CN110283163A - 4- tert-butoxycarbonyl-piperazine -3- nitro -1,8- naphthalimide derivative and its synthetic method and application - Google Patents
4- tert-butoxycarbonyl-piperazine -3- nitro -1,8- naphthalimide derivative and its synthetic method and application Download PDFInfo
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- CN110283163A CN110283163A CN201910611341.5A CN201910611341A CN110283163A CN 110283163 A CN110283163 A CN 110283163A CN 201910611341 A CN201910611341 A CN 201910611341A CN 110283163 A CN110283163 A CN 110283163A
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- 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
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
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Abstract
The invention discloses a kind of 4- tert-butoxycarbonyl-piperazine -3- nitro -1,8- naphthalimide derivative and its synthetic method and applications.Shown in the structure of the derivative such as following formula (I), 1) synthetic method, which mainly comprises the steps that, takes tert-butoxycarbonyl-piperazine and bromo- 1, the 8- naphthalene anhydride of 3- nitro -4- to be placed in organic solvent and be performed under heating conditions reaction, obtain intermediate product;2) it takes compound shown in intermediate product and formula (II) to be placed in organic solvent and is performed under heating conditions reaction to get target compound.Certain derivatives in derivative of the present invention are active higher compared with ammonia naphthalene Fitow, lower to the toxicity of GES1;R‑NH2(II);Wherein, R is methoxy-benzyl, N, N- dimethyl ethyl, ethoxy, 3,4- methylene-dioxy phenethyl, 4,5- dihydroxy benzenes ethyl, pridylamino, butyl, benzyl, furylethyl or p-chlorobenzyl.
Description
Technical field
The present invention relates to a kind of 4- tert-butoxycarbonyl-piperazine -3- nitro -1,8- naphthalimide derivative and its synthetic methods
And application, belong to pharmaceutical technology field.
Background technique
Existing research shows that 1,8- naphthalimide derivative has important anti-tumor activity, derivative ammonia naphthalene is luxuriant and rich with fragrance
Special (amonafide) and mitonafide (mitonafide) have entered the II clinical trial phase stage, but due to the two show compared with
Big toxic side effect, so that they should be severely limited.Therefore, it is desirable to which synthesizing to obtain both has significant biology
Activity, the smaller novel naphthoyl imide compounds of toxic side effect.It has had not yet to see in 4 upper introducing tertiary fourths of functional groups
Oxygen carbonyl piperazine prepares the open report of 4- tert-butoxycarbonyl-piperazine -3- nitro -1,8- naphthalimide derivative.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of structure novel and with the tertiary fourth of 4- of preferable bioactivity
Oxygen carbonyl piperazine -3- nitro -1,8- naphthalimide derivative and its synthetic method and application.
4- tert-butoxycarbonyl-piperazine -3- nitro -1,8- naphthalimide derivative of the present invention has such as following formula (I)
Shown structure:
Wherein, R N, N- dimethyl ethyl, ethoxy, 3,4- methylene-dioxy phenethyl, 4,5- dihydroxy benzenes ethyl,
Furylethyl or p-chlorobenzyl.
4- tert-butoxycarbonyl-piperazine -3- nitro -1,8- naphthalimide derivative of the present invention is closed by following routes
At (R is as previously described):
Specific synthetic method mainly comprises the steps that
1) take tert-butoxycarbonyl-piperazine (being also referred to as compound 1 in this application) and bromo- 1, the 8- naphthalene anhydride of 3- nitro -4- (at this
BNA is also referred to as in application) it is placed in organic solvent, it is reacted under heating condition, reactant is cooling, collect precipitating, obtains
Between product (in this application be also referred to as compound 2);The structure of the intermediate product is shown below:
2) it takes compound shown in intermediate product and formula (II) to be placed in organic solvent, is reacted under heating condition, instead
It answers object cooling, collects precipitating to get target compound (corresponding to NB1-NB6 totally 6 compounds in this application) is arrived;
R-NH2(II);
Wherein, R is methoxy-benzyl, N, N- dimethyl ethyl, ethoxy, 3,4- methylene-dioxy phenethyl, 4,5- bis-
Leptodactyline, pridylamino, butyl, benzyl, furylethyl or p-chlorobenzyl.
