CN110407747A - A kind of 4- methylamino acridine-N- phenyl benzoyl amine compound and its preparation method and application - Google Patents
A kind of 4- methylamino acridine-N- phenyl benzoyl amine compound and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of 4- aminomethyl acridine-N- phenyl benzoyl amine compounds and its preparation method and application, feature is that the compound is the compound with structural formula shown in Formulas I or compound pharmaceutically acceptable salt, ester or the solvate with structural formula shown in Formulas I, wherein R1For H, OCH3、OCH2CH3、Cl、Br、CF3、NO2Or carbon atom number is the straight chained alkyl of 1-5, R2For H, OCH3、OCH2CH3、Cl、Br、CF3、NO2Or carbon atom number is the straight chained alkyl of 1-5, R3For H, OCH3、OCH2CH3、Cl、Br、CF3、NO2Or carbon atom number be 1-5 straight chained alkyl, n=1,2,3 or 4, advantage be the compound can effectively inhibit DNA topoisomerase activity, inhibit eucaryote tumor cell proliferation, prevention and/or treatment tumour.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of 4- methylamino acridine-N- phenyl benzoyl amine compound and
Preparation method and application.
Background technique
Cancer is one of highest disease of global incidence of mortality, and incidence and mortality produces the health status of the people
Severe influence is given birth to.Therefore, it is extremely urgent to research and develop new and effective anticancer drug.Acridine compound is living with preferable anticancer
Property, structure fragment is able to suppress DNA relevant enzyme such as topoisomerase as one of small molecule parent nucleus important in medicament research and development
Deng.Have many acridine compounds in recent years and enters clinical and preclinical phase.Therefore, structure of modification is carried out with acridine parent nucleus
It imitates and studies with structure, there is great importance for research and development new type anticancer small-molecule drug.
Summary of the invention
It can effectively inhibit to inhibit topoisomerase I/II, inhibition technical problem to be solved by the invention is to provide one kind
Eucaryote tumor cell proliferation, prevention and/or treat tumour 4- methylamino acridine-N- phenyl benzoyl amine compound and
Preparation method and use.
The technical scheme of the invention to solve the technical problem is: a kind of 4- methylamino acridine-N- phenyl benzene first
Amides compound, the compound are the 4- methylamino acridine-N- phenyl benzoyl amine chemical combination with structural formula shown in Formulas I
The pharmaceutically acceptable salt of object or the 4- methylamino acridine-N- phenyl benzoyl amine compound with structural formula shown in Formulas I,
Ester or solvate,
(I)
Wherein, R1For H, OCH3、OCH2CH3、Cl、Br、CF3、NO2Or carbon atom number is the straight chained alkyl of 1-5, R2For H, OCH3、
OCH2CH3、Cl、Br、CF3、NO2Or carbon atom number is the straight chained alkyl of 1-5, R3For H, OCH3、OCH2CH3、Cl、Br、CF3、NO2
Or carbon atom number be 1-5 straight chained alkyl, n=1,2,3 or 4, the salt be inorganic acid salt or acylate, described is inorganic
Hydrochlorate is the salt that any one inorganic acid is formed in hydrochloric acid, sulfuric acid and phosphoric acid；The acylate be acetic acid, trifluoroacetic acid,
The salt that any one organic acid is formed in malonic acid, citric acid and p-methyl benzenesulfonic acid.
The preparation method of above-mentioned 4- methylamino acridine-N- phenyl benzoyl amine compound, comprising the following steps:
(1) react compound shown in Formula II with compound shown in formula III, to obtain compound shown in formula IV；
(2) compound shown in formula IV and phosphorus oxychloride reaction, to obtain compound shown in Formula V；
(3) compound shown in formula VI is reacted with di-tert-butyl dicarbonate, to obtain compound shown in Formula VII；
(4) react compound shown in Formula VII with compound shown in Formula VIII, to obtain compound shown in Formula IX；
(5) react compound shown in Formula IX with hydrochloric acid, to obtain compound shown in Formula X；
(6) react compound shown in Formula V with compound shown in Formula X, to obtain compound shown in Formulas I,
Wherein, R1For H, OCH3、OCH2CH3、Cl、Br、CF3、NO2Or carbon atom number is the straight chained alkyl of 1-5, R2For H, OCH3、
OCH2CH3、Cl、Br、CF3、NO2Or carbon atom number is the straight chained alkyl of 1-5, R3For H, OCH3、OCH2CH3、Cl、Br、CF3、NO2
Or carbon atom number be 1-5 straight chained alkyl, n=1,2,3 or 4.
Step (1) specifically: at 100-130 DEG C, be catalyst, potassium carbonate as alkali using copper, make chemical combination shown in Formula II
That 1-12 is reacted in anhydrous N,N-dimethylformamide is small according to the ratio that molar ratio is 1:1.5 for compound shown in object and formula III
When, that is, obtain compound shown in formula IV.
Step (2) specifically: at 50-100 DEG C, compound shown in formula IV with phosphorus oxychloride reaction 1-5 hours, that is, obtain
Obtain compound shown in formula V.
Step (3) specifically: at 25-80 DEG C, using triethylamine as alkali, compound shown in formula VI and two dimethyl dicarbonate fourths
Ester reacts 2-8 hours, i.e. compound shown in acquisition Formula VII in anhydrous methanol.
Step (4) specifically: at 10-70 DEG C, make compound shown in compound shown in Formula VII and Formula VIII with N, N'-
Carbonyl dimidazoles react 10-30 hours, i.e. chemical combination shown in acquisition Formula IX as condensing agent in anhydrous n,N-Dimethylformamide
Object.
Step (5) specifically: at 25-60 DEG C, make compound shown in Formula IX react 10-30 in methyl alcohol with hydrochloric acid small
When, that is, obtain compound shown in Formula X.
Step (6) specifically: under inert gas protection, at 25-120 DEG C, shown in compound shown in formula V and Formula X
Compound reacts 10-30 hours, i.e. compound shown in acquisition Formulas I in phenol.
Purposes of the above compound in preparation prevention and/or tumor.
Above compound inhibits DNA topoisomerase I/II in preparation and/or inhibits eucaryote tumor cell proliferation medicine
Purposes in object.
