CN102134220A - 9-amsacrine derivatives as well as preparation method and application thereof - Google Patents

9-amsacrine derivatives as well as preparation method and application thereof Download PDF

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CN102134220A
CN102134220A CN 201110020165 CN201110020165A CN102134220A CN 102134220 A CN102134220 A CN 102134220A CN 201110020165 CN201110020165 CN 201110020165 CN 201110020165 A CN201110020165 A CN 201110020165A CN 102134220 A CN102134220 A CN 102134220A
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蒋宇扬
栾旭东
高春梅
谭春燕
刘红霞
金一宝
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Shenzhen Graduate School Tsinghua University
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Shenzhen Graduate School Tsinghua University
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Abstract

The invention discloses 9-amsacrine derivatives as well as a preparation method and application thereof and particularly discloses acridine derivatives with multi-target protein kinase inhibition activity as well as a preparation method and application thereof. The structural formula of the acridine derivatives is shown in a formula I, wherein X1-X3 are C, or one of X1-X3 is N, and the other two of X1-X3 are C; R1-R5 are selected from the following substituted groups: H, OH, OCH3, OC2H5, F, Cl, Br, CH3, CF3, OCF3, NH2, COOH and NHCOCH3; R6-R13 are selected from the following substituted groups: H, F, Cl, Br, OCH3, COOH, CH3, NO2, NHCOCH3 and CF3; R7 and R11 are preferably selected from Cl and OCH3; and Z is selected from NH and NHCH2. An in vitro cell proliferation experiment indicates that the compound shown in the formula I can well inhibit the proliferation of leukemia cell K562. An in vitro protein kinase inhibition experiment shows that the compound shown in the formula I is a multiple target protein kinase inhibitor. The formula I is shown in the specification.

Description

9-anilino acridine derivatives and preparation method thereof and application
Technical field
The present invention relates to a kind of 9-anilino acridine derivatives and preparation method thereof and application.
Background technology
Malignant tumour is the common frdquently encountered disease of a class serious threat human life health, the first place that the human mortality ratio that causes because of malignant tumour has leapt to all disease death rates, and therefore, the research of its control is very urgent.Because the effect of cancer drug is the general performance of medicine and body interaction process, many factors are this process of possibility interfere with or compromise all, makes curative effect of medication weaken, and produces toxic side effect and resistance.The toxic side effect that the medicine that designs based on single target spot causes the effect of missing the target to bring easily, and the drug effect that the mutual compensation of network causes reduces.Therefore the research and development of many target spots antitumor drug might destroy the inherent basis of tumor growth, and the healing of tumour is become a reality.Protein tyrosine kinase plays an important role in malignant transformation of cells, the kinases inhibitor listing of FDA approval has been arranged at present, but found that clinically its antitumous effect is not fine, and may cause resistance.One of them very important reasons be since signal transduction be the network system of a complexity, may there be multiple contact between the signal of upstream and downstream, single inhibitor can not reach the effect that suppresses tumour fully, and therefore the design and the research and development of many target spots tyrosine kinase inhibitor have great importance.
The acridine compound has had bibliographical information as antitumor drug, but it also rarely has bibliographical information as kinases inhibitor.The objective of the invention is to design a series of acridine compounds, and study its anti-tumor activity with many target point proteins kinase inhibiting activity.
Summary of the invention
The purpose of this invention is to provide a class and have acridine compound of many target point proteins kinase inhibiting activity and preparation method thereof.
Acridine compound provided by the present invention, its structural formula is suc as formula shown in the I.
Wherein, Z is NH or NHCH 2
R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13All be selected from the following radicals any one: H, F, Cl, Br, OCH 3, COOH, CH 3, NO 2, NHCOCH 3And CF 3Described R 7Be preferably OCH 3, R 11Be preferably Cl.
X 1, X 2, X 3And R 1, R 2, R 3, R 4, R 5The group of representative is divided into following four kinds of situations:
A) work as X 1, X 2, X 3When being C, R 1, R 2, R 3, R 4, R 5All be selected from the following radicals any one: H, OH, OCH 3, OC 2H 5, F, Cl, Br, CH 3, CF 3, OCF 3, NH 2, COOH and NHCOCH 3
B) work as X 1Be N, X 2, X 3When being C, R 1Substituting group does not exist, R 2, R 3, R 4, R 5All be selected from the following radicals any one: H, OH, OCH 3, OC 2H 5, F, Cl, Br, CH 3, CF 3, OCF 3, NH 2, COOH and NHCOCH 3
C) work as X 2During for N, X 1, X 3When being C, R 1, R 3, R 4, R 5All be selected from the following radicals any one: H, OH, OCH 3, OC 2H 5, F, Cl, Br, CH 3, CF 3, OCF 3, NH 2, COOH and NHCOCH 3, R 2Substituting group does not exist;
D) work as X 3During for N, X 1, X 2When being C, R 1, R 2, R 4, R 5All be selected from the following radicals any one: H, OH, OCH 3, OC 2H 5, F, Cl, Br, CH 3, CF 3, OCF 3, NH 2, COOH and NHCOCH 3, R 3Substituting group does not exist.
