CN105481830B - One anti-tumor compounds and preparation method thereof - Google Patents

One anti-tumor compounds and preparation method thereof Download PDF

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CN105481830B
CN105481830B CN201510859499.6A CN201510859499A CN105481830B CN 105481830 B CN105481830 B CN 105481830B CN 201510859499 A CN201510859499 A CN 201510859499A CN 105481830 B CN105481830 B CN 105481830B
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methyl
acridone
compound
base
triazol
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CN105481830A (en
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孟繁浩
梁经纬
张廷剑
何鑫
杨苏
吴青霞
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China Medical University
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China Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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Abstract

The present invention is an anti-tumor compounds, belongs to field of medicaments, and in particular to a kind of compound of the specified chemical structure of anti-tumor activity, and produce the method and purposes of such compound.The compound is shown in general formula; n is the integer of 0-3 in formula; R1 is methyl, fluorine, chlorine, bromine, carboxyl and its methyl esters, ethyl ester, propyl ester, isopropyl ester, N-butyl, isobutyl ester and the tert-butyl ester; R2 is acetyl group, propiono, benzoyl and 1-5 carbon atom alkyl, and X is CH2 or CO (carbonyl)；The position of fragrant ring substituents can be 2,3,4 substitutions, and substitution can be monosubstituted, polysubstituted.And provide the preparation method of the compound.It is demonstrated experimentally that a kind of topoisomerase enzyme inhibitor of the compound as brand new type, good for inhibiting tumor promotion to play the role of.

Description

One anti-tumor compounds and preparation method thereof
Technical field: the invention belongs to field of medicaments, more particularly to a kind of change of the specified chemical structure of anti-tumor activity Close object, and the method for producing such compound.
Background technique: malignant tumour is to seriously threaten the disease of human health, and malignant tumour has been over painstaking effort at present Pipe disease becomes the first killer for leading to human death.World Health Organization, it is contemplated that the year two thousand thirty will have 12,000,000 people to die of Malignant tumour.Although current anti-tumor drug have certain curative effect, there are poor selectivity, toxic side effect is big the disadvantages of, medicine Object treats the new breakthrough that waits in expectation.Therefore, efficient, low toxicity, wide spectrum and cheap anti-tumor drug are found and has become current swell The important content of tumor research.
DNA topoisomerase is an important function target spot of current anti-tumor drug.Different from normal cell, Topo exists The high level expression not being affected by other factors is shown in tumour cell, therefore inhibits the activity of tumour cell Topo that can rise To containment tumour cell fast breeding, and then kill the effect of tumour cell.DNA topoisomerase enzyme inhibitor is by influencing Topo Each stage of enzyme effect process carrys out the activity of destructive enzyme.It can directly act on DNA, can also act on topoisomerase Enzyme may also act on DNA topoisomerase-DNA break compound, to complete the inhibition to topoisomerase active, and most Lead to Apoptosis eventually.
Summary of the invention:
Goal of the invention: it is an object of the present invention to by Etoposide in DNA and topoisomerase composite structure and Calculating simulation reality is studied and is docked in the analysis of the binding site of the inhibitor such as amsacrine to the structural model of the above inhibitor It tests, designs the topoisomerase enzyme inhibitor of a kind of brand new type.
Technical solution:
One anti-tumor compounds, it is characterised in that: the structural formula of the compound are as follows:
Wherein:
Wherein n is the integer of 0-3, and R1 is methyl, fluorine, chlorine, bromine, carboxyl and its methyl esters, ethyl ester, propyl ester, isopropyl ester, positive fourth Ester, isobutyl ester and the tert-butyl ester, R2 are acetyl group, propiono, benzoyl and 1-5 carbon atom alkyl, and X is CH2 or CO (carbonyl Base)；The position of fragrant ring substituents can be 2,3,4 substitutions, and substitution can be monosubstituted, polysubstituted.