Compared with the prior art, the advantages of the present invention are as follows: a kind of 4- methylamino acridine-N- phenylbenzamaide of the present invention
Class compound and its preparation method and application, the compound can effectively inhibit DNA topoisomerase I/II activity, inhibit true
Core tumor cell Proliferation, prevention and/or treatment tumour.Compound provided by the invention is tested by kinds of tumor cells system
(including leukaemia cell, lymphoma cell etc.) and DNA topoisomerase I/II test, protein electrophoresis experiment detection DNA damage
Hurt the up-regulation etc. of marker γ-H2AX expression, it was demonstrated that the compound of the present invention be it is a kind of it is potential inhibit DNA topoisomerase I/
II has the anti-tumor drug of certain inhibitory activity.Raw materials of compound provided by the invention is easy to get, and preparation method is simple, experiment card
Bright its has good anticancer effect, has good application prospect in anti-tumor drug design research and development field.
Detailed description of the invention
Fig. 1 shows according to one embodiment of present invention, the protein electrophoresis figure of compound 2；
Fig. 2 shows that according to one embodiment of present invention the Apoptosis of compound 2 detects figure.
Specific embodiment
The present invention will be described in further detail below with reference to the embodiments of the drawings.
The embodiments described below is exemplary, and for explaining only the invention, and should not be understood as to limit of the invention
System.Particular technique or condition are not specified in embodiment, described technology or conditions or presses according to the literature in the art
It is carried out according to product description.Reagents or instruments used without specified manufacturer is that can be produced by the routine of commercially available acquisition
Product.Herein, " compound shown in formula N " is otherwise referred to as " compound N " herein, and N herein is any whole of 1-7
Number, such as " compound shown in formula 2 " are referred to as " compound 2 " herein.
Specific embodiment one
A kind of 4- methylamino acridine-N- phenyl benzoyl amine compound, the compound are the chemical combination with structural formula shown in Formulas I
The pharmaceutically acceptable salt of object or the compound with structural formula shown in Formulas I, ester or solvate,
Formula
Above-mentioned formulaIn, R1For H, OCH3、OCH2CH3、Cl、Br、CF3、NO2Or carbon atom number is the straight chained alkyl of 1-5, R2For H,
OCH3、OCH2CH3、Cl、Br、CF3、NO2Or carbon atom number is the straight chained alkyl of 1-5, R3For H, OCH3、OCH2CH3、Cl、Br、
CF3、NO2Or carbon atom number be 1-5 straight chained alkyl, n=1,2,3 or 4.Above-mentioned formulaShown compound pharmaceutically acceptable salt,
Ester or solvate, wherein salt is inorganic acid salt or acylate；Inorganic acid salt is selected from what any one following inorganic acid were formed
Salt: hydrochloric acid, sulfuric acid or phosphoric acid；Acylate is selected from the salt that any one following organic acid are formed: acetic acid, trifluoroacetic acid, the third two
Acid, citric acid and p-methyl benzenesulfonic acid.
Above-mentioned formulaShown in 4- methylamino acridine-N- phenyl benzoyl amine compound be preferably it is following any one:
The compound can effectively inhibit DNA topoisomerase I/II activity, inhibit eucaryote tumor cell proliferation, prevention
And/or treatment tumour.Compound provided by the invention is by kinds of tumor cells system test (including leukaemia cell, lymthoma
Cell etc.) and DNA topoisomerase I/II test, protein electrophoresis, which is tested, detects the upper of DNA damage marker γ-H2AX expression
Adjust etc., it was demonstrated that the compound of the present invention is a kind of potential inhibition DNA topoisomerase I/II, there is the anti-swollen of certain inhibitory activity
Tumor medicine.
Specific embodiment two
The preparation method of 4- methylamino acridine-N- phenyl benzoyl amine compound in above-mentioned specific embodiment one, including it is following
Step:
(1) react compound shown in Formula II with compound shown in formula III, to obtain compound shown in formula IV；According to the present invention
Embodiment, the condition that compound shown in Formula II is reacted with compound shown in formula III is not particularly limited, it is also possible to have
Body are as follows: be catalyst, potassium carbonate as alkali using copper at 100-130 DEG C, make compound shown in compound shown in Formula II and formula III
1-12 hours, i.e. acquisition formula IV shownization are reacted in anhydrous n,N-Dimethylformamide according to the ratio that molar ratio is 1:1.5
Close object；Be conducive to improve reaction efficiency as a result, reduce side reaction, improves yield；
(2) compound shown in formula IV and phosphorus oxychloride reaction, to obtain compound shown in Formula V；It can be with specifically: in
At 50-100 DEG C, compound shown in formula IV and phosphorus oxychloride reaction 1-5 hours, i.e. compound shown in acquisition formula V；As a result, can
It is enough to be reacted under the most appropriate conditions, be conducive to improve reaction efficiency, reduce side reaction, improves yield；
(3) compound shown in formula VI is reacted with di-tert-butyl dicarbonate, to obtain compound shown in Formula VII；Can also have
Body are as follows: at 25-80 DEG C, using triethylamine as alkali, compound shown in formula VI and di-tert-butyl dicarbonate are anti-in anhydrous methanol
Answer 2-8 hours, i.e. compound shown in acquisition Formula VII；Be conducive to improve reaction efficiency as a result, reduce side reaction, improves yield；
(4) react compound shown in Formula VII with compound shown in Formula VIII, to obtain compound shown in Formula IX；It can be with
Specifically: at 10-70 DEG C, make compound shown in compound shown in Formula VII and Formula VIII with N, N'- carbonyl dimidazoles are as contracting
Mixture reacts 10-30 hours, i.e. compound shown in acquisition Formula IX in anhydrous n,N-Dimethylformamide；Thereby, it is possible to most
It is reacted under the conditions of suitable, is conducive to improve reaction efficiency, reduces side reaction, improve yield；
(5) react compound shown in Formula IX with hydrochloric acid, it, can be with to obtain compound shown in Formula X specifically: in 25-60
At DEG C, compound shown in Formula IX is made to react 10-30 hours, i.e. compound shown in acquisition Formula X in methyl alcohol with hydrochloric acid；Have as a result,
Conducive to reaction efficiency is improved, side reaction is reduced, improves yield；
(6) react compound shown in Formula V with compound shown in Formula X, it, can be with to obtain compound shown in Formulas I specifically:
Under inert gas protection, at 25-120 DEG C, compound shown in formula V reacts 10- with compound shown in Formula X in phenol
30 hours, i.e. compound shown in acquisition Formulas I are conducive to improve reaction effect thereby, it is possible to be reacted under the most appropriate conditions
Rate reduces side reaction, improves yield；
Wherein, R1For H, OCH3、OCH2CH3、Cl、Br、CF3、NO2Or carbon atom number is the straight chained alkyl of 1-5, R2For H, OCH3、
OCH2CH3、Cl、Br、CF3、NO2Or carbon atom number is the straight chained alkyl of 1-5, R3For H, OCH3、OCH2CH3、Cl、Br、CF3、NO2
Or carbon atom number be 1-5 straight chained alkyl, n=1,2,3 or 4.Before capable of fast and effeciently being prepared using above-mentioned preparation method
Compound described in face, and this method is simple, convenient fast, is suitable for large-scale production.
