CN100398540C - Aryl heterocyclic imidazole naphthaimide kind compound and its application - Google Patents
Aryl heterocyclic imidazole naphthaimide kind compound and its application Download PDFInfo
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- CN100398540C CN100398540C CNB2006100462275A CN200610046227A CN100398540C CN 100398540 C CN100398540 C CN 100398540C CN B2006100462275 A CNB2006100462275 A CN B2006100462275A CN 200610046227 A CN200610046227 A CN 200610046227A CN 100398540 C CN100398540 C CN 100398540C
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Abstract
The present invention relates to a compound with aromatic heterocyclic radical imidazoles and naphthyl imides and the application of the compound on inhibiting tumour cells. The compound is characterized in that the conjugate plane of a naphthyl imide is enlarged after being merged into an aromatic heterocyclic radical imidazole so that the capability of the compound for inserting DNA is enhanced. The compound has broad antineoplastic activity and particularly presents obvious inhibitory activity on the proliferation of a plurality of tumour cells with different tissue sources comprising mouse leukemia, human lung cancer, liver cancer, uterine cervix cancer, acute myelogenous leukemiaand the like, and the functional effects present an obvious dose-effect relationship.
Description
Technical field
The application that the present invention relates to aryl heterocyclic imidazole naphthaimide kind compound in the fine chemistry industry and tumour cell is suppressed.
Background technology
Naphthalimide compound is the compound that a class has antitumour activity, two lead compound amonafides (amonafide) and Mitonafide (mitonafide) have entered II phase clinical experiment (Malviya V.K.et al.Am.J.Clin.Oncol.1992,15,41; Rosell R.et al.Invest.New Drugs, 1992,10,171).This compounds can be gone between the base pair of DNA in intercalation, and the RNA that suppresses DNA is synthetic, and can suppress topoisomerase II, thereby reaches the purpose that suppresses tumour.
A large amount of work has been done by Remers study group and Brana study group, has proved to incorporate an effective way (Remers W.A.et al, J.Med.Chem.1993,36,765 that heterocycle has improved the naphthalimide compound anti-tumor activity on the naphthalimide chromophoric group into; Remers W.A.et al, J.Med.Chem.1995,38,983; Remers W.A.et al, J.Med Chem.1996,39,1609; Remers W.A.et al, J.Med.Chem.1996,39,4978; Remers W.A.et al, J.Med.Chem.2000,43,3067; Brana M.F.et al, J.Med.Chem.2002,45,5813; Brana M.F.et al, Org.Biomol.Chem.2003,1,648; Brana M.F.et al, J.Med.Chem.2004,47,1391; Brana M.F.et al, J.Med.Chem.2004,47,2236).For example, the Azonafide that replaces naphthalene nucleus to derive with anthracene nucleus modifies the naphthalene nucleus chromophoric group, promptly replaces naphthalene nucleus with anthracene nucleus, derives novel antineoplastic compound Azonafide.It to the tumors inhibition activity of UACC375 melanoma, OVCAR3 ovarian cancer, MCF7 mammary cancer, WiDr colorectal carcinoma, A-549 lung cancer apparently higher than Amonafide (IC
50By 10
-6The M order of magnitude is reduced to 10
-7M to 10
-8The M order of magnitude), to the inhibition IC of mouse L1210
50Reached 7nM; Pyrazine and naphthalimide compound all are significantly improved IC to the inhibition specific activity Amonafide of HT-29 human colon carcinoma, Hela people's uterus carcinoma and PC-3 prostate cancer
50Reach 1.05 μ M, 1.95 μ M and 4.60 μ M respectively.
In order to develop the very promising antitumor drug of this class, our design and synthesized a class heteroaryl imidazoles and a naphthoyl imide compounds.
Summary of the invention
The said aryl heterocyclic imidazole naphthaimide kind compound of the present invention has following general structure:
In the formula:
n＝1-6；
R
1, R
2Be selected from H, C
1-C
6Alkyl;
R
3, R
4, R
5Be selected from H, C
1-C
6Alkyl, OR
6, S (O) R
6, N (R
6)
2, NO
2, CN, F, Cl, Br, I, Ph, CF
3Or NHC (O) R
6
R
6Be selected from H, C
1-C
6Alkyl, Ph or CH
2Ph;
X is selected from and has 1-4 R
3Substituent phenyl ring; Have 1-2 R
3Substituent furans, thiophene or pyrrole heterocyclic, or have 1-2 R
3Substituent pyridine heterocycle.