The antitumoral compounds, it is characterised in that: the general formula I, general formula II compound be selected from it is following any one Kind:
10- ((1- (p-methylphenyl) -1H-1,2,3- triazole -4-) methyl) acridone；
10- ((1- (4- bromophenyl) -1H-1,2,3- triazole -4-) methyl) acridone；
10- ((1- phenyl -1H-1,2,3- triazole-4-yl) methyl) acridone；
2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) ethyl acetate；
2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) acetic acid；
2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) methyl acetate；
10- ((1- (2- ethoxy) -1H-1,2,3- triazole-4-yl) methyl) acridone；
Acetyl -2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) ester；
4- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) ethyl benzoate；
4- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) benzoic acid；
4- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) methyl benzoate；
4- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) n-butylbenzoate；
2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) ethyl benzoate；
2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) benzoic acid；
2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) methyl benzoate；
2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) n-butylbenzoate
The preparation method of one anti-tumor compounds, it is characterised in that the preparation of the compound according to the following steps into Row:
(1) synthesis of intermediate 3- propargyl acridone:
Specifically:
Aniline and 0-chloro-benzoic acid pass through ullmann reaction generation N- phenylanthranilic acid；
N- phenylanthranilic acid retaining ring under conditions of the concentrated sulfuric acid generates acridone；
Acridone, with 3- propargyl bromide hydrocarbonylation, generates N- propargyl acridone under the alkaline condition of NaH；
(2) replace the synthesis of phenylazide class intermediate:
Specifically:
Under conditions of low temperature acid, with sodium nitrite diazo-reaction occurs for substituted aniline, then is given birth to by Sodium azide nucleophilic At substitution nitrine benzene-like compounds；
(3) α-azide substitution class intermediate synthesis
With Sodium azide substitution reaction occurs for bromobenzyl or bromoacetate in polar solvent, generates corresponding α and replaces nitrine Compound；
(4) synthesis of target compound
The cyclization under cuprous ion catalysis of N- propargyl acridone and azide compounds, generates corresponding target chemical combination Object.
The compound, as the purposes for preparing anti-tumor drug.
Specific embodiment
By to the binding site of the inhibitor such as Etoposide and amsacrine in DNA and topoisomerase composite structure Calculating simulation experiment is studied and is docked in analysis to the structural model of the above inhibitor, devises a kind of brand new type Topoisomerase enzyme inhibitor.Pharmacological research shows that the compounds of this invention is thin to human gastric cancer, human gastric cancer MGC-803 Born of the same parents, K562 cell and human leukemia HL60 cell have certain inhibitory activity.
The general structure of New Topological isomerase inhibitors of the invention are as follows:
Wherein n is the integer of 0-3, R1For methyl, fluorine, chlorine, bromine, carboxyl and its methyl esters, ethyl ester, propyl ester, isopropyl ester, positive fourth Ester, isobutyl ester and the tert-butyl ester, R2For acetyl group, propiono, benzoyl and 1-5 carbon atom alkyl, X is CH2 or CO (carbonyl Base).The position of fragrant ring substituents can be 2,3,4 substitutions, and substitution can be monosubstituted, polysubstituted.
More preferable following any compound:
By taking L8 as an example, the compound of the present invention can be prepared with following method:
Other compounds can take corresponding raw material to use and prepare with reference to the above method.
By embodiment come the present invention will be described:
The synthesis of one compound
Embodiment 1
