CN108033912A - Low 1,8- Naphthalamide derivatives of a kind of toxicity and its preparation method and application - Google Patents
Low 1,8- Naphthalamide derivatives of a kind of toxicity and its preparation method and application Download PDFInfo
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- CN108033912A CN108033912A CN201711467388.6A CN201711467388A CN108033912A CN 108033912 A CN108033912 A CN 108033912A CN 201711467388 A CN201711467388 A CN 201711467388A CN 108033912 A CN108033912 A CN 108033912A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
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Abstract
The invention discloses 1,8 low Naphthalamide derivatives of a kind of toxicity and its preparation method and application.The preparation method of 1,8 Naphthalamide derivatives mainly includes the following steps that：Take Amonafide and 3 fluorobenzoyl chlorides to be dissolved in organic solvent, reacted, remove solvent after reaction, up to object crude product.Our experiments show that, the derivative has notable biological activity, significant inhibitory activity is particularly respectively provided with to non-small cell lung cancer cell strain HCC 827 and other tumor cell lines, and to the toxic side effect smaller of human normal cell line, is expected to exploitation into target therapeutic agent.Shown in the structure such as following formula (I) of 1,8 Naphthalamide derivatives of the present invention：
Description
Technical field
The present invention relates to low 1,8-naphthalimide derivative of a kind of toxicity and its preparation method and application, belong to doctor
Medicine technical field.
Background technology
Naphthalimide analog derivative has unique plane rigid structure, it is possessed the ability of the stronger intercalation of DNA, more
Come it is more researches show that naphthalimide and its derivative have good antitumor activity, its have to DNA molecular compared with
High affinity, can be combined by Insertion action with DNA, suppress to show micromole in the experiment of growth of tumour cell in vitro
The IC of rank50, but their toxic side effects to normal cell are also larger.
At present, having been enter into the naphthalimide derivative of clinical research has mitonafide (mitonafide), Amonafide
(amonafide), elinafide (elinafide) and bisnafide (bisnafide).The structure of wherein Amonafide is as follows
State shown in formula (II)：
Existing research shows that research of the Amonafide to breast cancer once entered II phases clinic, but was used as chemotherapeutics, its
There is certain adverse reaction to people's marrow；N- acetyl ammonia is easily generated by N- acetyltransferases II (NAT2) acetylation in vivo
The non-spy of naphthalene, the acetylate can produce uncertain toxic side effect because individual difference is metabolized in vivo, it is stayed at present
The clinical research of III phase.Therefore, it is desirable to synthesizing to obtain both has notable biological activity, the new naphthoyl Asia of toxic side effect smaller
Aminated compounds.
The content of the invention
1,8- naphthalene two formyl preferable and low toxicity the technical problem to be solved in the present invention is to provide a kind of bioactivity is sub-
Amine derivative, and its preparation method and application.
The present invention relates to compound shown in lower formula (I) or its pharmaceutically acceptable salt：
The chemical name of compound shown in above-mentioned formula (I) is N- (2-N, N- dimethylamino) ethylamino- -3- (3- fluorobenzoyls
Amido) -1,8-naphthalimide, molecular weight 405.1.
The synthetic method of compound, mainly includes the following steps that shown in above-mentioned formula (I)：Take Amonafide and 3- fluorobenzoyls
Chlorine is dissolved in organic solvent, is reacted, and removes solvent after reaction, up to object crude product.
In above-mentioned synthetic method, the organic solvent can be specifically to be selected from acetonitrile, dichloromethane chloroform and tetrahydrochysene furan
Combination more than one or both of muttering.When the combination of the selected as above two above material of organic solvent, they
Proportioning can be any proportioning.The dosage of the organic solvent can determine as needed, it is generally the case that with the ammonia naphthalene of 1mmol
It is non-specially for benchmark, all raw materials for participating in reaction share the organic solvent of 6-10mL to dissolve.In specific dissolving step
In, it is excessively violent in order to avoid reacting, after preferably Amonafide and 3- fluorobenzoyl chlorides are dissolved with organic solvent respectively again
Reaction is mixed by the way of being added dropwise or being slowly added to.
It is more violent due to reacting in above-mentioned synthetic method, to avoid slug, preferably react under conditions of less than 20 DEG C
Carry out, more preferably react and carried out under condition of ice bath.Whether reaction can pass through TLC tracing detections completely.When reaction is in ice bath
Under the conditions of when carrying out, react to the time of about 1-3h completely.
