CN105693609B

CN105693609B - Polysubstituted phenyl alkylamino acridone -4- amides compound and its preparation method and application

Info

Publication number: CN105693609B
Application number: CN201510998328.1A
Authority: CN
Inventors: 蒋宇扬; 章彬; 高春梅; 王宁; 孙钦升; 陈康; 刘红霞
Original assignee: Shenzhen Graduate School Tsinghua University
Current assignee: Shenzhen Graduate School Tsinghua University
Priority date: 2015-12-25
Filing date: 2015-12-25
Publication date: 2019-03-05
Anticipated expiration: 2035-12-25
Also published as: CN105693609A

Abstract

The present invention provides polysubstituted phenyl alkylamino acridone -4- amides compounds and its preparation method and application, wherein, the compound is polysubstituted phenyl alkylamino acridone -4- amides compound or its pharmaceutically acceptable salt, ester or solvate with structural formula shown in Formulas I, wherein, R₁、R₂、R₃It is as defined in description with n.The compound of the invention can effectively inhibit the expression of Survivin albumen in tumour cell, the activity for inhibiting DNA topoisomerase, inhibit eucaryote tumor cell proliferation, prevention and/or treatment tumour.

Description

Polysubstituted phenyl alkylamino acridone -4- amides compound and preparation method thereof and Purposes

Technical field

The present invention relates to field of medicaments, and in particular, to polysubstituted phenyl alkylamino acridone -4- amides compound and Preparation method and use compound and its preparation method and application.

Background technique

Cancer has become the second largest factor for seriously threatening human health.In the past 30 years, although the mankind recognize cancer Knowledge, which has, largely to improve, however does not have the improvement of same amplitude but for the treatment of cancer.For this purpose, for the side for the treatment of of cancer Method and means carry out necessary innovation and improve just to be particularly important.The novel targets for finding anticancer drug are currently treatment of cancer A hot spot.For example, attention rate of the survivin Survivin in anticancer drug field is higher and higher in recent years.Survivin makees For a frontier of oncotherapy, from starting to find to furtheing investigate the short history less than 20 years.It is ground around Survivin For the small-molecule drug YM155 and NSC80467 of hair although anticancer mechanism is also indefinite, experiment confirms that they are thin in a variety of cancers The expression of Survivin albumen can be effectively inhibited in born of the same parents, and very high anticancer activity is shown to kinds of tumor cells.

Summary of the invention

The present invention is directed to solve at least some of the technical problems in related technologies.For this purpose, of the invention One purpose be to propose a kind of expression that can effectively inhibit Survivin albumen in tumour cell, inhibit topoisomerase, Inhibit eucaryote tumor cell proliferation or prevention and/or treats the means of tumour.

In one aspect of the invention, the present invention provides a kind of polysubstituted phenyl alkylamino acridone -4- amides Close object.According to an embodiment of the invention, the compound is the polysubstituted phenyl alkylamino acridone-with structural formula shown in Formulas I 4- amides compound or its pharmaceutically acceptable salt, ester or solvate,

Wherein, R₁Be each independently H, the alkoxy that carbon atom number is 1~5, halogen, carbon atom number be 1~5 it is halogenated The straight chained alkyl or branched alkyl that alkyl, nitro, amido or carbon atom number are 1~5；

R₂The alkoxy or the optional amido that replaces for being 1~5 for carbon atom number；

R₃Be each independently for H, carbon atom number be 1~5 alkoxy, carbon atom number be 1~5 halogenated alkyl, nitre The straight chained alkyl or branched alkyl that base, amido or carbon atom number are 1~5；

The integer of m=1-4；

The integer of n=1~5；

The integer of p=1-4.

Inventors have found that the compound of the invention can effectively inhibit the expression of Survivin albumen in tumour cell, Inhibit the activity of DNA topoisomerase, inhibit eucaryote tumor cell proliferation or prevention and/or treatment tumour.

According to an embodiment of the invention, R₁It is each independently as H, OCH₃、OCH₂CH₃、OCH₂CH₂CH₃、 OCH₂CH₂CH₂CH₃、F、Cl、Br、CF₃、NO₂、NH₂Or carbon atom number is the straight chained alkyl of 1-5,

R₂For NH₂、N(CH₃)₂Or OCH₃,

R₃It is each independently as H ,-OCH₃、-NH₂、-NO₂、-CF₃、-CH₃、-CH₂CH₃、-CH₂CH₂CH₃Or- CH₂CH₂CH₂CH₃,

The integer of m=1-4；

The integer of n=1-4；

The integer of p=1-4.

According to an embodiment of the invention, R₁It is each independently as OCH₃、Cl、NO₂Or CH₃,

R₂For N (CH₃)₂Or OCH₃,

R₃It is each independently as H ,-OCH₃、-CF₃Or-CH₂CH₃,

M=1；

N=2 or 3；

P=1 or 3.

Some specific examples according to the present invention, compound according to an embodiment of the present invention are one of following:

1- benzamido group-N- (2- (dimethylamino) ethyl) -5- methyl -9- oxo -9,10- acridan -4- amide,

N- (2- (dimethylamino) ethyl) 1- ((3- methoxy-benzyl) amino) -5- methyl -9- oxo -9,10- dihydro Acridine -4- amide,

N- (2- (dimethylamino) ethyl) 1- ((4- methoxy-benzyl) amino) -5- methyl -9- oxo -9,10- dihydro The preparation of acridine -4- amide,

N- (3- (dimethylamino) propyl) 1- ((4- methoxy-benzyl) amino) -5- methyl -9- oxo -9,10- dihydro Acridine -4- amide,

1- benzamido group-N- (2- methoxy ethyl) -5- methyl -9- oxo -9,10- acridan -4- amide,

N- (2- (dimethylamino) ethyl) -5- methyl -9- oxo -1- ((3,4,5- trimethoxy benzyl) amino) -9, 10- acridan -4- amide,

1- benzamido group-N- (2- (dimethylamino) ethyl) -5- methoxyl group -9- oxo -9,10- acridan -4- amide,

N- (2- (dimethylamino) ethyl) -5- methoxyl group -1- ((4- methoxy-benzyl) amino) -9- oxo -9,10- two Hydrogen acridine -4- amide,

N- (3- (dimethylamino) propyl) -5- methoxyl group -1- ((4- methoxy-benzyl) amino) -9- oxo -9,10- two Hydrogen acridine -4- amide,

The chloro- N- of 5,7- bis- (2- (dimethylamino) ethyl) -1- ((4- methoxy-benzyl) amino) -9- oxo -9,10- two Hydrogen acridine -4- amide,

1- benzamido group-N- (2- (dimethylamino) ethyl) -5- nitro -9- oxo -9,10- acridan -4- amide,

N- (2- (dimethylamino) ethyl) -1- ((3- methoxy-benzyl) amino) -5- nitro -9- oxo -9,10- dihydro Acridine -4- amide,

N- (2- (dimethylamino) ethyl) -1- ((4- methoxy-benzyl) amino) -5- nitro -9- oxo -9,10- dihydro Acridine -4- amide,

N- (2- (dimethylamino) ethyl) -5- nitro -9- oxo -1- ((3,4,5- trimethoxy benzyl) amino) -9, 10- acridan -4- amide,

1- benzamido group-N- (3- (dimethylamino) propyl) -5- nitro -9- oxo -9,10- acridan -4- amide,

N- (3- (dimethylamino) propyl) -1- ((4- methoxy-benzyl) amino) -5- nitro -9- oxo -9,10- dihydro Acridine -4- amide,

N- (3- (dimethylamino) propyl) -1- ((4- Ethylbenzyl) amino) -5- nitro -9- oxo -9,10- dihydro a word used for translation Pyridine -4- amide.

In another aspect of this invention, the present invention provides a kind of methods for preparing compound noted earlier.According to this hair Bright embodiment, this method comprises: (1) reacts compound shown in Formula II with compound shown in formula III, to obtain IV institute of formula Show compound；(2) compound shown in formula IV and strong sulfuric acid response, to obtain compound shown in formula V；(3) shown in formula V Compound is reacted with kiber alkyl amine class compound, to obtain compound shown in formula VI；(4) compound shown in formula VI with take more It is reacted for phenylalkyl aminated compounds, to obtain compound shown in Formulas I,

Wherein, R₁、R₂、R₃, m, n, p it is as defined above.Inventors have found that can quickly have using method of the invention Mentioned-above compound is prepared to effect, and this method is simple, convenient fast, target compound yield is higher, fits In large-scale production.

According to an embodiment of the invention, kiber alkyl amine class compound has structure shown in one of formula 1- formula 3.Multi substituted benzenes Pheynylalkylamine class compound has structure as follows:

Some specific examples according to the present invention, Multi substituted benzenes pheynylalkylamine class compound have shown in one of formula 4- formula 9 Structure.Thereby, it is possible to effectively obtain mentioned-above compound.

According to an embodiment of the invention, being catalyst, potassium carbonate as alkali using copper, making Formula II shownization in step (1) It closes object to react in anhydrous dimethyl formamide with compound shown in formula III, to obtain compound shown in formula IV.According to this hair Bright specific example at 100-130 DEG C, is catalyst, potassium carbonate as alkali using copper, makes Formula II shownization in step (1) Compound shown in object and formula III is closed to react in anhydrous dimethyl formamide 1-12 hours according to the ratio that molar ratio is 1:1.5.

According to an embodiment of the invention, in step (2), at 50-100 DEG C, compound shown in formula IV and the concentrated sulfuric acid Reaction 1-5 hours.

According to an embodiment of the invention, at 0-50 DEG C, with N, N'- carbonyl dimidazoles are as condensation in step (3) Agent, compound shown in formula V react 10-30 hours with kiber alkyl amine class compound in anhydrous dimethyl formamide.As a result, Be conducive to reaction to carry out, reduce the generation of side reaction, yield is improved, to fast and effeciently obtain mentioned-above compound.

According to an embodiment of the invention, in step (4), at 50-100 DEG C, compound shown in formula VI with it is polysubstituted Phenylalkyl aminated compounds reacts 10-30 hours.Thereby, it is possible to make each reactant in items such as most suitable temperature, proportions It is reacted under part, advantageously reduces side reaction, improve yield and reaction efficiency.

In another aspect of the invention, the present invention provides a kind of pharmaceutical compositions.According to an embodiment of the invention, the medicine Compositions contain mentioned-above compound.Inventors have found that pharmaceutical composition of the invention can effectively inhibit tumour thin The expression of Survivin albumen intracellular, the activity for inhibiting DNA topoisomerase inhibit eucaryote tumor cell proliferation, prevention And/or treatment tumour, and then can be effective for the treatment of cancer.

According to an embodiment of the invention, topoisomerase is topoisomerase II.

According to an embodiment of the invention, eucaryote is mammal；Tumour cell is cancer cell；Further, cancer is thin Born of the same parents be leukaemia cancer cell, breast cancer cell, liver cancer cells, pancreatic cancer cell, lung carcinoma cell, brain cancer cell, ovarian cancer cell, Uterine cancer cells, testicular cancer cell, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, bladder cancer cell or Rectum cancer cell, wherein the chronic marrow original leukaemia cell of the preferred people of leukaemia cancer cell, the preferred human liver cancer cell of liver cancer cells.

In still another aspect of the invention, the present invention provides mentioned-above compounds or pharmaceutical composition to prepare drug In purposes.According to an embodiment of the invention, the drug can be used for effectively inhibiting the table of Survivin albumen in tumour cell Activity, inhibition eucaryote tumor cell proliferation or the prevention and/or treatment tumour for reaching, inhibiting DNA topoisomerase.