In synthetic method of the present invention, the organic solvent be alcohols solvent and/or non-protonic solvent,
In, the alcohols solvent specifically can be the group selected from one or more of methanol, ethyl alcohol, propyl alcohol and n-butanol
It closes;The non-protonic solvent specifically can be sub- selected from ethylene glycol monomethyl ether, N,N-dimethylformamide (DMF), dimethyl
The combination of one or more of sulfone (DMSO), toluene, carbon tetrachloride and acetone.The dosage of the organic solvent can basis
It needs to be determined that, it is generally the case that on the basis of bromo- 1, the 8- naphthalene anhydride of 3- nitro -4- of 1mmol, all reaction raw materials 25-50mL
Organic solvent dissolve.When the additional amount of organic solvent is larger, after fully reacting after preferred elder generation's recovery section organic solvent
(usually removing the organic solvent for accounting for additional amount 40-50%) is cooling by reactant again.
It is whether complete with the condensation reaction of thin-layer chromatography tracing detection in the step 1) of synthetic method of the present invention.Instead
It should preferably carry out, further preferably be carried out under the conditions of 60-130 DEG C, more preferably in 80-130 DEG C of condition under the conditions of≤130 DEG C
Lower progress.When reaction carries out under the conditions of 80-130 DEG C, reaction to the time for needing 6-8h completely.It is obtained by step 1) to be
The crude product of intermediate product, in order to be further reduced the impurity being introduced into step 2), preferably by intermediate product obtained by step 1)
It is used further in operation described in step 2) after purification.The purifying can be purification process conventional in the prior art,
In the application, it is used further in the operation of step 2) after preferably being recrystallized intermediate product with solvent.It is described to be used to tie again
Brilliant solvent is identical as being used to synthesize to obtain the organic solvent of intermediate product in synthetic method, preferably methanol or ethyl alcohol.
It is whether complete with the condensation reaction of thin-layer chromatography tracing detection in the step 2) of synthetic method of the present invention.Instead
It should preferably carry out, further preferably be carried out under the conditions of 50-100 DEG C, more preferably in 60-80 DEG C of condition under the conditions of≤100 DEG C
Lower progress.When reaction carries out under the conditions of 60-80 DEG C, reaction to the time for needing 3-6h completely.
What above-mentioned synthetic method synthesized is the crude product of target compound, and existing conventional purification process can be used to it
It is purified with the purity of compound shown in raising formula (I), can specifically be purified using recrystallization or silica gel column chromatography.
When being purified using recrystallization, for being used to synthesize to obtain having for target compound in the solvent and synthetic method of recrystallization
Solvent is identical, preferably methanol or ethyl alcohol.When being purified using column chromatography, specifically by the resulting targeted of step 2)
Close object on silica gel column chromatography, the eluent formed with the methylene chloride and methanol for being 1-50:1 by volume ratio (preferably with by
The eluent of methylene chloride and methanol composition that volume ratio is 15:1), solvent is evaporated off in eluent, obtains target after purification
Compound.
Further include the steps that purifying gained target compound.
The invention also includes above-mentioned formula (I) compound or its pharmaceutically acceptable salt answering in the preparation of antitumor drugs
With.
The present invention further comprises a kind of pharmaceutical composition, contains chemical combination shown in the above-mentioned formula (I) for treating upper effective dose
Object or its pharmaceutically acceptable salt.
Compared with prior art, the present invention provides 4- tert-butoxycarbonyl-piperazine -3- nitros -1,8- of a kind of structure novel
Naphthalimide derivative, short preparation period, post-processing is simple, at low cost, and obtained derivative purity is high, quality are stablized;
The in vitro test of applicant the result shows that, pass through 4 in 3- nitro -1,8- naphthalimide and upper introduce the tertiary fourth oxygen of functional groups
Carbonyl piperazine makes gained 4- tert-butoxycarbonyl-piperazine -3- nitro -1,8- naphthalimide derivative have preferable bioactivity,
The bioactivity of middle partial derivatives is significant, is expected to exploitation into anti-tumor drug.