Figure BDA0000044214210000021
(formula I)
The method of compound shown in the preparation formula I comprises the steps:
1) with copper be catalyzer, salt of wormwood as alkali, make that compound reacts shown in compound shown in the formula II and the formula III, obtain compound shown in the formula IV;
Figure BDA0000044214210000022
Formula II formula III formula IV
Wherein, the R among formula II and the formula IV 10, R 11, R 12, R 13I is identical with formula,
R in the formula among III and the formula IV 6, R 7, R 8, R 9I is identical with formula;
2) compound shown in the formula IV and anhydrous phosphorus oxychloride are reacted, obtain compound shown in the formula V;
3) when the substituting group of compound shown in the formula VI as A) as described in the time: aniline compound shown in compound shown in the formula V and the formula VI joined in chloroform and the alcohol mixed solution reacts, add concentrated hydrochloric acid (massfraction 36%-38%) catalyzed reaction, stirring at room 10-12 hour, obtain compound shown in the formula I;
Substituting group such as B when compound shown in the formula VI); C); when D) described: under argon shield; compound shown in the formula VI, sodium hydride are joined in the dry dimethyl formamide; after stirring at room 1-1.5 hour; compound and potassiumiodide shown in the adding formula V stirring at room 11-13 hour, obtain compound shown in the formula I.
Figure BDA0000044214210000031
Formula V formula VI
Wherein, reaction can be carried out in anhydrous dimethyl formamide (DMF) described in the step 1); The mol ratio of compound shown in compound shown in the formula II of initial adding and the formula III is 1.5: 1 in the described reaction system, and the temperature of reaction of described reaction can be 130-135 ℃, and the reaction times can be 11-13 hour.
Step 2) temperature of reaction of reaction can be 135-140 ℃ described in, and the reaction times can be 3-4 hour; Chloroform and alcoholic acid volume ratio are 4: 1 to 5: 1 in chloroform described in the step 3) and the alcohol mixed solution.
The compound process high resolution mass spectrum of the present invention's preparation, nucleus magnetic resonance, tests such as fusing point prove that prepared compound is correct, are compound shown in the general formula I.
The pharmacy acceptable salt of compound shown in the formula I, ester or its solvate also belong to protection scope of the present invention.
A further object of the present invention provides application of compound shown in the formula I.
Formula I compound of the present invention or its pharmacy acceptable salt, ester, solvate can be used for preparing VEGFR-2, SRC, EGFR, CDK, PI3K, ABL, AKT, PKA, PKC, kinases inhibitors such as PDGFR.
Formula I compound of the present invention or its pharmacy acceptable salt, ester, solvate can be used for preparing eukaryote tumour cell increment inhibitor.
Described eukaryote is a Mammals; Described tumour cell is a cancer cells; Described cancer cells is leukaemia cancer cell, breast cancer cell or liver cancer cell; The described leukaemia cancer cell former leukemia cell K562 of chronic marrow that specifically can behave, described breast cancer cell is that human breast cancer cell MCF-7, described liver cancer cell are human liver cancer cell HepG-2.
Formula I compound of the present invention or its pharmacy acceptable salt, ester, solvate also can be used for preparing the tumour medicine that prevents and/or treats.
Described tumour is a cancer; Described cancer is leukemia, mammary cancer, liver cancer.
With the compound shown in the formula I or its pharmacy acceptable salt, ester, solvate is the medicine that prevents and/or treats tumour of effective constituent preparation, also belongs to protection scope of the present invention.
The described tumour medicine that prevents and/or treats can import body such as muscle, intracutaneous, subcutaneous, vein, mucosal tissue by the method for injection, injection, collunarium, eye drip, infiltration, absorption, physics or chemistry mediation; Or mixed by other materials or wrap up the back and import body.
When needing, in said medicine, can also add one or more pharmaceutically acceptable carriers.Described carrier comprises thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant of pharmaceutical field routine etc.
Preventing and/or treating tumour medicine and can make various ways such as injection liquid, tablet, pulvis, granule, capsule, oral liquid, paste, creme with formula I compound or its pharmacy acceptable salt, ester, solvate preparation.The medicine of above-mentioned various formulations all can be according to the ordinary method preparation of pharmaceutical field.
Compound provided by the invention is through kinds of tumor cells system's test (comprising liver cancer cell, breast cancer cell, leukemia cell etc.) and multiple protein kinases test (VEGFR-2, SRC, EGFR, CDK, PI3K, ABL, AKT, PKA, PKC, PDGFR etc.), prove that compound shown in the formula I is the antitumor drug that a kind of potential is a target spot with two kinds of protein kinases.Raw materials of compound provided by the invention is easy to get, and the preparation method is simple, experimental results show that it has good anticancer effect, in antitumor drug design research and development field good prospects for application is arranged.
Embodiment
The present invention will be described below by specific embodiment, but the present invention is not limited thereto.
Experimental technique described in the following embodiment if no special instructions, is ordinary method; Described reagent and biomaterial if no special instructions, all obtain from commercial channels.
Embodiment 1, preparation 4-chloro-2 (4-methoxyl group amino) phenylformic acid (among the formula IV, R 7=OCH 3, R 11=Cl, all the other substituting groups are H)
Dimethyl formamide (DMF) add in (50.00ml) 2,4 dichloro benzene formic acid (2.00g, 10.47mmol), the 4-anisidine (0.86g, 6.99mmol), salt of wormwood (2.00g, 14.49mmol) and copper powder (0.20g, 3.15mmol).Under 130 ℃, stir and spend the night.Join in the 200ml water after the reaction mixture cooling, transfer to the pH value with acetic acid and be about 3.Use ethyl acetate extraction, separate with column chromatography chromatogram behind the organic phase evaporate to dryness, obtain yellow solid 1.24g.Productive rate 63.9%; Fusing point 198-201 ℃.
Compound structure conclusive evidence data are:
1H?NMR(400MHz，CDCl 3)δ9.16(s，1H)，δ7.93(d，J＝8.6Hz，1H)，δ7.17(d，J＝8.7Hz，2H)，δ6.95(d，J＝8.8Hz，2H)，δ6.87(d，J＝1.8Hz，1H)，δ6.64(dd，J＝8.6，1.7Hz，1H)，δ3.84(s，3H)； 13C?NMR(100.6MHz，CDCl 3)δ172.79，157.64，151.44，141.89，133.83，132.06，126.86，116.76，115.02，113.01，107.75，55.56.
