CN106083850A - One class pyrimido naphthalimide derivative and its preparation method and application - Google Patents

One class pyrimido naphthalimide derivative and its preparation method and application Download PDF

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CN106083850A
CN106083850A CN201610548327.1A CN201610548327A CN106083850A CN 106083850 A CN106083850 A CN 106083850A CN 201610548327 A CN201610548327 A CN 201610548327A CN 106083850 A CN106083850 A CN 106083850A
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compound
pyrimido
reaction
naphthalimide
preparation
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CN106083850B (en
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王超杰
张鑫
王玉霞
罗稳
常丽萍
李小敏
吴笑笑
王君
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Henan University
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

One class pyrimido naphthalimide derivative and its preparation method and application, described derivant has Formulas I to structure shown in III:Formula I, in II, III, a is 0,1 or 2；M is 2,3 or 4；N is 2,3 or 4；X is the integer of 0 to 6；R1For、、、、、、, R2For C1 C4 alkyl,、、Or；R3For、、、Or

Description

One class pyrimido naphthalimide derivative and its preparation method and application
Technical field
The invention belongs to medicinal chemistry art, particularly to class pyrimido naphthalimide derivative and preparation method thereof and Application.
Background technology
Naphthalimide is the organic micromolecule compound that a class has potential anti-tumor activity.Multiple naphthalimide derivatives Once entered into as antitumor drug such as amonafide (Amonafide), mitonafide (Mitonafide), Azonafide etc. Clinical experimental stage, but due to its stronger neurotoxicity and bone marrow depression, finally it is not approved listing.
In order to reduce the toxicity of naphthoyl imide compounds, improving its biological activity, various countries' researcher has done many Effort.Literature survey finds that structural modification based on naphthalimide is concentrated mainly on two aspects, and one is to naphthalimide side chain Carry out replacing and modify；Two is that the aromatic ring to naphthalimide replaces or and ring modification.Although having obtained some activity preferably Compound, but owing to the purposiveness of ring expansion is strong, can not effectively solve the highly toxic problem of naphthalimide.
Summary of the invention
One class pyrimido naphthalimide derivative, described derivant has Formulas I to structure shown in III:
Formula I, in II, III, a is 0,1 or 2；M is 2,3 or 4；N is 2,3 or 4；X is the integer of 0 to 6；R1For R2For C1-C4 alkyl, OrR3For Or
The preparation method of above-mentioned pyrimido naphthalimide derivative, synthetic route is as follows:
Concrete preparation process is as follows:
A acenaphthene is dissolved in glacial acetic acid by (), drip concentrated nitric acid and carry out nitration reaction under ice bath, and reactant liquor is added after terminating by reaction Entering in frozen water, have yellow mercury oxide to generate, through sucking filtration, distilled water wash filter cake, to neutral, obtains nitration product compound after drying 2；
B compound 2 is dissolved in glacial acetic acid by () after, add sodium dichromate, after being back to reaction completely, mixed liquor is poured into In frozen water, having yellow solid to separate out, through sucking filtration, washing to neutral, dry cake obtains oxidation product compound 3；
C () compound 3 is placed in dehydrated alcohol, add stannous chloride, concentrated hydrochloric acid, after being back to reaction completely, is cooled to Room temperature, sucking filtration, use ice washing with alcohol filter cake, obtain reduzate compound 4 after drying；
D compound 4 is placed in dichloromethane by (), drip bromine, and reaction i.e. obtains compound 5 through post processing after terminating；
E compound 5 is dissolved in N, N-dimethyl-acetamide by (), under four (triphenyl phosphorus) closes palladium chtalyst effect, micro- Under the conditions of ripple, react with zinc cyanide, obtain compound 6；
F () compound 6 and formic acid cyclization under sulphuric acid catalysis, generate compound 7；
G () compound 7 is dissolved in ethanol, add equimolar R1NH2, after backflow 3～4h, obtain compound 8, by compound 8 Stir in ethanol with hydrochloric acid to react and i.e. obtain compound 9；
H compound 8 is dissolved in acetonitrile by (), under Anhydrous potassium carbonate effect, potassium iodide is as catalyst:
(1) react with mono-substituted C1-C4 halogenated alkane；
(2) with 1,3-dibromopropane, glycol dibromide or 1,4-dibromobutane generation substitution reaction；
(3) compound of step (2) is replaced from different amine；
Above-mentioned (1) (2) (3) three kinds of situations all can get compoundCompound Stir reaction again with hydrochloric acid in ethanol and obtain compound 10；
(i) by compound 8 in toluene with phosphorus oxychloride back flow reaction, obtain compound 11；
(j) compound 11 and R3NH2Compound is obtained after reactionCompound Stir reaction with hydrochloric acid in ethanol and obtain compound 12.
