CN101323591A - 5- or 6-substited naphthoyl imines compounds and antineoplastic application - Google Patents

5- or 6-substited naphthoyl imines compounds and antineoplastic application Download PDF

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Publication number
CN101323591A
CN101323591A CNA2008100124988A CN200810012498A CN101323591A CN 101323591 A CN101323591 A CN 101323591A CN A2008100124988 A CNA2008100124988 A CN A2008100124988A CN 200810012498 A CN200810012498 A CN 200810012498A CN 101323591 A CN101323591 A CN 101323591A
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compound
hydrogen
nmr
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amonafide
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钱旭红
解丽娟
崔京南
肖义
徐玉芳
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Dalian University of Technology
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Dalian University of Technology
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Abstract

The invention relates to a 5-site or 6-site substituent naphthalimide compound and antitumor applications thereof, which belongs to the fine chemical field. The compound is characterized in that various aliphatic amidogen, heterocyclic amidogen, aryl and Ar aryl are respectively introduced into the 5-site or 6-site of the naphthalimide by a nucleophilic substitution reaction to obtain small molecule compound similar to a lead compound amonafide structure. The small molecule compound has obvious inhibiting activity in vitro test on Hela and P388D1, and wherein, some compounds have stronger cytotoxicity than the amonafide under the same test conditions. In addition, the structures of the compounds take on diversity; the compounds without acetylation sites can be prevented from having the side effect similar to the amonafide; the other compounds with the acetylation sites can be prevented from having the side effect by personalized administration, therefore, the compound has medical application prospect in curing diseases related to tumors.

Description

Naphthalimide compound and antitumor application that one class 5-position or 6-position replace
Technical field
The present invention relates to naphthalimide compound and antitumor application that a class 5-position or 6-position replace, it belongs to field of fine chemical.
Background technology
Cancer is seriously threatening human beings'health and life security, and exploitation is efficient, the antitumor drug of low toxicity is ten minutes active research direction in the medicinal chemistry field.Naphthoyl imide compounds is the compound that a class has fine antitumour activity, amonafide [amonafide (N-(beta-dimethyl-amido ethyl)-3-amido-1 wherein, and Mitonafide [mitonafide (N-(beta-dimethyl-amido ethyl)-3-nitro-1 the 8-naphthalimide)], the 8-naphthalimide)] phase ii clinical trial (Brana M.F., Santos A., Roldan C.M. have been entered, et al.Eur.J.Med.Chem.Chim.Ther., 1981,16,207).This compounds can be gone between the base pair of DNA in intercalation, suppresses the synthetic of DNA and RNA, and can suppress topoisomerase II, thereby reach the purpose that suppresses tumour.
But, find that in clinical application Mitonafide (mitonafide) has serious nervus centralis toxicity; Amonafide (amonafide) N-acetyltransferase effect in vivo forms N-acetyl amonafide (amonafide) down; different with other most medicines; amonafide (amonafide) causes bigger toxic side effect easily in the human body of fast metabolic pattern, and this because the toxic side effect that individual inheritance's difference causes is unpredictable.Therefore, develop the new anti-tumor activity that has, and the naphthalimide compound that can reduce above-mentioned side effect is very important.
Summary of the invention
The objective of the invention is to prepare naphthalimide compound new, that structure is various, make it have treatment tumour purposes, and these compounds are compared and are had better therapeutic and toxic side effect still less with the anticancer lead compound amonafide of existing naphthalimide (amonafide).
The technical solution adopted for the present invention to solve the technical problems is:, the naphthalimide compound that replaces of a class 5-position or 6-position has following general structure (1):
In a, (1) formula: R 1Be C 1~C 6Alkyl or by the substituted radical shown in (2) formula
In the formula (2): n=1~6, R 4, R 4Be selected from H, C 1~C 6A kind of or pyrrole ring in the alkyl;
In b, (1) formula, work as R 2During=H, R 3Be selected from following substituted radical or work as R 3During=H, R 2Also be selected from following substituted radical :-NHR 6R wherein 6Be C 1~C 6The straight or branched alkyl, Contain C 1~C 6The substituted-phenyl of alkyl, halogen, amino, nitro, thiophene, pyrroles, cumarone, pyridine and contain C 1~C 6These heterocycles that alkyl, halogen, amino, nitro replace.