Detailed description of the invention

Fig. 1 shows that according to one embodiment of present invention compound 16 inhibits the gel electrophoresis inspection of topoisomerase II Survey result figure.

Fig. 2 shows according to one embodiment of present invention, the protein electrophoresis figure of compound 16.

Specific embodiment

The embodiment of the present invention is described below in detail.The embodiments described below is exemplary, and is only used for explaining this hair It is bright, and be not considered as limiting the invention.Particular technique or condition are not specified in embodiment, according to text in the art It offers described technology or conditions or is carried out according to product description.Reagents or instruments used without specified manufacturer, For can be with conventional products that are commercially available.

Herein, " compound shown in formula N " is otherwise referred to as " compound N " herein, and N herein is 1-17's Arbitrary integer, such as " compound shown in formula 16 " are referred to as " compound 16 " herein.

As described in the present invention, substituent group draws one and is keyed to the ring system formed on the ring at center (such as Formula II institute Show) represent substituent R₁It can be replaced any substitutive position on ring.For example, Formula II represents any possibility on phenyl ring Substituted position can be substituted.

In addition, it is necessary to explanation, unless otherwise explicitly pointing out, describing mode as used throughout this document " ... it is each independently ", it indicates in the same group, mutual not shadow between expressed specific option between the same symbol It rings.For example, m R in compound shown in Formula II₁Between be independent of each other.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is for known to technical staff in fields on.

" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.

In one aspect of the invention, the present invention provides a kind of compounds.According to an embodiment of the invention, the compound For compound or its pharmaceutically acceptable salt, ester or solvate with structural formula shown in Formulas I,

The integer of m=1-4；

The integer of n=1~5；

The integer of p=1-4.

R₂For NH₂、N(CH₃)₂Or OCH₃,

R₃It is each independently H ,-OCH₃、-NH₂、-NO₂、-CF₃、-CH₃、-CH₂CH₃、-CH₂CH₂CH₃Or- CH₂CH₂CH₂CH₃,

The integer of m=1-4；

The integer of n=1-4；

The integer of p=1-4.

R₂For N (CH₃)₂Or OCH₃,

R₃It is each independently as H ,-OCH₃、-CF₃Or-CH₂CH₃,

M=1；

N=2 or 3；

P=1 or 3.

Compound provided by the invention by kinds of tumor cells system test (including liver cancer cells, breast cancer cell etc.) with And DNA connection experiment, topoisomerase active inhibit test, the downward of protein electrophoresis experiment detection Survivin protein expression It is a kind of potential to inhibit in tumour cell Survivin protein expression and to topoisomerase Deng, it was demonstrated that the compound of the present invention Enzyme II has the anti-tumor drug of certain inhibitory activity, can effectively inhibit the expression of Survivin albumen in tumour cell, inhibit The activity of DNA topoisomerase inhibits eucaryote tumor cell proliferation or prevention and/or treatment tumour.The present invention provides Raw materials of compound be easy to get, preparation method is simple, experiments have shown that it has good anticancer effect, designs and researches and develops in anti-tumor drug There is good application prospect in field.

In another aspect of this invention, the present invention provides a kind of methods for preparing compound noted earlier.According to this hair Bright embodiment, method includes the following steps:

(1) react compound shown in Formula II with compound shown in formula III, to obtain compound shown in formula IV.

According to an embodiment of the invention, the condition that compound shown in Formula II is reacted with compound shown in formula III is not by spy It does not limit.In one embodiment of the invention, it is catalyst, potassium carbonate as alkali using copper, makes compound and formula shown in Formula II Compound shown in III reacts in anhydrous dimethyl formamide, to obtain compound shown in formula IV.In another of the invention In embodiment, at 100-130 DEG C, it is catalyst, potassium carbonate as alkali using copper, makes compound shown in Formula II and III shownization of formula It closes object to react in anhydrous dimethyl formamide 1-12 hours according to the ratio that molar ratio is 1:1.5, to obtain shown in formula IV Compound.Thereby, it is possible to carry out reaction at most suitable temperature and conditions of mixture ratios to be conducive to improve reaction efficiency, reduce secondary anti- It answers, improves yield.

(2) compound shown in formula IV and strong sulfuric acid response, to obtain compound shown in formula V.

According to an embodiment of the invention, at 50-100 DEG C, compound shown in formula IV with strong sulfuric acid response 1-5 hours. Thereby, it is possible to be reacted under the most appropriate conditions, is conducive to improve reaction efficiency, reduces side reaction, improve yield.

(3) compound shown in formula V is reacted with kiber alkyl amine class compound, to obtain compound shown in formula VI.

According to an embodiment of the invention, the condition reacted with kiber alkyl amine class compound of compound shown in formula V not by Especially limitation, those skilled in the art can flexible choices according to the actual situation.In one embodiment of the invention, formula V Shown compound reacts in anhydrous dimethyl formamide with kiber alkyl amine class compound, to obtain compound shown in formula VI. In another embodiment of the present invention, at 0-50 DEG C, with N, N'- carbonyl dimidazoles are as condensing agent, V shownization of formula Object is closed to react in anhydrous dimethyl formamide 10-30 hours with kiber alkyl amine class compound.Thereby, it is possible to make each reactant It is reacted under the conditions ofs most suitable temperature, proportion etc., advantageously reduces side reaction, improve yield and reaction efficiency.

According to an embodiment of the invention, the type of the kiber alkyl amine class compound is not particularly limited, as long as can have Effect prepares mentioned-above compound, and those skilled in the art can be according to physical condition flexible choice.Reality according to the present invention Example is applied, the kiber alkyl amine class compound has structure shown in formula 1- formula 3.

(4) compound shown in formula VI and Multi substituted benzenes pheynylalkylamine class compound (including but not limited to single (double) pyridine First (second) aminated compounds) reaction, to obtain compound shown in Formulas I.According to an embodiment of the invention, compound shown in formula VI The condition reacted with Multi substituted benzenes pheynylalkylamine class compound is not particularly limited, and those skilled in the art can be according to reality Border situation flexible choice.In one embodiment of the invention, at 50-100 DEG C, compound shown in formula VI and Multi substituted benzenes Pheynylalkylamine class compound reacts 10-30 hours.Thereby, it is possible to be reacted under the most appropriate conditions, be conducive to improve anti- Efficiency is answered, side reaction is reduced, improves yield.

According to an embodiment of the invention, the type of the Multi substituted benzenes pheynylalkylamine class compound is not particularly limited.Root According to some embodiments of the present invention, the Multi substituted benzenes pheynylalkylamine class compound has structure as follows:

Some preferred embodiments according to the present invention, the Multi substituted benzenes pheynylalkylamine class compound have formula 4- formula 9 it Structure shown in one.Thereby, it is possible to effectively obtain mentioned-above compound.

Wherein, R₁、R₂、R₃It is as defined above with n.

Inventors have found that mentioned-above compound can be fast and effeciently prepared using method of the invention, and This method is simple, convenient fast, yield is higher, is suitable for large-scale production.

In another aspect of the invention, the present invention provides a kind of pharmaceutical compositions.According to an embodiment of the invention, the medicine Compositions contain mentioned-above compound.Inventors have found that pharmaceutical composition of the invention can effectively inhibit tumour thin The expression of Survivin albumen intracellular, the activity for inhibiting DNA topoisomerase inhibit eucaryote tumor cell proliferation, prevention And/or the effect for the treatment of tumour.

In still another aspect of the invention, the present invention provides compound noted earlier or pharmaceutical compositions in medicine preparation Purposes.According to an embodiment of the invention, the drug is for effectively inhibiting expression, the suppression of Survivin albumen in tumour cell The activity of DNA topoisomerase processed inhibits the effect of eucaryote tumor cell proliferation, prevention and/or treatment tumour.

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.

According to an embodiment of the invention, the topoisomerase is topoisomerase II.

According to an embodiment of the invention, the eucaryote is mammal；The tumour cell is cancer cell；The cancer Cell is that leukaemia cancer cell, breast cancer cell, liver cancer cells, pancreatic cancer cell, lung carcinoma cell, brain cancer cell, oophoroma are thin Born of the same parents, uterine cancer cells, testicular cancer cell, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, bladder cancer cell Or rectum cancer cell, wherein the chronic marrow original leukaemia cell of the preferred people of leukaemia cancer cell, the preferred people of liver cancer cells Liver cancer cells.

The embodiment of the present invention is described below in detail.

Embodiment 1:1- benzamido group-N- (2- (dimethylamino) ethyl) -5- methyl -9- oxo-acridan - The preparation of 4- amide

1,2- ((2- carbonyl -5- chlorphenyl) amino) -3- methyl benzoic acid is prepared

2,4- dichlorobenzoic acid (4.05mmol) is added in dimethylformamide (50ml), 2- amino -3- methylbenzene first Sour (5.26mmol), potassium carbonate (8.10mmol) and copper powder (2.03mmol), are then stirred overnight, then by institute at 130 DEG C It is added in 200ml water after obtained reaction mixture is cooling, it is about 3 that obtained mixture, which is adjusted to pH value with hydrochloric acid, is filtered simultaneously The precipitating drying that will be obtained obtains faint yellow solid, i.e. 2- ((2- carbonyl -5- chlorphenyl) amino) -3- methyl benzoic acid, yield 91.5%.Compound structure confirms data are as follows:¹H NMR(400MHz,DMSO-d₆)δ13.10(s,2H),9.90(s,1H),7.86 (d, J=8.2Hz, 1H), 7.72 (d, J=7.2Hz, 1H), 7.56 (t, J=7.5Hz, 1H), 7.31 (t, J=7.5Hz, 1H), 6.74 (d, J=7.5Hz, 1H), 6.08 (s, 1H), 2.12 (s, 3H)

2, the chloro- 5- methyl -9- oxo of 1--acridan -4- carboxylic acid is prepared

2- obtained in step 1 ((2- carbonyl -5- chlorphenyl) amino) -3- methyl benzoic acid (1.19mmol) is added to It in the concentrated sulfuric acid (10ml), flows back 5 hours in 80 DEG C, then will be slowly added into ice water (50mL) after the cooling of obtained reaction solution In, being then adjusted to pH value with NaOH solution is about 5, and mixed liquor continues after being stirred at room temperature 30 minutes, there is a large amount of Precipitations.It filters And the precipitating drying that will be obtained, obtain solid powder, i.e. chloro- 5- methyl -9- oxo -9, the 10- acridan -4- carboxylic acid of 1-.It produces Rate 95.0%.Compound structure confirms data are as follows:¹H NMR(400MHz,DMSO-d₆) δ 12.59 (s, 1H), 8.32 (d, J= 8.3Hz, 1H), 8.05 (d, J=8.0Hz, 1H), 7.66 (d, J=6.8Hz, 1H), 7.32 (d, J=8.3Hz, 1H), 7.24 (dd, J=7.9,7.3Hz, 1H), 2.54 (s, 3H)

3, the chloro- N- of 1- (2- (dimethylamino) ethyl) -5- methyl -9- oxo -9,10- dihydropyridine -4- amide is prepared