As: work as R
1=R
2=CH
3, R
3=R
4=R
5=H, the target compound synthetic route is as follows:
Compound is to the tumor cell growth activity determination experiment:
(microculture tetrozolium, MTT) reduction method is to the strain of P388 mouse leukemia cell, the strain of Hela human cervical carcinoma cell, SMMC-7721 human hepatoma cell strain and HL-60 people's acute myeloid leukaemia cell strain inhibition test to use tetrazolium respectively.(Sulforhodamine B, SRB) the protein staining method is carried out inhibition test to the A-549 human lung adenocarcinoma cell to the sulphonyl rhodamine B.
The concrete operations of tetrazolium (MTT) reduction method are: by different tumor growth rates, the tumour cell 90l/ hole that some amount is in logarithmic phase is inoculated in the 96 hole microtest plates, add soup 10l/ hole after cultivating 24h, to each cell strain, each concentration is three multiple holes.If establishing acellular zeroing hole medicine, other have color will do the acellular zeroing of relative medicine concentration hole.Tumour cell is at 37 ℃, 5%CO
2Cultivate after 48 hours under the condition, add MTT (Sigma) liquid 5mg/ml and prepare the 20l/ hole with physiological saline; Continue to cultivate after 4 hours, (the 50l/ hole of 10%SDS-5% isopropylcarbinol-0.01mol/lHCl) is in CO to add three liquid
2Spend the night in the incubator.Survey the OD570 value with microplate reader then.
Calculate the inhibiting rate of analyte by following formula to growth of cancer cells:
Tumor control rate=(control group OD value-treatment group OD value)/control group OD value * 100%
The sulphonyl rhodamine B (Sulforhodamine B, SRB) concrete operations of protein staining method are as follows: according to cell growth rate, the tumour cell that will be in logarithmic phase is inoculated in 96 well culture plates with 90 l/ holes, and adherent growth 24 hours is dosing 10l/ hole again.Each concentration is established three multiple holes.And the physiological saline solvent of establishing respective concentration contrasts and acellular zeroing hole.Tumour cell is at 37 ℃, 5%CO
2Cultivated 72 hours under the condition, the nutrient solution that inclines then with 10% cold TCA fixed cell, is placed for 4 ℃ and is used distilled water wash 5 times, seasoning in the air after 1 hour.Add SRB (Sigma) the 4mg/ml solution 100 l/ holes by the preparation of 1% Glacial acetic acid then, dyeing is 15 minutes in the room temperature, removes supernatant liquor, with 1% acetic acid washing 5 times, dry air.The Tris solution that adds 150 l/ holes at last, microplate reader 520nm wavelength are measured the A value down.
Calculate the inhibiting rate of analyte by following formula to growth of cancer cells:
Tumor control rate=(control group OD value-treatment group OD value)/control group OD value * 100%
Screening method: tetrazolium (microculture tetrozolium, MTT) reduction method
Sulphonyl rhodamine B (Sulforhodamine B, SRB) protein staining method
Cell strain: P388 mouse leukemia (MTT)
Hela human cervical carcinoma (MTT)
SMMC-7721 people's liver cancer (MTT)
HL-60 people's acute myeloid leukaemia (MTT)
A-549 human lung adenocarcinoma (SRB)
Action time: 48h (MTT)-72h (SRB)
Determination experiment the results are shown in following subordinate list:
Table 1 aryl heterocyclic imidazole naphthaimide kind compound is to the inhibiting rate % of P388 mouse leukemia growth
Table 2 aryl heterocyclic imidazole naphthaimide kind compound is to the inhibiting rate % of A-549 human lung adenocarcinoma growth
Table 3 aryl heterocyclic imidazole naphthaimide kind compound is to the inhibiting rate % of Hela human cervical carcinoma growth
Table 4 aryl heterocyclic imidazole naphthaimide kind compound is to the inhibiting rate % of SMMC-7721 people's liver cancer growth
Table 5 aryl heterocyclic imidazole naphthaimide kind compound is to the inhibiting rate % of HL-60 people's acute myeloid leukaemia growth
Table 6 aryl heterocyclic imidazole naphthaimide kind compound is to the growth inhibitory activity of various tumour cells
Embodiment
The present invention is further illustrated below by embodiment, its objective is to be better understanding content of the present invention.
Embodiment 1
3-nitro-1, the preparation of 8-naphthalene acid anhydride (2):
At 0～5 ℃, under the vigorous stirring, 17.62g 65% concentrated nitric acid (0.182mol) dropped to be dissolved with 30g 1, in 8-naphthalene acid anhydride 1 (0.152mol) and the 250ml glacial acetic acid solution, dripped off in 0.5 hour, continue to stir 3 hours, rise to room temperature, stir after 0.5 hour, in mixture impouring 500ml frozen water, separate out precipitation, filter washing, drying, the glacial acetic acid recrystallization obtains yellow needle-like crystal, productive rate: 75%.