Embodiment 2, preparation 6, and 9-two chloro-2-methoxyl group acridines (among the formula V, R 7=OCH 3, R 11=Cl, all the other substituting groups are H)
(2.00g 7.19mmol), joins in the anhydrous phosphorus oxychloride (25.00ml), and 140 ℃ were refluxed 3 hours with 2-chloro-2 (4-methoxyl group amino) phenylformic acid.Slowly join frozen water after the reaction solution cooling, ammoniacal liquor is in the mixed solution of chloroform (volume ratio is 1: 1: 1).Tell chloroform, use chloroform extraction again, merge all chloroform extraction liquid, evaporate to dryness, drying.Obtain yellow solid 1.98g.Productive rate 99%; Fusing point 160-163 ℃.
Compound structure conclusive evidence data are:
1H?NMR(400MHz，CDCl 3)δ8.34(d，J＝9.2Hz，1H)，δ8.20(d，J＝1.9Hz，1H)，δ8.09(d，J＝10.2Hz，1H)，δ7.56(dd，J＝9.2，2.0Hz，1H)，δ7.54-7.48(m，2H)，δ4.04(s，3H)。
The preparation of embodiment 3,6-chloro-2-methoxyl group-9-anilino-acridine
With 6, (50.00mg 0.18mmol) joins among mixed solution (volume ratio 4/1) 50.00ml of ethanol/chloroform with amino benzenes compounds (0.97mmol) 9-two chloro-2-methoxyl group acridines, splashes into several concentrated hydrochloric acid catalyzed reactions, stirred overnight at room temperature.The evaporate to dryness reaction solution, the solid that obtains washes twice with 20.00ml ethanol, and drying obtains required compound.
1) 6-chloro-2-methoxyl group-9-(3-glycyl) anilino-acridine (among the formula I, X 1, X 2, X 3Be C, R 2=NHCOCH 3, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 67%; Fusing point 161-163 ℃; High resolution mass spectrum (ESI) calculated value [C 22H 18ClN 3O 2+ H] +Be 392.1166, experimental value is 392.1162
Gained compound spectral data is: 1H NMR (400MHz, DMSO) δ 10.18 (s, 1H), δ 8.12-7.86 (m, 3H), δ 7.72-7.50 (m, 3H), δ 7.48-7.20 (m, 3H), δ 6.91-6.75 (m, 1H), δ 3.73 (s, 3H), δ 2.04 (s, 3H); 13C NMR (100.6MHz, DMSO) δ 169.08,156.12, and 151.21,143.74,141.93,141.23,138.02,130.34,128.24,127.70,124.39,120.16,117.47,116.36,114.15,113.28,103.89,56.12,24.52.
2) 6-chloro-2-methoxyl group-9-(3-hydroxyl-4-carboxyl) anilino-acridine (among the formula I, X 1, X 2, X 3Be C, R 2=OH, R 3=COOH, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 75%; Fusing point＞300 ℃; High resolution mass spectrum (ESI): calculated value is [C 21H 15ClN 2O 4+ H] +395.0799; Experimental value is 395.0793
The spectral data of gained compound is: 1H NMR (400MHz, DMSO) δ 11.47 (s, 1H), δ 8.24 (s, 1H), δ 8.16 (d, J=9.3Hz, 1H), δ 8.06 (d, J=9.3Hz, 1H), and δ 7.83 (s, 1H), δ 7.78 (t, J=8.0Hz, 2H), δ 7.51 (d, J=9.1Hz, 1H), and δ 6.93 (s, 1H), δ 6.82 (d, J=8.3Hz, 1H), δ 3.83 (s, 3H); 13C NMR (100.6MHz, DMSO) δ 171.83,162.71, and 156.90,152.32,148.76,140.36,139.45,137.14,132.08,129.63,128.47,125.57,122.11,119.07,118.25,114.62,113.61,110.20,110.03,103.69,56.56.
3) 6-chloro-2-methoxyl group-9-(4-methoxyl group) anilino-acridine (among the formula I, X 1, X 2, X 3Be C, R 3=OCH 3, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 64%; Fusing point＞300 ℃; High resolution mass spectrum (ESI): calculated value is [C 21H 17ClN 2O 2+ H] +365.1057; Experimental value is 365.1050
The spectral data of gained compound is: 1H NMR (400MHz, DMSO) δ 14.61 (s, 1H), δ 11.33 (s, 1H), δ 7.98-8.03 (m, 3H), δ 7.73 (d, J=7.8Hz, 2H), δ 7.40-7.45 (m, 3H), δ 7.12 (d, J=8.7Hz, 2H), δ 3.83 (s, 3H), δ 3.74 (s, 3H). 13(100.6MHz, DMSO) δ 158.39,155.51,153.41,139.75,138.63,135.57,133.17,128.00,127.70,126.35,123.66,120.82,117.71,115.07,114.66,111.28,103.58,55.70,55.47. for C NMR
4) 6-chloro-2-methoxyl group-9-(3-methoxyl group) anilino-acridine (among the formula I, X 1, X 2, X 3Be C, R 2=OCH 3, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 71%; Fusing point 280-282 ℃; High resolution mass spectrum (ESI): calculated value r[C 21H 17ClN 2O 2+ H] +365.1057; Experimental value: 365.1053
The spectral data of gained compound is: 1H NMR (400MHz, DMSO) δ 11.38 (s, 1H), δ 8.12 (s, J=12.4Hz, 1H), δ 8.06 (d, J=9.0Hz, 2H), and δ 7.75 (d, J=7.0Hz, 2H), δ 7.44 (dd, J=16.6,8.6Hz, 2H), δ 7.06 (s, 1H), δ 6.99 (d, J=8.0Hz, 2H), and δ 3.75 (m, J=7.1Hz, 6H); 13CNMR (101MHz, DMSO) δ 160.31,155.73, and 153.23,141.95,139.73,138.83,135.83,130.67,128.47,127.82,124.06,121.06,117.92,116.40,115.40,112.88,112.00,110.07,103,35,55,71,55.40.
