CN106083850B - A kind of pyrimido naphthalimide derivative and its preparation method and application - Google Patents
A kind of pyrimido naphthalimide derivative and its preparation method and application Download PDFInfo
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- 0 CCCCN(C(c1c(c2cc3c4N=C=NC3=O)*4ccc1)=O)C2=O Chemical compound CCCCN(C(c1c(c2cc3c4N=C=NC3=O)*4ccc1)=O)C2=O 0.000 description 2
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- 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
- C07D471/06—Peri-condensed systems
Abstract
A kind of pyrimido naphthalimide derivative and its preparation method and application, the derivative has structure shown in Formulas I to III:In formula I, II, III, a 0,1 or 2;M is 2,3 or 4;N is 2,3 or 4;X is 0 to 6 integer;R1For、、、、、、, R2For C1 C4 alkyl,、、Or;R3For、、、Or
Description
Technical field
The invention belongs to medicinal chemistry art, more particularly to a kind of pyrimido naphthalimide derivative and preparation method thereof and
Using.
Background technology
Naphthalimide is a kind of organic micromolecule compound with potential antitumor activity.Multiple naphthalimide derivatives
Such as Amonafide (Amonafide), mitonafide (Mitonafide), Azonafide once entered as antineoplastic
Clinical experimental stage, but due to its stronger neurotoxicity and bone marrow suppression, be not approved finally to list.
In order to reduce the toxicity of naphthoyl imide compounds, its bioactivity is improved, various countries researcher has done many
Effort.Literature survey finds that the structural modification based on naphthalimide is concentrated mainly on two aspects, first, to naphthalimide side chain
Carry out substitution modification;Second, the aromatic ring of naphthalimide is substituted or simultaneously ring modify.Although some activity are obtained preferably
Compound, but because the purpose of ring expansion is not strong, can not effectively solve the highly toxic problem of naphthalimide.
The content of the invention
A kind of pyrimido naphthalimide derivative, the derivative have structure shown in Formulas I to III:
In formula I, II, III, a 0,1 or 2;M is 2,3 or 4;N is 2,3 or 4;X is 0 to 6 integer;R1For R2For C1-C4 alkyl, OrR3For Or
The preparation method of above-mentioned pyrimido naphthalimide derivative, synthetic route are as follows:
Specific preparation process is as follows:
(a) acenaphthene is dissolved in glacial acetic acid, concentrated nitric acid is added dropwise under ice bath and carries out nitration reaction, reaction adds reaction solution after terminating
Enter in frozen water, there is yellow mercury oxide generation, through filtering, distillation water washing filter cake to neutrality, nitration product compound is obtained after drying
2;
(b) after compound 2 is dissolved in glacial acetic acid, sodium dichromate is added, after being back to reaction completely, mixed liquor is poured into
In frozen water, there is yellow solid precipitation, through filtering, washing to neutrality, dry cake obtains oxidation product compound 3;
(c) compound 3 is placed in absolute ethyl alcohol, adds stannous chloride, concentrated hydrochloric acid, after being back to reaction completely, is cooled to
Room temperature, filter, filter cake is washed with ice ethanol, reduzate compound 4 is obtained after drying;
(d) compound 4 is placed in dichloromethane, bromine is added dropwise, reacted and produce compound 5 through post-processing after terminating;
(e) compound 5 is dissolved in N, in N- dimethyl-acetamides, in the case where four (triphenyl phosphorus) close palladium chtalyst effect, micro-
Under the conditions of ripple, reacted 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, adds equimolar R1NH2, flow back 3~4h after obtain compound 8, by compound 8
Stirring reaction produces compound 9 in ethanol with hydrochloric acid;
(h) compound 8 is dissolved in acetonitrile, under Anhydrous potassium carbonate effect, KI is as catalyst:
(1) reacted with mono-substituted C1-C4 halogenated alkanes;
(2) substitution reaction occurs with 1,3- dibromopropanes, glycol dibromide or 1,4- dibromobutanes;
(3) compound of step (2) is substituted from different amine;
Above-mentioned (1) (2) (3) three kinds of situations can obtain compoundCompoundStirring reaction obtains compound 10 in ethanol with hydrochloric acid again;
(i) by compound 8 in toluene with POCl3 back flow reaction, obtain compound 11;
(j) compound 11 and R3NH2Compound is obtained after reactionCompoundStirring reaction obtains compound 12 in ethanol with hydrochloric acid.