The preparation of 10- ((1- (p-methylphenyl) -1H-1,2,3- triazole -4-) methyl) acridone (L1)
The preparation of a.N- phenylanthranilic acid
0-chloro-benzoic acid 1g, aniline 0.7ml are dissolved in 10ml DMF, add 2.65g Anhydrous potassium carbonate and 0.05g iodate Cuprous, 130 DEG C of microwave are reacted 13 minutes.Be evaporated off under reduced pressure DMF, be adjusted to pH=4 with 10% hydrochloric acid, suction filtration wash celadon is thick Product, the active carbon decoloring of crude product and with ethyl alcohol recrystallization obtain grey powder 0.63g, yield:46%
B. the preparation of acridone
1g N- phenylanthranilic acid is taken to be dissolved in the 10ml concentrated sulfuric acid, 70 DEG C are reacted 1 hour.Ice water is added in reaction solution In, it filters, is washed till neutrality with 5% sodium carbonate liquor, filter, dry solid 0.81g, yield:88%
The preparation of c.N- propargyl acridone
0.85g acridone is dissolved in 7ml DMF, and 0.2g NaH and 0.14g KI is added, lower dropwise addition 0.7ml is stirred at room temperature Simultaneously the reaction was continued 3 hours for 3- propargyl bromide.15ml water is added into reaction solution, filters to obtain crude product, active carbon decoloring and with ethyl alcohol weight Crystallize pale yellow needles crystallization 0.93g, yield:92%m.p.=207 DEG C (document report: 212-215 DEG C)
D. to the preparation of azido toluene
Open-chain crown ether 0.94g is dissolved in the in the mixed solvent of 10ml glacial acetic acid Yu 1ml water, and 0 DEG C of stirring is lower to be added dropwise 0.63g NaNO3Aqueous solution 2ml, drop finishes reacts 30 minutes again, and 0.55g NaN is added dropwise3Aqueous solution 2ml, there is bulk gas generation, and drop finishes again Reaction 30 minutes.Use CH2Cl2Extraction, anhydrous Na2SO4It is dry, product is concentrated to give to azido toluene 0.53g.Yield:42%
E.10- the preparation of ((1- (p-methylphenyl) -1H-1,2,3- triazole -4-) methyl) acridone (L1)
Five water of 0.1g and copper sulphate and 0.17g sodium ascorbate are dissolved in 3ml water, 30 DEG C microwave 3 minutes, make copper ion also Original is at active cuprous ion.It takes 0.2g N- propargyl acridone to be dissolved in 95% ethyl alcohol of 7ml, it is folded to add 0.15ml benzyl Nitrogen and the above-mentioned aqueous solution containing cuprous ion, 50 DEG C microwave 15 minutes, then 75 DEG C microwave 5 minutes, let cool suction filtration, dehydrated alcohol Recrystallize to obtain pale yellow powder 0.12g.Yield:39%.1HNMR(600MHz,DMSO-d6)δ2.34(s,3H),5.87(s, 2H), 7.30-7.42 (m, 4H), 7.72 (d, J=8.28Hz, 2H), 7.82 (t, J=7.34Hz, 2H), 7.96 (d, J= 8.66Hz, 2H), 8.37 (d, J=7.34Hz, 2H), 8.78 (s, 1H)；13C NMR(151MHz,DMSO-d6)δ20.9,40.5, 42.2,116.7,120.3,121.8,121.9,122.2,127.0,130.5,134.6,134.6,138.7,142.3,144.1, 177.1
Embodiment 2
The preparation of 10- ((1- (4- bromophenyl) -1H-1,2,3- triazole -4-) methyl) acridone (L2)
Using para-bromoaniline as raw material, synthesize according to embodiment 1d step to azido bromobenzene, and according to embodiment 1e step 10- ((1- (4- bromophenyl) -1H-1,2,3- triazole -4-) methyl) acridone (L2) light yellow solid is made.1H NMR (600MHz,DMSO-d6) δ 2.34 (s, 3H), 5.87 (s, 2H), 7.30-7.42 (m, 4H), 7.72 (d, J=8.28Hz, 2H), 7.82 (t, J=7.34Hz, 2H), 7.96 (d, J=8.66Hz, 2H), 8.37 (d, J=7.34Hz, 2H), 8.78 (s, 1H)；13C NMR(151MHz,DMSO-d6)δ20.9,40.5,42.2,116.7,120.3,121.8,121.9,122.2,127.0,130.5, 134.6,134.6,138.7,142.3,144.1,177.1
Embodiment 3
The preparation of 10- ((1- phenyl -1H-1,2,3- triazole-4-yl) methyl) acridone (L3)
It is raw material according to embodiment 1d step synthesis of phenyl nitrine using aniline, and 10- is made according to embodiment 1e step ((1- phenyl -1H-1,2,3- triazole-4-yl) methyl) acridone (L3) off-white powder.1H NMR(600MHz,DMSO-d6)δ 5.89(s,2H),7.33-7.39(m,2H),7.42-7.48(m,1H),7.52-7.58(m,2H),7.79-7.87(m,4H), 7.96 (d, J=8.85Hz, 2H), 8.37 (dd, J=8.00,1.60Hz, 2H), 8.83 (s, 1H)；13C NMR(151MHz, DMSO-d6)δ42.2,116.7,120.4,121.9,122.0,122.2,127.0,129.1,130.2,134.6,136.8, 142.3,144.2,177.1.