5) 6-chloro-2-methoxyl group-9-(2-methoxyl group) anilino-acridine (among the formula I, X 1, X 2, X 3Be C, R 1=OCH 3, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 82%; Fusing point 279-281 ℃; High resolution mass spectrum (ESI): calculated value [C 21H 17ClN 2O 2+ H] +365.1057; Experimental value: 365.1045;
The spectral data of gained compound is: 1H NMR (400MHz, DMSO) δ 14.88 (s, 1H), δ 11.18 (s, 1H), δ 8.10 (d, J=2.1Hz, 1H), δ 8.08 (d, J=9.6Hz, 1H), and δ 8.03 (d, J=9.3Hz, 1H), δ 7.73 (dd, J=9.3,2.6Hz, 1H), δ 7.69 (d, J=2.3Hz, 1H), δ 7.55 (dd, J=7.7,1.5Hz, 1H), and δ 7.53-7.46 (m, 1H), δ 7.43 (dd, J=9.4,2.1Hz, 1H), δ 7.26 (dd, J=8.4,0.9Hz, 1H), δ 7.18 (td, J=7.6,1.1Hz, 1H), δ 3.69 (s, 3H), δ 3.58 (s, 3H); 13C NMR (100.6MHz, DMSO) δ 155.66,153.96, and 153.37,139.30,138.86,135.38,129.50,128.54,128.22,126.94,126.72,124.05,121.42,120.93,117.79,114.52,112.88,111.62,102.82,55.68,55.55.
6) 6-chloro-9-(2-oxyethyl group) anilino-2-methoxyl group-acridine (among the formula I, X 1, X 2, X 3Be C, R 1=OC 2H 5, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 68%; Fusing point 193-195 ℃; High resolution mass spectrum (ESI): calculated value [C 22H 19ClN 2O 2+ H] +379.1213; Experimental value: 379.1213.
The spectral data of gained compound is: 1H NMR (400MHz, DMSO) δ 8.13 (d, J=9.4Hz, 1H), δ 7.99 (s, 1H), δ 7.95 (d, J=9.3Hz, 1H), δ 7.75 (dd, J=9.3,2.3Hz, 1H), and δ 7.67 (s, 1H), δ 7.61 (d, J=6.9Hz, 1H), δ 7.51-7.42 (m, 2H), δ 7.29-7.12 (m, 2H), and δ 3.79 (dd, J=13.6,6.7Hz, 2H), δ 3.68 (s, 2H), δ 0.68 (t, J=6.9Hz, 2H).
7) 6-chloro-9-(4-oxyethyl group) anilino-2-methoxyl group-acridine (among the formula I, X 1, X 2, X 3Be C, R 3=OC 2H 5, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 74%; Fusing point 280-281 ℃; High resolution mass spectrum (ESI): calculated value [C 22H 19ClN 2O 2+ H] +379.1213; Experimental value: 379.1202;
The spectral data of gained compound is: 1H NMR (400MHz, DMSO) δ 8.05 (d, J=1.9Hz, 1H), δ 8.01 (t, J=9.4Hz, 2H), δ 7.72 (d, J=7.5Hz, 2H), δ 7.42 (dd, J=9.4,2.0Hz, 1H), δ 7.38 (d, J=8.8Hz, 2H), δ 7.09 (d, J=8.9Hz, 2H), δ 4.09 (q, J=6.9Hz, 2H), δ 3.74 (s, 3H), and δ 1.36 (t, J=6.9Hz, 3H); 13C NMR (100.6MHz, DMSO) δ 157.49,155.45, and 153.07,139.91,138.43,135.77,133.29,127.80,127.68,126.13,123.58,120.99,117.88,115.51,114.77,111.42,103.57,63.42,55.67,14.48.
8) 6-chloro-2-methoxyl group-9-(3,4, the 5-trimethoxy) anilino-acridine (among the formula I, X 1, X 2, X 3Be C, R 2, R 3, R 4Be OCH 3, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 80%; Fusing point 251-253 ℃; High resolution mass spectrum (ESI): calculated value [C 23H 21ClN 2O 4+ H] +426.1268; Laboratory: 425.1267
The spectral data of gained compound is: 1H NMR (400MHz, DMSO) δ 15.05 (s, 1H), δ 11.38 (s, 1H), and δ 8.12 (s, 1H), δ 8.07 (t, J=9.6Hz, 2H), δ 7.74 (d, J=9.2Hz, 2H), and δ 7.47 (d, J=9.4Hz, 1H), δ 6.85 (s, 2H), δ 3.77 (s, 3H), δ 3.72 (s, 3H), δ 3.71 (s, 6H); 13C NMR (100.6MHz, DMSO) δ 155.56,153.62, and 153.18,139.64,138.65,136.62,136.36,135.69,128.19,127.80,123.80,120.78,117.70,115.04,111.75,103.48,102.77,60.18,56.23,55.73,40.13,39.92,39.71,39.50,39.29,39.08,38.88.