Application of the above-mentioned pyrimido naphthalimide derivative in prevention, tumor is prepared.
Application of the above-mentioned pyrimido naphthalimide derivative in terms of antineoplastic lead compound is prepared.
Application of the above-mentioned pyrimido naphthalimide derivative in prevention, tumor is prepared, the prevention, control
Tumour medicine is treated as prevention, treatment liver cancer, the medicine of breast cancer
Application of the above-mentioned pyrimido naphthalimide derivative in prevention, tumor is prepared, the pharmaceutical dosage form
For tablet, pill, capsule, injection, suspending agent or emulsion.
The invention provides one kind using acenaphthene as raw material, by introducing adjacent cyanamide, structure new pyrimidine and naphthalimide
Preparation method.Found out according to data with existing, through with targeting carrying capacity it is how amine-modified after, the antitumor activity of naphthalimide
It is obviously improved, and has stronger inhibitory action to metastases.According to this discovery, we design a series of pyrimidos of synthesis
Naphthalimide derivative.Preliminary survey result shows that such naphthalimide derivative shows good body to various tumor cell strains
Outer antitumor activity.Therefore, such pyrimido naphthoyl imide compounds is further studied, design synthesis has higher
The small derivative of antitumor activity, toxic side effect, it is significant for the new antineoplastic of development.
Embodiment
It is described in detail by the following examples, to be best understood from present disclosure.
Synthetic route in following embodiments is as follows, and specific 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
The preparation of (9a):
(a) take 10g acenaphthenes (i.e. compound 1) to be placed in 100mL glacial acetic acids, stirred under ice bath, 7.1mL mass point is added dropwise
Number is about 65% concentrated nitric acid, has a large amount of yellow mercury oxides to generate after 4h, TLC monitorings, is poured into after reaction completely in 500mL frozen water,
Filter, filter cake is washed till neutrality with distilled water, 45 DEG C of drying, produces 16.3g yellow compounds 2, yield 84%;
(b) take 20g compounds 2 to be placed in 100mL glacial acetic acids, add 10g sodium dichromates, flow back after 5h, be cooled to room
Temperature, pour into 500mL frozen water, filter, be washed with distilled water to neutrality, dry, obtain glassy yellow powdered compounds 3, yield
82%;
(c) take 10g compounds 3 to be placed in 50mL absolute ethyl alcohols, sequentially add 40g stannous chlorides, 50mL mass fractions are
37% concentrated hydrochloric acid solution, after 70 DEG C of backflow 2h, TLC monitoring raw materials disappear, room temperature is cooled to, is filtered, with ice ethanol and anhydrous
Each 80mL washings filter cake of ether, filter cake is put into vacuum desiccator and drained, produces bronzing compound 4, yield 85%;
(d) take 18.3g compounds 4 to be placed in grind in alms bowl, be added to after the shape solid that is crushed into powder in 100mL dichloromethane, ice
Side is stirred in water-bath, while 9mL bromines are added dropwise with constant pressure funnel, is finished, and 3h is stirred at room temperature, and TLC monitoring raw material reactions are complete
Afterwards, the rapid filtration under suction in fume hood, filter cake is alternately washed with absolute ethyl alcohol and each 200mL of dichloromethane, until filter liquor is bright
Yellow transparent liquid, filter cake is put into drier and drained, produce orange-yellow powdered compounds 5, yield 87%;
(e) 0.3g intermediates 5 are taken in 10mL microwave reaction pipe, 0.12g tetra- (triphenyl phosphorus) is sequentially added and closes palladium,
