CN103319403A - Tumor angiogenesis inhibitor jilintong, preparation method and uses thereof - Google Patents
Tumor angiogenesis inhibitor jilintong, preparation method and uses thereof Download PDFInfo
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- CN103319403A CN103319403A CN2013101712691A CN201310171269A CN103319403A CN 103319403 A CN103319403 A CN 103319403A CN 2013101712691 A CN2013101712691 A CN 2013101712691A CN 201310171269 A CN201310171269 A CN 201310171269A CN 103319403 A CN103319403 A CN 103319403A
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- 230000005747 tumor angiogenesis Effects 0.000 title abstract description 6
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- 229940121369 angiogenesis inhibitor Drugs 0.000 title abstract 3
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Abstract
The present invention provides a tumor angiogenesis inhibitor jilintong, a preparation method and uses thereof, and belongs to the technical field of medicine. Specifically the name is 2-hexa alkyl-3-methyl-4(1H)-quinolinone, the chemical formula is C16H21NO, and the tumor angiogenesis inhibitor is named jilintong. The invention further provides a preparation method of the compound, and a tumor angiogenesis inhibition effect of the compound. The jilintong is total synthesis. The compound represented by a formula I provides an inhibition effect for tumor angiogenesis, and has safety so as to provide possibility for development of a new tumor treatment drug.
Description
Technical field
The invention provides a kind of the have inhibiting novel quinoline ketone compound of neonate tumour blood vessel, Preparation Method And The Use, belong to medical technical field.
Background technology
Vasculogenesis (angiogenesis) refers to organize utilization both to deposit the process that blood vessel produces new blood vessel.Primary tumo(u)r has the ability of inducing new vessel to generate, and its growth and transfer all depend on tumor neovasculature generation.Tumor-blood-vessel growth has become brand-new, an antineoplaston target spot likely.The new vessel that destroys or suppress tumour generates, stop effectively the medicine of growth of tumor and transfer be referred to as the tumor neogenetic blood vessels formation inhibitor (tumor angiogenesis inhibtor, TAI).
Compare with the conventional cell drug toxicity, TAI has its advantage or characteristics, and is better as specificity; Can directly play a role, and effect has amplification; Be difficult for producing resistance; Toxic side effect is less, and the effect that also has prophylaxis of tumours recurrence and shift becomes one of the emphasis of present drug research and focus.
Since 1962 find first Comprecin Nalidixic Acid that contains 4-quinolinone parent nucleus, many scholars are devoted to research and develop this class medicine, particularly obtained the leap progress surplus in the of nearly ten over year, developed the 4th generation quinolones, be used for the treatment of Gram-negative bacteria and part gram-positive microorganism.In the prior art, many parts of documents disclose quinolinone and uses thereof.For example, CN1391896 discloses a kind of antianaphylactic novel quinoline ketone compound, CN1150420 discloses 4-qualone derivative and salt thereof and has been used for the recycle system and respiratory system disease, and CN1056305 discloses a kind of new 4(1H) quinoline ketone derivative is used for the treatment of the cardiovascular system respiratory system disease of unifying.
Up to now, do not see and the novel quinoline ketone that is used for the treatment of tumour of the present invention.
Summary of the invention
At the prior art above shortcomings, technical problem to be solved by this invention provides a kind of novel quinoline ketone compound that is used for the treatment of tumour.
Another object of the present invention provides the preparation method of this quinolinone compounds.
Solve the problems of the technologies described above, the present invention adopts following technical scheme:
The own quinoline ketone of a kind of neonate tumour blood vessel inhibitor is characterized in that, its structural formula is suc as formula I, and its name is called 2-hexyl-3-methyl-4(1H)-quinolinone, and its chemical formula is C
16H
21NO, the own quinoline ketone of called after.
Ⅰ
Further, the own quinoline ketone of described neonate tumour blood vessel inhibitor is amorphous substance or crystal type.
Further, the own quinoline ketone of described neonate tumour blood vessel inhibitor is used for preventing and/or treating the medicine of tumour.