Embodiment 1
4-((acridine -9- amino) methyl)-N- phenylbenzamaide preparation
1,2-(phenyl amino is prepared) benzoic acid
By 2- chlorobenzoic acid (25.64mmol) and aniline (12.82mmol), potassium carbonate (19.23mmol) and copper powder
(19.23mmol) is added sequentially in dimethylformamide (50 ml) solvent, is then heated to reflux and is stirred overnight at 130 DEG C,
TLC detection (solvent is ethyl acetate: petroleum ether acetic acid=1:1) reaction terminates.Then obtained reaction mixture is cooling
It is filtered afterwards with diatomite, gained filtrate is added in 200mL water, then it is about 3 that system, which is adjusted to pH value, with hydrochloric acid, filters and incites somebody to action
The precipitating drying arrived obtains dark green solid powder to get 2-(phenyl amino)-benzoic acid, yield 50.72%, fusing point 173.9
℃-178.0℃.Compound structure confirms data are as follows:1H NMR (600 MHz, CD3OD) δ 7.96 (dd, J = 8.0,
1.6 Hz, 1H), 7.35–7.27 (m, 3H), 7.24–7.17 (m, 3H), 7.07–7.02 (m, 1H), 6.71
(ddd, J = 8.0, 7.2, 1.1 Hz, 1H)。
2,9-chloroacridine is prepared
By 2-(phenyl amino obtained in step 1) benzoic acid (1.19 mmol) is added in phosphorus oxychloride (10 ml), and in
It flows back 3-5 hours under 100 DEG C of heating conditions, then will be slowly added into about 150-200 ml's after the cooling of obtained reaction solution
In mixture of ice and water, system pH value is then adjusted to about 8 with sodium hydroxide solution, mixed liquor continues stirring 30 at room temperature
After minute, there are a large amount of Precipitations, TLC detects (solvent is ethyl acetate: petroleum ether=1:1).The precipitating that filters and will obtain
It is dry, gray solid powder is obtained to get 9-chloroacridine.Yield 75%, 119.2 DEG C -119.8 DEG C of fusing point.Compound structure data
Characterization are as follows:1H NMR(600 MHz, d6-DMSO) δ 8.22 (dd, J = 8.1, 1.1 Hz, 2H), 7.75–7.68
(m, 2H), 7.64–7.56 (m, 2H), 7.24 (dd, J = 7.8, 7.1 Hz, 2H)。
3,4-(((tertbutyloxycarbonyl is prepared) amino) methyl) benzoic acid
By Aminomethylbenzoic Acid (13.2mmol), di-tert-butyl dicarbonate (15.9 mmol), triethylamine (19.9 mmol) and
Anhydrous methanol (30 ml) is added sequentially in reaction flask, is white opacity liquid after material mixing, is heated to reflux that be stirred to react 6 small
When.TLC detection reaction terminates (TLC solvent is prepared: methylene chloride: methanol=15:1), and reaction system is become clarifying from muddiness.
With petroleum ether layer after petroleum ether 2 times, is removed water is added in remaining solution, reaction system is become from clarification again in reaction system
It is muddy.It is 4-5 with citric acid regulation system pH value, constantly there is white precipitate precipitation.Then system is extracted with dichloromethane, it is organic
It is spin-dried for after being mutually washed with water 3 times, obtains white solid powder, i.e. 4-(((tertbutyloxycarbonyl) amino) methyl) benzoic acid.Yield is
78.8%, fusing point is 160.9 DEG C -161.0 DEG C.Compound structure data characterization are as follows:1H NMR (600 MHz, d6-DMSO) δ
7.89 (d, J = 8.1 Hz, 2H), 7.46 (t, J = 6.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H),
4.18 (d, J = 6.1 Hz, 2H), 1.39 (s, 9H)。
4, (4-(phenylcarbamoyl) benzyl is prepared) t-butyl carbamate
By N, N'- carbonyl dimidazoles (11.95 mmol) are added in dimethylformamide (10 ml), and solution is faint yellow, in room
Temperature is lower to stir 10 min.By 4-(((tertbutyloxycarbonyl obtained in step 3) amino) methyl) benzoic acid (7.96 mmol) is dissolved in
In dimethylformamide (10 ml), it is placed in constant pressure funnel, makes 4-(((tertbutyloxycarbonyl) amino) methyl) benzoic acid
Dimethyl formamide solution is slowly dropped into N, and in N'- carbonyl dimidazoles system (drop speed is 1 drop/sec average), reaction system is by light
Yellow gradually becomes orange red, stirs 30 min at room temperature.Aniline (15.93 mmol) is added in reaction system, in room temperature
Under continue to be stirred to react 12-24 hours, TLC detection reaction terminates (solvent proportion: ethyl acetate: petroleum ether=1:1).Reaction
After, methylene chloride (40 ml) is added in system and water (50 ml) extracts 2 times, and organic phase is washed with water 5 times, surplus to remove
Remaining solvent dimethylformamide removes water phase, retains organic phase.It is organic to be added to anhydrous sodium sulfate (desiccant), it filters, filter
Liquid is spin-dried for, and obtains white solid powder, i.e. (4-(phenylcarbamoyl) benzyl) t-butyl carbamate.Fusing point be 137.9 DEG C-
139.6 DEG C, yield 53.8%.Compound structure data characterization are as follows:1H NMR (600 MHz, d6-DMSO) δ 10.18 (s,
1H), 7.91 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 6.0 Hz,
1H), 7.42–7.30 (m, 4H), 7.09 (t, J = 7.4 Hz, 1H), 4.20 (d, J = 6.1 Hz, 2H),
1.40 (s, 9H)。
5,4-(amino methyl is prepared)-N- phenylbenzamaide