The chloro- 5- methyl-9- oxo of the 1- obtained in step 2-acridan-4- carboxylic acid (3.48mmol) is slow It is added dropwise to N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (5.22mmol) (10.00ml), in room after being added dropwise Temperature stirring 30 minutes, then by N, N- dimethyl -1,2- ethylenediamine (10.44mmol) is added in reaction system, was stirred at room temperature Night.After reaction, it is extracted with methylene chloride (50mL), gained organic phase is washed three times with water (40mL), dry organic phase, rotation Dry, gained residue purifies to obtain solid powder, the i.e. chloro- N- of 1- through column chromatography (eluant, eluent: ethyl acetate/ethyl alcohol (9:1v/v)) (2- (dimethylamino) ethyl) -5- methyl -9- oxo -9,10- dihydropyridine -4- amide.Yield 65.3%.Compound structure Confirm data are as follows:¹H NMR(400MHz,CDCl₃) δ 12.93 (s, 1H), 8.27 (d, J=8.0Hz, 1H), 7.72 (d, J= 8.3Hz, 1H), 7.50 (d, J=7.0Hz, 1H), 7.19 (t, J=7.7Hz, 1H), 7.15 (d, J=8.1Hz, 1H), 3.57 (dd, J=10.9,5.3Hz, 2H), 2.64-2.59 (m, 2H), 2.58 (s, 3H), 2.33 (s, 6H)

4,1- benzamido group-N- (2- (dimethylamino) ethyl) -5- methyl -9- oxo-acridan -4- amide Preparation

The chloro- N- of the 1- that step 3 is obtained (2- (dimethylamino) ethyl) -5- methyl -9- oxo -9,10- dihydropyridine - 4- amide (0.42mmol), benzylamine (2.10mmol) and triethylamine (0.50mL) are successively dissolved in cellosolvo solvent In (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC is detected after reaction, and reaction solution is cooled to room Temperature has Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), obtain sterling.If reacting liquid cooling But without Precipitation after, then DCM (50mL) and water (50mL) are added in the reaction system, gained organic phase is washed with water after extraction (40mL × 3) three times, dry organic phase simultaneously rotate removing organic solvent, and gained residue chromatographs (eluant, eluent: acetic acid second through column Ester/ethyl alcohol (9:1v/v)) purify to obtain yellow solid powder, yield 60.9%, 144-146 DEG C of fusing point.Compound structure tables of data Sign are as follows:¹H NMR(400MHz,CDCl₃) δ 13.58 (s, 1H), 11.41 (s, 1H), 8.22 (d, J=8.1Hz, 1H), 7.60 (d, J =8.9Hz, 1H), 7.46 (d, J=6.9Hz, 1H), 7.39 (d, J=7.3Hz, 2H), 7.34 (t, J=7.5Hz, 2H), 7.28- 7.24 (m, 1H), 7.15 (t, J=7.6Hz, 1H), 6.89 (s, 1H), 6.14 (d, J=8.7Hz, 1H), 4.55 (d, J= 5.5Hz, 2H), 3.50 (dd, J=10.6,5.2Hz, 2H), 2.60 (s, 3H), 2.53 (t, J=5.8Hz, 2H), 2.27 (s, 6H)；¹³C NMR(100MHz,DMSO-d₆)δ180.40,169.34,154.61,144.56,138.88,138.45,135.06, 134.12,129.11,127.82,127.64,125.14,123.72,121.70,121.48,106.22,101.52,100.32, 58.61,46.39,45.66,37.63,16.97；HR-MS(ESI):Calcd for[M+H]⁺429.2291；Found: 429.2300.

Embodiment 2:N- (2- (dimethylamino) ethyl) 1- ((3- methoxy-benzyl) amino) oxo-9-5- methyl-9-, The preparation of 10- acridan -4- amide

By the chloro- N- of 1- obtained in case study on implementation 1 (2- (dimethylamino) ethyl) -5- methyl -9- oxo -9,10- two Pyridinium hydroxide -4- amide (0.42mmol), 3- methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are successively dissolved in 2- second In ethoxy-ethanol solvent (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC is detected after reaction, will be anti- It answers liquid to be cooled to room temperature, there is Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), obtain sterling. If DCM (50mL) and water (50mL) are added in the reaction system without Precipitation after reaction solution is cooling, there is gained after extraction Machine is mutually washed with water (40mL × 3) three times, and dry organic phase simultaneously rotates removing organic solvent, and gained residue (is washed through column chromatography De- agent: ethyl acetate/ethyl alcohol (9:1v/v)) purify to obtain yellow solid powder, yield 27.3%, 164-166 DEG C of fusing point.Compound Structured data characterization are as follows:¹H NMR(400MHz,CDCl₃) δ 13.58 (s, 1H), 11.43 (s, 1H), 8.24 (d, J=8.1Hz, 1H), 7.63 (d, J=8.9Hz, 1H), 7.48 (d, J=7.0Hz, 1H), 7.28-7.24 (m, 1H), 7.16 (t, J=7.6Hz, 1H), 6.99 (d, J=7.6Hz, 1H), 6.93 (s, 2H), 6.81 (dd, J=8.1,2.0Hz, 1H), 6.17 (d, J=8.9Hz, 1H), 4.55 (d, J=5.7Hz, 2H), 3.80 (d, J=13.0Hz, 3H), 3.53 (dd, J=10.8,5.2Hz, 2H), 2.62 (s, 3H), 2.57 (t, J=5.8Hz, 2H), 2.30 (s, 6H)；¹³C NMR(100MHz,CDCl₃)δ181.24,169.38, 160.07,155.25,144.74,139.79,138.55,133.56,133.43,129.79,124.88,123.85,121.87, 121.37,119.36,112.76,112.73,106.81,101.32,99.98,57.69,55.23,46.83,45.05, 36.74,17.10；HR-MS(ESI):Calcd for[M+H]⁺459.2396；Found:459.2408.

Embodiment 3:N- (2- (dimethylamino) ethyl) 1- ((4- methoxy-benzyl) amino) oxo-9-5- methyl-9-, The preparation of 10- acridan -4- amide

By the chloro- N- of 1- obtained in case study on implementation 1 (2- (dimethylamino) ethyl) -5- methyl -9- oxo -9,10- two Pyridinium hydroxide -4- amide (0.42mmol), 4- methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are successively dissolved in 2- second In ethoxy-ethanol solvent (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC is detected after reaction, will be anti- It answers liquid to be cooled to room temperature, there is Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), obtain sterling. If DCM (50mL) and water (50mL) are added in the reaction system without Precipitation after reaction solution is cooling, there is gained after extraction Machine is mutually washed with water (40mL × 3) three times, and dry organic phase simultaneously rotates removing organic solvent, and gained residue (is washed through column chromatography De- agent: ethyl acetate/ethyl alcohol (9:1v/v)) purify to obtain yellow solid powder, yield 54.6%, 225-227 DEG C of fusing point.Compound Structured data characterization are as follows:¹H NMR(400MHz,CDCl₃) δ 13.59 (s, 1H), 11.34 (s, 1H), 8.22 (d, J=8.0Hz, 1H), 7.66 (d, J=9.0Hz, 1H), 7.47 (d, J=7.0Hz, 1H), 7.31 (d, J=8.5Hz, 2H), 7.15 (t, J= 7.6Hz, 1H), 6.98 (s, 1H), 6.88 (d, J=8.5Hz, 2H), 6.18 (d, J=9.0Hz, 1H), 4.48 (d, J=5.5Hz, 2H), 3.79 (s, 3H), 3.53 (dd, J=10.7,5.2Hz, 2H), 2.61 (s, 3H), 2.56 (t, J=5.7Hz, 2H), 2.29 (s,6H)；¹³C NMR(100MHz,CDCl₃)δ181.20,169.42,158.94,155.13,144.76,138.53,133.53, 133.47,130.00,128.40,124.87,123.82,121.86,121.35,114.24,106.73,101.14,99.86, 57.81,55.30,46.32,45.08,36.79,17.09；HR-MS(ESI):Calcd for[M+H]⁺459.2396；Found: 459.2401.

Embodiment 4:N- (3- (dimethylamino) propyl) 1- ((4- methoxy-benzyl) amino) oxo-9-5- methyl-9-, The preparation of 10- acridan -4- amide

1, the chloro- N- of 1- (3- (dimethylamino) propyl) -5- methyl -9- oxo -9,10- dihydropyridine -4- amide is prepared

By the chloro- 5- methyl-9- oxo of the 1- obtained in case study on implementation 1-acridan-4- carboxylic acid (1.74mmol) Be slowly added dropwise into N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (2.61mmol) (10ml), after being added dropwise in It is stirred at room temperature 30 minutes, then by N, N- dimethyl -1,3- propane diamine (5.22mmol) is added in reaction system, was stirred at room temperature Night.After reaction, it is extracted with methylene chloride (50mL), gained organic phase is washed three times with water (40mL), dry organic phase, rotation Dry, gained residue purifies to obtain solid powder, the i.e. chloro- N- of 1- through column chromatography (eluant, eluent: ethyl acetate/ethyl alcohol (9:1v/v)) (3- (dimethylamino) propyl) -5- methyl -9- oxo -9,10- dihydropyridine -4- amide.Yield 61.9%.Compound structure Confirm data are as follows:¹H NMR(400MHz,CDCl₃) δ 13.34 (s, 1H), 9.65 (s, 1H), 8.29 (d, J=8.1Hz, 1H), 7.65 (d, J=8.3Hz, 1H), 7.51 (d, J=7.1Hz, 1H), 7.21-7.15 (m, 2H), 3.64 (dd, J=10.2, 5.8Hz, 2H), 2.67-2.62 (m, 2H), 2.61 (s, 3H), 2.39 (s, 6H), 1.85 (dt, J=11.4,5.8Hz, 2H)

2, N- (3- (dimethylamino) propyl) 1- ((4- methoxy-benzyl) amino) -5- methyl -9- oxo -9,10- two The preparation of hydrogen acridine -4- amide

By the chloro- N- of 1- obtained in step 1 (3- (dimethylamino) propyl) -5- methyl -9- oxo -9,10- dihydro pyrrole Pyridine -4- amide (0.42mmol), 4- methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are successively dissolved in 2- ethyoxyl In alcohol solvent (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC is detected after reaction, by reaction solution It is cooled to room temperature, there is Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), obtain sterling.If Without Precipitation after reaction solution is cooling, then DCM (50mL) and water (50mL) are added in the reaction system, gained organic phase after extraction Be washed with water (40mL × 3) three times, dry organic phase simultaneously rotates removing organic solvent, gained residue chromatograph through column (eluant, eluent: Ethyl acetate/ethyl alcohol (9:1v/v)) purify to obtain yellow solid powder, yield 22.4%, 185-187 DEG C of fusing point.Compound structure Data characterization are as follows:¹H NMR(400MHz,CDCl₃) δ 13.82 (s, 1H), 11.32 (s, 1H), 8.68 (s, 1H), 8.22 (d, J= 7.8Hz, 1H), 7.60 (d, J=8.3Hz, 1H), 7.47 (d, J=6.1Hz, 1H), 7.33 (d, J=7.7Hz, 2H), 7.16 (d, J=7.2Hz, 1H), 6.89 (d, J=7.6Hz, 2H), 6.20 (d, J=8.8Hz, 1H), 4.49 (s, 2H), 3.80 (s, 3H), 3.59(br,2H),2.62(br,5H),2.39(s,6H),1.84(br,2H)；¹³C NMR(100MHz,CDCl₃)δ181.22, 169.51,158.95,154.97,144.86,138.59,133.48,133.37,130.01,128.48,124.92,123.80, 121.82,121.26,114.23,106.74,101.37,99.81,59.07,55.31,46.34,45.13,40.05,24.88, 17.18；HR-MS(ESI):Calcd for[M+H]⁺473.2552；Found:473.2571.