The application in preparation prevention, tumor of the above-mentioned pyrimido naphthalimide derivative.
The application in terms of preparing antitumor drug lead compound of the above-mentioned pyrimido naphthalimide derivative.
Above-mentioned pyrimido naphthalimide derivative in preparation prevention, application in tumor, described prevention, is controlled Treating tumour medicine is prevention, treatment hepatocarcinoma, the medicine of breast carcinoma.
The application in preparation prevention, tumor of the above-mentioned pyrimido naphthalimide derivative, described pharmaceutical dosage form For tablet, pill, capsule, injection, suspending agent or Emulsion.
The invention provides a kind of with acenaphthene as raw material, by introducing adjacent cyanamide, structure new pyrimidine naphthalimide Preparation method.Find out according to data with existing, through have targeting carrying capacity how amine-modified after, the anti-tumor activity of naphthalimide It is obviously improved, and neoplasm metastasis is had stronger inhibitory action.According to this discovery, we design a series of pyrimidos of synthesis Naphthalimide derivative.Preliminary survey result shows, such naphthalimide derivative shows good body to various tumor cell strains Outer anti-tumor activity.Therefore, studying such pyrimido naphthoyl imide compounds further, design synthesis has higher The derivant that anti-tumor activity, toxic and side effects are little, the antineoplastic agent new for development is significant.
Detailed description of the invention
It is described in detail by the following examples, in order to be best understood from present disclosure.
Synthetic route in following embodiment is as follows, and concrete synthesis step is shown in each specific embodiment.
Embodiment 1
5-(2-(dimethylamino) ethyl)-4H-isoquinolin [4,5-gh] quinazoline-4,6,8 (5H, 9H)-three keto hydrochloride (9a) preparation:
A () takes 10g acenaphthene (i.e. compound 1) and is placed in 100mL glacial acetic acid, stir, be added dropwise over 7.1mL mass and divide under ice bath Number is about the concentrated nitric acid of 65%, has a large amount of yellow mercury oxide to generate after 4h, and TLC monitors, and pours in 500mL frozen water after reaction completely, Sucking filtration, is washed till neutrality with distilled water by filter cake, 45 DEG C of drying, obtains 16.3g yellow compound 2, yield 84%；
B () takes 20g compound 2 and is placed in 100mL glacial acetic acid, add 10g sodium dichromate, after backflow 5h, be cooled to room Temperature, pours in 500mL frozen water, and sucking filtration is washed with distilled water to neutrality, dries, obtains glassy yellow powdered compounds 3, yield 82%；
C () takes 10g compound 3 and is placed in 50mL dehydrated alcohol, be sequentially added into 40g stannous chloride, and 50mL mass fraction is The concentrated hydrochloric acid solution of 37%, after 70 DEG C of backflow 2h, TLC monitoring raw materials disappear, is cooled to room temperature, sucking filtration, with ice ethanol and anhydrous The each 80mL of ether washs filter cake, is put in vacuum desiccator by filter cake and drains, and obtains bronzing compound 4, yield 85%；