Specific embodiment
The present invention is described in further detail combined with specific embodiments below, content to better understand the invention, but
The present invention is not limited to following embodiments.
In following embodiment, BNA indicates that bromo- 1, the 8- naphthalene anhydride of 3- nitro -4-, compound 1 indicate tert-butoxycarbonyl-piperazine,
Compound 2 indicates intermediate product (i.e. 4- tert-butoxycarbonyl-piperazine -3- nitro -1,8- naphthalene anhydride).
Embodiment 1: the synthesis of compound 2
5.7g (18mmol) BNA is weighed in 100 milliliters of round-bottomed flasks, 10.05g (54mmol) compound 1 is added, adds
Enter ethylene glycol monomethyl ether 50mL, 125 DEG C of reflux 6h, remove partial solvent while hot, stand cool overnight, filter, collects filter cake, use second
Alcohol recrystallization, obtains 4.25g yellow crystals, yield 46.6%.
Structural characterization is carried out to gained yellow crystals, data are as follows:
1H NMR(600MHz,CDCl3) δ 8.67-8.62 (m, 1H), 8.56 (dd, J=7.2,0.7Hz, 1H), 8.52 (s,
1H), 7.99-7.92 (m, 1H), 4.04 (t, J=7.2Hz, 2H), 3.66 (s, 4H), 3.18 (d, J=4.6Hz, 4H), 1.45
(s,9H).13C NMR(100MHz,DMSO-d6)δ162.95,161.84,153.98,147.01,142.23,132.80,
131.45,129.58,129.06,128.48,126.30,122.98,117.75,79.30,51.06,48.60,45.41,
28.03.MS m/z:428[M+H]+.
Accordingly, it can be determined that yellow crystals obtained by the present embodiment are compound 2, i.e. nitro -1 4- tert-butoxycarbonyl-piperazine -3-,
8- naphthalene anhydride, structural formula are shown below:
Embodiment 2: the synthesis of compound 2
2.88g (9mmol) BNA is weighed in 50mL round-bottomed flask, adds 1.67g (9mmol) compound 1, second is added
Alcohol 50mL, 100 DEG C of reflux 6h remove partial solvent while hot, stand cool overnight, filter, and collect filter cake, obtain 0.50g yellow
Powder, yield 10.4%.
Structural characterization is carried out to gained yellow crystals, data are as follows:
1H NMR(600MHz,CDCl3) δ 8.67-8.62 (m, 1H), 8.56 (dd, J=7.2,0.7Hz, 1H), 8.52 (s,
1H), 7.99-7.92 (m, 1H), 4.04 (t, J=7.2Hz, 2H), 3.66 (s, 4H), 3.18 (d, J=4.6Hz, 4H), 1.45
(s,9H).13C NMR(100MHz,DMSO-d6)δ162.95,161.84,153.98,147.01,142.23,132.80,
131.45,129.58,129.06,128.48,126.30,122.98,117.75,79.30,51.06,48.60,45.41,
28.03.MS m/z:428[M+H]+.
Accordingly, it can be determined that yellow powder obtained by the present embodiment is compound 2, i.e. nitro -1 4- tert-butoxycarbonyl-piperazine -3-,
8- naphthalene anhydride.
Embodiment 3: the synthesis of compound 2
2.88g (9mmol) NBA is weighed in 50mL round-bottomed flask, adds 1.67g (9mmol) 1, it is sub- that dimethyl is added
Mixed solvent 50mL, the 80 DEG C of reflux 6h that sulfone and n,N-Dimethylformamide are formed by the volume ratio of 1:1, it is molten to remove part while hot
After agent, cool overnight is stood, filter cake is collected, obtains 1.580g yellow powder, yield 34.5%.