Embodiment 5:1- benzamido group-N- (2- methoxy ethyl) -5- methyl -9- oxo-acridan -4- amide Preparation

1, the chloro- N- of 1- (2- methoxy ethyl) -5- methyl -9- oxo -9,10- dihydropyridine -4- amide is prepared

By the chloro- 5- methyl-9- oxo of the 1- obtained in case study on implementation 1-acridan-4- carboxylic acid (1.74mmol) It is slowly added dropwise into N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (2.61mmol) (10.00ml), after being added dropwise It is stirred at room temperature 30 minutes, then dimethoxy ethylenediamine (5.22mmol) is added in reaction system, is stirred overnight at room temperature.Instead It after answering, is extracted with methylene chloride (50mL), gained organic phase is washed three times with water (40mL), and dry organic phase is spin-dried for, gained Residue purifies to obtain solid powder, i.e. 1- chloro- N- (2- methoxyl group through column chromatography (eluant, eluent: ethyl acetate/ethyl alcohol (9:1v/v)) Ethyl) -5- methyl -9- oxo -9,10- dihydropyridine -4- amide.Yield 59.6%.Compound structure confirms data are as follows:¹H NMR(400MHz,CDCl₃) δ 12.79 (s, 1H), 8.27 (d, J=8.1Hz, 1H), 7.72 (d, J=8.2Hz, 1H), 7.51 (d, J=7.0Hz, 1H), 7.19 (t, J=7.6Hz, 1H), 7.14 (d, J=8.2Hz, 1H), 6.90 (s, 1H), 3.74 (dd, J= 9.7,4.8Hz, 2H), 3.65 (t, J=4.8Hz, 2H), 3.45 (s, 3H), 2.58 (s, 3H)

2,1- benzamido group-N- (2- methoxy ethyl) -5- methyl -9- oxo-acridan -4- amide preparation

By the chloro- N- of 1- obtained in step 1 (2- methoxy ethyl) -5- methyl -9- oxo -9,10- dihydropyridine -4- acyl Amine (0.42mmol), benzylamine (2.10mmol) and triethylamine (0.50mL) are successively dissolved in cellosolvo solvent (10mL) In, reaction system is stirred overnight under 90 DEG C of heating conditions.TLC is detected after reaction, reaction solution is cooled to room temperature, there have to be heavy Precipitation goes out.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), obtain sterling.Nothing after if reaction solution is cooling DCM (50mL) and water (50mL) is then added in Precipitation in the reaction system, and gained organic phase is washed with water three times after extraction (40mL × 3), dry organic phase simultaneously rotate removing organic solvent, and gained residue chromatographs (eluant, eluent: ethyl acetate/second through column Alcohol (9:1v/v)) purify to obtain yellow solid powder, yield 62.1%, 191-193 DEG C of fusing point.Compound structure data characterization are as follows:¹H NMR(400MHz,CDCl₃) δ 13.50 (s, 1H), 8.24 (d, J=8.0Hz, 1H), 7.60 (d, J=8.8Hz, 1H), 7.50 (d, J=7.0Hz, 1H), 7.41 (d, J=7.3Hz, 2H), 7.36 (t, J=7.4Hz, 2H), 7.30 (d, J=7.2Hz, 1H), 7.18 (t, J=7.6Hz, 1H), 6.49 (s, 1H), 6.18 (d, J=8.8Hz, 1H), 4.58 (s, 2H), 3.67 (br, 2H), 3.59 (t, J=4.7Hz, 2H), 3.42 (d, J=8.1Hz, 3H), 2.62 (s, 3H)；¹³C NMR(100MHz,CDCl₃)δ 181.23,169.30,155.24,144.73,138.49,137.92,133.65,133.27,128.80,127.35,127.16, 124.89,123.85,121.85,121.49,106.77,101.13,99.97,71.27,58.90,46.88,39.38, 17.13；HR-MS(ESI):Calcd for[M+H]⁺416.1974；Found:416.1980.

Embodiment 6:N- (2- (dimethylamino) ethyl) -5- methyl -9- oxo -1- ((3,4,5- trimethoxy benzyl) Amino)-acridan -4- amide preparation

By the chloro- N- of 1- obtained in case study on implementation 1 (2- (dimethylamino) ethyl) -5- methyl -9- oxo -9,10- two Pyridinium hydroxide -4- amide (0.42mmol), 3,4,5- trimethoxy benzylamines (2.10mmol) and triethylamine (0.50mL) successively dissolve In cellosolvo solvent (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC detection reaction terminates Afterwards, reaction solution is cooled to room temperature, there is Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), Obtain sterling.If DCM (50mL) and water (50mL), extraction are added in the reaction system without Precipitation after reaction solution is cooling Gained organic phase is washed with water (40mL × 3) three times afterwards, and dry organic phase simultaneously rotates removing organic solvent, and gained residue is through column Chromatography (eluant, eluent: ethyl acetate/ethyl alcohol (9:1v/v)) purifies to obtain yellow solid powder, yield 33.1%, fusing point 195-197 ℃.Compound structure data characterization are as follows:¹H NMR(400MHz,CDCl₃)δ13.61(s,1H),11.38(s,1H),8.23(d,J =8.1Hz, 1H), 7.71 (d, J=8.9Hz, 1H), 7.49 (d, J=6.9Hz, 1H), 7.23-7.13 (m, 1H), 7.06 (s, 1H), 6.62 (s, 2H), 6.18 (d, J=8.9Hz, 1H), 4.50 (d, J=5.5Hz, 2H), 3.84 (s, 9H), 3.56 (dd, J= 10.6,5.1Hz,2H),2.62(br,5H),2.35(s,6H)；¹³C NMR(100MHz,CDCl₃)δ181.26,169.40, 155.21,153.61,144.72,138.54,137.25,133.77,133.62,133.59,124.92,123.79,121.84, 121.44,106.78,104.11,101.36,100.07,60.84,57.83,56.19,47.24,45.01,36.62,17.11； HR-MS(ESI):Calcd for[M+H]⁺519.2607；Found:519.2623.

Embodiment 7:1- benzamido group-N- (2- (dimethylamino) ethyl) -5- methoxyl group -9- oxo -9,10- dihydro a word used for translation The preparation of pyridine -4- amide

1,2- ((2- carbonyl -5- chlorphenyl) amino) -3- methoxy benzoic acid is prepared

2,4- dichlorobenzoic acid (4.05mmol) is added in dimethylformamide (50ml), 2- amino -3- methoxybenzene Formic acid (5.26mmol), potassium carbonate (8.10mmol) and copper powder (2.03mmol), are then stirred overnight at 130 DEG C, then will It is added in 200ml water after obtained reaction mixture is cooling, it is about 3 that obtained mixture, which is adjusted to pH value with hydrochloric acid, is filtered And the precipitating drying that will be obtained, obtain faint yellow solid, i.e. 2- ((2- carbonyl -5- chlorphenyl) amino) -3- methoxy benzoic acid, Yield 98.9%.Compound structure confirms data are as follows:¹H NMR(400MHz,DMSO-d₆)δ13.12(s,2H),10.07(s, 1H), 7.85 (d, J=5.4Hz, 1H), 7.48 (d, J=5.2Hz, 1H), 7.41-7.21 (m, 2H), 6.76 (d, J=5.4Hz, 1H),6.28(s,1H),3.79(s,3H).

2,1- chloro-5-methoxyl -9- oxo-acridan -4- carboxylic acid is prepared

((2- carbonyl -5- chlorphenyl) the amino) -3- methoxy benzoic acid (1.19mmol) of 2- obtained in step 1 is added It in the concentrated sulfuric acid (10ml), flows back 5 hours in 80 DEG C, then will be slowly added into ice water after the cooling of obtained reaction solution In (50mL), being then adjusted to pH value with NaOH solution is about 5, and mixed liquor continues after being stirred at room temperature 30 minutes, there is a large amount of precipitating analysis Out.The precipitating drying that filters and will obtain, obtains solid powder, i.e. chloro- 5- methyl -9- oxo -9, the 10- acridan -4- of 1- Carboxylic acid.Yield 92.7%.Compound structure confirms data are as follows:¹H NMR(400MHz,DMSO-d₆)δ13.97(s,1H),12.56 (s, 1H), 8.26 (d, J=8.2Hz, 1H), 7.70 (d, J=8.1Hz, 1H), 7.34 (d, J=7.8Hz, 1H), 7.28 (d, J= 8.2Hz, 1H), 7.22 (t, J=7.9Hz, 1H), 4.02 (s, 3H)

3, the chloro- N- of 1- (2- (dimethylamino) ethyl) -5- methoxyl group -9- oxo -9,10- dihydropyridine -4- acyl is prepared Amine

1- chloro-5-methoxyl -9- oxo-acridan -4- the carboxylic acid (1.65mmol) obtained in step 2 is slow Slowly it is added dropwise to N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (2.48mmol) (D10.00ml), after being added dropwise It is stirred at room temperature 30 minutes, then by N, N- dimethyl -1,2- ethylenediamine (4.95mmol) is added in reaction system, is stirred at room temperature Overnight.After reaction, it is extracted with methylene chloride (50mL), gained organic phase is washed three times with water (40mL), dry organic phase, rotation Dry, gained residue purifies to obtain solid powder, the i.e. chloro- N- of 1- through column chromatography (eluant, eluent: ethyl acetate/ethyl alcohol (9:1v/v)) (2- (dimethylamino) ethyl) -5- methoxyl group -9- oxo -9,10- dihydropyridine -4- amide.Yield 58.7%.Compound knot Structure confirms data are as follows:¹H NMR(400MHz,CDCl₃) δ 12.90 (s, 1H), 7.97 (dd, J=8.2,0.9Hz, 1H), 7.75 (d, J=8.2Hz, 1H), 7.19 (dt, J=8.1,3.8Hz, 2H), 7.11 (dd, J=7.8,1.1Hz, 1H), 4.08 (s, 3H), 3.60 (dd, J=11.2,5.0Hz, 2H), 2.65-2.56 (m, 2H), 2.32 (s, 6H)；¹³C NMR(100MHz,DMSO-d₆)δ 176.02,168.82,155.70,147.73,144.89,132.92,130.22,123.41,121.16,117.57,112.37, 109.91,105.48,104.58,58.68,56.80,45.76,43.80,37.73.

4,1- benzamido group-N- (2- (dimethylamino) ethyl) -5- methoxyl group -9- oxo-acridan -4- acyl The preparation of amine

By the chloro- N- of 1- obtained in step 3 (2- (dimethylamino) ethyl) -5- methoxyl group -9- oxo -9,10- dihydro It is molten that pyridine -4- amide (0.42mmol), benzylamine (2.10mmol) and triethylamine (0.50mL) are successively dissolved in cellosolvo In agent (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC is detected after reaction, and reaction solution is cooled to Room temperature has Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), obtain sterling.If reaction solution Without Precipitation after cooling, then DCM (50mL) and water (50mL) are added in the reaction system, gained organic phase uses water again after extraction It washes (40mL × 3) three times, dry organic phase simultaneously rotates removing organic solvent, and gained residue chromatographs (eluant, eluent: acetic acid second through column Ester/ethyl alcohol (9:1v/v)) purify to obtain yellow solid powder, yield 57.1%, 230-231 DEG C of fusing point.Compound structure tables of data Sign are as follows:¹H NMR(400MHz,CDCl₃) δ 13.61 (s, 1H), 11.44 (s, 1H), 7.94 (d, J=8.1Hz, 1H), 7.67 (d, J =8.9Hz, 1H), 7.42 (d, J=7.2Hz, 2H), 7.36 (t, J=7.3Hz, 2H), 7.30 (d, J=7.2Hz, 1H), 7.18 (t, J=7.9Hz, 1H), 7.09 (d, J=7.6Hz, 1H), 6.97 (s, 1H), 6.17 (d, J=8.9Hz, 1H), 4.57 (d, J= 5.4Hz, 2H), 4.09 (s, 3H), 3.56 (d, J=5.2Hz, 2H), 2.56 (t, J=5.5Hz, 2H), 2.29 (s, 6H)；¹³C NMR(100MHz,CDCl₃)δ180.86,169.14,155.19,147.95,144.19,138.08,133.58,131.04, 128.78,127.29,127.16,122.48,121.10,117.14,111.31,107.24,101.79,99.82,57.85, 56.27,46.87,45.11,36.84；HR-MS(ESI):Calcd for[M+H]⁺445.2240；Found:445.2252.