9) 6-chloro-2-methoxyl group-9-(3-hydroxyl) anilino-acridine (among the formula I, X 1, X 2, X 3Be C, R 2=OH, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 71%; Fusing point＞300 ℃; High resolution mass spectrum (ESI): calculated value [C 20H 15ClN 2O 2+ H] +351.0900; Experimental value: 351.0896;
The spectral data of gained compound is: 1H NMR (400MHz, DMSO) δ 14.70 (s, 1H), δ 11.25 (s, 1H), δ 9.95 (s, 1H), δ 8.09 (d, J=9.4Hz, 1H), δ 8.05 (d, J=1.7Hz, 1H), δ 8.00 (d, J=9.3Hz, 1H), and δ 7.74 (d, J=8.4Hz, 2H), δ 7.47 (dd, J=9.4,1.9Hz, 1H), δ 7.31 (t, J=8.1Hz, 1H), δ 6.90-6.68 (m, 3H), δ 3.75 (s, 3H).
10) 6-chloro-2-methoxyl group-9-(2-hydroxyl) anilino-acridine (among the formula I, X 1, X 2, X 3Be C, R 1=OH, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 56%; Fusing point＞300 ℃; High resolution mass spectrum (ESI): calculated value [C 21H 15ClN 2O 2+ H] +351.0900; Experimental value; 351.0905;
The spectral data of gained compound is: 1H NMR (400MHz, DMSO) δ 14.76 (s, 1H), δ 11.17 (s, 1H), δ 10.19 (s, 1H), and δ 8.13 (d, J=9.2Hz, 1H), δ 8.07 (d, J=2.1Hz, 1H), and δ 8.01 (d, J=9.2Hz, 1H), δ 7.75 (s, 1H), δ 7.72 (dd, J=9.2,2.5Hz, 1H), δ 7.46 (ddd, J=11.5,8.6,1.8Hz, 2H), δ 7.38-7.28 (m, 1H), δ 7.05 (ddd, J=15.3,7.9,1.1Hz, 2H), δ 3.70 (s, 3H); 13C NMR (100.6MHz, DMSO) δ 156.13,154.71, and 152.44,139.85,139.40,135.81,129.96,128.66,127.73,127.67,127.46,124.48,121.36,120.61,118.21,117.39,115.02,112.14,103.52,56.09
11) 6-chloro-2-methoxyl group-9-(4-amino) anilino-acridine (among the formula I, X 1, X 2, X 3Be C, R 3=NH 2, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 63%; Fusing point＞300 ℃; High resolution mass spectrum (ESI): calculated value [C 20H 16ClN 3O+H] +350.1060; Experimental value: 350.1052;
The spectral data of gained compound is: 1H NMR (400MHz, DMSO) δ 8.04 (s, 2H), δ 7.97 (d, J=9.2Hz, 1H), δ 7.72 (s, 1H), δ 7.65 (d, J=8.8Hz, 1H), δ 7.36 (d, J=7.7Hz, 1H), δ 7.11 (d, J=8.1Hz, 2H), δ 6.71 (d, J=8.2Hz, 2H), δ 3.75 (s, 3H); 13(100.6MHz, DMSO) δ 155.31,153.20,148.36,139.93,138.52,135.42,127.68,127.59,125.99,123.35,120.83,117.72,114.50,111.17,103.72,55.59. for C NMR
12) 6-chloro-2-methoxyl group-9-(4-methyl) anilino-acridine (among the formula I, X 1, X 2, X 3Be C, R 3=CH 3, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 71%; Fusing point＞300 ℃; High resolution mass spectrum (ESI): calculated value [C 21H 17ClN 2O+H] +349.1108; Experimental value: 349.1105.
The spectral data of gained compound is: 1H NMR (400MHz, DMSO) δ 8.09-7.96 (m, 3H), δ 7.73 (dd, J=9.2,2.5Hz, 1H), δ 7.69 (s, 1H), δ 7.44 (dd, J=9.4,2.1Hz, 1H), δ 7.33 (q, J=8.5Hz, 4H), δ 3.72 (s, 3H), δ 2.38 (s, 3H); 13(100.6MHz, DMSO) δ 155.39,151.38,140.92,139.68,137.64,137.24,135.25,130.09,127.60,127.18,123.59,123.04,122.21,119.07,115.97,112.83,103.45,55.53,20.51. for C NMR
13) 6-chloro-2-methoxyl group-9-(4-trifluoromethyl) anilino-acridine (among the formula I, X 1, X 2, X 3Be C, R 3=CF 3, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 66%; Fusing point 287-289 ℃; High resolution mass spectrum (ESI): calculated value [C 21H 14ClF 3N 2O+H] +403.0825; Experimental value: 403.0817
The spectral data of gained compound is: 1H NMR (400MHz, DMSO) δ 11.36 (s, 1H), δ 8.19 (s, 1H), δ 8.11 (d, J=9.4Hz, 2H), and δ 7.75-7.85 (m, 3H), δ 7.69 (s, 1H), δ 7.55 (d, J=8.9Hz, 1H), δ 7.45-7.53 (m, 2H), δ 3.76 (s, 3H).
14) 6-chloro-2-methoxyl group-9-(4-trifluoromethoxy) anilino-acridine (among the formula I, X 1, X 2, X 3Be C, R 3=OCF 3, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 66% fusing point 288-290 ℃ high resolution mass spectrum (ESI): calculated value [C 21H 14ClF 3N 2O 2+ H] +419.0774; Experimental value: 419.0772;
The spectral data of gained compound is: 1H NMR (400MHz, DMSO) δ 8.09 (d, J=9.1Hz, 1H), δ 8.01 (s, 1H), δ 7.94 (d, J=9.1Hz, 1H), δ 7.57 (d, J=8.1Hz, 1H), δ 7.35-7.45 (m, 4H), δ 7.25 (d, J=7.9Hz, 2H), δ 3.66 (s, 3H). 13C NMR (100.6MHz, DMSO) δ 155.36,149.63, and 144.33,141.82,138.81,137.01,127.44,126.71,124.01,123.91,123.49,122.53,122.33,121.37,120.21,118.83,117.33,116.29,114.93,103.42,55.23.