Embodiment 4
The preparation of 2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) ethyl acetate (L4)
A. the preparation of ethyl azidoacetate
2g bromoacetate is dissolved in the in the mixed solvent of 10ml acetone Yu 2ml water, and 1.54g NaN3, back flow reaction 6 is added Hour, CH2Cl2The light yellow liquid 1.12g, yield:53% of extraction.
B.2- the preparation of (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) ethyl acetate (L4)
According to 2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) second obtained the step of embodiment 1e Acetoacetic ester (L4) off-white powder.1H NMR(600MHz,DMSO-d6) δ 1.15 (t, J=7.15Hz, 3H), 4.11 (q, J= 7.09Hz, 2H), 5.31 (s, 2H), 5.85 (s, 2H), 7.35 (t, J=7.34Hz, 2H), 7.82 (ddd, J=8.66,6.96, 1.69Hz, 2H), 7.96 (d, J=8.66Hz, 2H), 8.10 (s, 1H), 8.36 (dd, J=7.91,1.69Hz, 2H)；13C NMR (151MHz,DMSO-d6)δ14.3,41.8,50.8,61.8,116.7,121.9,122.1,125.2,127.0,134.6, 142.1,142.9,167.5,177.0
Embodiment 5
The preparation of 2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) acetic acid (L5) takes 0.9g 2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yls) ethyl acetate (L4) is dissolved in 10ml water, and 0.36g is added NaOH, return stirring are all dissolved until solid, then are precipitated with dilute hydrochloric acid tune acid to a large amount of light yellow flocculent deposits, and pumping is let cool Filter, dry solid 0.63g.Yield 74.1%.1H NMR(600MHz,DMSO-d6)δ5.17-5.26(m,2H),5.83(s, 2H), 7.34 (t, J=7.44Hz, 2H), 7.77-7.86 (m, 2H), 7.97 (d, J=8.66Hz, 2H), 8.13 (d, J= 2.45Hz,1H),8.32-8.40(m,2H),13.36(br.s.,1H)；13C NMR(151MHz,DMSO-d6)δ41.8,50.9, 116.7,121.9,122.1,125.1,127.0,134.6,142.1,142.7,168.8,177.0.
Embodiment 6
The preparation of 2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) methyl acetate (L6)
0.2g 2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) acetic acid (L5) is taken to be dissolved in 5ml In DMF, 50mg iodomethane is added, after being stirred at room temperature 30 minutes, cold water, which is added, has light yellow flocculent deposit to be precipitated, drying is filtered, Solid 80mg.Yield 38.7%.1H NMR(600MHz,DMSO-d6)δ3.66(s,3H),5.34(s,2H),5.85(s,2H), 7.30-7.38 (m, 2H), 7.83 (ddd, J=8.66,6.96,1.69Hz, 2H), 7.96 (d, J=8.85Hz, 2H), 8.11 (s, 1H), 8.36 (dd, J=7.91,1.69Hz, 2H)；13C NMR(151MHz,DMSO-d6)δ41.8,50.6,52.9,116.7, 121.9,122.1,125.2,127.0,134.6,142.1,142.9,168.0,177.0.
Embodiment 7
The preparation of 10- ((1- (2- ethoxy) -1H-1,2,3- triazole-4-yl) methyl) acridone (L7)
At 0 DEG C, by 0.7g NaBH4It is added in 10ml methanol, is gradually increased to room temperature, when having uniform bubble generation, add Enter 0.9g 2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yls) ethyl acetate (L4), it is small to be stirred at room temperature 1 When.It is spin-dried for solvent, crude product is washed with cold water, and with ethyl alcohol recrystallization, obtains yellow solid 0.34g.Yield 41.3%.1H NMR (600MHz,DMSO-d6) δ 3.71 (t, J=5.36Hz, 2H), 4.34 (t, J=5.36Hz, 2H), 4.96 (br.s., 1H), 5.79 (s, 2H), 7.35 (t, J=7.43Hz, 2H), 7.82 (ddd, J=8.66,6.96,1.69Hz, 2H), 7.97 (d, J= 8.66Hz, 2H), 8.08 (s, 1H), 8.35 (dd, J=7.91,1.51Hz, 2H)；13C NMR(151MHz,DMSO-d6)δ42.0, 52.6,60.1,116.8,121.9,122.1,124.1,127.0,134.6,142.2,142.5,177.0.
