CN108752315A - 3- benzimidazolyl-2 radicals (1H)-quinolinone-ytterbium complex and its preparation method and application - Google Patents

3- benzimidazolyl-2 radicals (1H)-quinolinone-ytterbium complex and its preparation method and application Download PDF

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Publication number
CN108752315A
CN108752315A CN201810729524.2A CN201810729524A CN108752315A CN 108752315 A CN108752315 A CN 108752315A CN 201810729524 A CN201810729524 A CN 201810729524A CN 108752315 A CN108752315 A CN 108752315A
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China
Prior art keywords
preparation
compound
complex
quinolinone
benzimidazolyl
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CN201810729524.2A
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Chinese (zh)
Inventor
张业
段小群
李芳耀
徐燕丽
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Guilin Medical University
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Guilin Medical University
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

Abstract

The invention discloses a kind of 3- benzimidazolyl-2 radicals (1H)-quinolinone-ytterbium complexes and its preparation method and application.The preparation method of the complex mainly includes the following steps that:Take compound and ytterbium nitrate hexahydrate or ytterbium nitrate pentahydrate shown in following formula (II) to be placed in organic solvent, under the conditions of being heated or not heated carry out complexation reaction to get.Complex of the present invention is suitable with tumor Drugs cis-platinum to the inhibitory activity of certain cell strains, while it is substantially less than cis-platinum to the toxicity of normal cell, is expected to be used for the preparation of antitumor drug.Shown in the structure of complex of the present invention such as following formula (I), the structure for preparing compound shown in the raw material formula (II) involved in the complex is as follows:

Description

3- benzimidazolyl-2 radicals (1H)-quinolinone-ytterbium complex and its preparation method and application
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of 3- benzimidazolyl-2 radicals (1H)-quinolinone-ytterbium complex and Preparation method and application.
Background technology
Since cis-platinum, carboplatin are developed into anticancer drug, the design of platinum metals base anticancer drug and screening by The highest attention of people.But in research and development in past more than 30 years, still without developing the platinum metals base for surmounting cis-platinum curative effect Anticancer drug, and platinum series antineoplastic medicament existing defects (toxic side effect big and drug resistance), therefore pharmaceutical chemists are sight Invest non-platinum metals complex.The design and synthesis of lanthanide series metal base antitumor drug are that one of people's highest attention is important The research hotspot that lanthanide series metal base anti-tumor complex efficiently, less toxic is current is researched and developed in direction.3- benzos are had not yet to see The relevant report of the preparation method of imidazoles -2 (1H)-quinolinone-ytterbium complex and its application.
Invention content
The technical problem to be solved in the present invention is to provide a kind of structure novel, to certain cytotoxicities with it is common anti-swollen Tumor medicine cis-platinum is suitable, but its 3- benzimidazolyl-2 radicals (1H)-quinolinone-ytterbium complex lower to normal liver cell toxicity, with And its preparation method and application.
The present invention relates to compound shown in following formula (I)s or its pharmaceutically acceptable salts:
The present invention also provides the preparation methods of above compound, mainly include the following steps that:Take following formula (II) shownization Close object and ytterbium nitrate hexahydrate (Yb (NO3)3·6H2) or ytterbium nitrate pentahydrate (Yb (NO O3)3·5H2O it) is placed in organic molten In agent, complexation reaction is carried out under the conditions of being heated or not heated to get target product;
In above-mentioned preparation method, compound shown in the formula (II) is that 3- benzimidazolyl-2 radicals (1H)-quinolinone can be according to public affairs The number of opening be CN105622574A patent of invention prepared, also can designed, designed synthetic route synthesized.Specifically it can be used Following methods are synthesized:
3- benzaldehydes -2 (1H)-quinolinone is stoichiometrically taken (to can refer to the invention of Publication No. CN105622574A It is prepared by patent) and o-phenylenediamine to be placed in polar solvent (can be specifically one kind in methanol, ethyl alcohol, toluene and DMF Or two or more combinations) in back flow reaction (about 4-8h), it is after reaction, cooling, have solid that (yellow crystals or powder is precipitated End), collect solid, it is dry to get to compound 3- benzimidazolyl-2 radicals (1H)-quinolinone shown in the formula (II), specifically Synthetic route is as follows:
In above-mentioned preparation method, compound and ytterbium nitrate hexahydrate or ytterbium nitrate pentahydrate shown in the formula (II) Molar ratio is stoichiometric ratio, in actual operation, compound and ytterbium nitrate hexahydrate or ytterbium nitrate five shown in formula (II) Hydrate also can be relatively excessive, but it is excessive can cause to post-process cumbersome or products therefrom it is impure.
In above-mentioned preparation method, the organic solvent can be selected from methanol, ethyl alcohol, chloroform, dichloromethane, toluene and The combination of one or more of DMF.When organic solvent is when being selected as mixtures two or more in above-mentioned selection, it Between proportioning can be arbitrary proportioning.The dosage of the organic solvent can determine as needed.In specific dissolving step, Compound shown in formula (II) and ytterbium nitrate hexahydrate or ytterbium nitrate pentahydrate can be dissolved with organic solvent respectively, be remixed It reacts together;Also again with having after compound shown in formula (II) and ytterbium nitrate hexahydrate or ytterbium nitrate pentahydrate being mixed Solvent dissolves.The dosage of the organic solvent is advisable with that can dissolve the raw material participated in and reacted, it is generally the case that with 1mmol's It is calculated on the basis of compound shown in formula (II), all raw materials for participating in reaction are dissolved with the organic solvent of 5-8mL.
Solwution method can be used in specific prepare in 3- benzimidazolyl-2 radicals (1H)-quinolinone-ytterbium complex of the present invention Or prepared by solvent-thermal method.No matter using which kind of method, reaction preferably carries out under conditions of >=40 DEG C, more preferably exists It is carried out under the conditions of 60-110 DEG C, when reaction carries out in this preferred range, the time of reaction is usually 48-72h.Into one The preferred reaction of step carries out in autoclave, can directly obtain the target product of lenticular in this way.
The invention also includes above-mentioned 3- benzimidazolyl-2 radicals (1H)-quinolinone-ytterbium complex or its pharmaceutically acceptable salts Application in preparation of anti-tumor drugs.
The present invention further comprises a kind of pharmaceutical composition, it contains the above-mentioned 3- benzimidazolyl-2 radicals of the upper effective dose for the treatment of (1H)-quinolinone-ytterbium complex or its pharmaceutically acceptable salt.
Compared with prior art, the present invention provides a kind of 3- benzimidazolyl-2 radicals (1H)-quinolinone-ytterbiums of structure novel to match Object is closed, short preparation period, yield is high, stable quality;Our experimental result show that the complex is to certain cell strains Inhibitory activity (such as people ovary adenocarcinoma cells SK-OV-3, Human skin melanoma cell A375 suitable with tumor Drugs cis-platinum With Non-small cell lung carcinoma cell A549), while it is substantially less than cis-platinum to the toxicity of normal cell, is expected to be used for antineoplastic The preparation of object.
Description of the drawings
Fig. 1 is the crystal structure figure of final product made from the embodiment of the present invention 1.
Specific implementation mode
With reference to specific embodiment, the present invention is described in further detail, to more fully understand present disclosure, but The present invention is not limited to following embodiments.
Compound (i.e. 3- benzimidazolyl-2 radicals (1H)-quinolinone) shown in formula (II) involved in following embodiment is by following Method is prepared:
- 2 (1H)-quinolinone of equimolar 3- benzaldehydes and o-phenylenediamine is taken to flow back in methyl alcohol 4h, it is cold after reaction But, there is solid precipitation, filter, collect solid, it is dry to get to compound 3- benzimidazolyl-2 radicals shown in the formula (II) (1H)-quinolinone (yellow powder) Yield, 80.2%;1H NMR(400MHz,DMSO-d6)δ12.66(s,1H,NH),12.48 (s, 1H, NH), 9.13 (s, 1H, HC=C), 7.97 (d, J=7.3Hz, 1H, H-Ar), 7.73 (s, 1H, H-Ar), 7.67 (s, 1H, H-Ar), 7.62 (s, 1H, H-Ar), 7.45 (d, J=8.2Hz, 1H, H-Ar), 7.30 (s, 1H, H-Ar), 7.22 (d, J= 6.1Hz,2H,H-Ar);13C NMR(101MHz,DMSO-d6)δ161.26,148.19,143.24,139.56,139.15, 134.90,132.08,129.53,123.13,122.75,122.39,120.48,119.62,118.76,115.72,113.26; ESI-HRMS,calculated m/zfor C16H11N3O[M+H]+:262.0980,found:262.0986.。