D () takes 18.3g compound 4 and is placed in stone roller alms bowl, join in 100mL dichloromethane, ice after grind up powder solid Limit stirring in water-bath, while drip 9mL bromine with constant pressure funnel, finishes, and 3h, TLC monitoring raw material reaction is stirred at room temperature complete After, rapid filtration under suction in fume hood, alternately washs filter cake with each 200mL of dehydrated alcohol and dichloromethane, until filter liquor is bright Yellow transparent liquid, puts into filter cake in exsiccator and drains, and obtains orange-yellow powdered compounds 5, yield 87%；
E () takes 0.3g intermediate 5 in the microwave reaction pipe of 10mL, be sequentially added into 0.12g tetra-(triphenyl phosphorus) and close palladium, 0.12g zinc cyanide, after putting into magneton, adds 5mL N, N-dimethyl-acetamide, seals and be placed in microwave reactor, power Being set to 150W, temperature is adjusted to 100 DEG C, reacts 30min, adds after cooling in 100mL distilled water, sucking filtration, divide by 20mL mass Number is the ammonia spirit washing filter cake of 5%, and 60 DEG C of drying obtain the compound 6 (compound 6 crude product) containing less impurity, yield 73%；
F () takes compound 6 crude product 3g in 100mL round-bottomed flask, add formic acid 50mL, mass fraction be 98% dense sulfur Acid 6mL, after backflow 3h, TLC monitoring raw material disappears, is cooled to room temperature, pours 200mL distilled water into, have a large amount of yellow-brown solid Generate, sucking filtration, with distilled water by Cake Wash to neutral, 60 DEG C of drying, must be containing the red brown solid compound of a small amount of impurity 7, yield 70%；
G (), successively by 2mol compound 7,2mol N, N-dimethyl-ethylenediamine, the dehydrated alcohol of 20mL are placed in 50mL round bottom In flask, after backflow 3h, TLC monitoring raw material disappears, cooling, solvent evaporated, directly crude product dry method is mixed sample, column chromatography, with two Chloromethanes: methanol=30:1 (volume ratio) eluting, obtains corresponding midbody compound 8a, after nuclear-magnetism identifies free from admixture, and will It is placed in 10mL dehydrated alcohol, is added dropwise over the concentrated hydrochloric acid that 1.5mL mass fraction is 37%, 24h is stirred at room temperature, centrifugal, heavy Form sediment successively with dehydrated alcohol, dichloromethane, each 20mL of absolute ether alternately washing, drained in exsiccator, obtain pure Hydrochlorate target product 9a, yield 84%.White powdery solids,1H NMR(300MHz,Deuterium Oxide)δ 8.22 (d, J=7.6Hz, 2H), 7.97 (s, 1H), 7.74 (s, 1H), 7.55 (t, J=8.1Hz, 1H), 4.27 (t, 2H), 3.41 (t, J=6.9Hz, 2H), 2.96 (s, 6H).13C NMR(75MHz,DMSO)δ163.12,162.42,160.20,150.51, 149.46,132.42,130.62,129.24,127.91,127.76,127.32,122.02,119.49,119.33,29.92, 20.33,14.18.Elemental Analysis for C18H17ClN4O3·3.2H2O:C,50.23；H,5.48；N,13.02； found:C,49.77；H,5.091；N,12.72.
Embodiment 2
The preparation of 5-normal-butyl-4H-isoquinolin [4,5-gh] quinazoline-4,6,8 (5H, 9H)-triketone (8b):
Except (g) step substitutes outside N, N-dimethyl-ethylenediamine with n-butylamine, other steps and the same embodiment of method of purification 1.Yield 91%, white powdery solids,1H NMR(300MHz,DMSO-d6) δ 12.85 (s, 1H), 8.66 (d, J=8.1Hz, 1H), 8.37 (d, J=3.7Hz, 1H), 8.31 (s, 1H), 8.27 (d, J=7.3Hz, 1H), 7.67 (t, J=7.9Hz, 1H), 3.87 (t, J=7.5Hz, 2H), 1.56 (p, J=7.3Hz, 2H), 1.35 (h, J=7.3Hz, 2H), 0.93 (t, J=7.3Hz, 3H).13C NMR(75MHz,DMSO)δ163.61,162.98,160.90,151.04,150.22,132.75,131.04, 129.77,128.25,128.21,127.84,122.44,119.78,119.57,56.42,45.32,37.68.Elemental Analysis for C18H15N3O3:C,67.28；H,4.71；N,13.08；found:C,67.66；H,4.616；N,12.98.