By (4-(phenylcarbamoyl) benzyl obtained in step 4) t-butyl carbamate (3.2 mmol), 3M hydrochloric acid (32
Mmol it) is added sequentially in methanol (8 ml), is stirred to react at room temperature 12-24 hours, TLC detection reaction terminates (solvent
Proportion: methylene chloride: methanol=10:1).Reaction system is poured into separatory funnel, methylene chloride (20 ml) and water (20ml) is added
It is extracted, is layered after standing, in organic phase plus water is extracted twice again, until contact plate detects dichloromethane layer without colour developing, water phase
It adds methylene chloride and is extracted twice again.Saturated sodium bicarbonate solution to bubble-free is added dropwise in the water phase finally obtained to generate, adjusts pH
For 8-9, water layer is spin-dried for obtaining white solid powder, as 4-(amino methyl)-N- phenylbenzamaide.Fusing point is greater than 300 DEG C, receives
Rate is 63.9%, compound structure data characterization are as follows:1H NMR (600 MHz, d6-DMSO) δ 10.18 (s, 1H), 7.92
(d, J = 6.4 Hz, 2H), 7.78 (d, J = 6.4 Hz, 2H), 7.49 (d, J = 7.3 Hz, 1H),
7.44–7.29 (m, 3H), 7.09 (t, J = 7.3 Hz, 1H), 4.34 (br, 2H), 4.22 (s, 2H)。13C
NMR (151 MHz, d6-DMSO) δ 165.3, 144.5, 139.2, 133.1, 132.9, 128.5, 127.5,
126.9, 126.7, 123.5, 120.3, 45.0, 43.6。
6,4-((acridine -9- amino is prepared) methyl)-N- phenylbenzamaide
Under inert gas protection, by 4-(amino obtained in 9-chloroacridine obtained in step 2 (1.71 mmol), step 4
Methyl)-N- phenylbenzamaide (2.23 mmol) is added in phenol (34.2 mmol), and it is small at 90-100 DEG C to be stirred to react 12
When, TLC detection reaction terminates (solvent proportion: methylene chloride: methanol=10:1).After reaction, it is cooled to room temperature.To anti-
It answers and 20 ml ethyl acetate is added in system, a large amount of yellow mercury oxides are precipitated.At room temperature reaction system continue stir 30 min after it is quiet
It sets, removes supernatant, add 20 ml ethyl acetate and continue to filter after stirring 30 min, take filter cake, 20 ml dichloromethanes are added
The sodium hydrate aqueous solution that alkane and 20 ml are newly prepared.30 min are stirred at room temperature, collect organic phase after standing.Organic phase is with 20
Vacuum is spin-dried for obtaining crude product after ml washes 2-3 times, 20 ml saturated sodium chloride solutions are washed 1 time.(eluant, eluent: petroleum is chromatographed through column
Ether/ethyl acetate) purifying, obtain yellow solid, i.e. 4-((acridine -9- amino) methyl)-N- phenylbenzamaide.Yield 71.2%,
Fusing point > 200 DEG C；Compound structure data characterization are as follows:1H NMR (600 MHz, DMSO-d 6 ) δ 10.19 (s, 1H),
8.34 (s, 2H), 8.08 (s, 1H), 8.01-7.83 (m, 3H), 7.76 (d, J = 7.7 Hz, 2H),
7.70-7.55 (m, 3H), 7.41 (s, 1H), 7.34 (t, J = 7.7 Hz, 3H), 7.19 (br, 1H),
7.14-6.99 (m, 2H), 5.12 (s, 2H). 13C NMR (126 MHz, DMSO-d 6 ) δ 165.8, 148.9,
142.2, 139.6, 138.7, 130.6, 130.4, 129.0, 128.3, 127.4, 125.9, 124.0, 120.9,
120.7, 113.5, 79.6. HR-MS(ESI): Calcd for [M+H]+404.1757；Found: 404.1768.
Embodiment 2
4-((4- methoxyacridine -9- amino) methyl)-N- phenylbenzamaide preparation
1,2-((2- Methoxyphenylamino is prepared) benzoic acid
2-((2- Methoxyphenylamino is prepared according to the step 1 of embodiment 1) benzoic acid, the difference is that: by embodiment 1
In step 1 in aniline change 2- aminoanisole into and reacted.Gained compound is dark green solid powder, yield
30.3%, 176.1 DEG C -186.8 DEG C of fusing point.Compound structure data characterization are as follows:1H NMR (600 MHz, d6-DMSO) δ
9.55 (s, 1H), 7.86 (s, 1H), 7.36 (t, J = 6.9 Hz, 2H), 7.25 (s, 1H), 7.10–7.00
(m, 2H), 6.92 (t, J = 7.3 Hz, 1H), 6.75 (s, 1H), 3.82 (s, 3H)。
2,9- chloro-4-methoxy acridine is prepared
9- chloro-4-methoxy acridine is prepared according to the step 2 of embodiment 1, the difference is that: it will be in the step 2 in embodiment 1
2-(phenyl amino) benzoic acid changes 2-((2- Methoxyphenylamino into) benzoic acid reacted.Gained compound is green
Solid powder, yield 85%, 126.7 DEG C -127.0 DEG C of fusing point.Compound structure data characterization are as follows:1H NMR (600 MHz, d6-
DMSO) δ 8.31 (d, J = 8.6 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 7.88 (dd, J =
8.2, 7.0 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.79–7.70 (m, 1H), 7.61 (t, J =
8.2 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 4.03 (s, 3H)。
3,4-(((tertbutyloxycarbonyl is prepared) amino) methyl) benzoic acid
4-(((tertbutyloxycarbonyl is prepared according to the step 3 in embodiment 1) amino) methyl) benzoic acid.
4, (4-(phenylcarbamoyl) benzyl is prepared) t-butyl carbamate
(4-(phenylcarbamoyl) benzyl is prepared according to the step 4 in embodiment 1) t-butyl carbamate.
5,4-(amino methyl is prepared)-N- phenylbenzamaide
4-(amino methyl is prepared according to the step 5 in embodiment 1)-N- phenylbenzamaide.