Embodiment 8
The preparation of acetyl -2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) ester (L8)
0.12g 10- ((1- (2- ethoxy) -1H-1,2,3- triazole-4-yl) methyl) acridone (L7) is taken to be dissolved in 5ml tetra- In hydrogen furans, addition 0.11g acetic anhydride, back flow reaction 2 hours.It is cooled to room temperature, reaction system is diluted with water, and white wadding is precipitated Shape solid filters dry white solid 80mg.Yield 59.3%.1H NMR(600MHz,DMSO-d6)δ1.85(s,3H), 4.32 (t, J=5.18Hz, 2H), 4.56 (t, J=5.18Hz, 2H), 5.80 (s, 2H), 7.35 (t, J=7.34Hz, 2H), 7.81 (ddd, J=8.61,7.01,1.69Hz, 2H), 7.94 (d, J=8.85Hz, 2H), 8.13 (s, 1H), 8.35 (dd, J= 8.09,1.51Hz,2H)；13C NMR(151MHz,DMSO-d6)δ20.8,42.0,48.9,62.5,116.7,121.9,122.1, 124.3,127.0,134.5,142.2,142.9,170.2,177.0.
Embodiment 9
The preparation of 4- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) ethyl benzoate (L9)
Using ethylaminobenzoate as raw material, 4- triazobenzene Ethyl formate is synthesized according to embodiment 1d step, and press 4- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) ethyl benzoate (L9) is made according to embodiment 1e step Light yellow solid.1H NMR(600MHz,DMSO-d6) δ 1.32 (t, J=7.06Hz, 3H), 4.32 (q, J=7.15Hz, 2H), 5.91 (s, 2H), 7.36 (t, J=7.34Hz, 2H), 7.78-7.86 (m, 2H), 7.94 (d, J=8.66Hz, 2H), 8.01- 8.06 (m, J=8.66Hz, 2H), 8.06-8.12 (m, J=8.85Hz, 2H), 8.37 (dd, J=8.00,1.41Hz, 2H), 8.94(s,1H)；13C NMR(151MHz,DMSO-d6)δ14.5,42.2,61.5,116.7,120.3,122.0,122.1, 122.2,127.0,130.0,131.2,134.7,139.9,142.3,144.7,165.2,177.1.
Embodiment 10
The preparation of 4- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) benzoic acid (L10)
With 4- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yls) ethyl benzoate (L9) for raw material, According to 4- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) benzoic acid (L10) obtained the step of embodiment 5 White powder.1H NMR(600MHz,DMSO-d6) δ 5.90 (s, 2H), 7.35 (t, J=7.43Hz, 2H), 7.82 (td, J= 7.86,1.60Hz, 2H), 7.95 (d, J=8.66Hz, 2H), 7.98-8.03 (m, J=8.85Hz, 2H), 8.04-8.11 (m, J =8.66Hz, 2H), 8.37 (dd, J=7.91,1.51Hz, 2H), 8.98 (s, 1H), 13.24 (br.s., 1H)；13C NMR (151MHz,DMSO-d6)δ42.2,116.7,120.1,121.9,122.2,127.0,131.1,131.4,134.7,139.7, 142.3,144.6,166.7,177.1.
Embodiment 11
The preparation of 4- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) methyl benzoate (L11)
With 4- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yls) ethyl benzoate (L9) for raw material, According to 4- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) methyl benzoate obtained the step of embodiment 6 (L11) white powder.1H NMR(600MHz,DMSO-d6) δ 3.86 (s, 3H), 5.91 (s, 2H), 7.36 (t, J=7.34Hz, 2H), 7.82 (td, J=7.81,1.51Hz, 2H), 7.94 (d, J=8.85Hz, 2H), 8.04 (d, J=8.66Hz, 2H), 8.10 (d, J=8.66Hz, 2H), 8.37 (dd, J=7.91,1.51Hz, 2H), 8.94 (s, 1H)；13C NMR(151MHz,DMSO-d6) δ42.2,52.8,116.7,120.3,122.0,122.1,122.2,127.0,129.8,131.3,134.7,140.0,142.3, 144.7,165.7,177.1.