Structural characterization is carried out to gained yellow crystals, data are as follows:
1H NMR(600MHz,CDCl3) δ 8.67-8.62 (m, 1H), 8.56 (dd, J=7.2,0.7Hz, 1H), 8.52 (s,
1H), 7.99-7.92 (m, 1H), 4.04 (t, J=7.2Hz, 2H), 3.66 (s, 4H), 3.18 (d, J=4.6Hz, 4H), 1.45
(s,9H).13C NMR(100MHz,DMSO-d6)δ162.95,161.84,153.98,147.01,142.23,132.80,
131.45,129.58,129.06,128.48,126.30,122.98,117.75,79.30,51.06,48.60,45.41,
28.03.MS m/z:428[M+H]+.
Accordingly, it can be determined that yellow powder obtained by the present embodiment is compound 2, i.e. nitro -1 4- tert-butoxycarbonyl-piperazine -3-,
8- naphthalene anhydride.
The conjunction of embodiment 4:4- tert-butoxycarbonyl-piperazine -3- nitro-N- piperonyl -1,8- naphthalimide (compound N B1)
At
It weighs 0.54g compound 2 (1.40mmol) in a round bottom flask, adds 0.23g (1.41mmol) homopiperony lamine,
The dissolution of 50mL ethyl alcohol is added, 80 DEG C of reflux 3h, thin-layer chromatography monitoring reaction, after reaction, cooling, filtering obtains yellow
Powder NB1 0.462g, Yield, 56.7%;1H NMR(600MHz,CDCl3) δ 8.68 (d, J=8.5Hz, 1H), 8.60-8.51
(m, 2H), 7.97 (t, J=7.9Hz, 1H), 6.83 (s, 1H), 6.78 (t, J=6.8Hz, 1H), 6.67 (d, J=8.0Hz,
1H),5.96(s,2H),4.23–4.13(m,2H),3.66(s,4H),3.19(s,4H),2.86–2.77(m,2H),1.46(s,
9H).13C NMR(100MHz,DMSO-d6)δ162.81,161.69,153.98,147.25,147.10,145.68,142.27,
132.87,132.36,131.57,129.62,129.13,128.52,126.38,122.96,121.90,121.50,117.70,
108.98,108.18,100.70,79.30,51.07,41.25,33.09,28.03.MS m/z:562[M+H]+.
Accordingly, it can be determined that yellow powder NB1 obtained by the present embodiment is 4- tert-butoxycarbonyl-piperazine -3- nitro-N- piperonyl -
1,8- naphthalimide, structural formula are shown below:
Embodiment 5:4- tert-butoxycarbonyl-piperazine -3- nitro-N- (N, N- dimethyl) ethylenediamine base -1,8- naphthalimide
The synthesis of (compound N B2)
It weighs 0.54g compound 2 (1.40mmol) in a round bottom flask, adds 0.125g (1.40mmol) N, N- diformazan
Base ethylenediamine adds the dissolution of 50mL ethyl alcohol, and 80 DEG C of reflux 6h, thin-layer chromatography monitoring reaction is after reaction, cooling, filters,
Obtain yellow powder NB2 0.345g, Yield, 47.5%;1H NMR(400MHz,DMSO-d6) δ 8.67 (d, J=8.5Hz,
1H), 8.59 (d, J=7.2Hz, 1H), 8.56 (s, 1H), 8.02-7.94 (m, 1H), 4.13 (t, J=6.8Hz, 2H), 3.66
(s, 4H), 3.19 (d, J=4.0Hz, 4H), 2.29 (s, 2H), 2.20 (s, 6H), 1.45 (s, 9H)13C NMR(100MHz,
DMSO-d6)δ162.92,161.79,153.99,147.09,142.29,132.91,131.55,129.60,129.14,
128.51,126.44,122.93,117.68,79.30,56.35,51.06,45.36,37.71,28.04..MS m/z:498[M
+H]+.