In above-mentioned synthetic method, in order to further improve reaction yield, preferably react and carried out under the conditions of atmosphere protection, have
Body can carry out under nitrogen or inert gas (such as argon gas, neon, argon gas) protective condition.
Raw material Amonafide involved in synthetic method of the present invention directly can be obtained commercially, can also be joined
Examine existing literature Van Q E, Mahieu T, Dumont P, et al.2,2,2-Trichloro-N- ({ 2- [2-
(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-5-
ylcarbamoyl)acetamide(UNBS3157),a novel nonhematotoxic naphthalimid e
derivative with potent antitumor activity[J].Journal of Medicinal Chemistr y,
2007,50(17):4122-4134. synthesized.
In synthetic method of the present invention, the amount ratio of Amonafide and 3- fluorobenzoyl chlorides is stoichiometric ratio, in reality
In the experimental implementation on border, the ratio between amount of material of Amonafide and 3- fluorobenzoyl chlorides is usually taken to be：1：1-5.
It is the crude product of compound shown in formula (I) made from above-mentioned synthetic method, existing conventional purification process pair can be used
It is purified with the purity of compound shown in raising formula (I).Generally use silica gel column chromatography is purified, specifically will system
The target compound crude product obtained is 20~40 with by volume ratio through silica gel column chromatography：The elution of 1 dichloromethane and methanol composition
Agent elutes, and eluent is evaporated off solvent, obtains object after purification.
Present invention additionally comprises compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I) in antitumor drug is prepared
Application, particularly prepare suppress human lung carcinoma cell medicine in application.
The present invention also provides a kind of pharmaceutical composition, which contains above-mentioned formula (I) shownization of the upper effective dose for the treatment of
Compound or its pharmaceutically acceptable salt.
Compared with prior art, the present invention provides a kind of novel 1,8-naphthalimide derivative of structure, and
Its synthetic method and application.Our experiments show that the derivative has notable biological activity, particularly to non-small cell
Lung cancer cell line HCC-827 and other tumor cell lines are respectively provided with significant inhibitory activity, and secondary to the poison of human normal cell line
Smaller is acted on, is expected to exploitation into target therapeutic agent.
Embodiment
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.
Amonafide synthesizes as follows in following embodiment：
1) 1,8- naphthalic anhydrides (5g, 0.025mol) are taken to be added to the dense H of 20ml2SO4, ice bath stirring, is slowly added dropwise nitration mixture
(1.57g (0.025mmol) dense HNO3The dense H of+5ml2SO4, dense H2SO4It is slowly added to HNO3In), reaction temperature is no more than 20 DEG C.Drop
After adding, slowly recover to 90min is stirred at room temperature, after reaction, pour into frozen water, filter, then tied again with glacial acetic acid
Crystalline substance obtains intermediate product 1, and numbering is：MX-1.
2) take intermediate product MX-1 (1mmol) to add 5ml absolute ethyl alcohols, be heated to 65 DEG C, add 2mmol N, N- diformazans
Base ethylenediamine, is heated to 78 DEG C of reflux 45min to 1h, after reaction, reaction system is gradually cooling to 5 DEG C, has grey to sink
Precipitation goes out, and filtering precipitation, is washed 2 times, each 5ml using n-hexane.Washed 2 times using absolute ethyl alcohol, each 5ml, in obtaining
Between product 2, numbering MX-A2.
3) intermediate product MX-A2 1mmol are taken, are added in 3ml absolute ethyl alcohols, appropriate 10%Pd/C is added, is heated to 65
DEG C, 5mmol triethylamines and 4.8mmol formic acid (rapidly joining) are added, reaction is warming up to 80 DEG C, reaction time 1.5h.Reaction knot
Filtered while hot after beam, filter cake is rinsed with as far as possible few absolute ethyl alcohol.Reaction is cooled to 5 DEG C, there is Precipitation, filters, uses nothing
Water-ethanol and n-hexane respectively wash twice, each 5mL, and vacuum drying obtains Amonafide.