Embodiment 3
5-(4-aminobutyl)-4H-isoquinolin [4,5-gh] quinazoline-4,6,8 (5H, 9H)-three keto hydrochloride (9c) Preparation:
Except (g) step substitutes outside N, N-dimethyl-ethylenediamine with N-tertbutyloxycarbonyl-Putriscine, other steps and Method of purification is with embodiment 1.Yield 58%, white powdery solids,1H NMR(300MHz,DMSO-d6) δ 9.05 (d, J= 8.4Hz, 1H), 8.78 (s, 1H), 8.59 8.47 (m, 2H), 7.94 (t, J=8.0Hz, 1H), 4.03 (d, J=7.4Hz, 2H), 2.95 (d, J=6.4Hz, 2H), 1.61 (d, J=7.8Hz, 2H), 1.45 (s, 2H) .Elemental Analysis for C18H17ClN4O3·0.4H2O:C,56.89；H,4.72；N,14.74；found:C,57.07；H,4.73；N,14.97.
Embodiment 4
5-(4-morpholinyl butyl)-4H-isoquinolin [4,5-gh] quinazoline-4,6,8 (5H, 9H)-three keto hydrochloride (9d) Preparation:
Except (g) step substitutes outside N, N-dimethyl-ethylenediamine with 1-amino-4-morpholinyl-butane, other steps and carrying Pure method is with embodiment 1.Yield 68%, white powdery solids,1H NMR(300MHz,Deuterium Oxide)δ7.89– 7.66 (m, 3H), 7.17 (q, J=7.9,7.2Hz, 2H), 4.06 (s, 2H), 3.79 (s, 2H), 3.52 (d, J=25.7Hz, 4H), 3.17 (d, J=8.2Hz, 4H), 1.72 (s, 2H), 1.51 (d, J=9.3Hz, 2H) .Elemental Analysis for C22H23ClN4O4·0.4H2O:C,58.71；H,5.33；N,12.45；found:C,58.97；H,5.303；N,12.48.
Embodiment 5
5-(3-((3-aminopropyl) amino) propyl group)-4H-isoquinolin [4,5-gh] quinazoline-4,6,8 (5H, 9H)-triketone The preparation of dihydrochloride (9e):
Except (g) step substitutes with the tert-butyl group (3-aminopropyl) (3-((tertbutyloxycarbonyl) amino) propyl group) carbamate Outside N, N-dimethyl-ethylenediamine, other steps and method of purification are with embodiment 1.Yield 78%, white powdery solids,1H NMR (300MHz, Deuterium Oxide) δ 8.20 7.93 (m, 3H), 7.64 (d, J=38.1Hz, 1H), 7.50 7.37 (m, 1H), 3.95 3.64 (m, 2H), 3.05 (tq, J=17.5,7.5Hz, 5H), 2.02 (dd, J=19.0,11.4Hz, 2H), 1.65 (d, J=26.8Hz, 3H) .Elemental Analysis for C20H23Cl2N5O3·H2O·0.3C2H6O:C,51.10；H, 5.58；N,14.46；found:C,51.20；H,5.614；N,14.12.