1H?NMR(400MHz，DMSO-d
6)δ9.55(s，1H)，8.95(s，1H)，8.85(d，J＝8.4，1H)，8.72(d，J＝7.2，1H)，8.10(dd，J＝8.4，7.2)；mp：253-255℃.
Embodiment 2
3-amino-1, the preparation of 8-naphthalene acid anhydride (3):
Reflux temperature, under the vigorous stirring, the drips of solution that 80.0g tin protochloride and 80.0g 37% hydrochloric acid are formed is added to and contains 20.0g 3-nitro-1, in the ethanol of 8-naphthalimide 2 (0.082mol), reacts after adding 30 minutes again.Cooling is filtered, and drying obtains yellow solid, productive rate 86%.
1H?NMR(400MHz，DMSO-d
6)δ8.06(d，J＝7.6，1H)，8.05(d，J＝7.6)，7.91(s，1H)，7.62(t，J＝7.6，1H)，7.33(s，1H)；mp：＞300℃.
Embodiment 3
3-ethanoyl-1, the preparation of 8-naphthalene acid anhydride (4):
With 18.5g 3-amino-1,8 naphthalene acid anhydrides 3 (0.087mol), the mixture that 13.3g aceticanhydride (0.130mol) and 30ml acetic acid are formed is under the vigorous stirring, after the reflux 4 hours, reaction solution is poured in the 500ml frozen water, separated out precipitation, filter, washing, drying, the glacial acetic acid recrystallization obtains yellow crystals, productive rate: 79%.
1H?NMR(400MHz，DMSO-d
6)δ10.52(s，NH，1H)，8.68(s，1H)，8.53(s，1H)，8.36(d，J＝8.4，1H)，8.33(d，J＝7.2，1H)，7.80(dd，J＝8.4，7.2，1H)，2.15(COCH
3，3H).
Embodiment 4
3-ethanoyl-4-nitro-1, the preparation of 8-naphthalene acid anhydride (5):
Under the vigorous stirring; 98% nitrosonitric acid and 35ml sulfuric acid mixture are added drop-wise to-8 ℃ 10.0g 3-ethanoyl-1, in the solution that 8-naphthalene acid anhydride 4 (0.039) and 50ml sulfuric acid are formed (ice/NaCl cooling), add in 50 minutes; reaction is after 2 hours under the room temperature; reaction solution is poured in the 500ml frozen water, separated out precipitation, filter; washing; drying, the glacial acetic acid recrystallization obtains yellow solid, productive rate: 40%.
1H?NMR(400MHz，DMSO-d
6)δ10.71(s，NH，1H)，8.66(s，1H)，8.54(d，J＝6.8，1H)，8.26(d，J＝8.4，1H)，8.04(dd，J＝8.4，6.8，1H)，2.16(COCH
3，3H)；mp：218-219℃.
Embodiment 5
3-ethanoyl-4-amino-1, the preparation of 8-naphthalene acid anhydride (6):
With 10.0g 3-ethanoyl-4-nitro-1,8-naphthalene acid anhydride 5 is dissolved among the DMF, adds 0.3g 10%Pd/C catalyzer; feed the hydrogen of 40 kilograms/pressure under the room temperature, stirred 4 hours, after reaction finishes; cross and filter out Pd/C; filtrate is poured in the 500ml frozen water, separate out precipitation, filter; washing; drying, the DMF recrystallization obtains red solid, productive rate: 88%.
1H?NMR(400MHz，DMSO-d
6)δ9.37(s，NH，1H)，8.75(d，J＝8.4，1H)，8.43(d，J＝6.8，1H)，8.22(s，1H)，7.72(dd，J＝8.4，6.8，1H)，7.40(s，NH
2，2H)，2.17(COCH
3，3H)；mp：＞300℃.
Embodiment 6
3, the 4-diaminostilbene, the preparation of 8-naphthalene acid anhydride (7):
4.86g 3-ethanoyl-4-amino-1, under 8-naphthalene acid anhydride 6 (0.018mol) vigorous stirring, 25ml H
2SO
4, 150ml alcohol heating reflux 24 hours, reaction solution is poured in the 500ml frozen water, separate out precipitation, filter, washing, drying, the glacial acetic acid recrystallization obtains brown solid, productive rate 83%.