Embodiment 12
The preparation of 4- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) n-butylbenzoate (L12)
Using p-aminobenzoic acid N-butyl as raw material, 4- triazobenzene n-buty formate is synthesized according to embodiment 1d step, And 4- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) positive fourth of benzoic acid is made according to embodiment 1e step Ester (L12) light yellow solid.1H NMR (600MHz, DMSO-d6) δ 0.92 (t, J=7.43Hz, 3H), 1.41 (dq, J= 14.94,7.44Hz, 2H), 1.64-1.72 (m, 2H), 4.28 (t, J=6.49Hz, 2H), 5.90 (s, 2H), 7.36 (t, J= 7.34Hz, 2H), 7.78-7.85 (m, 2H), 7.94 (d, J=8.66Hz, 2H), 8.00-8.05 (m, J=8.66Hz, 2H), 8.06-8.13 (m, J=8.66Hz, 2H), 8.37 (dd, J=7.91,1.32Hz, 2H), 8.94 (s, 1H)；13C NMR (151MHz,DMSO-d6)δ14.0,19.1,30.6,42.2,65.1,116.7,120.3,121.9,122.1,122.2, 127.0,130.0,131.2,134.7,140.0,142.3,144.7,165.2,177.1.
Embodiment 13
2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) ethyl benzoate (L13)
Using ethyl o-aminobenzoate as raw material, according to 2- (4- ((acridone -10- base) first obtained the step of embodiment 9 Base) -1H-1,2,3- triazol-1-yl) ethyl benzoate (L13) light yellow solid.1H NMR(600MHz,DMSO-d6)δ0.68 (t, J=7.15Hz, 3H), 3.84 (q, J=7.03Hz, 2H), 5.90 (s, 2H), 7.36 (t, J=7.43Hz, 2H), 7.61 (d, J=7.91Hz, 1H), 7.67 (t, J=7.53Hz, 1H), 7.76 (t, J=7.62Hz, 1H), 7.81-7.90 (m, 3H), 8.05 (d, J=8.85Hz, 2H), 8.37 (d, J=7.15Hz, 2H), 8.67 (s, 1H)；13C NMR(151MHz,DMSO-d6)δ13.6, 41.6,61.4,116.8,121.9,122.1,125.4,126.7,127.0,128.0,130.5,130.9,133.2,134.5, 135.4,142.2,143.1,165.6,177.0.
Embodiment 14
The preparation of 2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) benzoic acid (L14)
With 2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yls) ethyl benzoate (L13) for raw material, According to 2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) benzoic acid (L14) obtained the step of embodiment 5 White powder.1H NMR(600MHz,DMSO-d6) δ 5.87 (s, 2H), 7.33-7.39 (m, 2H), 7.55 (dd, J=7.91, 1.13Hz, 1H), 7.65 (td, J=7.58,1.22Hz, 1H), 7.69-7.73 (m, 1H), 7.83 (ddd, J=8.71,6.92, 1.69Hz, 2H), 7.90 (dd, J=7.62,1.41Hz, 1H), 8.01 (d, J=8.66Hz, 2H), 8.36 (dd, J=8.09, 1.69Hz,2H),8.64(s,1H),13.12(br.s.,1H)；13C NMR(151MHz,DMSO-d6)δ42.0,116.9, 121.9,122.1,125.6,127.0,128.8,130.4,130.8,132.8,134.6,135.6,142.3,142.9, 166.8,177.1
Embodiment 15
The preparation of 2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) methyl benzoate (L15)
With 2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yls) ethyl benzoate (13) for raw material, According to 2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) methyl benzoate obtained the step of embodiment 6 (L15) white powder.1H NMR(600MHz,DMSO-d6) δ 3.42 (s, 3H), 5.90 (s, 2H), 7.36 (t, J=7.43Hz, 2H), 7.62 (d, J=7.91Hz, 1H), 7.67 (t, J=7.43Hz, 1H), 7.75 (t, J=7.43Hz, 1H), 7.84 (t, J= 7.34Hz, 2H), 7.89 (d, J=7.34Hz, 1H), 8.00 (d, J=8.85Hz, 2H), 8.37 (dt, J=7.95,0.92Hz, 2H),8.62(s,1H)；13C NMR(151MHz,DMSO-d6)δ41.9,52.6,116.8,121.9,122.2,125.4, 126.8,127.0,127.4,130.4,130.9,133.3,134.6,135.5,142.3,143.2,165.9,177.1
Embodiment 16
The preparation of 2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) n-butylbenzoate (L16)