0.12g zinc cyanides, after being put into magneton, 5mL N, N- dimethyl-acetamides are added, are placed in after sealing in microwave reactor, power
150W is set to, temperature is adjusted to 100 DEG C, reacts 30min, adds after cooling in 100mL distilled water, filters, with 20mL mass point
Number washs filter cake for 5% ammonia spirit, 60 DEG C of drying, produces the compound 6 (crude product of compound 6) containing less impurity, yield
73%;
(f) the crude product 3g of compound 6 is taken in 100mL round-bottomed flasks, adds formic acid 50mL, the dense sulphur that mass fraction is 98%
Sour 6mL, flow back 3h, after TLC monitoring raw materials disappear, is cooled to room temperature, pours into 200mL distilled water, there is a large amount of yellow-brown solids
Generation, filter, with distilled water by Washing of Filter Cake to neutrality, 60 DEG C dry, and obtain the red brown solid compound containing a small amount of impurity
7, yield 70%;
(g) 2mol compounds 7,2mol N, N- dimethyl-ethylenediamines, 20mL absolute ethyl alcohol are placed in 50mL round bottoms successively
In flask, flow back 3h, after TLC monitoring raw materials disappear, cooling, solvent evaporated, crude product dry method directly is mixed into sample, column chromatography, with two
Chloromethanes:Methanol=30:1 (volume ratio) elutes, and obtains corresponding midbody compound 8a, will after nuclear-magnetism identifies free from admixture
It is placed in 10mL absolute ethyl alcohols, and the concentrated hydrochloric acid that 1.5mL mass fractions are 37% is added dropwise, 24h is stirred at room temperature, centrifuges, sinks
Form sediment and alternately washed with absolute ethyl alcohol, dichloromethane, each 20mL of absolute ether successively, drained, produced pure in drier
Hydrochloride 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 substituting N, outside N- dimethyl-ethylenediamines, other steps and the same embodiment of method of purification with n-butylamine in (g) step
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
The keto hydrochloride (9c) of 5- (4- aminobutyls) -4H- isoquinolin [4,5-gh] quinazolines -4,6,8 (5H, 9H)-three
Prepare:
Except using N- tertbutyloxycarbonyls-Putriscine to substitute N in (g) step, outside N- dimethyl-ethylenediamines, other steps and
Method of purification is the same as 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
The keto hydrochloride (9d) of 5- (4- morpholinyls butyl) -4H- isoquinolin [4,5-gh] quinazoline -4,6,8 (5H, 9H)-three
Preparation:
Except using 1- amino -4- morpholinyls-butane to substitute N in (g) step, outside N- dimethyl-ethylenediamines, other steps and carry
Pure method is the same as 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- aminopropyls) amino) propyl group) -4H- isoquinolin [4,5-gh] quinazoline -4,6,8 (5H, 9H)-triketone
The preparation of dihydrochloride (9e):
Except in (g) step use the tert-butyl group (3- aminopropyls) (3- ((tertbutyloxycarbonyl) amino) propyl group) carbamate substitute
Outside N, N- dimethyl-ethylenediamine, other steps and method of purification are the same as 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- (pyrrolidines -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 compounds 8b is placed in 50mL round-bottomed flasks, adds 0.5g Anhydrous potassium carbonate, 1.25g 1,3- bis-
In N-Propyl Bromide, 25mL acetonitriles, flow back 5h, after TLC monitoring raw material reactions completely, is cooled to room temperature, 30mL is added after solvent evaporated
Distilled water fully shaking, then extracted (3 × 30mL) with dichloromethane, merge organic layer, anhydrous sodium sulfate drying, be evaporated, post layer
Analysis, uses dichloromethane:Methanol=60:1 (volume ratio) elutes, and produces Bromo-intermediates.