1H?NMR(400MHz，DMSO-d
6)δ8.78(d，J＝8.4，1H)，8.43(d，J＝6.8，1H)，8.28(s，1H)，7.76(d，J＝8.4，6.8，1H)；mp：238-240℃.
Embodiment 7
5-[2-(dimethylamino) ethyl]-9-phenyl-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9a) synthetic
200.0mg 3,4-diaminostilbene, 8-naphthalimide 7 (0.877mmol), 1 37.3mg NaHSO
3(1.32mmol), 15ml ethanol and aromatic aldehyde (0.877mol), vigorous stirring is heated to 100 ℃, reacts 1 hour, cooling is poured reaction solution in the 500ml frozen water into, separates out precipitation, filter, washing, drying, the DMF recrystallization obtains Aryimidazole and naphthalene acid anhydride.
With 100mg phenylimidazole and naphthalene acid anhydride and N, N-dimethyl-ethylenediamine (0.041mol) mixes in 15ml ethanol, and the reflux state stirred 3 hours down, cooling, and rotary evaporation removes and desolvates silica gel column chromatography (developping agent: CHCl
3: CH
3OH=10: 1, v/v), obtain pure product.
Productive rate: 75%.
1H?NMR(400MHz，DMSO-d
6)δ8.86(d，J＝8.0，1H)，8.61(s，1H)，8.42(d，J＝6.8，1H)，8.28(d，J＝6.8，2H)，7.89(dd，J＝8.0，6.8，1H)，7.61(d，J＝6.8，2H)，7.60(m，1H)4.15(t，J＝6.4，CH
2NCO，2H)，2.54(t，J＝6.4，CH
2N，2H)，2.23(s，2x?CH
3，6H)；IR(neat，cm
-1)3250.3，1691.6，1642.0；HRMS-EI(70eV)m/z?calcd?for?C
23H
20N
4O
2?384.1586，found?384.1584；mp：275.1-276.3℃.
Embodiment 8
5-[2-(dimethylamino) ethyl]-9-(4-chloro-phenyl-)-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9b) synthetic
Except that using the 4-chlorobenzaldehyde to replace the phenyl aldehyde, other synthetic method of purification that reaches is with embodiment 7.Productive rate: 77%.
1H?NMR(400MHz，DMSO-d
6)δ8.81(d，J＝8.0，1H)，8.57(s，1H)，8.40(d，J＝7.6，1H)，8.23(d，J＝8.4，2H)，7.88(dd，J＝8.0，7.6，1H)，7.66(d，J＝8.4，2H)，4.15(t，J＝6.4，CH
2NCO，2H)，2.55(t，J＝6.4，CH
2N，2H)，2.25(s，2x?CH
3，6H)；IR(neat，cm
-1)3274.7，1682.5，1647.7；HRMS-EI(70eV)m/zcalcd?for?C
23H
19ClN
2O
4?418.1197，found?418.1198；mp：274.0-275.0℃.
Embodiment 9
5-[2-(dimethylamino) ethyl]-9-[4-(methyl) phenyl]-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9c) synthetic
Except that using the 4-tolyl aldehyde to replace the phenyl aldehyde, other synthetic method of purification that reaches is with embodiment 7.Productive rate: 79%.
1H?NMR(400MHz，DMSO-d
6)δ8.84(d，J＝8.8，1H)，8.58(s，1H)，8.40(d，J＝7.2，1H)，8.15(d，J＝8.0，2H)，7.88(dd，J＝8.8，7.2，1H)，7.41(d，J＝8.0，2H)，4.15(t，J＝6.4，CH
2NCO，2H)，2.54(t，J＝6.4，CH
2N，2H)，2.23(s，2x?CH
3，6H)；IR(neat，cm
-1)，3294.0，1692.7，1638.6；HRMS-EI(70eV)m/zcalcd?for?C
24H
22N
4O
2?398.1743，found?398.1745；mp：269.0-270.4℃.
Embodiment 10
5-[2-(dimethylamino) ethyl]-9-[4-(methoxyl group) phenyl]-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9d) synthetic
Except that using the 4-methoxybenzaldehyde to replace the phenyl aldehyde, other synthetic method of purification that reaches is with embodiment 7.Productive rate: 80%.
1H?NMR(400MHz，DMSO-d
6)δ8.84(d，J＝8.0，1H)，8.57(s，1H)，8.40(d，J＝6.8，1H)，8.20(d，J＝8.8，2H)，7.87(dd，J＝8.0，6.8，1H)，7.16(d，J＝8.8，2H)，4.15(t，J＝6.4，CH
2NCO，2H)，3.72(s，OCH
3，3H)2.54(t，J＝6.4，CH
2N，2H)，2.23(s，2x?CH
3，6H)；IR(neat，cm
-1)3288.0，1685.3，1640.3；HRMS-EI(70eV)m/z?calcd?for?C
24H
22N
4O
3?414.1692，found?414.1700；mp：249.6-250.6℃.