The antitumor application method of the naphthalimide compound that one class 5-position or 6-position replace is that described compound adopts the tetrazolium reduction method to the strain of HeLa human cervical carcinoma cell to the extracorporeal suppression tumor cell growth activity, P388D1 mouse lymph sample tumor cell strain is tested, method is by different tumor growth rates, the tumor cell inoculation that some amount is in logarithmic phase is in 96 hole microtest plates, cultivate and add soup 10 μ L/ holes after 24 hours, each concentration of each cell strain is all established three multiple holes, other establishes acellular withered hole, when having color, medicine to do the acellular withered hole of relative medicine concentration, tumour cell is at 37 ℃, cultivate after 24 hours under the 5%CO2 condition, add MTT (Sigma) liquid 5mg/mL and dispose 20 μ L/ holes with physiological saline, continue to cultivate after 4 hours, add three liquid (the 50 μ L/ holes of 10%SDS-5% isopropylcarbinol-0.01mol/LHCl), in CO2gas incubator, spend the night, survey the OD570 value with microplate reader then;
Calculate the growth inhibition ratio of tested medicine by following formula to tumour cell:
Tumor control rate=(control group OD value-treatment group OD value)/control group OD value * 100%.
Synthetic route
R 2Contain substituted radical, simultaneously R 3Be H, the synthetic route of target compound:
4a:R=NH(CH 2) 2N(CH 3) 2
4b:R=NH(CH 2) 3N(CH 3) 2
4c:R=NH(CH 2) 3CH 3
Reaction reagent and condition: a.Br 2, concentrated nitric acid, 70 ℃, ambient temperature overnight; B.N, the N-dimethyl-ethylenediamine, ethanol refluxes 2 hours; The c.CuI/ proline, various amine, cesium carbonate, dimethyl sulfone (DMSO), 110 ℃, 8-12 hour; D. four triphenyl phosphorus palladium [Pd (PPh 3) 4] various boric acid, salt of wormwood, toluene refluxes 28 hours.
The naphthalimide compound that the 5-position replaces is a raw material with industrial goods naphthalene acid anhydride, stays strange (Suzuki) linked reaction by bromination, ammonification and Liv Ullmann (Ullmann) or Soviet Union and makes.Because the strong sucting electronic effect of carbonyl, make 5-position electric charge accumulation, be difficult to take place nucleophilic substitution reaction with traditional synthetic method, utilize improvement Liv Ullmann (Ullmann) reaction and the Soviet Union of CuI/ amino acid catalytic to stay strange (Suzuki) linked reaction, the naphthalimide compound that synthetic multiple 5-position replaces.
R 2Be H, simultaneously R 3Contain substituted radical, the synthetic route of target compound:
7a:R=NH(CH 2) 2N(CH 3) 2
7b:R=NH(CH 2) 3N(CH 3) 2
7c:R=NH(CH 2) 3CH 3
Reaction reagent and condition: a.N, the N-dimethyl-ethylenediamine, ethanol refluxes 2 hours; B. various amine, salt of wormwood, ethylene glycol monomethyl ether, reflux, 8-12 hour.
The naphthalimide compound that the 6-position replaces is with 4-bromo-1, and 8-naphthalene acid anhydride is a raw material, obtains target product by ammonification, nucleophilic substitution reaction (comprising the reaction of above-mentioned Liv Ullmann coupling and Soviet Union connection in the odd even).
Determine that by the MTT testing method above-claimed cpd is inhibited to the normal growth of the tumour cell of multiple different tissue sources such as tumour cells such as human cervical carcinoma, mouse lymph sample knurl in the laboratory, wherein the cytotoxicity of some compound is being better than lead compound amonafide (amonafide) under same experiment condition.
Beneficial effect of the present invention: described compound is compared with amonafide (amonafide), and some compound is 4a for example, 4b, and 4h, 7a, 7b, 7h demonstrate stronger cytotoxicity.And described compound presents structure diversity, and the compound that does not wherein have the acidylate site can be avoided the toxic side effect of similar amonafide (amonafide) fully; And the compound with acidylate site can be avoided toxic side effect by personalized administration.