Embodiment 1
By compound (10mmol) shown in 0.261g formulas (II) and 0.50g (11mmol) Yb (NO3)3·6H2O, 10mL dichloros It is fitted into autoclave in methane and 10mL methanol, 72h is reacted under the conditions of 110 DEG C, has light yellow crystal precipitation after cooling, Crystal is collected, it is dry, obtain light yellow crystal 27.57mg, yield 56.15%.
The characterizations such as infrared, mass spectrum and X- single crystal diffractions are carried out to this implementation products therefrom, it is specific as follows:
(1)IR(KBr):3432 (m, NH), 2967,2923 (w, Ar-H), 2289 (w, C=C), 1634 (m, C=O), 1631(m,Ar-H)cm–1
(2)MS m/z:848[Yb(L)2(NO3)(DMF)(H2O)]+, wherein L is compound shown in ligand, that is, formula (II), matter Stave is levied using DMF as solvent.
(3) gained yellow crystals are parsed through X-Ray single crystal diffractions, crystallographic data is as described in Table 1, part key Long and bond angle is as described in Table 2, and the crystal structure of products therefrom is as shown in Figure 1.
Table 1:The crystallography and structural modifications data of product
Table 2:The part bond distance of productWith bond angle [°]
Accordingly, it can be determined that light yellow crystal obtained by the present embodiment is target product 3- benzimidazolyl-2 radicals (1H)-quinolinone-ytterbium Complex, shown in structural formula such as following formula (I):
Embodiment 2
By compound (20mmol) shown in 0.522g formulas (II) and 1.00g (22mmol) Yb (NO3)3·6H2O, 20mL dichloros Methane is fitted into autoclave, and 48h is reacted at 90 DEG C, there is light yellow crystal precipitation after cooling, collects crystal, dry, is obtained To light yellow crystal 49.10mg, yield 50.00%.
Infrared, mass spectrum and the analysis of X-ray single crystal diffraction are carried out to the present embodiment products therefrom, determine production obtained by the present embodiment Object is target compound.
Embodiment 3
By compound (10mmol) shown in 0.261g formulas (II) and 0.50g (11mmol) Yb (NO3)3·6H2O, 10mL methanol It is fitted into autoclave, 56h is reacted at 100 DEG C, there is light yellow crystal precipitation after cooling, collect crystal, it is dry, it obtains light Yellow crystals 27.00mg, yield 55.00%.
Infrared, mass spectrum and the analysis of X-ray single crystal diffraction are carried out to the present embodiment products therefrom, determine production obtained by the present embodiment Object is target compound.
Embodiment 4
By compound (20mmol) shown in 0.522g formulas (II) and 1.00g (22mmol) Yb (NO3)3·6H2O, 15mL dichloros It is fitted into autoclave in methane and 5mL methanol, 72h is reacted at 40 DEG C, there is light yellow crystal precipitation after cooling, collected brilliant Body, it is dry, obtain light yellow crystal 19.64mg, yield 20.00%.
Infrared, mass spectrum and the analysis of X-ray single crystal diffraction are carried out to the present embodiment products therefrom, determine production obtained by the present embodiment Object is target compound.
Embodiment 5
By compound (20mmol) shown in 0.522g formulas (II) and 1.00g (22mmol) Yb (NO3)3·6H2O, 12mL chloroforms It is fitted into autoclave in 8mL ethyl alcohol, 72h is reacted at 100 DEG C, there is light yellow crystal precipitation after cooling, collects crystal, It is dry, obtain light yellow crystal 56.17mg, yield 57.20%.
Infrared, mass spectrum and the analysis of X-ray single crystal diffraction are carried out to the present embodiment products therefrom, determine production obtained by the present embodiment Object is target compound.
Embodiment 6
Embodiment 3 is repeated, unlike, reaction temperature is room temperature, with Yb (NO3)3·5H2O replaces Yb (NO3)3·6H2O。
Finally obtain light yellow crystal 3.93mg, yield 8.00%.
Infrared, mass spectrum and the analysis of X-ray single crystal diffraction are carried out to the present embodiment products therefrom, determine production obtained by the present embodiment Object is target compound.
Experimental example 1:Target compound of the present invention tests the anti tumor activity in vitro of a variety of human tumor cell lines:
The antitumor action of 3- benzimidazolyl-2 radicals (1H)-quinolinone-ytterbium complex to illustrate the invention, applicant couple The antitumor activity experiment (with common antitumor drug cis-platinum (Cis-platin) for reference) that complex has carried out, and to upper Chemical combination development made from embodiment is stated to the toxicity test of normal cell.
Mtt assay ([4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazoliumbromide) i.e. four The micro enzyme reaction colorimetric method of methyl- azoles salt.By the preferable test-compound of primary dcreening operation antitumous effect with DMSO hydrotropies after, make Half-and-half be diluted to successively with complete medium five gradients, 20 times of final concentrations working solution, remove drug concentration between each gradient Different outer, the uniform content of cosolvent DMSO causes.The filtering with microporous membrane degerming for using d=0.22 μm of diameter again, is placed at 4 DEG C and protects It deposits.
The panel of tumor cell strain in exponential phase is inoculated in 96 orifice plates, cell respectively with 190 μ L of every hole respectively Concentration is about 0.5 × 104/ hole cultivates 12 hours, after cell is adherent, is separately added into the test-compound of various concentration, per hole 10 μ L, it is respectively 12 μ g/mL, 6 μ g/mL, 3 μ g/mL, 1.5 μ g/mL and 0.75 μ g/mL to make its final concentration, and each gradient is parallel to be set 4 multiple holes, wherein DMSO final concentration≤0.5%, while setting corresponding negative control group and (there was only cell and equivalent in culture solution DMSO, no drug) and blank control group (there was only the drug of equivalent in culture solution, acellular), each group is also parallel to set 4 again Hole, drug treating time are 48 hours.Culture terminates 10 μ L MTT (5mg/mL PBS) to be added per hole in first 4 hours, continues culture 4 After hour, incline culture solution, and 150 holes μ L/ DMSO are added, and plate shaker vibrates 5min, so that crystal is fully dissolved, blank Control group returns to zero, and measures absorbance (A) value after removal background absorbance value with 570nm/630nm dual wavelengths with microplate reader, then The IC of 11 kinds of tumor cell lines of each compound pair is calculated separately with Bliss methods50Value, all experiments are averaged after being repeated 3 times.It is real It tests the results detailed in the following table 3.
Table 3:Semi-inhibit rate concentration (C of the compound to different tumor cell lines50, μM)
It indicates without activity.
From the data in table 3, complex to people's ovary adenocarcinoma cells SK-OV-3, Human skin melanoma cell A375, Non-small cell lung carcinoma cell A549 shows good sensibility, and inhibitory activity is superior to common antitumor drug cis-platinum, and It is to the toxicity of people's normal cell lines of human liver HL-7702 significantly less than cis-platinum.The above result shows that by by 3- benzimidazolyl-2 radicals (1H)-quinolinone occurs complexation reaction with zinc and 3- benzimidazolyl-2 radicals (1H)-quinolinone-ytterbium complex is made, and can filter out efficiently Object is closed in the new antitumoral cooperation of low toxicity.