15) 6-chloro-2-methoxyl group-9-(2-fluorine) anilino-acridine (among the formula I, X 1, X 2, X 3Be C, R 1=F, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 69%; Fusing point 280-282 ℃; High resolution mass spectrum (ESI): calculated value [C 20H 14ClFN 2O+H] +353.0857; Experimental value: 353.0847;
The spectral data of gained compound is: 1H NMR (400MHz, DMSO) δ 15.16 (s, 1H), δ 11.33 (s, 1H), δ 8.15 (s, 1H), δ 8.13-8.04 (m, 2H), δ 7.76 (d, J=9.3Hz, 1H), δ 7.71 (s, 1H), δ 7.65 (t, J=7.5Hz, 1H), δ 7.50 (d, J=9.4Hz, 2H), δ 7.43 (dd, J=14.4,7.1Hz, 2H), and δ 3.72 (s, 3H); 13C NMR (100.6MHz, DMSO) δ 157.45,156.55, and 154.98,154.08,139.94,139.56,136.30,129.81,129.74,129.20,128.03,127.28,126.40,126.37,125.22,121.68,118.58,117.53,117.33,115.75,112.64,103.31,56.30.
16) 6-chloro-2-methoxyl group-9-(2-chlorine) anilino-acridine (among the formula I, X 1, X 2, X 3Be C, R 1=Cl, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 62%; Fusing point 287-289 ℃; High resolution mass spectrum (ESI): calculated value [C 20H 14Cl 2N 2O+H] +369.0561; Experimental value: 369.0550
The spectral data of gained compound is: 1H NMR (400MHz, DMSO) δ 15.15 (s, 1H), δ 11.44 (s, 1H), δ 8.12 (d, J=14.4Hz, 1H), δ 8.07 (d, J=8.8Hz, 1H), δ 8.00 (d, J=9.3Hz, 1H), and δ 7.74 (d, J=8.0Hz, 2H), δ 7.67 (dd, J=6.4Hz 1H), and δ 7.56-7.60 (m, 2H), δ 7.46-7.54 (m, 2H), δ 3.65 (s, 3H); 13(100.6MHz, DMSO) δ 155.60,153.00,139.42,138.59,135.50,130.51,128.87,128.74,127.68,127.52,126.83,124.11,120.78,117.68,115.14,112.27,103.18,55.55. for C NMR
The preparation of embodiment 4,6-chloro-2-methoxyl group-9-pyridine amido-acridine
Under the dry argon gas protection, with aminopyridines (0.94mmol), sodium hydride (2.34mmol) joins among the exsiccant DMF (15.00ml), stirs after 1 hour under the room temperature.Add 6 again, 9-two chloro-2-methoxyl group acridines (0.18mmol), potassiumiodide (0.25mmol), stirred overnight at room temperature, whole process argon shield.Reaction solution is poured in 50 ml waters, uses ethyl acetate extraction, the evaporate to dryness organic phase is separated with column chromatography chromatogram, obtains final product.
1) 6-chloro-2-methoxyl group-9-(4-pyridine) amido-acridine (among the formula I, X 1, X 2Be C, X 3Be N, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 56%; Fusing point＞300 ℃ high resolution mass spectrums (ESI): calculated value [C 19H 14ClN 3O+H] +336.0904; Experimental value: 336.0904;
Gained compound spectral data is: 1H NMR (400MHz, DMSO) δ 9.65 (s, 1H), δ 8.36-7.82 (m, 5H), δ 7.55 (s, 2H), δ 7.27 (s, 1H), δ 6.62 (s, 2H), δ 3.78 (s, 3H).
2) 6-chloro-2-methoxyl group-9-(2-amino-3-pyridine) amido-acridine (among the formula I, X 1, X 3Be C, X 2Be N, R 1=NH 2, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
159-161 ℃ of productive rate 60.4%. fusing point; High resolution mass spectrum (ESI): calculated value [C 19H 15ClN 4O+H] +351.1013; Experimental value: 351.1016
Gained compound spectral data is: 1H NMR (400MHz, DMSO) δ 7.96 (s, 1H), δ 7.68 (d, J=4.0Hz, 1H), δ 7.60-7.16 (m, 4H), δ 7.06 (s, 1H), δ 6.68 (d, J=7.1Hz, 1H), δ 6.59-6.32 (m, 1H), δ 5.65 (s, 2H), δ 3.59 (s, 3H). 13(100.6MHz, DMSO) δ 171.90,170.21,153.80,151.48,150.26,142.12,140.91,135.07,134.50,131.95,128.30,123.55,122.34,120.87,119.86,118.09,112.59,106.16,54.92. for C NMR
3) 6-chloro-2-methoxyl group-9-(2-pyridine-3-amino) amido-acridine (among the formula I, X 1Be N, X 2, X 3Be C, R 2=NH 2, R 7=OCH 3, R 11=Cl, Z are NH, and all the other substituting groups are H)
Productive rate 68%; Fusing point 224-226 ℃; High resolution mass spectrum (ESI): calculated value [C 19H 15ClN 4O+H] +351.1013; Experimental value: 351.1012
Gained compound spectral data is: 1H NMR (400MHz, DMSO) δ 8.11-7.84 (m, 3H), δ 7.48 (d, J=9.0Hz, 1H), δ 7.40 (s, 2H), δ 7.25 (t, J=7.7Hz, 1H), δ 5.94 (t, J=10.8Hz, 1H), δ 5.85 (dd, J=31.1,7.9Hz, 1H), δ 5.63 (s, 2H), δ 3.81 (s, 3H).