Embodiment
Embodiment 1
3-bromo-1, the preparation of 8-naphthalene acid anhydride (2):
(8.2g 51.3mmol) is added drop-wise to 1 to the liquid bromine in the time of 25 ℃, (10g is 50.5mmol) and in the mixing solutions of 70% nitric acid (200mL) for 8-naphthalene acid anhydride.Stirring is after 2 hours down at 70 ℃ for mixture, and cooling, filtration, washing, drying obtain the solid target compound.
Embodiment 2
The preparation of 5-bromo-[2-(dimethylin) ethyl]-1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (3):
3-bromo-1,8-naphthalene acid anhydride (2) (277mg, 1mmol) and N, removed and desolvate after 2 hours, obtains target product by the mixture of N-dimethyl-ethylenediamine (1.2mmol) reflux in ethanol (20mL).
Yield 92%, light brown solid, mp 77.2-78.6 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.65 (s, 1H) 8.59 (dd, 1H, J=1.0 and 7.2Hz), 8.35 (s, 1H) 8.11 (dd, 1H, J=0.7 and 8.3Hz) 7.77 (t, 1H, J=7.8Hz) 4.34 (t, 2H, J=6.9Hz) 2.70 (t, 2H, J=6.9Hz) 2.39 (s, 6H)
Embodiment 3
5-(dimethylin-ethamine)-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (4a):
Compound 3 (174mg, 0.5mmol), CuI (9.6mg, 0.05mmol), proline (11.5mg, 0.1mmol), Cs 2CO 3(247.5mg, 0.6mmol) and N, the mixture of N-dimethyl-ethylenediamine (0.75mmol), in DMSO (2mL), under 110 ℃ and nitrogen protection, stirring reaction 8 hours.Crude product is with methylene dichloride: methyl alcohol is developping agent, and column chromatography obtains pure product target compound.
Yield 52%, orange solids, mp 97.2-98.6 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.265 (dd, 1H, J=0.8 and 7.2Hz) 8.02 (s, 1H) 7.93 (d, 1H, J=7.6Hz) 7.58 (t, 1H, J=7.2Hz) 7.11 (s, 1H) 4.94 (t, 1H, J=4.4Hz) 4.32 (t, 2H, J=7.2Hz) 3.32-3.28 (m, 2H) 2.67-2.64 (m, 4H) 2.37 (s, 6H) 2.30 (s, 6H); 13C NMR (100MHz CDCl 3) δ (ppm) 164.6,164.4,147.1,133.8,131.6,127.1,126.6,123.3,122.4,122.0,121.9,110.0,57.4,57.0,45.7,45.1,41.0,38.1; IR (KBr cm -1) 3377,2955,1,684 1654; HRMS (ESI) m/z (M+H) +Calcd for C 20H 27N 4O 22355.2134 found 355.2169.
Embodiment 4
5-(dimethylin-propylamine)-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (4b):
Synthetic method is with embodiment 3,8 hours reaction times.
Yield 50%, orange solids, mp115.8-116.3 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.25 (d, 1H, J=0.8 and 7.2Hz) 7.97 (s, 1H, 4-H) 7.92 (d, 1H, J=8.4Hz) 7.57 (t, 1H, J=7.2Hz) 7.08 (s, 1H) 5.53 (s, 1H) 4.34-4.30 (m, 2H) 3.36 (s, 2H) 2.67-2.64 (m, 2H) 2.52-2.49 (m, 2H) 2.37 (s, 6H) 2.31 (s, 6H) 1.90-1.87 (m, 2H); 13C NMR (100MHz CDCl 3) δ (ppm) 164.7,164.5,147.2,133.9,131.6,127.0,126.4,123.2,122.4,122.2,121.9,109.3,58.6,57.0,45.7,43.5,38.1,25.9; IR (KBr cm -1) 3370,1691,1654; HRMS (ESI) m/z (M+H) +Calcd for C 21H 29N 4O 2369.2291 found 369.2294.
Embodiment 5
5-butylamine-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (4c)
Synthetic method is with embodiment 3,9 hours reaction times.