Embodiment 6
5-butyl-9-(3-(pyrrolidine-1-yl) propyl group)-4H-isoquinolin [4,5-gh] quinazoline-4,6,8 (5H, 9H)- The preparation of three keto hydrochlorides (10a):
H 0.5g compound 8b is placed in 50mL round-bottomed flask by (), add the Anhydrous potassium carbonate of 0.5g, 1.25g 1,3-bis- In N-Propyl Bromide, 25mL acetonitrile, after backflow 5h, TLC monitoring raw material reaction is complete, it is cooled to room temperature, after solvent evaporated, adds 30mL Distilled water fully shakes, then extracts (3 × 30mL) with dichloromethane, merges organic layer, and anhydrous sodium sulfate is dried, and is evaporated, post layer Analysis, with dichloromethane: methanol=60:1 (volume ratio) eluting, obtains Bromo-intermediates.
The Bromo-intermediates of 1mmol is placed in 25mL round-bottomed flask, is sequentially added into 4mol Anhydrous potassium carbonate, 1.2mol pyrrole Cough up alkane, 10mL acetonitrile, after backflow 5h, TLC monitoring raw material reaction is complete, be cooled to room temperature, after solvent evaporated, add 30mL distillation Water fully shakes, then extracts (3 × 20mL) with dichloromethane, merges organic layer, and anhydrous sodium sulfate is dried, and is evaporated, column chromatography, uses Dichloromethane: methanol=40:1 (volume ratio) eluting, obtains target product, then is placed in the round-bottomed flask of 25mL, adds 10mL dehydrated alcohol, dropping 1.5mL mass fraction is the concentrated hydrochloric acid of 37%, and 24h is stirred at room temperature, by corresponding pelleting centrifugation, and With 20mL absolute ethanol washing three times, drained in exsiccator, obtained pure hydrochlorate target compound 10a.Yield 46%, white powdery solids,1H NMR (300MHz, Chloroform-d) δ 12.49 (s, 1H), 8.92 (d, J=11.6Hz, 2H), 8.83 (s, 1H), 8.56 (d, J=7.3Hz, 1H), 7.79 (t, J=7.7Hz, 1H), 4.55 4.40 (m, 2H), 4.14 (t, J=7.7Hz, 2H), 3.93 (s, 2H), 3.43 (d, J=7.0Hz, 2H), 2.99 (s, 2H), 2.63 (s, 2H), 2.41 2.06 (m, 4H), 1.70 (q, J=7.7Hz, 2H), 1.46 (dd, J=15.1,7.5Hz, 2H), 1.00 (t, J=7.3Hz, 3H) .Elemental Analysis for C25H29ClN4O3·0.4H2O:C,63.06；H,6.31；N,11.77；found:C, 62.89；H,6.184；N,11.72.
Embodiment 7
5-(2-(dimethylamino) ethyl)-8-((2-(dimethylamino) ethyl) amino)-4H-isoquinolin [4,5-gh] quinoline azoles The preparation of quinoline-4,6 (5H)-diketone tri hydrochloride (12a):
I 1g compound 8a is placed in 100mL toluene by (), add 10mL phosphorus oxychloride, and nitrogen is protected, after backflow 12h, cold But to room temperature, solvent evaporated, directly by crude mixture 11 next step.