Gained Amonafide is identified：
(1) nuclear magnetic resonance spectroscopy and carbon modal data difference are as follows:
1H NMR (500MHz, DMSO) δ 8.07 (d, J=7.1Hz, 1H), 8.03 (d, J=8.2Hz, 1H), 7.96 (d, J
=2.2Hz, 1H), 7.64-7.57 (m, 1H), 7.28 (d, J=2.2Hz, 1H), 5.99 (s, 2H), 4.13 (t, J=6.9Hz,
2H),2.50–2.44(m,2H),2.20(s,6H).
13C NMR(126MHz,DMSO)δ164.18,164.00,148.33,133.99,131.93,127.39,125.88,
122.98,122.20,121.03,112.18,99.98,56.99,45.87,37.97.
(2) electrospray ionization mass spectrum：ESI-MS m/z:284.1[M+H]+.
Embodiment 1
Take Amonafide 1mmol to be added to stirring and dissolving in 4mL acetonitriles, 1.5mmol 3- fluorobenzoyl chlorides are dissolved in
In 2mL acetonitriles, it is placed in constant pressure funnel, reaction system is protected using nitrogen, is slowly dripped into Amonafide-acetonitrile solution
Add the chloro- acetonitrile solution of 3- fluorobenzoyls, 2.5h is reacted after being added dropwise to complete, after reaction, remove solvent, use silica gel column chromatography
Purify (dichloromethane：Methanol=20：1, v/v), obtain faint yellow solid (yield is about 90%).
Gained faint yellow solid is identified：
(1) nuclear magnetic resonance spectroscopy and carbon spectrum, their spectral data are as follows：
1H NMR (500MHz, DMSO-d6) δ 11.05 (s, 1H), 9.00 (d, J=1.9Hz, 1H), 8.93 (d, J=
2.0Hz, 1H), 8.42 (dd, J=12.0,7.7Hz, 2H), 8.02-7.91 (m, 2H), 7.85 (t, J=7.7Hz, 1H), 7.65
(dd, J=13.9,7.9Hz, 1H), 7.51 (td, J=8.5,2.1Hz, 1H), 4.30 (t, J=5.8Hz, 2H), 2.98 (s,
2H),2.55(s,6H).
13C NMR(125MHz,DMSO-d6)δ165.11,164.15,163.94,138.29,136.93,134.39,
132.35,131.14,129.74,128.01,125.62,124.91,124.70,123.05,122.40,119.44,119.27,
115.36,115.17,55.69,44.16,36.58.
(2) electrospray ionization mass spectrum：ESI-MS m/z:406[M+H]+
Accordingly, it can be determined that above-mentioned faint yellow solid is target product N- (2-N, N- dimethylamino) ethylamino- -3- (3- fluorine
Benzamido) -1,8-naphthalimide, shown in its chemical structural formula such as following formula (I)：
Embodiment 2
Embodiment 1 is repeated, unlike：
It will be changed to 1h the reaction time, remaining reaction condition is constant (yield is about 73%).
Nuclear magnetic resonance spectroscopy, carbon-13 nmr spectra analysis are carried out to the present embodiment products therefrom, is determined as target product.
Embodiment 3
Embodiment 1 is repeated, unlike：
It will be changed to 3h the reaction time, remaining reaction condition is constant (yield is about 88%).
Nuclear magnetic resonance spectroscopy, carbon-13 nmr spectra analysis are carried out to the present embodiment products therefrom, is determined as target product.
Embodiment 4
Embodiment 1 is repeated, unlike：
The dosage of 3- fluorobenzoyl chlorides is changed to 1mmol, and solvent is made into dichloromethane, remaining reaction condition is constant
(yield is about 85%).
Nuclear magnetic resonance spectroscopy, carbon-13 nmr spectra analysis are carried out to the present embodiment products therefrom, is determined as target product.
Embodiment 5
Embodiment 1 is repeated, unlike：
3- fluorobenzoyl chlorine doses are changed to 2mmol, and solvent is made into chloroform, remaining reaction condition is constant, and (yield is about
90%).
Nuclear magnetic resonance spectroscopy, carbon-13 nmr spectra analysis are carried out to the present embodiment products therefrom, is determined as target product.
Embodiment 6
Embodiment 1 is repeated, unlike：
Reaction system is protected without nitrogen, and remaining reaction condition is constant (yield is about 68%).
