantity.
6. the application of pharmaceutical composition claimed in claim 4 in preparation treatment leukemia, colorectal carcinoma, skin carcinoma, cancer of the stomach, liver cancer, mammary cancer or prostate cancer medicine.
7. the application of the compound of any one in the preparation antitumor drug in the claim 1～3.
8. application according to claim 7 is characterized in that tumour is leukemia, colorectal carcinoma, skin carcinoma, cancer of the stomach, liver cancer, mammary cancer or prostate cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010299621 CN102153508B (en) | 2010-10-08 | 2010-10-08 | 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone and application of the 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone in preparing antitumour drugs |
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| CN106083704B (en) * | 2016-06-06 | 2018-07-27 | 福建医科大学 | Application of-two aryl methylene-N- cyclopropyl piperidine -4- ketone compounds of 3,5- (E) as Hsp90 inhibitor |
| CN112955217A (en) * | 2018-08-29 | 2021-06-11 | 贝勒医学院 | Small molecule stimulators of steroid receptor co-activator-3 and methods of their use as cardioprotective and/or revascularizing agents |
| CN114907190A (en) * | 2021-02-10 | 2022-08-16 | 杭州师范大学 | Polyphenol compound based on meta-substituted phenol and preparation method and application thereof |
| CN114907189A (en) * | 2021-02-10 | 2022-08-16 | 杭州师范大学 | Polyphenol-substituted 3-aryl-2-aryl methacrylic compound and preparation method and application thereof |
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| 刘洋 等.3, 5-二亚苄基哌啶- 4-酮类化合物的合成及其体外抗肿瘤活性.《中国药物化学杂志》.2009,第19卷(第5期),全文. * |
| 刘洋等.3 5-二亚苄基哌啶- 4-酮类化合物的合成及其体外抗肿瘤活性.《中国药物化学杂志》.2009 |
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