Embodiment 11
5-[2-(dimethylamino) ethyl]-9-[4-(dimethylamino) phenyl]-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9e) synthetic
Except that using 4-(dimethylamino) phenyl aldehyde to replace the phenyl aldehyde, other synthetic method of purification that reaches is with embodiment 7.Productive rate: 75%.
1H?NMR(400MHz，DMSO-d
6)δ8.82(d，J＝7.6，1H)，8.52(s，1H)，8.38(d，J＝7.2，1H)，8.07(d，J＝8.8，2H)，7.84(dd，J＝7.6，7.2，1H)，6.86(d，J＝8.8，2H)，4.14(t，J＝6.8，CH
2NCO，2H)，3.18(s，ArN(CH
3)
2，6H)，2.51(t，J＝6.8，CH
2N，2H)，2.51(s，2x?CH
3，6H)，2.22(s，2x?CH
3，6H)；IR(neat，cm
-1)3261.4，1691.0，1642.3；HRMS-EI(70eV)m/z?calcd?for?C
25H
25N
5O
2?427.2008，found427.1998；mp：272.0-273.5℃.
Embodiment 12
5-[2-(dimethylamino) ethyl]-9-[4-(trifluoromethyl) phenyl]-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9f) synthetic
Except that using the 4-trifluoromethylated benzaldehyde to replace the phenyl aldehyde, other synthetic method of purification that reaches is with embodiment 7.Productive rate: 74%.
1H?NMR(400MHz，DMSO-d
6)δ8.67(d，J＝8.4，1H)，8.40(s，1H)，8.34(d，J＝8.0，2H)，8.31(d，J＝7.6，1H)，7.90(d，J＝8.0，2H)，7.80(dd，J＝8.4，7.6，1H)，4.08(t，J＝6.8，CH
2NCO，2H)，2.51(t，J＝6.8，CH
2N，2H)，2.25(s，2x?CH
3，6H)；IR(neat，cm
-1)3254.8，1700.4，1642.7；HRMS-EI(70eV)m/z?calcd?for?C
24H
19F
3N
4O
2?452.1460，found?452.1464；mp：268.2-270.0℃.
Embodiment 13
5-[2-(dimethylamino) ethyl]-9-[4-(hydroxyl) phenyl]-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9g) synthetic
Except that using the 4-hydroxy benzaldehyde to replace the phenyl aldehyde, other synthetic method of purification that reaches is with embodiment 7.Productive rate: 78%.
1H?NMR(400MHz，DMSO-d
6)δ8.85(d，J＝8.4，1H)，8.58(s，1H)，8.41(d，J＝7.2，1H)，8.12(d，J?＝?8.8，2H)，7.88(dd，J＝8.4，7.2，1H)，6.99(d，J＝8.8，2H)，4.16(t，J＝6.8，CH
2NCO，2H)，2.55(t，J＝6.8，CH
2N，2H)，2.25(s，2x?CH
3，6H)；IR(neat，cm
-1)3442.0，3190.8，1687.3，1646.6；HRMS-EI(70eV)m/z?calcd?for?C
23H
20N
4O
3?400.1535，found?400.1534；mp：＞300℃.
Embodiment 14
5-[2-(dimethylamino) ethyl]-9-[4-(oxyethyl group) phenyl]-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9h) synthetic
Except that using the 4-ethoxy-benzaldehyde to replace the phenyl aldehyde, other synthetic method of purification that reaches is with embodiment 7.Productive rate: 75%.
1H?NMR(400MHz，DMSO-d
6)δ8.84(d，J＝8.8，1H)，8.58(s，1H)，8.40(d，J＝7.2，1H)，8.15(d，J＝8.0，2H)，7.88(dd，J＝8.8，7.2，1H)，7.41(d，J＝8.0，2H)，4.15(t，J＝6.4，CH
2NCO，2H)，2.54(t，J＝6.4，CH
2N，2H)，2.23(s，2x?CH
3，6H)；IR(neat，cm
-1)3257.4，1690.2，1642.6；HRMS-EI(70eV)m/zcalcd?for?C
25H
24N
4O
3?428.1848，found?428.1849；mp：287.3-288.4℃.