J the mixture 11 of step (i) is added 0.3g N, N-dimethyl-ethylenediamine in 30mL oxolane by (), then add Enter 0.5mL triethylamine, after backflow 3h, after TLC monitoring raw material reaction is complete, be cooled to room temperature, solvent evaporated, be directly added into appropriate Silica gel dry method mixes sample, column chromatography, with dichloromethane: methanol=30:1+0.5% ammonia (volume ratio) eluting, identifies nothing through nuclear-magnetism After impurity, it is placed in the round-bottomed flask of 25mL, adds 10mL dehydrated alcohol, the concentrated hydrochloric acid of 2mL mass fraction 37%, room temperature Stirring 24h, centrifugal, precipitation is washed three times with dehydrated alcohol, dichloromethane, each 15mL of absolute ether successively, will in exsiccator It is drained, and obtains pure 12a.Yield 74%, yellow powdery solid,1H NMR(300MHz,Deuterium Oxide)δ 8.82 8.61 (m, 3H), 8.54 (d, J=7.6Hz, 1H), 7.89 (d, J=7.7Hz, 1H), 4.44 (d, J=6.1Hz, 2H), 4.15 (t, J=5.8Hz, 2H), 3.57 3.52 (m, 2H), 3.49 (t, J=6.6Hz, 2H), 2.97 (s, 12H) .Elemental Analysis for C22H29Cl3N6O2·2H2O:C,47.88；H,6.03；N,15.23；found:C,47.49；H,6.041；N, 14.96. embodiment 8
5-(2-(dimethylamino) ethyl)-8-((morpholinyl propyl group) amino)-4H-isoquinolin [4,5-gh] quinazoline- The preparation of 4,6 (5H)-diketone tri hydrochloride (12b):
Except (j) step substitutes outside N, N-dimethyl-ethylenediamine with 1-amino-morpholinyl-propane, other steps and carrying Pure method is with embodiment 7.Yield 85%, yellow powdery solid,1H NMR(300MHz,Deuterium Oxide)δ8.73– 8.65 (m, 1H), 8.63 (d, J=8.4Hz, 1H), 8.53 (d, J=7.4Hz, 1H), 7.89 (t, J=8.0Hz, 1H), 4.45 (t, J=6.1Hz, 1H), 4.06 (d, J=13.3Hz, 1H), 3.86 3.70 (m, 2H), 3.59 3.48 (m, 3H), 3.32 (t, J =8.3Hz, 1H), 3.25 3.12 (m, 1H), 2.98 (d, J=1.7Hz, 3H), 2.21 (t, J=8.2Hz, 1H) .Elemental Analysis for C25H33Cl3N6O3·3H2O:C,47.97；H,6.28；N,13.43；found:C,47.59；H,5.89；N, 13.10.
Embodiment 9
8-((4-aminobutyl) amino)-5-(2-(dimethylamino) ethyl)-4H-isoquinolin [4,5-gh] quinazoline-4,6 (5H) preparation of-diketone tri hydrochloride (12c):
Except (j) step substitutes outside N, N-dimethyl-ethylenediamine with N-tertbutyloxycarbonyl-Putriscine, other steps and Method of purification is with embodiment 7.Yield 88%, white powdery solids,1H NMR(300MHz,Deuterium Oxide)δ8.70 (d, J=10.2Hz, 2H), 8.63 8.52 (m, 2H), 7.90 (t, J=7.9Hz, 1H), 4.42 (d, J=6.9Hz, 2H), 3.69 (s, 2H), 3.46 (d, J=6.8Hz, 2H), 3.03 2.89 (m, 8H), 1.75 (s, 4H).13C NMR(75MHz,D2O)δ 164.37,163.28,159.96,153.07,142.27,134.08,129.53,129.21,128.72,125.64,122.39, 121.54,120.22,109.89,55.20,43.36,41.75,39.07,35.59,24.88,24.24.Elemental Analysis for C22H29Cl3N6O2·2H2O:C,47.88；H,6.03；N,15.23；found:C,48.22；H,5.829；N, 15.19.
Embodiment 10
5-(2-(dimethylamino) ethyl)-8-((3-methoxyphenyl) amino)-4H-isoquinolin [4,5-gh] quinazoline- The preparation of 4,6 (5H)-diketone tri hydrochloride (12d):
Except substituting outside N, N-dimethyl-ethylenediamine with 3-aminoanisole in (j) step, other steps and method of purification are same Embodiment 7.Yield 62%, yellow powdery solid,1H NMR (300MHz, Deuterium Oxide) δ 8.14 (d, J= 8.2Hz, 1H), 8.01 (d, J=7.3Hz, 1H), 7.92 (s, 1H), 7.74 (s, 1H), 7.48 7.39 (m, 1H), 6.94 (t, J =8.2Hz, 1H), 6.54 (s, 1H), 6.47 (d, J=7.4Hz, 2H), 3.88 (s, 2H), 3.51 (s, 3H), 3.04 (s, 2H), 2.81(s,5H).13C NMR(75MHz,D2O_salt)δ163.61,162.50,158.67,156.83,154.95,147.05, 137.09,133.26,129.93,129.74,128.60,127.55,124.80,120.40,118.55,114.52,110.56, 109.14,108.02,55.10,54.32,43.17,34.98.Elemental Analysis for C25H25Cl2N5O3·H2O: C,56.40；H,5.11；N,13.15；found:C,56.01；H,4.975；N,12.99.