Embodiment 8:N- (2- (dimethylamino) ethyl) -5- methoxyl group -1- ((4- methoxy-benzyl) amino) -9- oxygen The preparation of generation-acridan -4- amide

By the chloro- N- of 1- obtained in case study on implementation 7 (2- (dimethylamino) ethyl) -5- methoxyl group -9- oxo -9,10- Dihydropyridine -4- amide (0.42mmol), 4- methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are successively dissolved in 2- In ethoxy ethanol solvent (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC is detected after reaction, will Reaction solution is cooled to room temperature, and has Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), it obtains pure Product.If DCM (50mL) and water (50mL), institute after extraction are added in the reaction system without Precipitation after reaction solution is cooling It obtains organic phase to be washed with water (40mL × 3) three times, dry organic phase simultaneously rotates removing organic solvent, and gained residue is chromatographed through column (eluant, eluent: ethyl acetate/ethyl alcohol (9:1v/v)) purifies to obtain yellow solid powder, yield 70.8%, and 245-246 DEG C of fusing point.Change Close object structured data characterization are as follows:¹H NMR(400MHz,CDCl₃) δ 13.57 (s, 1H), 11.36 (s, 1H), 7.92 (d, J= 8.1Hz, 1H), 7.67 (d, J=8.9Hz, 1H), 7.32 (d, J=8.4Hz, 2H), 7.17 (t, J=8.0Hz, 1H), 7.07 (d, J=7.5Hz, 1H), 6.96 (s, 1H), 6.89 (d, J=8.5Hz, 2H), 6.20 (d, J=8.9Hz, 1H), 4.49 (d, J= 5.4Hz, 2H), 4.08 (s, 3H), 3.80 (s, 3H), 3.61-3.48 (m, 2H), 2.60 (t, J=5.6Hz, 2H), 2.33 (s, 6H)；¹³C NMR(100MHz,CDCl₃)δ180.79,169.14,158.93,155.16,147.92,144.21,1]33.59, 131.00,130.01,128.42,122.49,121.04,117.13,114.23,111.25,107.17,101.56,99.82, 57.86,56.25,55.30,46.35,45.03,36.64；HR-MS(ESI):Calcd for[M+H]⁺475.2345；Found: 475.2336.

Embodiment 9:N- (3- (dimethylamino) propyl) -5- methoxyl group -1- ((4- methoxy-benzyl) amino) -9- oxygen The preparation of generation-acridan -4- amide

1, the chloro- N- of 1- (3- (dimethylamino) propyl) -5- methoxyl group -9- oxo -9,10- dihydropyridine -4- acyl is prepared Amine

1- chloro-5-methoxyl -9- oxo-acridan -4- the carboxylic acid that will be obtained in case study on implementation 7 (1.65mmol) is slowly added dropwise into N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (2.48mmol) (10ml), drop It is stirred at room temperature after adding 30 minutes, then by N, N- dimethyl -1,3- propane diamine (5.22mmol) is added in reaction system, It is stirred overnight at room temperature.After reaction, it is extracted with methylene chloride (50mL), gained organic phase is washed three times with water (40mL), dry Organic phase is spin-dried for, and gained residue purifies to obtain solid powder through column chromatography (eluant, eluent: ethyl acetate/ethyl alcohol (9:1v/v)), i.e., The chloro- N- of 1- (3- (dimethylamino) propyl) -5- methoxyl group -9- oxo -9,10- dihydropyridine -4- amide.Yield 60.5%. Compound structure confirms data are as follows:¹H NMR(400MHz,CDCl₃) δ 13.27 (s, 1H), 9.51 (s, 1H), 7.97 (d, J= 8.4Hz, 1H), 7.63 (d, J=8.3Hz, 1H), 7.18 (t, J=8.4Hz, 1H), 7.17 (d, J=8.0Hz, 1H), 7.10 (d, J=8.0Hz, 1H), 4.08 (s, 3H), 3.65 (dd, J=10.0,5.7Hz, 2H), 2.69-2.57 (m, 2H), 2.36 (s, 6H), 1.83 (dt, J=11.3,5.8Hz, 2H)

2, N- (3- (dimethylamino) propyl) -5- methoxyl group -1- ((4- methoxy-benzyl) amino) -9- oxo -9,10- The preparation of acridan -4- amide

By the chloro- N- of 1- obtained in step 1 (3- (dimethylamino) propyl) -5- methoxyl group -9- oxo -9,10- dihydro Pyridine -4- amide (0.42mmol), 4- methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are successively dissolved in 2- ethoxy In base alcohol solvent (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC is detected after reaction, will be reacted Liquid is cooled to room temperature, and has Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), obtain sterling.Such as Without Precipitation after fruit reaction solution is cooling, then DCM (50mL) and water (50mL) are added in the reaction system, gained is organic after extraction It is mutually washed with water (40mL × 3) three times, dry organic phase simultaneously rotates removing organic solvent, and gained residue chromatographs (elution through column Agent: ethyl acetate/ethyl alcohol (9:1v/v)) purify to obtain yellow solid powder, yield 63.4%, 260-261 DEG C of fusing point.Compound knot Structure data characterization are as follows:¹H NMR(400MHz,CDCl₃)δ13.84(s,1H),11.32(s,1H),8.66(s,1H),7.91(d,J =8.1Hz, 1H), 7.53 (d, J=8.9Hz, 1H), 7.33 (d, J=8.5Hz, 2H), 7.16 (t, J=8.0Hz, 1H), 7.07 (d, J=7.5Hz, 1H), 6.89 (d, J=8.5Hz, 2H), 6.18 (d, J=8.9Hz, 1H), 4.49 (d, J=5.4Hz, 2H), 4.07 (s, 3H), 3.80 (s, 3H), 3.60 (dd, J=10.4,5.4Hz, 2H), 2.59-2.50 (m, 2H), 2.33 (s, 6H), 1.84-1.72(m,2H)；¹³C NMR(100MHz,CDCl₃)δ180.84,169.12,158.88,154.90,147.97, 144.28,133.26,131.04,130.00,128.49,122.38,120.97,117.01,114.19,111.14,107.17, 101.89,99.63,59.65,56.24,55.33,46.35,45.48,40.66,24.95；HR-MS(ESI):Calcd for[M +H]⁺489.2502；Found:489.2493.

The chloro- N- of embodiment 10:5,7- bis- (2- (dimethylamino) ethyl) -1- ((4- methoxy-benzyl) amino) -9- oxygen The preparation of generation-acridan -4- amide

1,2- ((2- carbonyl -5- chlorphenyl) amino) -3,5- dichlorobenzoic acid is prepared

2,4- dichlorobenzoic acid (04.05mmol) is added in dimethylformamide (50ml), 2- amino -3,5- dichloro-benzenes Formic acid (5.26mmol), potassium carbonate (8.10mmol) and copper powder (2.03mmol), are then stirred overnight at 130 DEG C, then will It is added in 200ml water after obtained reaction mixture is cooling, it is about 3 that obtained mixture, which is adjusted to pH value with hydrochloric acid, is filtered And the precipitating drying that will be obtained, obtain faint yellow solid, i.e. 2- ((2- carbonyl -5- chlorphenyl) amino) -3,5- dichlorobenzoic acid, Yield 45.6%.Compound structure confirms data are as follows:¹H NMR(400MHz,DMSO-d₆)δ13.36(s,2H),10.10(s, 1H), 7.99 (d, J=2.4Hz, 1H), 7.89 (d, J=8.5Hz, 1H), 7.86 (d, J=2.4Hz, 1H), 6.85 (dd, J= 8.5,1.9Hz, 1H), 6.34 (d, J=1.8Hz, 1H)

2, the chloro- 9- oxo of 1,5,7- tri--acridan -4- carboxylic acid is prepared

((2- carbonyl -5- chlorphenyl) the amino) -3,5- dichlorobenzoic acid (1.19mmol) of 2- obtained in step 1 is added It in the concentrated sulfuric acid (10ml), flows back 5 hours in 80 DEG C, then will be slowly added into ice water after the cooling of obtained reaction solution In (50mL), being then adjusted to pH value with NaOH solution is about 5, and mixed liquor continues after being stirred at room temperature 30 minutes, there is a large amount of precipitating analysis Out.The precipitating drying that filters and will obtain, obtains solid powder, i.e., 1,5,7- tri- chloro- 9- oxo -9,10- acridan -4- carboxylics Acid.Yield 90.5%.Compound structure confirms data are as follows:¹H NMR(400MHz,DMSO-d₆)δ13.60(s,1H),8.30(s, 1H),8.13-8.04(m,2H),8.02(s,1H),7.35-7.33(m,1H).

3, the chloro- N- of 1,5,7- tri- (2- (dimethylamino) ethyl) -9- oxo -9,10- dihydropyridine -4- amide is prepared

The chloro- 9- oxo of the 1,5,7- tri--acridan -4- carboxylic acid (2.35mmol) obtained in step 2 is slowly dripped N is added to stir after being added dropwise in room temperature in the dimethyl formamide solution of N '-carbonyl dimidazoles (3.52mmol) (10ml) It mixes 30 minutes, then by N, N- dimethyl -1,2- ethylenediamine (7.04mmol) is added in reaction system, is stirred overnight at room temperature.Instead It after answering, is extracted with methylene chloride (50mL), gained organic phase is washed three times with water (40mL), and dry organic phase is spin-dried for, gained Residue purifies to obtain solid powder, i.e., 1,5,7- tri- chloro- N- (2- through column chromatography (eluant, eluent: ethyl acetate/ethyl alcohol (9:1v/v)) (dimethylamino) ethyl) -9- oxo -9,10- dihydropyridine -4- amide.Yield 49.2%.