Yield 34%, orange solids, mp126-127 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.25 (d, 1H, J=7.2Hz) 7.95-7.91 (m, 2H) 7.58 (t, 1H, J=7.2Hz) 7.07 (s, 1H) 4.33 (t, 2H, J=6.8Hz) 4.19 (s, 1H) 3.29-3.24 (m, 2H) 2.68 (t, 2H, J=7.2Hz) 2.39 (s, 6H) 1.74-1.67 (m, 2H) 1.55-1.45 (m, 2H) 1.01 (t, 3H, J=7.6Hz); 13C NMR (100MHz CDCl 3) δ (ppm) 164.6,164.4,146.9,133.8,131.7,127.1,126.6,123.2,122.3,122.0,121.8,109.6,56.9,45.6,43.6,38.0,31.3,20.3,13.9; IR (KBr cm -1) 3237,2948,1704,1648; HRMS (ESI) m/z (M+H) +Calcd for C 20H 26N 3O 2340.2025 found 340.2037.
Embodiment 6
5-[(thiophene-2-methyl)-amido]-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (4d):
Synthetic method is with embodiment 3,12 hours reaction times.
Yield 31%, orange solids, mp 144.7-146.1 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.29 (d, 1H, J=7.2Hz) 8.04 (s, 1H) 7.94 (d, 1H, J=8.0Hz) 7.60 (t, 1H, J=8.0Hz) 7.22-7.18 (m, 1H) 7.18 (s, 1H) 7.09 (s, 1H) 7.02-7.00 (m, 1H) 4.70 (s, 3H) 4.38 (t, 2H, J=6.8Hz) 2.84 (t, 2H, and J=6.0Hz) 2.50 (s, 6H); 13C NMR (400MHz CDCl 3) δ (ppm) 164.6,164.3,146.0,141.5,133.6,132.1,127.2,127.1,126.8,125.5,125.0,124.9,123.3,122.4,122.3,121.9,110.7,56.5,45.1,43.2,37.3,29.7; IR (KBr cm -1) 3377,2918,1695,1651; HRMS (ESI) m/z (M+H) +Calcd for C 21H 22N 3O 2S 380.1433, and found 380.1451.
Embodiment 7
The preparation of 5-morpholine-2-[2-(dimethylin) ethyl]-1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (4e):
Synthetic method is with embodiment 3,10 hours reaction times.
Yield 30%, orange solids, mp 147.8-149.6 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.38-8.35 (m, 2H) 8.02 (d, 1H, J=8.0Hz) 7.65 (t, 1H, J=8.0Hz) 7.43 (s, 1H) 4.37 (t, 2H, J=6.8Hz) 3.94 (t, 4H, J=4.8Hz) 3.38 (t, 4H, and J=4.8Hz) 2.78 (t, 2H, J=6.8Hz) 2.46 (s, 6H); 13C NMR (100MHz CDCl 3) δ (ppm) 164.4,149.8,134.0,133.2,132.6,131.3,128.2,127.3,126.9,123.3,123.1,122.8,122.3,115.1,66.7,56.7,49.0,45.3,37.6; IR (KBr cm -1) 3414,2955,1691,1651,1261; HRMS (ESI) m/z (M+H) +Calcd for C 20H 24N 3O 3354.1818 found 354.1829.
Embodiment 8
5-parathiazan-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (4f):
Synthetic method is with embodiment 3,11 hours reaction times.
Yield 27%, orange solids, mp167.5-168.8 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.35 (d, 1H, J=7.6Hz) 8.31 (s, 1H) 8.00 (d, 1H, J=8.4Hz) 7.64 (t, 1H, J=7.6Hz) 7.40 (s, 1H) 4.37 (t, 2H, J=6.8Hz) 3.78 (t, 4H, J=5.2Hz) 2.81 (t, 4H, J=5.2Hz) 2.73 (t, 2H, and J=6.8Hz) 2.43 (s, 6H); 13C NMR (100MHz CDCl 3) δ (ppm) 164.4,149.3,133.4,132.3,128.0,127.3,126.9,123.8,123.6,122.8,122.2,115.9,57.0,51.6,45.7,38.2,26.5; IR (KBr cm -1) 2948,1691,1654; HRMS (ESI) m/z (M+H) +Calcd for C 20H 24N 3O 2S 370.2349, and found 370.2358.