Embodiment 11
8-((3-((3-aminopropyl) amino) propyl group) amino)-5-(2-(dimethylamino) ethyl)-4H-isoquinolin [4, 5-gh] preparation of quinazoline-4,6 (5H)-diketone four hydrochlorate (12e):
Except (j) step substitutes with the tert-butyl group (3-aminopropyl) (3-((tertbutyloxycarbonyl) amino) propyl group) carbamate Outside N, N-dimethyl-ethylenediamine, other steps and method of purification are with embodiment 7.Yield 32%, white powdery solids,1H NMR (300MHz,Methanol-d4) δ 9.37 (s, 1H), 9.15 (d, J=8.5Hz, 1H), 9.01 (s, 1H), 8.88 (d, J= 7.3Hz, 1H), 8.19 (t, J=8.1Hz, 1H), 4.63 (s, 2H), 4.02 (d, J=7.0Hz, 2H), 3.67 (s, 3H), 3.23 (dd, J=17.6,8.3Hz, 2H), 3.10 (s, 9H), 2.30 (d, J=9.2Hz, 2H), 2.16 (d, J=9.7Hz, 2H) .Elemental Analysis for C24H35Cl4N7O2·2H2O:C,45.65；H,6.23；N,15.53；found:C, 45.96；H,6.345；N,15.20.
Embodiment 12
Anti tumor activity in vitro is tested
Experiment material:
Using mtt assay that the compound of embodiment 1～11 is carried out tumor cell in vitro Cell suppression test, control drug is Amonafide (Amonafide), tumor cell line is: HepG2 (human liver cancer cell), SMMC-7721 (human liver cancer cell),
Three kinds of tumor cells of MDA-MB-231 (human breast cancer cell), are purchased from Chinese Academy of Sciences's Shanghai cell bank.
Experimental technique:
It is amonafide by the target compound in embodiment 1～11 and control drug, trophophase of taking the logarithm respectively HepG2 (human liver cancer cell), SMMC-7721 (human liver cancer cell), three kinds of tumor cells of MDA-MB-231 (human breast cancer cell) Strain, imbeds 96 orifice plates, 90 μ L/ holes with 5000-8000, every hole cell.After cultivating 24h, add the sample of concentration known, to often Individual cell strain, each concentration has four multiple holes, at 37 DEG C, 5%CO2Under the conditions of cultivate after 48h, add MTT 50 μ L, continue training Abandoning supernatant after supporting 4h, every hole adds 100 μ L DSMO, and vibrate 15min gently, surveys its absorbance by microplate reader at 570nm wavelength A value.By equation below calculate by difference survey thing to the suppression ratio of growth of tumour cell (growth of tumour cell suppression ratio (%)= (OD comparison-OD experiment)/(OD comparison-OD is blank) × 100%), experiment in triplicate, and is obtained IC by statistical software50Value.Knot Fruit is shown in Table 1.
The table 1 each embodiment compound growth inhibitory activity to different tumor cells
Note: in table, ND represents and do not surveys
As shown in Table 1, the pyrimido naphthoyl imide compounds prepared in the present invention has certain extracorporeal anti-tumor and lives Property, particularly compound 9a, 12a, 12b, 12c, 12e compares control drug amonafide to be had and preferably suppresses tumor cell proliferation Ability, therefore can be applied to preparation prevention and the medicine for the treatment of tumor.