The preparation method of the own quinoline ketone of described neonate tumour blood vessel inhibitor comprises the steps:
(1) get adjacent PAPP 13mmol, oenanthyl chloro 20mmol puts in the two neck round-bottomed flasks of 250ml, add pyridine 18mmol, methylene dichloride 60-80ml, at room temperature stirring reaction 4-20 hour, add saturated ammonium chloride solution 60-100ml, get organic phase, concentrating under reduced pressure, residual thing silica gel column chromatography, collect object, concentrating under reduced pressure, drying obtains the heptanamido Propiophenone;
(2) with step (1) heptanamido Propiophenone 11mmol, put in the two neck round-bottomed flasks of 250ml, add tertiary butyl sodium alkoxide 30-40mmol, anhydrous organic solvent 180-240ml, back flow reaction 4-36 hour, concentrating under reduced pressure reclaimed ethanol, adds water 100-200ml wash-out once, residual thing silica gel column chromatography, collect object, concentrating under reduced pressure, drying, obtain 2-hexyl-3-methyl-4(1H)-quinolinone, be formula I compound.
In the present invention, term " treatment " has its general implication, and refer to especially adopt formula I compound of the present invention or pharmaceutical composition to handle to tumour patient at this paper, in the hope of effect such as described tumor disease patient is produced treatment, cure, alleviate, alleviate.Similarly, as used herein, term " prevention " has its general implication, and refer to especially adopt formula I compound of the present invention or pharmaceutical composition to handle to suffering from tumor disease of the present invention or tumor disease of the present invention being had the risk person of suffering from this paper, prevent in the hope of described tumor disease is produced, prevent, stop, effect such as partition.As used herein, term " tumor disease " has the general sense of its medical field.
Formula I compound of the present invention, through physical and chemical property determining, ultraviolet, infrared, mass spectrum and NMR (Nuclear Magnetic Resonance) spectrum are resolved, and finally prove conclusively its structure.
The present invention discovers in the Ministry of Science and Technology that the applicant bears great new drug initiative scientific research project, through testing the conclusive evidence formula repeatedly
IHas the neonate tumour blood vessel restraining effect.To formula
IThe compound exploitation will bring glad tidings to tumour patient, and prospects for commercial application of the present invention is very good.
Description of drawings
Fig. 1 is blank group Photomicrograph;
Fig. 2 is that blank contains DMSO group Photomicrograph;
Fig. 3 is positive drug group Photomicrograph;
Fig. 4 is formula I treatment group Photomicrograph;
Fig. 5 is blank group flow cytometry peak value;
Fig. 6 adds DMSO blank group flow cytometry peak value;
Fig. 7 is formula I treatment group flow cytometry peak value.
Embodiment
For showing effect of the present invention, further specify the present invention below by specific embodiment and test example.But, should be understood to, these embodiment or test example are only used for the more detailed usefulness that specifically describes, and should not be construed as for limiting the present invention in any form.
The present invention carries out general and or concrete description to the material and the test method that use in the test.Though for realizing that the employed many materials of the object of the invention and working method are well known in the art, the present invention still does to describe in detail as far as possible at this.Those skilled in the art know that hereinafter, if do not specify that material therefor of the present invention and working method are well known in the art.
Embodiment 1, and the synthetic own quinoline ketone of neonate tumour blood vessel inhibitor of preparation comprises following steps:
1, get adjacent PAPP 13mmol, oenanthyl chloro 20mmol puts in the two neck round-bottomed flasks of 250ml, add pyridine 18mmol, methylene dichloride 60-80ml, at room temperature stirring reaction 4-20 hour, add saturated ammonium chloride solution 60-100ml, get organic phase, concentrating under reduced pressure, residual thing silica gel column chromatography, collect object, concentrating under reduced pressure, drying obtains the heptanamido Propiophenone;
2, the heptanamido Propiophenone 11mmol that step 1 is obtained puts in the two neck round-bottomed flasks of 250ml, adds tertiary butyl sodium alkoxide 30-40mmol, anhydrous organic solvent 180-240ml, back flow reaction 4-36 hour, concentrating under reduced pressure reclaimed ethanol, adds water 100-200ml wash-out once, residual thing silica gel column chromatography, collect object, concentrating under reduced pressure, drying, obtain 2-hexyl-3-methyl-4(1H)-quinolinone, be formula I compound.
Detected result: unformed powder, crystallization obtains tabular crystal in methyl alcohol or the ethanol, fusing point: 231-233 ℃, IR υ
Cm
-1: 3500(NH), 1740 (C=O); ESI-MS m/z [M+H]
+: 242;
1H NMR (DMSO-
d6,500 MHz): 8.24 (d,
J=8.0 Hz, 1H), 7.43-7.52 (m, 2H), 7.22 (t,
J=8.0 Hz, 1H), 2.06 (s, 3H), 1.56 (m, 2H), 1.20-1.29 (m, 8H), 0.80 (t,
J=6.0 Hz, 3H);
13C NMR (DMSO-
d6,500MHz): 177.2,139.0,131.1,125.3,123.3,123.0,117.6,115.1,71.8,49.6,49.4,49.2,32.6,31.4,29.1,28.7,27.7,22.4,19.0,13.8,10.5.