Embodiment 9
5-piperidines-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (4g):
Synthetic method is with embodiment 3,11 hours reaction times.
Yield 25%, orange solids, mp 130.3-131.6 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.38 (s, 1H) 8.32 (d, 1H, J=7.2Hz) 7.98 (d, 1H, J=8.0Hz) 7.61 (t, 1H, J=8.0Hz) 7.41 (s, 1H) 4.34 (t, 2H, J=7.6Hz) 3.39 (t, 4H, J=5.6Hz) 2.68 (t, 2H, J=7.2Hz) 2.38 (s, 6H) 1.79-1.76 (m, 4H) 1.70-1.67 (m, 2H); 13C NMR (100MHz CDCl 3) δ (ppm) 164.6,150.4,133.5,132.3,131.3,127.6,127.0,123.8,123.1,122.6,122.3,115.1,56.9,50.1,45.6,38.0,25.5,24.2; IR (KBr cm -1) 2926,1695,1654; HRMS (ESI) m/z (M+H) +Calcd for C 21H 26N 3O 2352.2025 found 352.2030.
Embodiment 10
5-(4 '-methyl-piperazine)-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (4h):
Synthetic method is with embodiment 3,12 hours reaction times.
Yield 22%, orange solids, mp 121.2-122.8 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.38 (s, 1H) 8.35 (d, 1H, J=6.8Hz) 8.01 (d, 1H, J=8.0Hz) 7.64 (t, 1H, J=8.0Hz) 7.43 (s, 1H) 4.34 (t, 2H, J=6.8Hz) 3.44 (t, 4H, J=4.8Hz) 2.68-2.64 (m, 6H) 2.40 (s, 3H) 2.37 (s, 6H); 13C NMR (400MHz CDCl 3) δ (ppm) 164.5,149.7,133.3,132.4,127.9,127.2,123.2,122.3,115.1,57.0,54.8,48.8,46.1,45.7,38.1; IR (KBr cm -1) 3414,1688,1647; HRMS (ESI) m/z (M+H) +Calcd for C 21H 27N 4O 2367.2134 found 367.2142.
Embodiment 11
5-thiophene-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (4i):
Compound 3 (174mg, 0.5mmol), thienyl boric acid (96mg, 0.75mmol), Pd (PPh 3) 4(25mg, 0.02mmol) and K 2CO 3(in toluene (3mL), reflux is 28 hours under the nitrogen protection for 103.5mg, mixture 0.75mmol).Crude product utilizes methylene dichloride and methyl alcohol to be eluent, makes pure target product by column chromatographic isolation and purification.
Yield 55%, grass green solid, mp 110.5-112.2 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.87 (s, 1H) 8.55 (dd, 1H, J=0.8 and 7.2Hz), 8.36 (s, 1H) 8.21 (d, 1H, J=7.6Hz) 7.76 (t, 1H, J=7.6Hz) 7.58 (dd, 1H, J=0.8 and J=3.6Hz) 7.43 (dd, 1H, J=0.8 and J=4.8Hz) 7.20-7.18 (m, 1H) 4.40 (t, 2H, J=6.8Hz) 2.78 (t, 2H, and J=6.8Hz) 2.45 (s, 6H); 13C NMR (100MHz CDCl 3) δ (ppm) 164.1,142.3,140.6,136.9,133.9,133.4,132.2,130.9,129.4,129.3,128.6,127.6,127.3,126.4,124.9,123.2,122.6,56.8,45.5,37.8; IR (KBr cm -1) 3348,3103,2370,1691,1654; HRMS (ESI) m/z (M+H) +Calcdfor C 20H 19N 2O 2S 351.1123, and found 351.1144.
Embodiment 12
5-phenyl-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (4j):
Synthetic method is with embodiment 11.