Accordingly, it can be determined that yellow powder NB2 obtained by the present embodiment is 4- tert-butoxycarbonyl-piperazine -3- nitro-N- (N, N- bis-
Methyl) ethylenediamine base -1,8- naphthalimide, structural formula is shown below:
The conjunction of embodiment 6:4- tert-butoxycarbonyl-piperazine -3- nitro-N-hydroxyethyl -1,8- naphthalimide (compound N B3)
At
It weighs 0.54g compound 2 (1.40mmol) in a round bottom flask, adds 0.120g (1.40mmol) ethanol amine,
The dissolution of 50mL methanol is added, 70 DEG C of reflux 6h, thin-layer chromatography monitoring reaction, after reaction, cooling, filtering obtains yellow
Powder NB3 0.386g, Yield, 53.6%;1H NMR(400MHz,DMSO-d6) δ 8.60 (dd, J=8.5,0.7Hz, 1H),
8.51 (dd, J=7.3,0.8Hz, 1H), 8.47 (s, 1H), 7.92 (dd, J=8.4,7.4Hz, 1H), 4.79 (t, J=5.9Hz,
1H), 4.08 (t, J=6.5Hz, 2H), 3.66 (s, 4H), 3.61-3.56 (m, 2H), 3.22-3.08 (m, 4H), 1.46 (s,
9H).13C NMR(100MHz,DMSO-d6)δ162.90,161.79,153.98,146.90,142.13,132.71,131.30,
129.47,128.94,128.42,126.18,122.95,117.71,79.30,57.64,51.05,41.91,28.03.MS m/
z:471[M+H]+.
Accordingly, it can be determined that yellow powder NB2 obtained by the present embodiment is 4- tert-butoxycarbonyl-piperazine -3- nitro-N-hydroxyethyl -
1,8- naphthalimide, structural formula are shown below:
Embodiment 7:4- tert-butoxycarbonyl-piperazine -3- nitro-N- (4,5- dihydroxy base) phenethyl -1,8- naphthalimide
The synthesis of (compound N B4)
It weighs 0.54g compound 2 (1.40mmol) in a round bottom flask, adds 0.266g (1.40mmol) hydrochloric acid DOPA
Amine adds the dissolution of 50mL methanol, and 80 DEG C of reflux 5h, thin-layer chromatography monitoring reaction, after reaction, cooling, filtering obtains Huang
Color powder NB4 0.292g, Yield, 36.5%;1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.70–8.61(m,
2H), 8.57 (d, J=0.7Hz, 1H), 8.53 (s, 1H), 7.95 (dd, J=8.4,7.4Hz, 1H), 6.63 (dd, J=11.0,
5.0Hz, 2H), 6.47 (dd, J=8.0,2.0Hz, 1H), 4.12 (dd, J=8.9,6.8Hz, 2H), 3.66 (s, 4H), 3.25-
3.08(m,4H),2.77–2.63(m,2H),1.46(s,9H).13C NMR(100MHz,DMSO-d6)δ162.73,161.61,
153.98,147.06,145.16,143.73,142.20,132.82,131.49,129.54,129.27,129.07,128.48,
126.33,122.91,119.21,117.64,115.93,115.58,79.30,51.07,41.48,32.80,28.04.MS m/
z:564[M+H]+.
Accordingly, it can be determined that yellow powder NB4 obtained by the present embodiment is 4- tert-butoxycarbonyl-piperazine -3- nitro-N- (4,5- bis-
Hydroxyl base) phenethyl -1,8- naphthalimide, structural formula is shown below:
Embodiment 8:4- tert-butoxycarbonyl-piperazine -3- nitro-N- methyl-propyl -1,8- naphthalimide (compound N B5)
Synthesis
It weighs 0.54g compound 2 (1.40mmol) in a round bottom flask, adds 0.125g (1.40mmol) N- methyl-prop
Amine adds 50 milliliters of dehydrated alcohol dissolutions, 80 DEG C of reflux 3h, thin-layer chromatography monitoring reaction, after reaction, in solvent evaporated
(eluant, eluent is methylene chloride-methanol (V to silica gel column chromatographyMethylene chloride:VMethanol=15:1)), yellow compound NB5 0.311g is obtained,
Yield, 43.2%;1H NMR(400MHz,DMSO-d6) δ 8.67-8.62 (m, 1H), 8.56 (dd, J=7.2,0.7Hz, 1H),
8.52 (s, 1H), 7.99-7.92 (m, 1H), 4.04 (t, J=7.2Hz, 2H), 3.66 (s, 4H), 3.18 (d, J=4.6Hz,
4H),2.60–2.57(m,2H),2.29(s,3H),1.82–1.71(m,2H),1.45(s,9H).13C NMR(100MHz,DMSO-
d6)δ162.95,161.84,153.98,147.01,142.23,132.80,131.45,129.58,129.06,128.48,
126.30,122.98,117.75,79.30,51.06,48.60,45.41,38.11,35.43,28.03.MS m/z:499[M+
H]+.