Embodiment 15
5-[2-(dimethylamino) ethyl]-9-(3-methoxyl group-4-hydroxy phenyl)-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9i) synthetic
Except that using 3-methoxyl group-4-hydroxy benzaldehyde to replace the phenyl aldehyde, other synthetic method of purification that reaches is with embodiment 7.Productive rate: 78%.
1HNMR(400MHz，DMSO-d
6)δ8.89(d，J＝7.6，1H)，8.60(s，1H)，8.44(d，J＝6.8，1H)，7.91(dd，J＝7.6，6.8，1H)，7.83(s，1H)，7.74(d，J＝8.0，1H)，6.98(d，J＝8.0，1H)，4.19(t，J＝6.4，CH
2NCO，2H)，3.98(s，OCH
3，3H)，2.56(t，J＝6.4，CH
2N，2H)，2.22(s，2x?CH
3，6H)；IR(neat，cm
-1)3369.8，3189.8，1683.5，1648.7；HRMS-EI(70eV)m/z?calcd?for?C
24H
22N
4O
4?430.1641，found?430.1641；mp：＞300℃
Embodiment 16
5-[2-(dimethylamino) ethyl]-9-[3,4-(dimethoxy) phenyl]-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9j) synthetic
Remove with 3, the 4-dimethoxy benzaldehyde replaces outside the phenyl aldehyde, and other synthetic method of purification that reaches is with embodiment 7.Productive rate: 79%.
1H?NMR(400MHz，DMSO-d
6)δ8.77(d，J＝7.6，1H)，8.46(s，1H)，8.33(d，J＝7.2，1H)，7.81(dd，J＝7.6，7.2，1H)，7.78-7.77(m，2H)，7.12(d，J＝8.4，1H)，4.10(t，J＝7.2，CH
2NCO，2H)，3.92(s，OCH
3，3H)，3.87(s，OCH
3，3H)，2.52(t，J＝6.4，CH
2N，2H)，2.24(s，2x?CH
3，6H)；IR(neat，cm
-1)3294.7，1686.5，1639.8；HRMS-EI(70eV)m/z?calcd?for?C
25H
24N
4O
4?444.1798，found?444.1799；mp：248.3-249.1℃.
Embodiment 17
5-[2-(dimethylamino) ethyl]-9-(2-furyl)-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9k) synthetic
Except that replacing with 2 furan carboxyaldehyde the phenyl aldehyde, other synthetic and method of purification is with embodiment 7.Productive rate: 81%.
1H?NMR(500MHz，DMSO-d
6)δ8.77(d，J＝8.1，1H)，8.52(s，1H)，8.37(d，J＝7.2，1H)，8.01(bs，1H，FuranH)，7.83(dd，J＝8.1，7.2，1H)，7.34(d，J＝3.4，1H，FuranH)，6.78(q，1H，FuranH)，4.14(t，J＝6.9，CH
2NCO，2H)，2.56(t，J＝4.7，CH
2N，2H)，2.25(s，2x?CH
3，6H)；IR(neat，cm
-1)3113.3，1690.3，1651.2；HRMS-EI(70eV)m/z?calcd?for?C
21H
18N
4O
3?374.1379，found?374.1375；mp：239.8-241.0℃.
Embodiment 18
5-[2-(dimethylamino) ethyl]-9-(3-furyl)-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9l) synthetic
Except that using the 3-furtural to replace the phenyl aldehyde, other synthetic method of purification that reaches is with embodiment 7.Productive rate: 77%.
1H?NMR(500MHz，DMSO-d
6)δ8.73(d，J＝6.7，1H)，8.51(bs，2H，ArH?and?FuranH)，8.36(d，J＝7.0)，7.90(s，1H，FuranH)，7.83(dd，J＝6.7，7.0)，7.16(s，1H，FuranH)，4.12(t，J＝6.7，CH
2NCO，2H)，2.55(t，J＝6.9，CH
2N，2H)，2.24(s，2x?CH
3，6H)；IR(neat，cm
-1)3284.9，1686.7，1646.0；HRMS-EI(70eV)m/z?calcd?for?C
21H
18N
4O
3?374.1379，found?374.1377；mp：212.4-213.0℃.
Embodiment 19
5-[2-(dimethylamino) ethyl]-9-(2-thienyl)-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9m) synthetic
Except that replacing with 2 thiophene carboxaldehyde the phenyl aldehyde, other synthetic and method of purification is with embodiment 7.Productive rate: 79%.