4) 6-chloro-2-methoxyl group-9-(2-methoxyl group) benzamido group-acridine (among the formula I, X 1, X 2, X 3Be C, R 1=OCH 3, R 7=OCH 3, R 11=Cl, Z are NHCH 2, all the other substituting groups are H)
Productive rate 81%; Fusing point 144-146 ℃; High resolution mass spectrum (ESI): calculated value [C 22H 19ClN 2O 2+ H] +379.1213; Experimental value: 379.1203;
Gained compound spectral data is: 1H NMR (400MHz, DMSO) δ 8.26 (d, J=9.3Hz, 1H), δ 7.88 (s, 1H), δ 7.82 (d, J=8.8Hz, 1H), δ 7.52 (d, J=6.6Hz, 1H), δ 7.48 (d, J=1.7Hz, 1H), δ 7.37 (dd, J=9.2,1.7Hz, 1H), and δ 7.29 (t, J=7.0Hz, 2H), δ 7.02 (d, J=8.1Hz, 1H), and δ 6.96 (t, J=7.4Hz, 1H), δ 4.87 (s, 2H), and δ 3.73 (s, 3H), δ 3.65 (s, 3H); 13C NMR (100.6MHz, DMSO) δ 156.32,154.73, and 150.42,147.87,146.21,133.33,130.64,128.40,127.75,127.42,127.11,125.82,124.18,122.71,120.27,116.60,114.52,110.48,100.67,55.18,54.98,47.42.
Embodiment 5, mtt assay cell inhibitory effect screening active ingredients
Body outer cell proliferation suppresses experiment and adopts mtt assay, adopts following three kinds of clones: human chronic myelogenous leukemia (CML) cell line k562, human liver cancer cell HepG2, mammary cancer MCF-7.
HepG2 cell and MCF7 cell are the adherent growth cell, with containing the DMEM nutrient solution that volume fraction is 10% foetal calf serum, are 5% CO at 37 ℃, volume fraction 2The conventional cultivation under the condition.
K562 is a suspension cell, with containing the RPIM-1640 nutrient solution that volume fraction is 10% foetal calf serum, is 5% CO at 37 ℃, volume fraction 2The conventional cultivation under the condition.
The HepG2 cell of taking the logarithm vegetative period, MCF7 cell or K562 cell are inoculated in 96 orifice plates, and density is 1.5 * 10 5Individual/mL, 99 μ L/well, every hole adds sample solution 1 μ L, and making the drug effect final concentration is 0.5,1,5,10,25,50 μ M.Every kind of sample is established three multiple holes, and positive control and blank are set.Add MTT solution behind the effect 48h, 10 μ L/well continue to cultivate after 4 hours, 2000rpm, 4 ℃, centrifugal 5 minutes, inhale and go to add DMSO behind the supernatant, 100 μ L/well, about 10 minutes of 37 ℃ of insulations, and vibrate with micro oscillator and to make crystallization dissolving fully in about 5 minutes, with microplate reader in 490nm place measurement OD value, be calculated as follows cell proliferation inhibition rate (Inhibition Rate, IR%):
IR%=(contrast OD-sample OD)/(the blank OD of contrast OD-) * 100%
Through calculating, the body outer cell proliferation that obtains the prepared compound of the present invention suppresses active, the results are shown in Table 1,
Table 1 is that the body outer cell proliferation of the compound of embodiment 3,4 preparations suppresses active
Figure BDA0000044214210000111
Figure BDA0000044214210000121
Embodiment 6, compound provided by the present invention carry out the vitro kinase shaker test
Prepare part:
The preparation reaction solution: HEPES 25mM, MgCl210mM, TritonX-1000.01%, BSA 100 μ g/ml, DTT 2.5mM, regulating pH value is 7.4, HEPES wherein, MgCl2 and TritonX-100 at first mix, and add BSA and DTT then
Reaction substrate:
Table 2, kinases are tested used substrate
Figure BDA0000044214210000122
With testing compound and positive control compound S taurosporine (Staurosporine), SB202190, PI103, Gefitinib (Gefitinib), CI1033 is mixed with 5mM solution with DMSO, get 2 μ L 5mM solution, add 18 μ L reaction solutions, diluted compounds to 500 μ M (10X) solution.ATP dilution is 4X, with reaction solution substrate is diluted to 4X, with reaction solution with kinase dilution to 2.5X.Arrange 384 orifice plates, wherein: HPE (the full inhibition contrasts) for not adding kinases and compound, adds ATP, substrate and 1%DMSO; ZPE (null suppression contrast) for not adding compound, adds kinases, ATP, substrate and 1%DMSO; Positive control compound hole is for adding kinases, ATP, substrate and different concns positive compound; The testing compound hole is for adding kinases, ATP, substrate and testing compound.
Experimental section:
In each hole, add 1 μ L10X compound (testing compound or various kinase whose positive control) solution, full inhibition contrast and null suppression control wells add 1 μ L reaction solution, every hole adds 4 μ L 2.5X kinase solution, suppresses control wells entirely and adds 4 μ L reaction solutions.Check-out console 1000rpm is centrifugal with mixing, 4X ATP solution is mixed with 4X substrate solution equal-volume, obtain 2X ATP-substrate solution, according to arranging that every hole adds the above-mentioned 2X ATP-of 5 μ L substrate solution.Check-out console 1000rpm is centrifugal with mixing, place 30 ℃ of reactions 1 hour.Every hole adds 10 μ L Kinase glo plus or ADP-Glo reaction reagents, places 20 minutes for 27 ℃, and every hole adds 20 μ L Kinase Detection reagent, places 30 minutes for 27 ℃.Read fluorescence numerical value with Envision.