Compound structure confirms data are as follows:¹H NMR(400MHz,CDCl₃) δ 13.43 (s, 1H), 8.28 (d, J=2.3Hz, 1H), 7.83 (d, J=8.3Hz, 1H), 7.72 (d, J=2.3Hz, 1H), 7.39 (d, J=8.3Hz, 1H), 7.25 (s, 1H), 3.60 (dd, J=10.0,5.2Hz, 2H), 2.68-2.56 (m, 2H), 2.33 (s, 6H)

4, the chloro- N- of 5,7- bis- (2- (dimethylamino) ethyl) -1- ((4- methoxy-benzyl) amino) -9- oxo -9,10- The preparation of acridan -4- amide

By the chloro- N- of 1,5,7- tri- obtained in step 3 (2- (dimethylamino) ethyl) -9- oxo -9,10- dihydro pyrrole Pyridine -4- amide (0.42mmol), 4- methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are successively dissolved in 2- ethyoxyl In alcohol solvent (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC is detected after reaction, by reaction solution It is cooled to room temperature, there is Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), obtain sterling.If Without Precipitation after reaction solution is cooling, then DCM (50mL) and water (50mL) are added in the reaction system, gained organic phase after extraction Be washed with water (40mL × 3) three times, dry organic phase simultaneously rotates removing organic solvent, gained residue chromatograph through column (eluant, eluent: Ethyl acetate/ethyl alcohol (9:1v/v)) purify to obtain yellow solid powder, yield 69.6%, 238-240 DEG C of fusing point.Compound structure Data characterization are as follows:¹H NMR(400MHz,CDCl₃) δ 11.11 (d, J=5.1Hz, 1H), 8.23 (d, J=2.3Hz, 1H), 7.70- 7.67 (m, 2H), 7.32 (d, J=8.6Hz, 2H), 7.02 (s, 1H), 6.91 (dd, J=6.7,4.8Hz, 2H), 6.25 (d, J= 9.0Hz, 1H), 4.50 (d, J=5.5Hz, 2H), 3.81 (s, 3H), 3.56 (dd, J=10.7,5.3Hz, 2H), 2.62-2.55 (m,2H),2.32(s,6H)；¹³C NMR(100MHz,CDCl₃)δ179.19,168.93,159.06,154.89,144.56, 135.35,134.02,132.49,129.58,128.41,126.67,124.38,123.42,122.49,114.31,106.73, 101.45,100.86,57.73,55.32,46.41,45.05,36.72；HR-MS(ESI):Calcd for[M+H]⁺ 513.1460；Found:513.1467.

Embodiment 11:1- benzamido group-N- (2- (dimethylamino) ethyl) -5- nitro -9- oxo-acridan - The preparation of 4- amide

1,2- ((2- carbonyl -5- chlorphenyl) amino) -3- nitrobenzoic acid is prepared

2,4- dichlorobenzoic acid (4.05mmol) is added in dimethylformamide (50ml), 2- amino -3- nitrobenzoyl Sour (5.26mmol), potassium carbonate (8.10mmol) and copper powder (2.03mmol), are then stirred overnight, then by institute at 130 DEG C It is added in 200ml water after obtained reaction mixture is cooling, it is about 3 that obtained mixture, which is adjusted to pH value with hydrochloric acid, is filtered simultaneously The precipitating drying that will be obtained obtains faint yellow solid, i.e. 2- ((2- carbonyl -5- chlorphenyl) amino) -3- nitrobenzoic acid, yield 59.6%.Compound structure confirms data are as follows:¹H NMR(400MHz,DMSO-d₆)δ13.12(s,2H),10.07(s,1H), 7.85 (d, J=5.4Hz, 1H), 7.48 (d, J=5.2Hz, 1H), 7.41-7.21 (m, 2H), 6.76 (d, J=5.4Hz, 1H), 6.28(s,1H),3.79(s,3H).

1, the chloro- 5- nitro -9- oxo of 1--acridan -4- carboxylic acid is prepared

2- obtained in step 1 ((2- carbonyl -5- chlorphenyl) amino) -3- nitrobenzoic acid (1.19mmol) is added to It in the concentrated sulfuric acid (10.00ml), flows back 5 hours in 80 DEG C, then will be slowly added into ice water after the cooling of obtained reaction solution In (50mL), being then adjusted to pH value with NaOH solution is about 5, and mixed liquor continues after being stirred at room temperature 30 minutes, there is a large amount of precipitating analysis Out.The precipitating drying that filters and will obtain, obtains red solid powder, i.e. chloro- 5- nitro -9- oxo -9, the 10- dihydro a word used for translation of 1- Pyridine -4- carboxylic acid, yield 73.9%.Compound structure data characterization are as follows:¹H NMR(400MHz,d₆-DMSO)δ14.62(s,1H), 8.72 (dd, J=8.1,1.4Hz, 1H), 8.60 (d, J=7.8Hz, 1H), 8.35 (d, J=8.3Hz, 1H), 7.46 (t, J= 8.0Hz, 1H), 7.42 (d, J=8.3Hz, 1H)

2, the chloro- N- of 1- (2- (dimethylamino) ethyl) -5- nitro -9- oxo -9,10- dihydropyridine -4- amide is prepared

The chloro- 5- nitro-9- oxo of the 1- obtained in step 2-acridan-4- carboxylic acid (1.65mmol) is slow It is added dropwise to N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (2.48mmol) (10ml), in room temperature after being added dropwise Stirring 30 minutes, then by N, N- dimethyl -1,2- ethylenediamine (4.95mmol) is added in reaction system, is stirred overnight at room temperature. After reaction, it is extracted with methylene chloride (50mL), gained organic phase is washed three times with water (40mL), and dry organic phase is spin-dried for, institute It obtains residue and purifies to obtain red solid powder, the i.e. chloro- N- (2- of 1- through column chromatography (eluant, eluent: ethyl acetate/ethyl alcohol (9:1v/v)) (dimethylamino) ethyl) -5- nitro -9- oxo -9,10- dihydropyridine -4- amide.Yield 61.5%.Compound structure number According to characterization are as follows:¹H NMR(400MHz,CDCl₃) δ 8.67 (dd, J=13.7,7.9Hz, 2H), 7.83 (d, J=8.2Hz, 1H), 7.32 (t, J=7.9Hz, 1H), 7.27-7.25 (m, 1H), 3.63-3.61 (m, 2H), 2.61 (t, J=5.5Hz, 2H), 2.32 (s,6H).

4,1- benzamido group-N- (2- (dimethylamino) ethyl) -5- nitro -9- oxo-acridan -4- amide Preparation

By the chloro- N- of 1- obtained in step 3 (2- (dimethylamino) ethyl) -5- nitro -9- oxo -9,10- dihydro pyrrole Pyridine -4- amide (0.42mmol), benzylamine (2.10mmol) and triethylamine (0.50mL) are successively dissolved in cellosolvo solvent In (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC is detected after reaction, and reaction solution is cooled to room Temperature has Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), obtain sterling.If reacting liquid cooling But without Precipitation after, then DCM (50mL) and water (50mL) are added in the reaction system, gained organic phase is washed with water after extraction (40mL × 3) three times, dry organic phase simultaneously rotate removing organic solvent, and gained residue chromatographs (eluant, eluent: acetic acid second through column Ester/ethyl alcohol (9:1v/v)) purify to obtain yellow solid powder, yield 33.8%, 243-245 DEG C of fusing point.Compound structure tables of data Sign are as follows:¹H NMR(400MHz,DMSO-d₆) δ 15.00 (s, 1H), 10.92 (s, 1H), 8.65 (d, J=7.2Hz, 1H), 8.57 (d, J=7.2Hz, 1H), 8.46 (s, 1H), 8.03 (d, J=8.8Hz, 1H), 4.40-7.37 (m, 5H), 7.29 (d, J= 6.5Hz, 1H), 6.45 (d, J=8.6Hz, 1H), 4.61 (s, 2H), 2.53 (br, 2H), 2.27 (s, 6H)；¹³C NMR (100MHz,d₆-DMSO)δ178.84,168.23,154.26,138.67,135.93,135.24,134.43,131.72, 129.15,127.81,127.72,124.24,120.66,106.50,103.23,102.50,58.41,46.41,45.40, 37.33；HR-MS(ESI):Calcd for[M+H]⁺460.1985；Found:460.2000.

Embodiment 12:N- (2- (dimethylamino) ethyl) -1- ((3- methoxy-benzyl) amino) -5- nitro -9- oxo - The preparation of acridan -4- amide

By the chloro- N- of 1- obtained in case study on implementation 11 (2- (dimethylamino) ethyl) -5- nitro -9- oxo -9,10- two Pyridinium hydroxide -4- amide (0.42mmol), 3- methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are successively dissolved in 2- second In ethoxy-ethanol solvent (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC is detected after reaction, will be anti- It answers liquid to be cooled to room temperature, there is Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), obtain sterling. If DCM (50mL) and water (50mL) are added in the reaction system without Precipitation after reaction solution is cooling, there is gained after extraction Machine is mutually washed with water (40mL × 3) three times, and dry organic phase simultaneously rotates removing organic solvent, and gained residue (is washed through column chromatography De- agent: ethyl acetate/ethyl alcohol (9:1v/v)) purify to obtain yellow solid powder, yield 19.8%, 155-157 DEG C of fusing point.Compound Structured data characterization are as follows:¹H NMR(400MHz,CDCl₃) δ 15.02 (s, 1H), 11.08 (s, 1H), 8.71 (d, J=7.6Hz, 1H), 8.66 (d, J=8.0Hz, 1H), 7.70 (d, J=8.9Hz, 1H), 7.30-7.26 (m, 2H), 6.98 (d, J=7.4Hz, 2H), 6.92 (s, 1H), 6.83 (d, J=7.6Hz, 1H), 6.29 (d, J=8.9Hz, 1H), 4.54 (d, J=5.3Hz, 2H), 3.80 (s, 3H), 3.59 (d, J=4.6Hz, 2H), 2.65-2.56 (m, 2H), 2.31 (s, 6H)；¹³C NMR(100MHz, CDCl₃)δ179.39,168.17,160.09,154.66,144.06,139.31,135.01,134.85,134.52,134.42, 131.18,129.95,124.60,119.77,119.33,112.87,112.75,107.06,103.29,102.19,57.75, 55.29,46.90,45.11,36.82；HR-MS(ESI):Calcd for[M+H]⁺490.2090；Found:490.2070.

Embodiment 13:N- (2- (dimethylamino) ethyl) -1- ((4- methoxy-benzyl) amino) -5- nitro -9- oxo - The preparation of acridan -4- amide

By the chloro- N- of 1- obtained in case study on implementation 11 (2- (dimethylamino) ethyl) -5- nitro -9- oxo -9,10- two Pyridinium hydroxide -4- amide (0.42mmol), 4- methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are successively dissolved in 2- second In ethoxy-ethanol solvent (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC is detected after reaction, will be anti- It answers liquid to be cooled to room temperature, there is Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), obtain sterling. If DCM (50mL) and water (50mL) are added in the reaction system without Precipitation after reaction solution is cooling, there is gained after extraction Machine is mutually washed with water (40mL × 3) three times, and dry organic phase simultaneously rotates removing organic solvent, and gained residue (is washed through column chromatography De- agent: ethyl acetate/ethyl alcohol (9:1v/v)) purify to obtain yellow solid powder, yield 27.7%, 228-230 DEG C of fusing point.Compound Structured data characterization are as follows:¹H NMR(400MHz,CDCl₃) δ 15.01 (s, 1H), 10.99 (s, 1H), 8.69 (d, J=6.8Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 7.75 (d, J=8.1Hz, 1H), 7.31 (d, J=7.5Hz, 2H), 7.12 (s, 1H), 6.90 (d, J=7.3Hz, 2H), 6.31 (d, J=8.2Hz, 1H), 4.48 (s, 2H), 3.80 (s, 3H), 3.62 (br, 2H), 2.65(br,2H),2.37(s,6H)；¹³C NMR(100MHz,CDCl₃)δ179.27,168.23,159.06,154.56, 144.07,134.96,134.79,134.52,134.44,131.08,129.49,128.45,124.58,119.70,114.30, 106.93,103.00,102.11,57.94,55.32,46.43,45.00,36.61；HR-MS(ESI):Calcd for[M+H]⁺ 490.2090；Found:490.2099.