1H?NMR(400MHz，DMSO-d
6)δ8.80(d，J＝8.0，1H)，8.57(s，1H)，8.41(d，J＝6.4)，7.95(d，J＝3.2，1H，ThiopheneH)，7.87(dd，J＝8.0，6.4，1H)，7.82(d，J＝4.0，ThiopheneH)，7.30(d，J＝3.2，4.0，ThiopheneH)，4.16(t，J＝6.8，1H)，2.54(t，J＝7.2，CH
2N，2H)，2.24(s，2x?CH
3，6H)；IR(neat，cm
-1)3287.3，1685.1，1615.2；HRMS-EI(70eV)m/z?calcd?for?C
21H
18N
4O
2S?390.1150，found?390.1147；mp：248.6-249.6℃.
Embodiment 20
5-[2-(dimethylamino) ethyl]-9-(3-thienyl)-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9n) synthetic
Except that using the 3-thiophenecarboxaldehyde to replace the phenyl aldehyde, other synthetic method of purification that reaches is with embodiment 7.Productive rate: 82%.
1H?NMR(500MHz，DMSO-d
6)δ8.76(d，J＝7.8，1H)，8.53(s，1H)，8.36(d，J＝9.5)，8.35(s，1H，ThiopheneH)，7.85(dd，J＝7.8，9.5，1H)，7.77(q，ThiopheneH)，4.11(t，7.0，CH
2NCO，2H)，2.51(t，J＝6.9，CH
2N，2H)，2.21(s，2x?CH
3，6H)；IR(neat，cm
-1)3332.3，1683.8，1637.2；HRMS-EI(70eV)m/z?calcd?forC
21H
18N
4O
2S?390.1150，found?390.1147；mp：249.0-249.8℃.
Embodiment 21
5-[2-(dimethylamino) ethyl]-9-(2-pyrryl)-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9o) synthetic
Except that using the 2-pyrrole aldehyde to replace the phenyl aldehyde, other synthetic method of purification that reaches is with embodiment 7.Productive rate 81%.
1H?NMR(500MHz，DMSO-d
6)δ8.82(d，J＝8.1，1H)，8.57(s，1H)，8.41(d，J＝7.3，1H)，7.87(dd，J＝8.1，7.3，1H)，7.03(bs，1H，PyrioleH)，7.00(d，J＝2.8，1H，PyrioleH)，6.27(dd，J＝3.5，2.8，1H，PyrioleH)，4.15(t，J＝7.0，CH
2NCO，2H)，2.51(t，J＝7.1，CH
2N，2H)，2.21(s，2x?CH
3，6H)；IR(neat，cm
-1)3311.5，1692.2，1651.9；HRMS-EI(70eV)m/z?calcd?for?C
21H
19N
5O
2?373.1539，found?373.1537；mp：247.3-249.1℃.
Embodiment 22
5-[2-(dimethylamino) ethyl]-9-[N-methyl-2-pyrryl]-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9p) synthetic
Except that using N-methyl-2-pyrrole aldehyde to replace the phenyl aldehyde, other synthetic method of purification that reaches is with embodiment 7.Productive rate: 79%.
1H?NMR(500MHz，DMSO-d
6)δ8.81(d，J＝6.6，1H)，8.53(s，1H)，8.40(d，J＝6.2，1H)，7.85(dd，J＝6.6，6.2，1H)，7.09(bs，1H，PyrioleH)，7.02(d，J＝2.8，1H，PyrioleH)，6.23(dd，J＝3.5，2.8，1H，PyrioleH)，4.19(s，N-CH
3，3H)4.14(t，J＝6.9，CH
2NCO，2H)，2.51(t，J＝7.2，CH
2N，2H)，2.21(s，2x?CH
3，6H)；IR(neat，cm
-1)3265.0，1693.8，1640.0；HRMS-EI(70eV)m/z?calcd?forC
22H
21N
5O
2?387.1695，found?387.1698；mp：251.6-253.3℃..
Embodiment 23
5-[2-(dimethylamino) ethyl]-9-(2-pyridyl)-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9q) synthetic
Except that using the 2-pyridylaldehyde to replace the phenyl aldehyde, other synthetic method of purification that reaches is with embodiment 7.Productive rate: 81%.
1H?NMR(500MHz，DMSO-d
6)δ8.73(m，2H，ArH?and?PyridineH)，8.49(s，1H)，8.29(m，2H，ArH?andPyridineH)，7.99(t，J＝7.3，1H，PyridineH)，7.77(t，J＝7.7)，7.53(q，1H，PyridineH)，4.09(t，J＝6.9，CH
2NCO，2H)，2.56(t，J＝6.8，CH
2N，2H)，2.26(s，2x?CH
3，6H)；IR(neat，cm
-1)3189.8，1692.1，1650.6；HRMS-EI(70eV)m/z?calcd?for?C
22H
19N
5O
2?385.1539，found?385.1538；mp：231.3-232.8℃.