Claims (7)

1. compound or its pharmaceutically acceptable salt shown in following formula (I)s:
2. the preparation method of compound described in claim 1, it is characterised in that:It mainly includes the following steps that:Take following formula (II) Shown compound and ytterbium nitrate hexahydrate or ytterbium nitrate pentahydrate are placed in organic solvent, under the conditions of being heated or not heated Complexation reaction is carried out to get target product;
3. the preparation method of compound according to claim 1, it is characterised in that:The organic solvent be selected from methanol, The combination of one or more of ethyl alcohol, chloroform, dichloromethane, toluene and n,N-Dimethylformamide.
4. the preparation method of compound according to claim 1, it is characterised in that:It is described reaction under conditions of >=40 DEG C into Row.
5. the preparation method of compound according to claim 1, it is characterised in that:It is described reaction under the conditions of 60-110 DEG C into Row.
6. compound described in claim 1 or its pharmaceutically acceptable salt application in preparation of anti-tumor drugs.
7. a kind of pharmaceutical composition, it is characterised in that:Compound or its medicine described in claim 1 containing the upper effective dose for the treatment of Acceptable salt on.
CN201810729524.2A 2018-07-05 2018-07-05 3- benzimidazolyl-2 radicals (1H)-quinolinone-ytterbium complex and its preparation method and application Pending CN108752315A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113024584A (en) * 2021-03-24 2021-06-25 玉林师范学院 8-hydroxyquinoline complex for treating lung cancer and preparation method thereof
CN113024584B (en) * 2021-03-24 2022-04-19 玉林师范学院 8-hydroxyquinoline complex for treating lung cancer and preparation method thereof

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