Using Concentrated sulfuric acid as raw material, adjacent triazobenzene n-buty formate is synthesized according to embodiment 1d step, And 2- (4- ((acridone -10- base) methyl) -1H-1,2,3- triazol-1-yl) positive fourth of benzoic acid is made according to embodiment 1e step Ester (L16) light yellow solid.1H NMR(600MHz,DMSO-d6) δ 0.57 (t, J=7.43Hz, 3H), 0.89 (dq, J= 14.92,7.39Hz, 2H), 0.99-1.08 (m, 2H), 3.78 (t, J=6.78Hz, 2H), 5.87 (s, 2H), 7.36 (t, J= 7.25Hz, 2H), 7.60-7.63 (m, 1H), 7.67 (td, J=7.62,1.13Hz, 1H), 7.74-7.78 (m, 1H), 7.84 (ddd, J=8.71,6.92,1.69Hz, 2H), 7.87 (dd, J=7.72,1.32Hz, 1H), 8.06 (d, J=8.85Hz, 2H), 8.37 (dd, J=8.00,1.60Hz, 2H), 8.72 (s, 1H)；13C NMR(151MHz,DMSO-d6)δ13.6,18.5,29.9, 41.7,65.1,116.8,121.9,122.2,125.4,126.7,127.0,127.9,130.5,130.9,133.2,134.5, 135.3,142.2,143.1,165.7,177.0.
Two inhibit tumor proliferation experiment
Cytostatic to tumor cell experiment is carried out to the compound of the present invention, test method is using conventional mtt assay.
The culture of tumour cell:
Cell strain selects BGC-823 (gastric carcinoma cells), MGC-803 (gastric carcinoma cells), K562 (human leukemia cell) With HL60 (human leukemia cell), with RPMI 1640+15%NBS+ dual anti-(100 units of penicillin/ml, 100 μ g/ of streptomysin Ml culture solution culture).
Sample preparation:
After DMSO (Merck) dissolution, solution or uniform suspension that PBS (-) is made into 1000 μ g/ml is added, then With PBS (-) dilution containing DMSO.Ultimate density is respectively as follows: 100 μ g/mL, 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/ mL,0.001μg/mL.Using Etoposide (Etoposide) as control.
The test method of cell inhibitory effect:
It is 4~5 × 10 that concentration, which is added, in the every hole of 96 orifice plates4The 100 μ l of cell suspension of a/ml, sets 37 DEG C, 5%CO2Incubator It is interior.After 24 hours, it is separately added into sample liquid and reference substance liquid, 10 holes μ l/, if duplicate hole, 37 DEG C, 5%CO2Effect 72 hours. The 20 μ l of MTT (3- (4,5- dimethylthiazole -2- base) -2,5- diphenyltetrazoliumbromide father-in-law bromide) solution of 5mg/ml is added in every hole, Lysate DMSO is added after effect 4 hours, 100 holes μ l/ are set in incubator, survey 570nm with the full-automatic microplate reader of MK-2 after dissolution OD value calculates this number inhibition concentration IC50。
Experimental result:
In-vitro multiplication inhibitory activity IC50 value of the sample to human body tumour cell
The above experimental data shows that the compound in the present invention has certain anti-tumor activity, thus is further investigation New approach is opened with the anti-tumor drug for developing new.

Claims (3)

1. an anti-tumor compounds, it is characterised in that: the structural formula of the compound is following general formula:
Wherein:
R2For acetyl group, propiono, benzoyl and 1-5 carbon atom alkyl, X CH2Or carbonyl.
2. a kind of preparation method of an anti-tumor compounds as described in claim 1, it is characterised in that: the system of the compound It is standby to sequentially include the following steps:
(1) synthesis of intermediate 3- propargyl acridone:
(2) α-azide substitution class intermediate synthesis
(3) synthesis of target compound
3. the purposes that a kind of compound as described in claim 1 prepares anti-tumor drug.
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