Nuclear magnetic resonance spectroscopy, carbon-13 nmr spectra analysis are carried out to the present embodiment products therefrom, is determined as target product.
Embodiment 7
Embodiment 1 is repeated, unlike：
The eluant, eluent volume ratio that column chromatography purifies is changed to dichloromethane：Methanol=40：1, the constant (production of remaining reaction condition
71%) rate is about.
Nuclear magnetic resonance spectroscopy, carbon-13 nmr spectra analysis are carried out to the present embodiment products therefrom, is determined as target product.
In order to absolutely prove N- of the present invention (2-N, N- dimethylamino) ethylamino- -3- (3- fluorobenzoyls amido) -1,
Purposes of the 8- naphthalimides in pharmacy, applicant have carried out anti tumor activity in vitro experiment to it.
1st, cell line and cell culture
Human lung carcinoma cell HCC-827, H1299, NCI-H460, A549, gastric carcinoma cells MGC-803, people are selected in this experiment
Transitional cell bladder carcinoma cell line T24, Proliferation of Human Ovarian Cell SKOV3, human cervical carcinoma cell Hela, human hepatoma cell strain Hep G2 and people are normal
Cell HL-7702, WI-38, LX2, LO2 totally 13 kinds of cell lines.
The tumour cells such as HCC-827, H1299, NCI-H460, A549, human cervical carcinoma cell Hela, human normal cell line LO2
Strain cultivate containing the small ox bloods of 10wt%, 100U/mL penicillin, 100U/mL streptomysins RPMI-1640 nutrient solutions in, put 37
DEG C 5%CO containing volumetric concentration2Cultivated in incubator；Gastric carcinoma cells MGC-803, human bladder cancer cell T24, Proliferation of Human Ovarian Cell
SKOV3, human hepatoma cell strain Hep G2 and human normal cell line HL-7702, WI-38, LX2 cell line are then cultivated containing 10wt%
Small ox blood, 100U/mL penicillin, 100U/mL streptomysins DMEM nutrient solutions in.
2nd, the preparation of testing compound
N- (2-N, N- dimethylamino) ethylamino- -3- (2- fluorobenzoyls amido) -1,8-naphthalimide used is
It is made by the embodiment of the present invention 1, purity >=99% is dilute successively by culture medium by its DMSO liquid storage (concentration 0.001mol/L)
Five concentration gradients are interpreted into, are respectively 20,10,5,2.5,1.25 μm of ol/L, wherein cosolvent DMSO final concentration≤1%.First
The target product of 20 μm of ol/L is tested for the inhibiting rate of tumor cell proliferation, is considered as primary dcreening operation result；Test different ladders respectively again
Spend under concentration that target product is to the Proliferation Ability degree of various tumour cells, to the Fitting Calculation half-inhibition concentration, i.e. IC50
Value.
3rd, cell growth inhibition test (mtt assay)
(1) take the logarithm the cell in growth period, after Trypsin Induced, be configured to the nutrient solution containing 10% calf serum
Concentration is the cell suspension of 5000/mL, is inoculated in every 180 μ L of hole in 96 well culture plates, makes cell density to be measured to 1000
~10000/hole (edge hole is filled with sterile PBS)；
(2) 5%CO2, 37 DEG C of incubation 24h, are paved with bottom hole to cell monolayer, the medicine 20 of a certain concentration gradient are added per hole
μ L, each concentration gradient set 5 multiple holes；
(3) 5%CO2, 37 DEG C are incubated 48h, are observed under inverted microscope；
(4) the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L is added per hole, continues to cultivate 4h；
(5) culture is terminated, carefully sucks nutrient solution in hole, 100 μ L DMSO are added per hole and fully dissolve first a ceremonial jade-ladle, used in libation precipitation, are shaken
Swing after device mixes, with wavelength be 570nm in microplate reader, reference wavelength measures the OD value in each hole for 630nm；
(6) while zeroing hole (culture medium, MTT, DMSO) is set, (the medicine dissolving of cell, same concentrations is situated between control wells
Matter, nutrient solution, MTT, DMSO).
(7) according to the OD value (OD values) measured, to judge living cells quantity, OD values are bigger, and cytoactive is stronger.