The final conclusive evidence of above-mentioned synthetic The compounds of this invention is 2-hexyl-3-methyl-4(1H)-quinolinone, and chemical formula is C
16H
21NO.The own quinoline ketone of called after generically.Chemical structure is as follows:
Biological test 1:Tubule forms the restraining effect that the measuring qualone derivative forms new vessel:
Human umblilical vein endothelial EA.hy926 cell strain draws the cell bank from typical case's culture collection council of the Chinese Academy of Sciences; The RPMI1640 substratum is Hyclone company product; Foetal calf serum is Gibco company product; Matrigel is BD company product, and positive drug SU5416 is Merck company product; Inverted microscope and image software system (Japan, Nikon company); Formula I is with DMSO dissolving and to be diluted to respective concentration standby.Human umblilical vein endothelial EA.hy926 cell strain is that the immortality cell strain that the back produces is merged in epithelium A549 clone and Human umbilical vein endothelial cells hybridization, (contains 10% inactivated fetal bovine serum, 10 with the RPMI1640 substratum
5The U/L penicillin and streptomycin) in 37 ℃, saturated air humidity, contain 5% CO
2Incubator in the routine cultivation of going down to posterity.Getting artificial basilar membrane (Matrigel) places in 4 ℃ of ice baths, the first-class use articles for use of 96 well culture plates, application of sample rifle that use are remained on 0 ℃, Matrigel behind the mixing is joined in 96 well culture plates, each hole adds 50 ul, shakeout, place 1 h for 37 ℃, with pancreas enzyme-EDTA digestion EA.hy926 cell, every hole places 10
4Individual cell is put 37 ℃, 5%CO
2Incubator is cultivated, and giving concentration is 6 * 10
-5The positive drug SU5416(VEGF acceptor FLK-1/KDR tyrosine-kinase enzyme inhibitor of the qualone derivative 1-7 sample of M and concentration 1 μ M) directly adds in the substratum, cultivate and observe the restraining effect that qualone derivative forms new vessel behind 18 h.When qualone derivative concentration is 6 * 10
-5During M, compare with solvent control with the normal control group, formula I group almost can not form complete lumen of vessels (seeing Fig. 1-4).
Biological test 2:Flow cytometry is measured the influence of qualone derivative to the EA.hy926 cell strain cell cycle:
Get EA.hy926 cell exponential phase of growth, centrifugal 5 min of 1000 rpm with the RPMI1640 substratum that contains 10% foetal calf serum, make cell suspension after the abandoning supernatant, and being diluted to concentration behind the counting is 10
5The cell suspension of individual cell/ml is inoculated in the culturing bottle, the 5ml/ bottle, and after hungry synchronization 24 h of serum free medium, giving concentration is 6 * 10
-5The qualone derivative 1-7 sample of M, collecting cell behind continuation effect 24 h.During collecting cell, after cell in the culturing bottle scraped with cell, be transferred to centrifuge tube, the centrifugal 5min of 1000 rpm, cell precipitation is washed 70% ice ethanol fixed cell of the precooling (being stored in 4 ℃) of cell twice, 2 ml with PBS liquid, dropwise add ice ethanol during fixed cell, and constantly vibration guarantees that cell suspension does not evenly become agglomerate, fixedly spends the night centrifugation in 4 ℃, abandon supernatant, 200 ul propidium iodide dye liquor re-suspended cells add the RNA enzyme simultaneously, fully mixing, 4 ℃ leave standstill 30 min, detect period profile situation (each sample counting 2 * 10 of cell with flow cytometer FL2 passage
4Individual cell).Find that by flow cytometry in the normal control group, nearly 58.1% and 8.43% cell is distributed in G0/G1 and G2/M phase respectively, and through 6 * 10
-5After the formula I of M handled, the G2/M phase, shared cell proportion rose to 17.85% respectively, and the corresponding decline of G0/G1 phase cell proportion (seeing Fig. 5-7), these results suggest Human umbilical vein endothelial cells strains are arrested in the G2/M phase by qualone derivative.