6,4-((4- methoxyacridine -9- amino is prepared) methyl)-N- phenylbenzamaide
4-((4- methoxyacridine -9- amino is prepared according to the step 6 of embodiment 1) methyl)-N- phenylbenzamaide, difference
Be in: change the 9-chloroacridine in the step 6 in embodiment 1 into 9- chloro-4-methoxy acridine and react.Gained compound
For yellow solid, yield 68.1%;188.6-189.8 DEG C of fusing point;Compound structure data characterization are as follows:1H NMR (600
MHz, DMSO-d 6 ) δ 10.19 (s, 1H), 8.25 (s, 1H), 7.93 (d, J = 7.9 Hz, 2H), 7.90-
7.79 (m, 2H), 7.78-7.74 (m, 2H), 7.60 (d, J = 7.8 Hz, 2H), 7.55 (br, 1H),
7.34 (dd, J = 8.5, 7.3 Hz, 2H), 7.24-7.11 (m, 2H), 7.09 (tt, J = 7.4, 1.2 Hz,
2H), 5.12 (s, 2H), 3.97 (s, 3H). 13C NMR (126 MHz, DMSO-d 6 ) δ 165.5, 158.5,
148.5, 141.1, 139.6, 135.3, 134.6, 134.4, 129.2, 129.0, 128.8, 128.3, 127.1,
124.1, 120.9, 119.9, 115.7, 113.6, 57.2, 51.1. HR-MS(ESI): Calcd for [M+H]+
434.1863; Found: 434.1878。
Embodiment 3
4-((3- methoxyacridine -9- amino) methyl)-N- phenylbenzamaide preparation
1,2-((3- Methoxyphenylamino is prepared) benzoic acid
2-((3- Methoxyphenylamino is prepared according to the step 1 of embodiment 1) benzoic acid, the difference is that: by embodiment 1
In step 1 in aniline change 3- aminoanisole into and reacted.Gained compound be gray solid powder, yield 42.1%,
136.9 DEG C -137.0 DEG C of fusing point.Compound structure data characterization are as follows:1H NMR(600 MHz, d6-DMSO) δ 13.04 (s,
1H), 9.60 (s, 1H), 7.89 (d, J = 6.7 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.29
(d, J = 7.1 Hz, 1H), 7.24 (t, J = 8.1 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.79
(d, J = 8.3 Hz, 2H), 6.64 (dd, J = 8.2, 2.0 Hz, 1H), 3.75 (s, 3H)。
2, the chloro- 3- methoxyacridine of 9- is prepared
The chloro- 3- methoxyacridine of 9- is prepared according to the step 2 of embodiment 1, the difference is that: it will be in the step 2 in embodiment 1
2-(phenyl amino) benzoic acid changes 2-((3- Methoxyphenylamino into) benzoic acid reacted.Gained compound is yellow
Solid powder, yield 65%, 144.6 DEG C -144.8 DEG C of fusing point.Compound structure data characterization are as follows:1H NMR (600 MHz,
CDCl3) δ 8.35–8.30 (m, 1H), 8.23 (d, J = 9.4 Hz, 1H), 8.11 (d, J = 8.7 Hz,
1H), 7.79–7.72 (m, 1H), 7.53 (ddd, J = 8.5, 6.6, 1.0 Hz, 1H), 7.39 (d, J =
2.4 Hz, 1H), 7.27–7.21 (m, 1H), 3.97 (s, 3H)。
3,4-(((tertbutyloxycarbonyl is prepared) amino) methyl) benzoic acid
4-(((tertbutyloxycarbonyl is prepared according to the step 3 in embodiment 1) amino) methyl) benzoic acid.
4, (4-(phenylcarbamoyl) benzyl is prepared) t-butyl carbamate
(4-(phenylcarbamoyl) benzyl is prepared according to the step 4 in embodiment 1) t-butyl carbamate.
5,4-(amino methyl is prepared)-N- phenylbenzamaide
4-(amino methyl is prepared according to the step 5 in embodiment 1)-N- phenylbenzamaide.
6,4-((3- methoxyacridine -9- amino is prepared) methyl)-N- phenylbenzamaide
4-((3- methoxyacridine -9- amino is prepared according to the step 6 of embodiment 1) methyl)-N- phenylbenzamaide, difference
Be in: change the 9-chloroacridine in the step 6 in embodiment 1 into 9- chloro- 3- methoxyacridine and react.Gained compound
For yellow solid, yield 63.9%;176.2-178.3 DEG C of fusing point;Compound structure data characterization are as follows:1H NMR (600
MHz, DMSO-d 6 ) δ 10.19 (s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 8.20 (d, J = 9.4 Hz,
1H), 7.92 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.0 Hz,
3H), 7.33 (t, J = 7.9 Hz, 2H), 7.31-7.15 (m, 2H), 7.08 (t, J = 7.4 Hz, 2H),
6.94-6.85 (m, 1H), 5.09 (s, 2H), 3.89 (s, 3H). HR-MS(ESI): Calcd for [M+H]+
434.1863; Found: 434.1863。
Embodiment 4
4-((2- methoxyacridine -9- amino) methyl)-N- phenylbenzamaide preparation
1,2-((4- Methoxyphenylamino is prepared) benzoic acid
2-((4- Methoxyphenylamino is prepared according to the step 1 of embodiment 1) benzoic acid, the difference is that: by embodiment 1
In step 1 in aniline change 4- aminoanisole into and reacted.Gained compound be black solid powder, yield 67.6%,
180.8 DEG C -187.2 DEG C of fusing point.Compound structure data characterization are as follows:1H NMR (600 MHz, d6-DMSO) δ 12.93 (s,
1H), 9.42 (s, 1H), 7.86 (s, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 8.2
Hz, 2H), 6.95 (d, J = 8.2 Hz, 3H), 6.68 (s, 1H), 3.75 (s, 3H)。
2, the chloro- 2- methoxyacridine of 9- is prepared
The chloro- 2- methoxyacridine of 9- is prepared according to the step 2 of embodiment 1, the difference is that: it will be in the step 2 in embodiment 1
2-(phenyl amino) benzoic acid changes 2-((4- Methoxyphenylamino into) benzoic acid reacted.Gained compound is black
Solid powder, 80 % of yield, 151.6 DEG C -152.8 DEG C of fusing point.Compound structure data characterization are as follows:1H NMR (600 MHz,
d6-DMSO) δ 8.35 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.12 (d, J =
9.4 Hz, 1H), 7.89–7.82 (m, 1H), 7.79–7.73 (m, 1H), 7.60 (dd, J = 9.4, 2.5 Hz,
1H), 7.52 (d, J = 2.3 Hz, 1H), 4.01 (s, 3H)。
3,4-(((tertbutyloxycarbonyl is prepared) amino) methyl) benzoic acid
4-(((tertbutyloxycarbonyl is prepared according to the step 3 in embodiment 1) amino) methyl) benzoic acid.