Embodiment 14:N- (2- (dimethylamino) ethyl) -5- nitro -9- oxo -1- ((3,4,5- trimethoxy benzyl) Amino)-acridan -4- amide preparation

By the chloro- N- of 1- obtained in case study on implementation 11 (2- (dimethylamino) ethyl) -5- nitro -9- oxo -9,10- two Pyridinium hydroxide -4- amide (0.42mmol), 3,4,5- trimethoxy benzylamines (2.10mmol) and triethylamine (0.50mL) successively dissolve In cellosolvo solvent (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC detection reaction terminates Afterwards, reaction solution is cooled to room temperature, there is Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), Obtain sterling.If DCM (50mL) and water (50mL), extraction are added in the reaction system without Precipitation after reaction solution is cooling Gained organic phase is washed with water (40mL × 3) three times afterwards, and dry organic phase simultaneously rotates removing organic solvent, and gained residue is through column Chromatography (eluant, eluent: ethyl acetate/ethyl alcohol (9:1v/v)) purifies to obtain yellow solid powder, yield 49.4%, fusing point 243-244 ℃.Compound structure data characterization are as follows:¹H NMR(400MHz,CDCl₃)δ15.04(s,1H),11.01(s,1H),8.68(dd,J =15.5,7.3Hz, 2H), 7.71 (d, J=8.7Hz, 1H), 7.30-7.28 (m, 1H), 6.95 (s, 1H), 6.61 (s, 2H), 6.30 (d, J=8.7Hz, 1H), 4.48 (d, J=4.0Hz, 2H), 3.85 (s, 9H), 3.59 (br, 2H), 2.57 (br, 2H), 2.31(s,6H)；¹³C NMR(100MHz,CDCl₃)δ179.39,168.12,154.58,153.68,144.01,137.41, 135.04,134.81,134.42,134.38,133.24,131.15,124.56,119.77,107.04,104.17,103.44, 102.14,60.86,57.74,56.23,47.35,45.10,36.82；HR-MS(ESI):Calcd for[M+H]⁺ 550.2302；Found:550.2308.

Embodiment 15:1- benzamido group-N- (3- (dimethylamino) propyl) -5- nitro -9- oxo-acridan - The preparation of 4- amide

1, the chloro- N- of 1- (3- (dimethylamino) propyl) -5- nitro -9- oxo -9,10- dihydropyridine -4- amide is prepared

By the chloro- 5- nitro-9- oxo of the 1- obtained in case study on implementation 11-acridan-4- carboxylic acid (1.65mmol) Be slowly added dropwise into N, in the dimethyl formamide solution of N '-carbonyl dimidazoles (2.48mmol) (10ml), after being added dropwise in It is stirred at room temperature 30 minutes, then by N, N- dimethyl -1,3- propane diamine (5.22mmol) is added in reaction system, was stirred at room temperature Night.After reaction, it is extracted with methylene chloride (50mL), gained organic phase is washed three times with water (40mL), dry organic phase, rotation Dry, gained residue purifies to obtain red solid powder through column chromatography (eluant, eluent: ethyl acetate/ethyl alcohol (9:1v/v)), i.e. 1- is chloro- N- (3- (dimethylamino) propyl) -5- nitro -9- oxo -9,10- dihydropyridine -4- amide.Yield 28.6%.Compound knot Structure data characterization are as follows:¹H NMR(400MHz,CDCl₃) δ 14.78 (s, 1H), 9.53 (s, 1H), 8.77 (d, J=7.6Hz, 1H), 8.70 (d, J=7.9Hz, 1H), 7.72 (d, J=8.1Hz, 1H), 7.33 (dd, J=14.3,7.9Hz, 2H), 3.69 (br, 2H),2.63(br,2H),2.37(s,6H),1.85(br,2H).

2,1- benzamido group-N- (3- (dimethylamino) propyl) -5- nitro -9- oxo-acridan -4- amide Preparation

By the chloro- N- of 1- obtained in step 1 (3- (dimethylamino) propyl) -5- nitro -9- oxo -9,10- dihydro pyrrole Pyridine -4- amide (0.42mmol), benzylamine (2.10mmol) and triethylamine (0.50mL) are successively dissolved in cellosolvo solvent In (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC is detected after reaction, and reaction solution is cooled to room Temperature has Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), obtain sterling.If reacting liquid cooling But without Precipitation after, then DCM (50mL) and water (50mL) are added in the reaction system, gained organic phase is washed with water after extraction (40mL × 3) three times, dry organic phase simultaneously rotate removing organic solvent, and gained residue chromatographs (eluant, eluent: acetic acid second through column Ester/ethyl alcohol (9:1v/v)) purify to obtain red solid powder, yield 73.7%, 222-224 DEG C of fusing point.Compound structure tables of data Sign are as follows:¹H NMR(400MHz,CDCl₃) δ 15.25 (s, 1H), 11.06 (s, 1H), 8.71 (d, J=7.6Hz, 2H), 8.65 (d, J =7.9Hz, 1H), 7.61 (d, J=9.0Hz, 1H), 7.46-7.33 (m, 4H), 7.33-7.26 (m, 2H), 6.31 (d, J= 8.9Hz, 1H), 4.57 (d, J=5.3Hz, 2H), 3.64 (br, 2H), 2.58 (br, 2H), 2.35 (s, 6H), 1.82 (br, 2H) ；¹³C NMR(100MHz,CDCl₃)δ179.41,168.14,154.50,144.20,137.58,135.08,134.86, 134.40,134.12,131.07,128.86,127.50,127.15,124.59,119.59,107.07,103.57,101.96, 59.42,46.94,45.30,40.47,24.94；HR-MS(ESI):Calcd for[M+H]⁺474.2141；Found: 474.2126.

Embodiment 16:N- (3- (dimethylamino) propyl) -1- ((4- methoxy-benzyl) amino) -5- nitro -9- oxo - The preparation of acridan -4- amide

By the chloro- N- of 1- obtained in case study on implementation 15 (3- (dimethylamino) propyl) -5- nitro -9- oxo -9,10- two Pyridinium hydroxide -4- amide (0.42mmol), 4- methoxybenzylamine (2.10mmol) and triethylamine (0.50mL) are successively dissolved in 2- second In ethoxy-ethanol solvent (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC is detected after reaction, will be anti- It answers liquid to be cooled to room temperature, there is Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), obtain sterling. If DCM (50mL) and water (50mL) are added in the reaction system without Precipitation after reaction solution is cooling, there is gained after extraction Machine is mutually washed with water (40mL × 3) three times, and dry organic phase simultaneously rotates removing organic solvent, and gained residue (is washed through column chromatography De- agent: ethyl acetate/ethyl alcohol (9:1v/v)) purify to obtain red solid powder, yield 63.9%, 251-252 DEG C of fusing point.Compound Structured data characterization are as follows:¹H NMR(400MHz,CDCl₃)δ15.27(s,1H),10.97(s,1H),8.76(s,1H),8.70(d, J=7.6Hz, 1H), 8.65 (d, J=7.9Hz, 1H), 7.59 (d, J=9.0Hz, 1H), 7.33 (d, J=8.2Hz, 2H), 7.27-7,24 (m, 1H), 6.91 (d, J=8.3Hz, 2H), 6.32 (d, J=8.9Hz, 1H), 4.49 (d, J=5.1Hz, 2H), 3.81(s,3H),3.64(br,2H),2.56(br,2H),2.35(s,6H),1.80(br,2H)；¹³C NMR(100MHz, CDCl₃)δ179.36,168.12,159.09,154.38,144.21,135.05,134.85,134.39,134.08,131.07, 129.52,128.49,124.58,119.58,114.31,106.99,103.43,101.91,59.61,55.33,46.45, 45.41,40.67,24.92；HR-MS(ESI):Calcd for[M+H]⁺504.2247；Found:504.2245.

Embodiment 17:N- (3- (dimethylamino) propyl)-1- ((4- Ethylbenzyl) amino) oxo-9-5- nitro-9-, The preparation of 10- acridan -4- amide

By the chloro- N- of 1- obtained in case study on implementation 15 (3- (dimethylamino) propyl) -5- nitro -9- oxo -9,10- two Pyridinium hydroxide -4- amide (0.42mmol), 4- ethyl benzyl amine (2.10mmol) and triethylamine (0.50mL) are successively dissolved in 2- ethoxy In base alcohol solvent (10mL), reaction system is stirred overnight under 90 DEG C of heating conditions.TLC is detected after reaction, will be reacted Liquid is cooled to room temperature, and has Precipitation.Solid powdery head product is filtered to obtain, it is dry after being washed with water (40mL), obtain sterling.Such as Without Precipitation after fruit reaction solution is cooling, then DCM (50mL) and water (50mL) are added in the reaction system, gained is organic after extraction It is mutually washed with water (40mL × 3) three times, dry organic phase simultaneously rotates removing organic solvent, and gained residue chromatographs (elution through column Agent: ethyl acetate/ethyl alcohol (9:1v/v)) purify to obtain red solid powder, yield 24.0%, 266-267 DEG C of fusing point.Compound knot Structure data characterization are as follows:¹H NMR(400MHz,CDCl₃)δ15.27(s,1H),11.03(s,1H),8.79-8.71(m,1H),8.66 (dd, J=8.1,1.4Hz, 1H), 7.69 (d, J=9.0Hz, 1H), 7.32 (d, J=8.0Hz, 2H), 7.28 (d, J=8.1Hz, 1H), 7.21 (d, J=8.0Hz, 2H), 6.35 (d, J=9.1Hz, 1H), 4.53 (d, J=5.5Hz, 2H), 3.66-3.65 (m, 2H), 2.68-2.66 (m, 2H), 2.65-2.63 (m, 2H), 2.41 (s, 6H), 1.86-1.85 (m, 2H), 1.24 (t, J= 7.6Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ179.39,168.28,154.55,144.25,143.60,135.06, 134.88,134.71,134.44,134.31,131.06,128.36,127.24,124.63,119.59,107.02,103.29, 102.09,59.00,46.77,45.04,39.97,28.53,24.82,15.54；HR-MS(ESI):Calcd for[M+H]⁺ 502.2454；Found:502.2467.