The applicant chances on the formula I and has the neonate tumour blood vessel restraining effect in bearing national great new drug initiative subject study, thereby overcome to have showed technological deficiency is arranged, and provides possibility for the present invention is used for the treatment of tumor disease.
In yet another aspect, the own quinoline ketone of neonate tumour blood vessel inhibitor in pharmaceutical composition of the present invention or the medicine box product can with one or more nontoxic physiology can tolerance or acceptable diluent, carrier, auxiliary material or vehicle (this paper can be referred to as carrier with them〉be mixed with composition, with solid or liquid form oral administration or topical etc., be used for preventing and/or treating the medicine of tumour.Formula I compound in pharmaceutical composition of the present invention or the medicine box product also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.
Need to prove at last, above embodiment is only in order to illustrate technical scheme of the present invention but not the restriction technologies scheme, those of ordinary skill in the art is to be understood that, those are made amendment to technical scheme of the present invention or are equal to replacement, and do not break away from aim and the scope of the technical program, all should be encompassed in the middle of the claim scope of the present invention.
Claims (5)
1. the own quinoline ketone of neonate tumour blood vessel inhibitor is characterized in that its chemical structure is the formula I, and its name is called 2-hexyl-3-methyl-4(1H)-quinolinone, and its chemical formula is C
16H
21NO, the own quinoline ketone of called after;
Ⅰ。
2. the own quinoline ketone of neonate tumour blood vessel inhibitor according to claim 1 is characterized in that, the formula I is amorphous substance or crystal type.
3. the own quinoline ketone of neonate tumour blood vessel inhibitor according to claim 1 and 2 is characterized in that having the angiogenesis restraining effect, in the medicine that prevents and/or treats tumor disease.
4. one kind prepares the preparation method of the own quinoline ketone of neonate tumour blood vessel inhibitor according to claim 1, it is characterized in that, comprises the steps:
(1) get adjacent PAPP 13mmol, oenanthyl chloro 20mmol puts in the two neck round-bottomed flasks of 250ml, add pyridine 18mmol, methylene dichloride 60-80ml, at room temperature stirring reaction 4-20 hour, add saturated ammonium chloride solution 60-100ml, get organic phase, concentrating under reduced pressure, residual thing silica gel column chromatography, collect object, concentrating under reduced pressure, drying obtains the heptanamido Propiophenone;
(2) with step (1) heptanamido Propiophenone 11mmol, put in the two neck round-bottomed flasks of 250ml, add tertiary butyl sodium alkoxide 30-40mmol, anhydrous organic solvent 180-240ml, back flow reaction 4-36 hour, concentrating under reduced pressure reclaimed ethanol, adds water 100-200ml wash-out once, residual thing silica gel column chromatography, collect object, concentrating under reduced pressure, drying, obtain 2-hexyl-3-methyl-4(1H)-quinolinone, be formula I compound.
5. according to the preparation method of the own quinoline ketone of the described neonate tumour blood vessel inhibitor of claim 4, it is characterized in that described synthesis step 1 reacts under 10-30 ℃; Described synthesis step 2 refluxes under 60-80 ℃ temperature, preferred 5 to 8 hours of described backflow.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310171269.1A CN103319403B (en) | 2013-05-10 | 2013-05-10 | Own quinoline ketone of a kind of neonate tumour blood vessel inhibitor and its production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310171269.1A CN103319403B (en) | 2013-05-10 | 2013-05-10 | Own quinoline ketone of a kind of neonate tumour blood vessel inhibitor and its production and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103319403A true CN103319403A (en) | 2013-09-25 |
| CN103319403B CN103319403B (en) | 2016-03-30 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103664777A (en) * | 2013-10-09 | 2014-03-26 | 重庆理工大学 | 2-undecyl-3-methyl-hydroxyl-quinoline compound as well as preparation method, pharmaceutical composition and use thereof |
| CN110286080A (en) * | 2018-10-25 | 2019-09-27 | 中国科学院苏州生物医学工程技术研究所 | Ejaculated sperm cells rapid typing detection reagent box and detection method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664777A (en) * | 2013-10-09 | 2014-03-26 | 重庆理工大学 | 2-undecyl-3-methyl-hydroxyl-quinoline compound as well as preparation method, pharmaceutical composition and use thereof |
| CN110286080A (en) * | 2018-10-25 | 2019-09-27 | 中国科学院苏州生物医学工程技术研究所 | Ejaculated sperm cells rapid typing detection reagent box and detection method |
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