4, (4-(phenylcarbamoyl) benzyl is prepared) t-butyl carbamate
(4-(phenylcarbamoyl) benzyl is prepared according to the step 4 in embodiment 1) t-butyl carbamate.
5,4-(amino methyl is prepared)-N- phenylbenzamaide
4-(amino methyl is prepared according to the step 5 in embodiment 1)-N- phenylbenzamaide.
6,4-((3- methoxyacridine -9- amino is prepared) methyl)-N- phenylbenzamaide
4-((3- methoxyacridine -9- amino is prepared according to the step 6 of embodiment 1) methyl)-N- phenylbenzamaide, difference
Be in: change the 9-chloroacridine in the step 6 in embodiment 1 into 9- chloro- 2- methoxyacridine and react.Gained compound
For yellow solid, yield 69.2%;119.4-121.2 DEG C of fusing point;Compound structure data characterization are as follows:1H NMR (600
MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 8.29 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 7.9 Hz,
2H), 7.89 (s, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.58
(s, 2H), 7.48 (s, 1H), 7.41-7.36 (m, 1H), 7.34 (t, J = 7.7 Hz, 3H), 7.09 (t,
J = 7.4 Hz, 1H), 5.04 (s, 2H), 3.77 (s, 3H). 13C NMR (151 MHz, DMSO-d 6 ) δ
165.1, 154.8, 149.4, 144.1, 139.1, 133.4, 130.8, 128.7, 128.5, 127.8, 126.7,
124.2, 124.2, 123.8, 123.5, 122.8, 120.2, 116.8, 100.4, 55.3, 48.5. HR-MS
(ESI): Calcd for [M+H]+ 434.1863; Found: 434.1871。
Embodiment 5
The chloro- 2- methoxyacridine -9- amino of 4-((6-) methyl)-N- phenylbenzamaide preparation
1, the chloro- 2-((4- Methoxyphenylamino of 4- is prepared) benzoic acid
The chloro- 2-((4- Methoxyphenylamino of 4- is prepared according to the step 1 of embodiment 4) benzoic acid, the difference is that: it will be real
It applies the 2- chlorobenzoic acid in the step 1 in example 4 and changes 2,4 dichloro benzene formic acid into and reacted.Gained compound is gray solid
Powder, yield 82.76%, 180.1 DEG C -189.1 DEG C of fusing point.
2, the chloro- 2- methoxyacridine of 6,9- bis- is prepared
The chloro- 2- methoxyacridine of 6,9- bis- is prepared according to the step 2 of embodiment 1, the difference is that: by the step in embodiment 1
2-(phenyl amino in rapid 2) benzoic acid changes the chloro- 2-((4- Methoxyphenylamino of 4- into) benzoic acid reacted.Gained
Conjunction object is yellow solid powder, and yield 93.75%, fusing point is greater than 200 DEG C.Compound structure data characterization are as follows:1H NMR (600
MHz, d6-DMSO) δ 8.36 (d, J = 9.1 Hz, 1H), 8.22 (s, 1H), 8.11 (d, J = 9.4 Hz,
1H), 7.76 (d, J = 9.4 Hz, 1H), 7.64 (d, J = 9.4 Hz, 1H), 7.50 (s, 1H), 4.02
(s, 3H)。
3,4-(((tertbutyloxycarbonyl is prepared) amino) methyl) benzoic acid
4-(((tertbutyloxycarbonyl is prepared according to the step 3 in embodiment 1) amino) methyl) benzoic acid.
4, (4-(phenylcarbamoyl) benzyl is prepared) t-butyl carbamate
(4-(phenylcarbamoyl) benzyl is prepared according to the step 4 in embodiment 1) t-butyl carbamate.
5,4-(amino methyl is prepared)-N- phenylbenzamaide
4-(amino methyl is prepared according to the step 5 in embodiment 1)-N- phenylbenzamaide.
6, the chloro- 2- methoxyacridine -9- amino of 4-((6- is prepared) methyl)-N- phenylbenzamaide
The chloro- 2- methoxyacridine -9- amino of 4-((6- is prepared according to the step 6 of embodiment 1) methyl)-N- phenylbenzamaide,
The difference is that: it changes the 9-chloroacridine in the step 6 in embodiment 1 into 6,9- bis- chloro- 2- methoxyacridine and carries out instead
It answers.Gained compound be yellow solid, yield 56.7%, 125.6-127.1 DEG C of fusing point;Compound structure data characterization are as follows:1H
NMR (600 MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 8.31 (d, J = 9.3 Hz, 1H), 7.96-7.92
(m, 2H), 7.89 (s, 1H), 7.85 (d, J = 9.4 Hz, 1H), 7.78-7.74 (m, 2H), 7.68 (s,
1H), 7.60 (d, J = 8.4 Hz, 3H), 7.43-7.38 (m, 1H), 7.36-7.32 (m, 2H), 7.30 (d,
J = 9.1 Hz, 1H), 7.09 (tt, J = 7.4, 1.2 Hz, 1H), 5.06 (s, 2H), 3.77 (s, 3H).13C NMR (151 MHz, DMSO-d 6 ) δ 165.6, 155.5, 139.6, 134.1, 131.2, 129.3, 129.1,
129.0, 128.4, 127.2, 126.5, 124.9, 124.0, 120.8, 117.4, 115.0, 110.7, 101.1,
55.9, 49.0. HR-MS(ESI): Calcd for [M+H]+468.1473；Found: 468.1477.
Specific embodiment three
The purposes of compound prepared by above-mentioned specific embodiment one or specific embodiment two in medicine preparation.The drug is used
In effectively inhibition DNA topoisomerase I/II activity, inhibit eucaryote tumor cell proliferation, prevention and/or treatment tumour
The effect of.
Above-mentioned eucaryote is mammal；Above-mentioned tumour cell is cancer cell；Wherein cancer cell is leukaemia cell, cream
Adenocarcinoma cell, liver cancer cells, pancreatic cancer cell, lung carcinoma cell, brain cancer cell, ovarian cancer cell, uterine cancer cells, carcinoma of testis are thin
Born of the same parents, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, bladder cancer cell or rectum cancer cell, wherein white blood
The sick chronic marrow original leukaemia cell of the preferred people of cancer cell, the preferred human liver cancer cell of liver cancer cells.
It should be noted that said medicine of the invention can pass through injection, injection, collunarium, eye drip, infiltration, absorption, physics
Or the method for chemistry mediation imports body, such as muscle, intradermal, subcutaneous, vein, mucosal tissue；Can also by other material mixings or
Body is imported after package.When needs, one or more pharmaceutically acceptable carriers can also be added in said medicine.