Compound rejection coefficient=(compound hole fluorescent value-zero control wells fluorescent value)/(suppressing control wells fluorescent value-zero control wells fluorescent value entirely) * 100%
Through calculating, obtain the prepared compound of the present invention under 50 μ M concentration, to the inhibiting rate of SRC and two kinds of protein kinases of VEGFR-2, inhibiting rate is as shown in table 2.
Table 2, compound are under 50 μ M, to the inhibiting rate of SRC and two kinds of protein kinases of VEGFR-2
Figure BDA0000044214210000131

Claims (10)

1. compound shown in the formula I or its pharmacy acceptable salt, ester and solvate;
Figure FDA0000044214200000011
(formula I)
Wherein, Z is NH or NHCH 2
R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13All be selected from the following radicals any one: H, F, Cl, Br, OCH 3, OC 2H 5, COOH, CH 3, NO 2, NHCOCH 3And CF 3
X 1, X 2, X 3And R 1, R 2, R 3, R 4, R 5The group of representative is any in following four kinds of situations:
A) X 1, X 2, X 3Be C, R 1, R 2, R 3, R 4, R 5All be selected from the following radicals any one: H, OH, OCH 3, OC 2H 5, F, Cl, Br, CH 3, CF 3, OCF 3, NH 2, COOH and NHCOCH 3
B) X 1Be N, X 2, X 3Be C, R 1Substituting group does not exist, R 2, R 3, R 4, R 5All be selected from the following radicals any one: H, OH, OCH 3, OC 2H 5, F, Cl, Br, CH 3, CF 3, OCF 3, NH 2, COOH and NHCOCH 3
C) X 2Be N, X 1, X 3Be C, R 1, R 3, R 4, R 5All be selected from the following radicals any one: H, OH, OCH 3, OC 2H 5, F, Cl, Br, CH 3, CF 3, OCF 3, NH 2, COOH and NHCOCH 3, R 2Substituting group does not exist;
D) X 3Be N, X 1, X 2Be C, R 1, R 2, R 4, R 5All be selected from the following radicals any one: H, OH, OCH 3, OC 2H 5, F, Cl, Br, CH 3, CF 3, OCF 3, NH 2, COOH and NHCOCH 3, R 3Substituting group does not exist.
2. compound according to claim 1 or its pharmacy acceptable salt, ester and solvate is characterized in that: described R 7Be OCH 3, R 11Be Cl.
3. the method for compound shown in the preparation formula I comprises the steps:
1) is being that catalyzer, salt of wormwood are under the condition of alkali with copper, making that compound reacts shown in compound shown in the formula II and the formula III, obtaining compound shown in the formula IV;
Figure FDA0000044214200000021
Formula II formula III formula IV
Wherein, the R among formula II and the formula IV 10, R 11, R 12, R 13I is identical with formula,
R in the formula among III and the formula IV 6, R 7, R 8, R 9I is identical with formula;
2) compound shown in the formula IV and anhydrous phosphorus oxychloride are reacted, obtain compound shown in the formula V;
Figure FDA0000044214200000022
Formula V formula VI
3) obtain compound shown in the formula I according to following two kinds of methods respectively:
(a) compound shown in compound shown in the formula V and the formula VI is joined in chloroform and the alcohol mixed solution react, add the concentrated hydrochloric acid catalyzed reaction, stirring at room 11-13 hour, obtain compound shown in the formula I; A in the substituting group of compound shown in the formula VI and the claim 1) identical:
(b) under argon shield, compound shown in the formula VI, sodium hydride are joined in the dry dimethyl formamide, after stirring at room 1-1.5 hour, add compound and potassiumiodide shown in the formula V, stirring at room 11-13 hour, obtain compound shown in the formula I; B in the substituting group of compound shown in the formula VI and the claim 1), C) or D) identical.
4. method according to claim 3 is characterized in that: be reflected at described in the step 1) in the dimethyl formamide and carry out; The mol ratio of compound shown in compound shown in the formula II of initial adding and the formula III is 1.5: 1 in the described reaction system, and the temperature of reaction of described reaction is 130-135 ℃, and the reaction times is 11-13 hour; Step 2) temperature of reaction of reaction is 140-145 ℃ described in, and the reaction times is 3-3.5 hour; Described in the step 3) (a) in chloroform and the alcohol mixed solution chloroform and alcoholic acid volume ratio be 4: 1 to 5: 1.
5. compound shown in the formula I or its pharmacy acceptable salt, ester and the solvate application in the following product of preparation: 1) kinases inhibitor; 2) the value-added inhibitor of eukaryote tumour cell; 3) prevent and/or treat the medicine of tumour.
6. application according to claim 5 is characterized in that: described protein kinase is VEGFR-2 or SRC.
7. application according to claim 5 is characterized in that: described eukaryote is a Mammals; Described tumour cell is a cancer cells; Described cancer cells is leukaemia cancer cell, breast cancer cell or liver cancer cell; The former leukemia cell K562 of the chronic marrow of the preferred people of described leukaemia cancer cell, the preferred human breast cancer cell MCF-7 of described breast cancer cell, the preferred human liver cancer cell HepG-2 of described liver cancer cell.
8. application according to claim 5 is characterized in that: described tumour is a cancer, and described cancer is preferably leukemia, mammary cancer or liver cancer.
9. medicine that prevents and/or treats tumour, its activeconstituents is compound shown in the formula I or its pharmacy acceptable salt, ester and solvate.
10. medicine according to claim 9 is characterized in that: described tumour is a cancer, and described cancer is preferably leukemia, mammary cancer or liver cancer.
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Application publication date: 20110727