Embodiment 24
5-[2-(dimethylamino) ethyl]-9-(3-pyridyl)-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9r) synthetic
Except that using the 3-pyridylaldehyde to replace the phenyl aldehyde, other synthetic method of purification that reaches is with embodiment 7.Productive rate: 82%.
1H?NMR(500MHz，DMSO-d
6)δ9.31(s，1H，PyridineH)，8.67(d，J＝4.3，1H，PyridineH)，8.64(d，J＝7.9，1H)，8.45(d，J＝7.10，1H)，8.40(s，1H，PyridineH)，8.27(d，J＝7.2，1H，PyridineH)，7.76(dd，J＝7.9，7.1，1H)，7.56(q，1H，PyridineH)，4.06(t，J＝6.9，CH
2NCO，2H)，2.55(t，J＝7.0，CH
2N，2H)，2.26(s，2x?CH
3，6H)；IR(neat，cm
-1)3184.3，1696.8，1650.0；HRMS-EI(70eV)m/z?calcd?forC
22H
19N
5O
2?385.1539，found?385.1549；mp：243.3-244.3℃.
Embodiment 25
5-[2-(dimethylamino) ethyl]-9-(4-pyridyl)-5,8-dihydrobenzo [de] imidazoles [4,5-g] isoquinoline 99.9-4,6-diketone (9s) synthetic
Except that using the 4-pyridylaldehyde to replace the phenyl aldehyde, other synthetic method of purification that reaches is with embodiment 7.Productive rate: 78%.
1H?NMR(400MHz，DMSO-d
6)δ8.74(d，J＝8.4，2H，PyridineH)，8.67(d，J＝8.0，1H)，8.41(s，1H)，8.28(d，J＝7.2，1H)，8.07(d，2H，PyridineH)，7.77(t，J＝8.0，7.2，1H)，4.07(bs，CH
2NCO，2H)，2.52(bs，CH
2N，2H)，2.28(s，2x?CH
3，6H)；IR(neat，cm
-1)3332.3，1692.4，1645.5；HRMS-EI(70eV)m/zcalcd?for?C
22H
19N
5O
2[M+H]
+386.1617，found?386.1626；mp：204.2-205.6℃.
Table 1 aryl heterocyclic imidazole naphthaimide kind compound is to the inhibiting rate % of P388 mouse leukemia growth
Table 2 aryl heterocyclic imidazole naphthaimide kind compound is to the inhibiting rate % of A-549 human lung carcinoma cell line growth
Table 3 aryl heterocyclic imidazole naphthaimide kind compound is to the inhibiting rate % of Hela human cervical carcinoma cell strain growth
Table 4 aryl heterocyclic imidazole naphthaimide kind compound is to the inhibiting rate % of SMMC-7721 human hepatoma cell strain growth
Table 5 aryl heterocyclic imidazole naphthaimide kind compound is to the inhibiting rate % of HL-60 people's acute myeloid leukaemia cell strain growth
Aryl heterocyclic imidazole naphthaimide kind compound has anti-tumor activity widely, especially the propagation to the tumour cell of multiple different tissue sources such as people's lung cancer, cancer of the stomach, liver cancer and leukemia demonstrates obvious inhibiting activity, and action effect is tangible dose-effect relationship.
Table 6 aryl heterocyclic imidazole naphthaimide kind compound is to the growth inhibitory activity of various tumour cells
Most of aryl heterocyclic imidazole naphthaimide kind compound is compared with amonafide (Amonafide), has improved antitumor inhibition activity.Wherein, compound 9j has improved 21.6 times to A-549, and SMMC-7721 has been improved about 18.9 times.Compound 9n improves 28.5 times to P388, and compound 9d improves 6.7 times to Hela, and compound 9q improves 5.4 times to HL-60.
Claims (1)
1. aryl heterocyclic imidazole naphthaimide kind compound is characterized in that described compound has following general structure:
In the formula:
n＝1-6；
R
1, R
2Be selected from H, C
1-C
6Alkyl;
R
3, R
4, R
5Be selected from H, C
1-C
6Alkyl, OR
6, S (O) R
6, N (R
6)
2, NO
2, CN, F, Cl, Br, I, Ph, CF
3Or NHC (O) R
6
R
6Be selected from H, C
1-C
6Alkyl, Ph or CH
2Ph;
X is selected from and has 1-4 R
3Substituent phenyl ring; Have 1-2 R
3Substituent furans, thiophene or pyrrole heterocyclic, or have 1-2 R
3Substituent pyridine heterocycle.
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