The carrier includes diluent, excipient, filler, adhesive, wetting agent, disintegrating agent, the absorption enhancement of pharmaceutical field routine
Agent, surfactant, absorption carrier, lubricant etc..In addition, drug of the invention can be made injection, tablet, pulvis,
The diversified forms such as granula, capsule, oral solution, paste, creme.The drug of above-mentioned various dosage forms can be according to the normal of pharmaceutical field
The preparation of rule method.
Embodiment 1
Mtt assay cell inhibitory effect screening active ingredients
By mtt assay, (suspended using human chronic myelogenous leukemia's (CML) cell line k562 cell in logarithmic growth phase
Cell), people acute lymphatic leukaemia cell CCRF-CEM(suspension cell) and human tissue cell lymphoma cell U937(suspend it is thin
Born of the same parents), detect the cell in vitro proliferation inhibition activity for the compound that embodiment 1-5 is prepared in above-mentioned specific embodiment two.Its
In, the tumour cell RPIM-1640 culture solution for containing volume fraction being 10% fetal calf serum, in 37 DEG C, volume fraction be 5%
CO2Under the conditions of routine culture；The specific steps of cell inhibitory effect active testing are as follows: (a), prepare the compound of test respectively
The dimethyl sulfoxide DMSO solution for being 5 mM at initial concentration, then gained initial concentration solution is subjected to gradient dilution, 2.5 mM are obtained,
The compound solution of the multiple concentration gradients of 1 mM, 0.5 mM, 0.1 mM, 0.01 mM etc.；(b), by tumour cell with every milliliter
1.5×105The cell density of a (suspension cell) is inoculated in 96 orifice plates (every 99 μ L of hole), is then added 1 μ L's toward every hole
Compound solution is tested, final compound concentration is made to respectively reach 0.1 μM, 1 μM, 5 μM, 10 μM, 25 μM and 50 μM.Each
Each concentration of compound is all provided with three multiple holes.In addition, a blank control is arranged in 96 orifice plates, testization is not added in blank control
Close object；(c), MTT solution (every 10 μ L of hole) is added after 96 orifice plates are placed 72 hours in the incubator, then proceedes in incubator
Middle culture 4 hours, at 4 DEG C, centrifugal speed is centrifuged 5 minutes under conditions of being 2000 rpm.Supernatant is sucked, and is added
100 μ L are added in the every hole DMSO(), then vibrated 96 orifice plates about 3-5 minutes with micro oscillator；(d), finally existed with microplate reader
OD value is measured at 490 nm, and calculates the inhibiting rate (IR%) of cell Proliferation.Calculation formula are as follows: IR%=(positive control OD-
Drug sample OD)/(positive control OD- blank control OD) × 100%.Experimental result is shown in Table 1.
The active ingredients result of 1 4- aminomethyl acridine-N- phenyl benzoyl amine compound of table
Formula
Note: IC50Indicate half-inhibitory concentration.
The MTT result of 4- aminomethyl acridine-N- phenyl benzoyl amine compound is shown in table 1.It can be with from result
Find out, as R on acridine parent nucleus C ring2When substituent group is methoxyl group, compound is to leukaemia CCRF-CEM cell activity compared with R2For H
When, activity about improves 2 times, as the inhibitory activity value of 2,3 and 4 pairs of CCRF-CEM cells of compound reaches 0.8-0.9 μM；
Secondly, on C ring methoxy substitution base change in location, it is living to the Proliferation Ability of two kinds of leukaemia cells (CCRF-CEM and K562)
Property influence it is little；Retain R2For 2-OCH3It is constant, R on A ring1When substituent group replaces with-Cl by-H, compound is to leukemia K 562
The inhibitory activity of cell significantly reduces, such as the IC of compound 550Value is 2 times lower than compound 4, thus speculates, A ring substituents
Electronic effect it is more apparent to activity influence.In subsequent structure optimization, the electricity of different substituents on A ring will be further considered
Sub- effect；In addition, be directed to lymthoma U937 cell, unsubstituted or methoxyl group exist on introducing-Cl substituent group or C ring on A ring
At 3 of acridine parent nucleus, activity, which has, significantly to be declined.Inhibitory activity performance such as compound 2 and 4 pair U937 cell is prominent
Out, IC50Value respectively reaches 0.23 and 0.33 μM.Nearly 8 times are improved compared to the activity value with compound 5, compound 2.
Embodiment 7
Topoisomerase experiment
Further test DNA topoisomerase I/II(english abbreviation Topo I/II of compound 1 and 2) activity suppression experiment,
Positive control drug selects camptothecine (Topo I inhibitor) and etoposide (Topo II inhibitor).Pass through experiment, it has been found that
Compound 1 and 2 has preferable inhibitory activity under 100 μM of concentration, to Topo I and Topo II.From Table 2, it can be seen that
Compound 1 respectively reaches 44.94 % and 23.96 % to the inhibiting rate of Topo I and Topo II, compound 2 to Topo I and
The inhibiting rate of Topo II can also respectively reach 7.20 % and 17.76 %.The above result shows that compound 1 and 2 may be by pressing down
Topo I/II activity processed causes the damage of DNA, so as to cause cancer cell-apoptosis.
2 target active test result of table
Note: camptothecine is topoisomerase I inhibitor, and etoposide is Topoisomerase II inhibitors, and "-" expression is not tested.
Embodiment 8
Protein electrophoresis experiment
Topo I/II inhibitor can cause DNA chain in tumour cell to be broken, and cause DNA damage and then induce cell apoptosis.DNA
When damage occurs, intracellular histone H2AX phosphorylation can be promoted to form γ-H2AX, so γ-H2AX is considered as
The important biomolecule marker of DNA damage.DNA damage, this hair can be effectively resulted in tumour cell in order to verify compound
It is bright that compound 2 is selected to carry out protein electrophoresis experiment as test sample.From figure 1 it appears that with compound concentration from
0.5 μM when increasing to 2 μM, the expression of γ-H2AX is obviously raised in leukaemia CCRF-CEM cell.This phenomenon explanation
Closing object 2 is strictly the activity by inhibiting Topo I/II in leukaemia CCRF-CEM cell, in turn results in DNA damage, thus pushes away
Surveying compound 2 may be by this approach induction of the apoptosis of cancer cell.