Accordingly, it can be determined that yellow powder NB5 obtained by the present embodiment is 4- tert-butoxycarbonyl-piperazine -3- nitro-N- methyl-prop
Base -1,8- naphthalimide, structural formula are shown below:
Embodiment 9:4- tert-butoxycarbonyl-piperazine -3- nitro-N- p-chlorobenzyl -1,8- naphthalimide (compound N B6)
Synthesis
It weighs 0.54g compound 2 (1.40mmol) in a round bottom flask, adds 0.199g (1.40mmol) to benzyl chloride
Amine adds the dissolution of 50mL ethyl alcohol, and 80 DEG C of reflux 4h, thin-layer chromatography monitoring reaction, after reaction, cooling, filtering obtains Huang
Color powder NB6 0.392g, Yield, 49.3%;1H NMR (400MHz, DMSO) δ 8.66 (d, J=8.4Hz, 1H), 8.58 (d,
J=7.2Hz, 1H), 8.55 (s, 1H), 7.96 (dd, J=8.3,7.6Hz, 1H), 7.35 (q, J=8.7Hz, 4H), 5.18 (s,
2H),3.66(s,4H),3.23–3.11(m,4H),1.45(s,9H).13C NMR(100MHz,DMSO-d6)δ162.97,
161.86,153.97,147.24,142.21,136.01,133.07,131.73,129.71,129.51,129.08,128.49,
128.27,126.67,122.81,117.47,79.29,51.10,42.41,28.02.MS m/z:552[M+H]+.
Accordingly, it can be determined that yellow powder NB6 obtained by the present embodiment is 4- tert-butoxycarbonyl-piperazine -3- nitro-N- to benzyl chloride
Base -1,8- naphthalimide, structural formula are shown below:
The antitumor work of the 4- tert-butoxycarbonyl-piperazine -3- nitro -1,8- naphthalimide derivative to illustrate the invention
With, applicant to carried out by target compound made from above-described embodiment 4-9 the method anti-tumor activity experiment (with
Mitonafide and ammonia naphthalene Fitow are reference), and carry out to by target compound made from the various embodiments described above the method to just
The toxicity test of normal cell.
Using the anti tumor activity in vitro of mtt assay test compound and to the toxicity of normal cell.It takes in logarithmic growth
The cell of phase, the celliferous culture medium inoculated of every 180 μ L of hole (about 4500-5000 cell) in 96 well culture plates, in 37 DEG C,
5%CO2It is cultivated for 24 hours under the conditions of abundant humidifying.After cell is adherent, sample is added by the amount of every 20 μ L of hole, each sample sets 6
Multiple holes concurrently set corresponding blank control.To continue after cultivating 48h, 10 μ L MTT reagents (concentration 5mg/mL) are added in every hole,
Continue after being incubated for 4h, inhales and abandon supernatant, every hole, which adds 150 μ L DMSO, slight 5~8min of concussion reaction, fills crystalline particle
Divide dissolution.Blank control group zeroing, with microplate reader with 490nm wavelength measure removal background absorbance value after absorbance value (
Value), cell proliferation inhibition rate is calculated, the test-compound good to primary dcreening operation antitumous effect continues to continue to do with 5 concentration gradients
The IC of corresponding cell strain50Value, all experiments are averaged after being repeated 3 times.Experimental result is detailed in the following table 1.