1mmol Bromo-intermediates are placed in 25mL round-bottomed flasks, sequentially add 4mol Anhydrous potassium carbonates, 1.2mol pyrroles
Alkane is coughed up, 10mL acetonitriles, flow back 5h, after TLC monitoring raw material reactions completely, is cooled to room temperature, 30mL distillations are added after solvent evaporated
Water fully shaking, then extracted (3 × 20mL) with dichloromethane, merge organic layer, anhydrous sodium sulfate drying, be evaporated, column chromatography, use
Dichloromethane:Methanol=40:1 (volume ratio) elutes, and produces target product, then is placed in 25mL round-bottomed flask, adds
10mL absolute ethyl alcohols, the concentrated hydrochloric acid that 1.5mL mass fractions are 37% is added dropwise, 24h is stirred at room temperature, by corresponding pelleting centrifugation, and
Washed three times with 20mL absolute ethyl alcohols, drained in drier, produce pure hydrochloride 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 compounds 8a is placed in 100mL toluene, adds 10mL POCl3s, nitrogen is protected, cold after the 12h that flows back
But to room temperature, solvent evaporated, directly by the next step of crude mixture 11.
(j) mixture 11 of step (i) is added into 0.3g N, N- dimethyl-ethylenediamines in 30mL tetrahydrofurans, then added
Enter 0.5mL triethylamines, after the 3h that flows back, after TLC monitoring raw material reactions completely, be cooled to room temperature, solvent evaporated, be directly added into appropriate
Silica gel dry method mixes sample, column chromatography, uses dichloromethane:Methanol=30:1+0.5% ammoniacal liquor (volume ratio) is eluted, and nothing is identified through nuclear-magnetism
After impurity, it is placed in 25mL round-bottomed flask, adds 10mL absolute ethyl alcohols, the concentrated hydrochloric acid of 2mL mass fractions 37%, room temperature
24h, centrifugation are stirred, precipitation is washed three times with absolute ethyl alcohol, dichloromethane, each 15mL of absolute ether successively, will in drier
It is drained, and produces 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 hydrochlorides (12b):
Except using 1- amino-morpholinyls-propane to substitute N in (j) step, outside N- dimethyl-ethylenediamines, other steps and carry
Pure method is the same as 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- aminobutyls) amino) -5- (2- (dimethylamino) ethyl) -4H- isoquinolin [4,5-gh] quinazoline -4,6
The preparation of (5H)-diketone tri hydrochloride (12c):
Except using N- tertbutyloxycarbonyls-Putriscine to substitute N in (j) step, outside N- dimethyl-ethylenediamines, other steps and
Method of purification is the same as 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- methoxyphenyls) amino) -4H- isoquinolin [4,5-gh] quinazoline -
The preparation of 4,6 (5H)-diketone tri hydrochlorides (12d):
Except using 3- aminoanisoles to substitute N in (j) step, outside N- dimethyl-ethylenediamines, 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- aminopropyls) amino) propyl group) amino) -5- (2- (dimethylamino) ethyl) -4H- isoquinolin [4,
5-gh] quinazoline -4,6 (5H)-hydrochloride of diketone four (12e) preparation:
Except in (j) step use the tert-butyl group (3- aminopropyls) (3- ((tertbutyloxycarbonyl) amino) propyl group) carbamate substitute
Outside N, N- dimethyl-ethylenediamine, other steps and method of purification are the same as 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:
Tumor cell in vitro Cell suppression test is carried out to the compound of embodiment 1~11 using mtt assay, control drug is
Amonafide (Amonafide), tumor cell line are:HepG2 (human liver cancer cell), SMMC-7721 (human liver cancer cell),
Three kinds of tumour cells of MDA-MB-231 (human breast cancer cell), are purchased from Chinese Academy of Sciences's Shanghai cell bank.
Experimental method:
It is Amonafide by the target compound in embodiment 1~11 and control drug, takes the logarithm respectively growth period
Three kinds of HepG2 (human liver cancer cell), SMMC-7721 (human liver cancer cell), MDA-MB-231 (human breast cancer cell) tumour cells
Strain, 96 orifice plates, 90 μ L/ holes are embedded to every 5000-8000 cell in hole.After cultivating 24h, the sample of concentration known is added, to every
Individual cell line, each concentration have four multiple holes, at 37 DEG C, 5%CO2Under the conditions of cultivate 48h after, add the μ L of MTT 50, continue to train
Supernatant is abandoned after supporting 4h, 100 μ L DSMO are added per hole, 15min is gently vibrated, its absorbance is surveyed at 570nm wavelength with ELIASA
A values.By following formula calculate by different survey things to the inhibiting rate of growth of tumour cell (growth of tumour cell inhibiting rate (%)=
(OD controls-OD experiments)/(OD control-OD blank) × 100%), experiment in triplicate, and obtains IC by statistical software50Value.Knot
Fruit is shown in Table 1.