Embodiment 9
Apoptosis detection
By using Annexin V-FITC cell apoptosis detection kit, whether compound 2 is further verified induction of white blood
The apoptosis of sick CCRF-CEM cell.Early stage apoptosis, different types of cell (including leukaemia CCRF-CEM is thin
Born of the same parents) phosphatidylserine is translated on the outside of cell membrane can outside.And Annexin V and the phosphatidylserine for translating into cell surface outside
The rush blood coagulation and proinflammatory activity of phosphatidylserine can be blocked in conjunction with after.With the fluorescence probe with green fluorescence
The Annexin V, i.e. Annexin V-FITC of FITC label, so that it may which directly detect phosphatidylserine turns up this carefully
The important feature of born of the same parents' apoptosis.In addition, propidium iodide (Propidium Iodide, PI) can dye non-viable non-apoptotic cell or apoptosis advanced stage
The cell of cell membrane integrity is lost, red fluorescence is presented.Test results are shown in figure 2.The results show that compound 2 is with dense
The increase (increasing to 2 μM from 0.5 μM) of degree, the early apoptosis of the significant leukemogenesis CCRF-CEM cell of energy.Therefore, pass through
The above biology test and Mechanism Validation, showing compound 2 is the activity by inhibiting Topo I/II in leukaemia cell,
The damage of intracellular DNA is caused, and then induces the apoptosis of cancer cell.
Above description is not limitation of the present invention, and the present invention is also not limited to the example above.The art it is common
Within the essential scope of the present invention, the variations, modifications, additions or substitutions made also should belong to protection of the invention to technical staff
Range.
Claims (10)
1. a kind of 4- methylamino acridine-N- phenyl benzoyl amine compound, it is characterised in that: the compound is with Formulas I
The 4- methylamino acridine-N- phenyl benzoyl amine compound of shown structural formula or the 4- methylamino with structural formula shown in Formulas I
Pharmaceutically acceptable salt, ester or the solvate of acridine-N- phenyl benzoyl amine compound,
(I)
Wherein, R1For H, OCH3、OCH2CH3、Cl、Br、CF3、NO2Or carbon atom number is the straight chained alkyl of 1-5, R2For H, OCH3、
OCH2CH3、Cl、Br、CF3、NO2Or carbon atom number is the straight chained alkyl of 1-5, R3For H, OCH3、OCH2CH3、Cl、Br、CF3、NO2
Or carbon atom number be 1-5 straight chained alkyl, n=1,2,3 or 4, the salt be inorganic acid salt or acylate, described is inorganic
Hydrochlorate is the salt that any one inorganic acid is formed in hydrochloric acid, sulfuric acid and phosphoric acid；The acylate be acetic acid, trifluoroacetic acid,
The salt that any one organic acid is formed in malonic acid, citric acid and p-methyl benzenesulfonic acid.
2. a kind of preparation method of 4- methylamino acridine-N- phenyl benzoyl amine compound described in claim 1, feature
Be the following steps are included:
(1) react compound shown in Formula II with compound shown in formula III, to obtain compound shown in formula IV；
(2) compound shown in formula IV and phosphorus oxychloride reaction, to obtain compound shown in Formula V；
(3) compound shown in formula VI is reacted with di-tert-butyl dicarbonate, to obtain compound shown in Formula VII；
(4) react compound shown in Formula VII with compound shown in Formula VIII, to obtain compound shown in Formula IX；
(5) react compound shown in Formula IX with hydrochloric acid, to obtain compound shown in Formula X；
(6) react compound shown in Formula V with compound shown in Formula X, to obtain compound shown in Formulas I,
Wherein, R1For H, OCH3、OCH2CH3、Cl、Br、CF3、NO2Or carbon atom number is the straight chained alkyl of 1-5, R2For H, OCH3、
OCH2CH3、Cl、Br、CF3、NO2Or carbon atom number is the straight chained alkyl of 1-5, R3For H, OCH3、OCH2CH3、Cl、Br、CF3、NO2
Or carbon atom number be 1-5 straight chained alkyl, n=1,2,3 or 4.
3. a kind of preparation method of 4- methylamino acridine-N- phenyl benzoyl amine compound according to claim 2,
It is characterized in that step (1) specifically: at 100-130 DEG C, be catalyst, potassium carbonate as alkali using copper, make chemical combination shown in Formula II
That 1-12 is reacted in anhydrous N,N-dimethylformamide is small according to the ratio that molar ratio is 1:1.5 for compound shown in object and formula III
When, that is, obtain compound shown in formula IV.
4. a kind of preparation method of 4- methylamino acridine-N- phenyl benzoyl amine compound according to claim 2,
Be characterized in that step (2) specifically: at 50-100 DEG C, compound shown in formula IV with phosphorus oxychloride reaction 1-5 hours, that is, obtain
Obtain compound shown in formula V.
5. a kind of preparation method of 4- methylamino acridine-N- phenyl benzoyl amine compound according to claim 2,
It is characterized in that step (3) specifically: at 25-80 DEG C, using triethylamine as alkali, compound shown in formula VI and two dimethyl dicarbonate fourths
Ester reacts 2-8 hours, i.e. compound shown in acquisition Formula VII in anhydrous methanol.
6. a kind of preparation method of 4- methylamino acridine-N- phenyl benzoyl amine compound according to claim 2,
It is characterized in that step (4) specifically: at 10-70 DEG C, make compound shown in compound shown in Formula VII and Formula VIII with N, N'-
Carbonyl dimidazoles react 10-30 hours, i.e. chemical combination shown in acquisition Formula IX as condensing agent in anhydrous n,N-Dimethylformamide
Object.
7. a kind of preparation method of 4- methylamino acridine-N- phenyl benzoyl amine compound according to claim 2,
It is characterized in that step (5) specifically: at 25-60 DEG C, so that compound shown in Formula IX is reacted 10-30 in methyl alcohol with hydrochloric acid small
When, that is, obtain compound shown in Formula X.
8. a kind of preparation method of 4- methylamino acridine-N- phenyl benzoyl amine compound according to claim 2,
It is characterized in that step (6) specifically: under inert gas protection, at 25-120 DEG C, shown in compound shown in formula V and Formula X
Compound reacts 10-30 hours, i.e. compound shown in acquisition Formulas I in phenol.
9. purposes of the compound of any of claims 1-8 in preparation prevention and/or tumor.
10. compound of any of claims 1-8 inhibits DNA topoisomerase I/II in preparation and/or inhibits true
Purposes in core tumor cell proliferation.
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