Utilize formula：
The inhibiting rate of compounds on cell growth is calculated, further the inhibiting rate by SPSS softwares to five concentration gradients
Data are fitted, and obtain half-inhibition concentration (IC of the compound to different cell lines50Value, unit μm ol/L), compound pair
In the IC of different pneumonocyte strains50Value is as shown in table 1.
Table 1：IC of the compound of the present invention to lung cancer cell line and its lung normal cell strain50It is worth (μM)
IC of the compound of the present invention to other tumor cell lines such as stomach cancer, liver cancer, breast cancer and human normal cell line strain50
Value is as shown in table 2：
Table 2：To the IC of other tumor cell lines and its normal liver cell strain described in compound50It is worth (μM)
From the point of view of anti tumor activity in vitro test result, the selection of compound on tumor cell strain of the present invention suppresses to make
With more obvious and small to normal cytotoxicity, exploitation is expected into target therapeutic agent.
In conclusion 1,8-naphthalimide derivative aggregate performance of the present invention has gone out preferable extracorporeal anti-tumor
Activity, particularly has preferable selective inhibitory to non-small cell lung cancer cell strain, is expected to exploitation into targeted therapy medicine
Thing.
Claims (10)
1. compound or its pharmaceutically acceptable salt shown in lower formula (I)：
2. the synthetic method of compound described in claim 1, it is characterised in that：Mainly include the following steps that：Take Amonafide and
3- fluorobenzoyl chlorides are dissolved in organic solvent, are reacted, and remove solvent after reaction, up to object crude product.
3. synthetic method according to claim 2, it is characterised in that：The organic solvent is selected from acetonitrile, dichloromethane
Combination more than one or both of alkane, chloroform and tetrahydrofuran.
4. synthetic method according to claim 2, it is characterised in that：Reaction carries out under conditions of less than 20 DEG C.
5. synthetic method according to claim 2, it is characterised in that：Reaction carries out under condition of ice bath.
6. according to the synthetic method any one of claim 2-5, it is characterised in that：Reaction under the conditions of atmosphere protection into
OK.
7. according to the synthetic method any one of claim 2-5, it is characterised in that：Further include purification step：Specifically
Obtained object crude product is subjected to silica gel column chromatography, obtains object after purification.
8. the application of compound described in claim 1 or its pharmaceutically acceptable salt in antitumor drug is prepared.
9. application according to claim 8, it is characterised in that：It is to prepare the application in suppressing human lung carcinoma cell medicine.
10. a kind of pharmaceutical composition, goes up compound described in the claim 1 of effective dose containing treatment or its is pharmaceutically acceptable
Salt.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108623638A (en) * | 2018-07-05 | 2018-10-09 | 桂林医学院 | 12- chloro benzimidazoles -1,8- naphthalimides-platinum complex and its preparation method and application |
| CN110194741A (en) * | 2019-07-08 | 2019-09-03 | 桂林医学院 | 4- benzoyl piperazine -3- nitro -1,8- naphthalimide derivative and its preparation method and application |
| CN110272388A (en) * | 2019-07-08 | 2019-09-24 | 桂林医学院 | 4- dithiocarbonic acid piperazine -3- nitro -1,8- naphthalimide derivative and its synthetic method and application |
| CN115385890A (en) * | 2022-07-19 | 2022-11-25 | 杭州庆正鸿科技有限公司 | 1,8 naphthalimide derivative and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108623638A (en) * | 2018-07-05 | 2018-10-09 | 桂林医学院 | 12- chloro benzimidazoles -1,8- naphthalimides-platinum complex and its preparation method and application |
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| CN110272388A (en) * | 2019-07-08 | 2019-09-24 | 桂林医学院 | 4- dithiocarbonic acid piperazine -3- nitro -1,8- naphthalimide derivative and its synthetic method and application |
| CN110272388B (en) * | 2019-07-08 | 2022-06-17 | 桂林医学院 | 4-dithioformic acid piperazine-3-nitro-1, 8-naphthalimide derivative and synthesis method and application thereof |
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| CN115385890A (en) * | 2022-07-19 | 2022-11-25 | 杭州庆正鸿科技有限公司 | 1,8 naphthalimide derivative and preparation method and application thereof |
| CN115385890B (en) * | 2022-07-19 | 2023-08-08 | 杭州庆正鸿科技有限公司 | 1,8 naphthalimide derivative and preparation method and application thereof |
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Application publication date: 20180515 |