Embodiment 18:MTT method cell inhibitory effect screening active ingredients

By mtt assay, using the human hepatocellular carcinoma HepG2 cell and MCF-7 Human Breast Cancer Cells for being in logarithmic growth phase, The cell in vitro proliferation inhibition activity for the compound that detection embodiment 1-17 is prepared, wherein positive control drug is selected YM155.Human hepatocellular carcinoma HepG2 cell and MCF-7 Human Breast Cancer Cells are attached cell, are 10% tire ox with containing volume fraction The DMEM culture solution of serum, in 37 DEG C, the CO that volume fraction is 5%₂Under the conditions of routine culture；In addition, for compound 16 into The in vitro toxicity test gone to normal liver cell QGY-7701.Wherein, normal liver cell QGY-7701 is attached cell, with containing Volume fraction is the DMEM culture solution of 10% fetal calf serum, in 37 DEG C, the CO that volume fraction is 5%₂Under the conditions of routine culture；Tool Gymnastics is made as follows:

Firstly, it is 5mM/L that the compound (i.e. sample) that embodiment 1-17 is prepared is configured to compound concentration respectively DMSO (dimethyl sulfoxide) solution, then by the solution of acquisition through gradient dilution, a series of sample for obtaining concentration gradients is molten Liquid.Then, logarithmic growth phase human hepatocellular carcinoma HepG2 cell and MCF-7 Human Breast Cancer Cells, respectively with 6 × 10³A/mL Cell density be inoculated in 96 orifice plates, 99 holes μ L/ first have at 37 DEG C, 5% CO₂Incubator in cultivate 12 hours, make 1 μ L of sample solution is added followed by every hole after cell is adherent, making sample effect final concentration is respectively 0.1 μM, 1 μM, 5 μM, 10 μ M, 25 μM and 50 μM.Every kind of sample, each concentration set three multiple holes, and a positive control and blank control is arranged, wherein Positive controls be added positive control medicine cis-platinum with sample solution with the solution of concentration, it is molten that sample is not added in blank control group Liquid.MTT solution is added after acting on 48h, dimethyl sulfoxide is added after sucking supernatant after continuing culture 4 hours in 10 holes μ L/ (DMSO), 100 hole μ L/ keeps the temperature about 10 minutes in 37 DEG C, is then vibrated about 5 minutes with micro oscillator, dissolved crystallization Entirely, OD value is measured at 490nm with microplate reader, be calculated as follows cell proliferation inhibition rate (Inhibition Rate, IR%): IR%=(positive control OD- sample OD)/(positive control OD- blank control OD) × 100%, part of test results It is shown in Table 1.Again, the normal liver cell QGY-7701 of logarithmic growth phase, with 6 × 10³The cell density of a/mL is inoculated in 96 holes In plate, 99 holes μ L/, in 37 DEG C, 5% CO₂Under the conditions of cultivate about 12 hours.Then the DMSO solution of compound 16 is added in every hole 1 μ L, making the effect final concentration of this compound is respectively 0.1 μM, 1 μM, 5 μM, 10 μM, 25 μM and 50 μM.Each concentration sets three Multiple holes, and blank control is set, wherein sample solution is not added in blank control group.MTT solution, 10 μ L/ are added after acting on 48h Hole, after continuing culture 4 hours, is added dimethyl sulfoxide (DMSO) after sucking supernatant, and 100 holes μ L/ keep the temperature about 10 points in 37 DEG C Then clock is vibrated about 5 minutes with micro oscillator, make crystallization dissolution completely, measure OD value at 490nm with microplate reader, by such as Lower formula calculates cell proliferation inhibition rate (Inhibition Rate, IR%): IR%=(positive control OD- sample OD)/(sun Property control OD- blank control OD) × 100%, experimental result is shown in Table 2.

The active ingredients result for the acridones compound that 1 benzylamine of table replaces

Note: IC₅₀Indicate half-inhibitory concentration.

Toxic test results of 2 compound 16 of table to normal liver cell QGY-7701

Note: IC₅₀Indicate half-inhibitory concentration.

The MTT result of the acridones compound replaced containing benzamido group is shown in table 1.As can be seen from the results, R₃When substituent group is 4- methoxyl group, compound activity performance is more prominent.Such as compound 3 is to the IC of HepG2 cell₅₀Reach 2.11 μM, and compound 13 is to the IC of MCF-7 cell₅₀Also it can reach 1.05 μM.In addition, data are it is found that compound pair from table 1 The external activity IC of HepG2 cell₅₀It is worth 4 compounds (compound 2,3,15 and 16) its corresponding MCF-7 cell less than 4 μM The also more satisfactory (IC of activity₅₀Between 2.92 to 6.84 μM).Simultaneously as can be seen from the table, compound 13 is thin to MCF-7 The antiproliferative activity of born of the same parents is best, and the IC of the corresponding HepG2 cell of compound 13₅₀Value can also reach 4.50 μM.These phenomenons are said It is almost the same to the inhibitory effect of two kinds of solid tumor cells that benzamido group acridones compound is illustrated.It is worth noting that, chemical combination Object 13 and 16 in chemical structure difference be only acridone parent the position 4- amide side chains length (i.e. methylene number n, N selects 2 and 3) different in this patent, and this two kinds of compounds are to the IC of HepG2 cell₅₀It is worth almost the same.It can be seen that acyl The length of amine side chain influences anti-tumor activity little.

Table 2 is the in vitro toxicity test result for compound 16 to normal liver cell QGY-7701.Data can from table Know, compound 16 has been worth low more than 11 times to the inhibitory activity of the toxicity ratio HepG2 cell of normal liver cell.This showing of phenomenon Closing object 16 has good external hypotoxicity.

Embodiment 24:DNA topoisomerase enzyme test

The present invention tests DNA topoisomerase II (english abbreviation Topo II) the activity suppression experiment of compound 16.Hair The activity of existing 16 energy selective depression Topo II of compound.From Fig. 1, (wherein, Dox10 is the Doxorubicin of 10 μM of concentration；Dox1 For the Doxorubicin of 1 μM of concentration；8u is the untested compound 16 of 50 μM of concentration；NC is non-treated group；KDNA is that kinetoplast dna is empty White control group) in as can be seen that compound 16 can have certain inhibitory activity (average inhibition of two times result to Topo II For 10.99%).Positive control selects 1 μM and 10 μM of Doxorubicin DMSO solution in this experiment.Based on described above, chemical combination Object 16 has certain selectivity to the inhibitory activity of Topo II.This shows that 16 can make indirectly by inhibiting Topo II activity At the damage of DNA, so as to cause cancer cell-apoptosis.

Embodiment 25: protein electrophoresis experiment

The expression of Survivin can be effectively inhibited in order to verify compound 16 in tumour cell, the present invention carries out Protein electrophoresis experiment.From figure 2 it can be seen that as compound concentration is from when increasing to 10 μM for 1 μM, human hepatocellular carcinoma HepG2 The expression of Survivin albumen is obviously lowered in cell.This phenomenon illustrates that compound 16 can effectively press down in tumour cell The expression of Survivin processed.In addition, the expression of apoptosis inhibitory protein Bcl2 has obvious downward with the increase of compound concentration, And Caspase-7 and PARP expression has up-regulation trend.It is possible thereby to infer, compound 16 can induce HepG2 Apoptosis.

In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or spy described in conjunction with this embodiment or example Point is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are not It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be in office It can be combined in any suitable manner in one or more embodiment or examples.In addition, without conflicting with each other, the skill of this field Art personnel can tie the feature of different embodiments or examples described in this specification and different embodiments or examples It closes and combines.

Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, modifies, replacement and variant.

Claims

1. a kind of compound, which is characterized in that the compound is the polysubstituted phenyl alkylamino a word used for translation with structural formula shown in Formulas I Pyridine ketone -4- amides compound,

Wherein, R₁It is each independently OCH₃、Cl、NO₂Or CH₃,

R₂For N (CH₃)₂Or OCH₃,

R₃It is each independently H ,-OCH₃、-CF₃Or-CH₂CH₃,

M=1；

N=2 or 3；

P=1 or 3.

2. compound according to claim 1, which is characterized in that be one of following:

N- (2- (dimethylamino) ethyl) 1- ((3- methoxy-benzyl) amino) -5- methyl -9- oxo-acridan - 4- amide,

N- (2- (dimethylamino) ethyl) 1- ((4- methoxy-benzyl) amino) -5- methyl -9- oxo-acridan - The preparation of 4- amide,

N- (3- (dimethylamino) propyl) 1- ((4- methoxy-benzyl) amino) -5- methyl -9- oxo-acridan - 4- amide,

N- (2- (dimethylamino) ethyl) -5- methyl -9- oxo -1- ((3,4,5- trimethoxy benzyl) amino) -9,10- bis- Hydrogen acridine -4- amide,

N- (2- (dimethylamino) ethyl) -5- methoxyl group -1- ((4- methoxy-benzyl) amino) -9- oxo -9,10- dihydro a word used for translation Pyridine -4- amide,

N- (3- (dimethylamino) propyl) -5- methoxyl group -1- ((4- methoxy-benzyl) amino) -9- oxo -9,10- dihydro a word used for translation Pyridine -4- amide,

The chloro- N- of 5,7- bis- (2- (dimethylamino) ethyl) -1- ((4- methoxy-benzyl) amino) -9- oxo -9,10- dihydro a word used for translation Pyridine -4- amide,

N- (2- (dimethylamino) ethyl) -1- ((3- methoxy-benzyl) amino) -5- nitro -9- oxo -9,10- dihydro a word used for translation Pyridine -4- amide,

N- (2- (dimethylamino) ethyl) -1- ((4- methoxy-benzyl) amino) -5- nitro -9- oxo -9,10- dihydro a word used for translation Pyridine -4- amide,

N- (2- (dimethylamino) ethyl) -5- nitro -9- oxo -1- ((3,4,5- trimethoxy benzyl) amino) -9,10- bis- Hydrogen acridine -4- amide,

N- (3- (dimethylamino) propyl) -1- ((4- methoxy-benzyl) amino) -5- nitro -9- oxo -9,10- dihydro a word used for translation Pyridine -4- amide,

N- (3- (dimethylamino) propyl) -1- ((4- Ethylbenzyl) amino) -5- nitro -9- oxo-acridan - 4- amide.

3. a kind of method for preparing compound as claimed in claim 1 or 2 characterized by comprising

(1) react compound shown in Formula II with compound shown in formula III, to obtain compound shown in formula IV；

(2) make compound and strong sulfuric acid response shown in the formula IV, to obtain compound shown in formula V；

(3) react compound shown in the formula V with kiber alkyl amine class compound, to obtain compound shown in formula VI；

(4) react compound shown in the formula VI with Multi substituted benzenes pheynylalkylamine class compound, to obtain chemical combination shown in Formulas I Object,

The kiber alkyl amine class compound has structure shown in one of formula 1- formula 3:

The Multi substituted benzenes pheynylalkylamine class compound has structure shown in one of formula 4- formula 9:

4. according to the method described in claim 3, it is characterized in that, in step (1), using copper as catalyst, potassium carbonate as Alkali reacts compound shown in the Formula II in anhydrous dimethyl formamide with compound shown in the formula III, to obtain Compound shown in the formula V；

Optionally, in step (3), with N, N'- carbonyl dimidazoles make compound and alkyl shown in the formula V as condensing agent Primary amine compound reacts in anhydrous dimethyl formamide, to obtain compound shown in the formula VI.

5. according to the method described in claim 4, it is characterized in that, being catalysis with copper at 100-130 DEG C in step (1) Agent, potassium carbonate make compound shown in compound shown in the Formula II and the formula III according to the ratio of molar ratio 1:1.5 as alkali Example is reacted 1-12 hours in anhydrous dimethyl formamide；

Optionally, in step (2), at 50-100 DEG C, make compound shown in described IV and strong sulfuric acid response 1-5 hours；

Optionally, in step (3), at 0-50 DEG C, with N, N'- carbonyl dimidazoles make shown in the formula V as condensing agent Compound reacts 10-30 hours with kiber alkyl amine class compound in anhydrous dimethyl formamide；

Optionally, in step (4), at 50-100 DEG C, make compound shown in the formula VI and the polysubstituted phenylalkyl Aminated compounds reacts 10-30 hours.

6. a kind of pharmaceutical composition, which is characterized in that containing compound of any of claims 1 or 2,

Optionally, described pharmaceutical composition is used for:

1) inhibit the expression of Survivin albumen in human liver cancer cell；

2) inhibit topoisomerase II；

3) inhibit human liver cancer cell and human breast cancer cell proliferation；Or

4) prevent and/or treat liver cancer and breast cancer.

7. the purposes of compound of any of claims 1 or 2 or pharmaceutical composition as claimed in claim 6 in medicine preparation, The drug is used for:

1) inhibit the expression of Survivin albumen in human liver cancer cell；

2) inhibit topoisomerase II；

4) prevent and/or treat liver cancer and breast cancer.