Half-suppressed rate concentration (IC of 1. target compound of table to different tumor cell lines50, μM)
From data in table 1:
In the inhibitory activity test experiments to gastric carcinoma cells MGC-803, compound N B2, NB5 and NB6 show good
Good inhibitory activity, activity are better than ammonia naphthalene Fitow, and wherein the activity of compound N B2 and NB5 is even better than mitonafide, and NB5
With NB6 to the toxicity of people's stomach normal cell GES1 significantly less than mitonafide.
In the inhibitory activity test experiments to human liver cancer cell HepG2, compound N B2, NB5 and NB6 are shown well
Inhibitory activity, activity is significantly better than ammonia naphthalene Fitow.
In the inhibitory activity test experiments to Proliferation of Human Ovarian Cell SKOV-3 and human bladder cancer cell T24, compound N B2
Good inhibitory activity is shown, activity is better than ammonia naphthalene Fitow and mitonafide.
The above result shows that by the way that tert-butoxycarbonyl-piperazine introducing 1,8- naphthalimide structure is prepared novel uncle 4-
Butoxy carbonyl piperazine -3- nitro -1,8- naphthalimide antitumoral compounds be it is feasible, be expected to filter out the novel of high-efficiency low-toxicity
Antitumoral compounds, compared with ammonia naphthalene Fitow, certain 4- tert-butoxycarbonyl-piperazine -3- nitro -1,8- naphthalimide derivatives are (such as
Compound N B5) activity it is more efficient, it is lower to the toxicity of people's stomach normal cell GES1.
Claims (10)
1. compound shown in following formula (I)s or its pharmaceutically acceptable salt:
Wherein, R is methoxy-benzyl, N, N- dimethyl ethyl, ethoxy, 3,4- methylene-dioxy phenethyl, 4,5- dihydroxy
Phenethyl, pridylamino, butyl, benzyl, furylethyl or p-chlorobenzyl.
2. the synthetic method of compound described in claim 1, it is characterised in that: mainly comprise the steps that
1) it takes tert-butoxycarbonyl-piperazine and bromo- 1, the 8- naphthalene anhydride of 3- nitro -4- to be placed in organic solvent, is carried out under heating condition anti-
It answers, reactant is cooling, collects precipitating, obtains intermediate product;The structure of the intermediate product is shown below:
2) it takes compound shown in intermediate product and formula (II) to be placed in organic solvent, is reacted under heating condition, reactant
It is cooling, precipitating is collected to get target compound is arrived;
R-NH2(II);
Wherein, R is methoxy-benzyl, N, N- dimethyl ethyl, ethoxy, 3,4- methylene-dioxy phenethyl, 4,5- dihydroxy
Phenethyl, pridylamino, butyl, benzyl, furylethyl or p-chlorobenzyl.
3. synthetic method according to claim 2, it is characterised in that: the organic solvent is alcohols solvent and/or non-
Protonic solvent.
4. synthetic method according to claim 3, it is characterised in that: the alcohols solvent is selected from methanol, ethyl alcohol, third
The combination of one or more of pure and mild n-butanol.
5. synthetic method according to claim 3, it is characterised in that: the non-protonic solvent is selected from ethylene glycol first
The combination of one or more of ether, N,N-dimethylformamide, dimethyl sulfoxide, toluene, carbon tetrachloride and acetone.
6. synthetic method according to claim 2, it is characterised in that: in step 1), reaction under the conditions of≤130 DEG C into
Row;In step 2), reaction carries out under the conditions of≤100 DEG C.
7. synthetic method according to claim 2, it is characterised in that: in step 1), gained intermediate product is carried out after purification
It is used further to subsequent operation.
8. synthetic method according to claim 2, it is characterised in that: further include being purified to gained target compound
Step.
9. compound described in claim 1 or its pharmaceutically acceptable salt application in preparation of anti-tumor drugs.
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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