Above-described embodiment is the preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment Limiting, other any change made without departing from the present invention all should be the substitute mode of equivalence, is included in the guarantor of the present invention Within the scope of protecting.

Claims (6)

1. a class pyrimido naphthalimide derivative, it is characterised in that described derivant has Formulas I to structure shown in III:
Formula I, in II, III, a is 0,1 or 2；M is 2,3 or 4；N is 2,3 or 4；X is the integer of 0 to 6；R1For R2For C1-C4 alkyl, R3For
The preparation method of pyrimido naphthalimide derivative the most according to claim 1, it is characterised in that synthetic route is such as Under:
Concrete preparation process is as follows:
A acenaphthene is dissolved in glacial acetic acid by (), drip concentrated nitric acid and carry out nitration reaction under ice bath, and reactant liquor is added ice after terminating by reaction In water, having yellow mercury oxide to generate, through sucking filtration, distilled water wash filter cake, to neutral, obtains nitration product compound 2 after drying；
B compound 2 is dissolved in glacial acetic acid by () after, add sodium dichromate, after being back to reaction completely, pour mixed liquor into frozen water In, there is yellow solid to separate out, through sucking filtration, washing to neutral, dry cake obtains oxidation product compound 3；
C () compound 3 is placed in dehydrated alcohol, add stannous chloride, concentrated hydrochloric acid, after being back to reaction completely, is cooled to room temperature, Sucking filtration, use ice washing with alcohol filter cake, obtain reduzate compound 4 after drying；
D compound 4 is placed in dichloromethane by (), drip bromine, and reaction i.e. obtains compound 5 through post processing after terminating；
E compound 5 is dissolved in N, N-dimethyl-acetamide by (), under four (triphenyl phosphorus) closes palladium chtalyst effect, in micro-strip Under part, react with zinc cyanide, obtain compound 6；
F () compound 6 and formic acid cyclization under sulphuric acid catalysis, generate compound 7；
G () compound 7 is dissolved in ethanol, add equimolar R1NH2, after backflow 3～4h, obtain compound 8, by compound 8 and salt Acid is stirred in ethanol to react and is i.e. obtained compound 9；
H compound 8 is dissolved in acetonitrile by (), under Anhydrous potassium carbonate effect, potassium iodide is as catalyst:
(1) react with mono-substituted C1-C4 halogenated alkane；
(2) with 1,3-dibromopropane, glycol dibromide or 1,4-dibromobutane generation substitution reaction；
(3) compound of step (2) is replaced from different amine；
Above-mentioned (1) (2) (3) three kinds of situations all can get compoundCompoundAgain Stir reaction with hydrochloric acid in ethanol and obtain compound 10；
(i) by compound 8 in toluene with phosphorus oxychloride back flow reaction, obtain compound 11；
(j) compound 11 and R3NH2Compound is obtained after reactionCompound Stir reaction with hydrochloric acid in ethanol and obtain compound 12.
3. the application in preparation prevention, tumor of the pyrimido naphthalimide derivative described in claim 1.
4. the answering in terms of preparing antitumor drug lead compound of the pyrimido naphthalimide derivative described in claim 1 With.
5. the application in preparation prevention, tumor of the pyrimido naphthalimide derivative described in claim 4, it is special Levying and be, described prevention, tumor are prevention, treatment hepatocarcinoma, the medicine of breast carcinoma.
Pyrimido naphthalimide derivative application in preparation prevention, tumor the most according to claim 5, its Being characterised by, described pharmaceutical dosage form is tablet, pill, capsule, injection, suspending agent or Emulsion.
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CN112876414A (en) * 2021-01-29 2021-06-01 河南大学 Polyamine-modified naphthalimide conjugate, and preparation method and application thereof
CN112898301A (en) * 2021-01-29 2021-06-04 河南大学 Naphthalimide indole heterocyclic compound, and preparation method and application thereof

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