Growth inhibitory activity of each embodiment compound of table 1 to different tumour cells
Note:ND represents not survey in table
As shown in Table 1, there is the pyrimido naphthoyl imide compounds prepared in the present invention certain extracorporeal anti-tumor to live
Property, particularly compound 9a, 12a, 12b, 12c, 12e has compared to control drug Amonafide preferably suppresses tumor cell proliferation
Ability, therefore the medicine for preparing prevention and treatment tumour can be applied to.
Above-described embodiment is the preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes made without departing from the present invention should be equivalent substitute mode, are included in the guarantor of the present invention
Within the scope of shield.
Claims (6)
1. the preparation method of a kind of pyrimido naphthalimide derivative, it is characterised in that synthetic route is as follows:
Specific preparation process is as follows:
(a)Acenaphthene is dissolved in glacial acetic acid, concentrated nitric acid is added dropwise under ice bath and carries out nitration reaction, reacts and reaction solution is added into ice after terminating
In water, there is yellow mercury oxide generation, through filtering, distillation water washing filter cake to neutrality, nitration product compound 2 is obtained after drying;
(b)After compound 2 is dissolved in glacial acetic acid, sodium dichromate is added, after being back to reaction completely, mixed liquor is poured into frozen water
In, there is yellow solid precipitation, through filtering, washing to neutrality, dry cake obtains oxidation product compound 3;
(c)Compound 3 is placed in absolute ethyl alcohol, adds stannous chloride, concentrated hydrochloric acid, after being back to reaction completely, is cooled to room temperature,
Filter, filter cake is washed with ice ethanol, reduzate compound 4 is obtained after drying;
(d)Compound 4 is placed in dichloromethane, bromine is added dropwise, reacts and produces compound 5 through post-processing after terminating;
(e)Compound 5 is dissolved in N, in N- dimethyl-acetamides, four(Triphenyl phosphorus)Close under palladium chtalyst effect, in micro-strip
Under part, reacted 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, adds equimolar R1NH2, flow back 3 ~ 4 h after obtain compound 8, by compound 8 and salt
Stirring reaction produces compound 9 to acid in ethanol, the R in compound 81For、、、Or;
(h)Compound 8 is dissolved in acetonitrile, under Anhydrous potassium carbonate effect:
(1)Reacted with mono-substituted C1-C4 halogenated alkanes;
(2)Substitution reaction occurs with 1,3- dibromopropanes, glycol dibromide or 1,4- dibromobutanes;
(3)By step(2)In 8 substituted with the products of 1,3- dibromopropanes with pyrrolidines;
It is above-mentioned(1)(2)(3)Three kinds of situations can obtain compound, R2For C1-C4 alkyl,、、Or, compoundAgain with
Stirring reaction obtains compound 10 to hydrochloric acid in ethanol;
(i)By compound 8 in toluene with POCl3 back flow reaction, obtain compound 11;
(j)Compound 11 and R3NH2Compound is obtained after reaction, R3For、、、Or, compoundStirring reaction obtains compound 12 in ethanol with hydrochloric acid.
2. utilize a kind of pyrimido naphthalimide derivative made from the preparation method of claim 1.
3. application of the pyrimido naphthalimide derivative in prevention, tumor is prepared described in claim 2.
4. the answering in terms of antineoplastic lead compound is prepared of the pyrimido naphthalimide derivative described in claim 2
With.
5. application of the pyrimido naphthalimide derivative in prevention, tumor is prepared described in claim 3, it is special
Sign is that the prevention, tumor are prevention, treatment liver cancer, the medicine of breast cancer.
6. application of the pyrimido naphthalimide derivative in prevention, tumor is prepared according to claim 5, its
It is characterised by, the pharmaceutical dosage form is tablet, pill, capsule, injection, suspending agent or emulsion.
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