Yield 48%, white solid, mp 126.4-128.2 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.87 (s, 1H) 8.58 (dd, 1H, J=1.0 and 7.2Hz) 8.38 (s, 1H) 8.25 (dd, 1H, J=0.7 and 8.2Hz) 7.78-7.76 (m, 2H) 7.75 (s, 1H) 7.55-7.52 (m, 2H) 7.47-7.44 (m, 1H) 4.38 (t, 2H, J=7.0Hz) 2.73 (t, 2H, J=7.0Hz) 2.41 (s, 6H); 13C NMR (100MHz CDCl 3) δ (ppm) 164.2,140.1,139.3,134.1,132.2,131.3,131.0,130.8,129.2,128.4,127.5,127.4,127.3,123.2,122.6,57.0,45.6,38.0; IR (KBr cm -1) 3444,2948,1688,1654; HRMS (EI) m/z (M+H) +Calcd for C 22H 20N 2O 2344.1525 found 344.1526.
Embodiment 13
5-(4 '-methyl-phenyl)-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (4k):
Synthetic method is with embodiment 11.
Yield 51%, white solid, mp 219.8-220.9 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.87 (s, 1H) 8.57 (dd, 1H, J=0.8 and 7.2Hz) 8.37 (s, 1H) 8.25 (d, 1H, J=8.0Hz) 7.79 (t, 1H, J=7.2Hz) 7.68 (d, 2H, J=8.0Hz) 7.35 (d, 2H, J=8.4Hz) 4.41 (t, 2H, J=6.8Hz) 2.79 (t, 2H, and J=6.8Hz) 2.45 (s, 9H); 13C NMR (100MHz CDCl 3) δ (ppm) 164.3,140.0,138.4,136.3,134.1,132.2,130.9,130.8,130.0,129.9,127.2,123.0,122.5,56.8,45.4,37.8,21.2; IR (KBr cm -1) 3370,2940,1694,1663; HRMS (ESI) m/z (M+H) +Calcd for C 23H 23N 2O 2359.1735 found 359.1736.
Embodiment 14
5-(3 ', 4 '-2F-phenyl)-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (41):
Synthetic method is with embodiment 11.
Yield 43%, white solid, mp 115.1-116.3 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.78 (s, 1H) 8.62 (d, 1H, J=7.2Hz) 8.32 (s, 1H) 8.26 (d, 1H, J=8.0Hz) 7.80 (t, 1H, J=7.6Hz) 7.61-7.56 (m, 1H) 7.553-7.49 (m, 1H) 7.37-7.30 (m, 1H) 4.37 (t, 2H, J=6.8Hz) 2.69 (t, 2H, J=6.8Hz) 2.37 (s, 6H); 13C NMR (100MHz CDCl 3) δ (ppm) 164.0,151.9,149.4,137.9,136.4,136.3,134.0,132.1,131.3,131.1,130.0,127.6,127.5,123.5,122.7,118.2,118.0,116.5,116.4,57.0,45.8,38.3; 19F NMR δ (ppm)-136.4 ,-138.1; IR (KBr cm -1) 2940,1703,1654,1142; HRMS (ESI) m/z (M+H) +Calcd for C 22H 19F 2N 2O 2381.1415.found 381.1396.
Embodiment 15
5-(3 '-nitro-phenyl)-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (4m):
Synthetic method is with embodiment 11.
Yield 40%, faint yellow solid, mp 188.2-183.6 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.87 (s, 1H) 8.64-8.63 (m, 2H) 8.45 (s, 1H) 8.33-8.30 (m, 2H) 8.11 (d, 1H, J=8.0Hz) 7.83 (t, 1H, J=8.0Hz) 7.74 (t, 1H, J=8.0Hz) 4.39 (t, 2H, and J=6.8Hz) 2.74 (t, 2H, J=6.8Hz) 2.41 (s, 6H); 13C NMR (100MHz CDCl 3) δ (ppm) 165.2,149.0,141.0,137.4,134.2,133.3,132.1,131.7,130.3,130.0,127.8,123.7,123.1,122.7,122.2,56.9,49.9,45.6,38.1,29.7,22.7; IR (KBr cm -1) 3333,2933,1695,1658,1385; HRMS (ESI) m/z (M+H) +Calcd for C 22H 20N 3O4 390.1430, and found 390.1434.
Embodiment 16
The preparation of 6-bromo-[2-(dimethylin) ethyl]-1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (6):
4-bromo-1,8-naphthalene acid anhydride (277mg, 1mmol) and N, removed and desolvate after 2 hours, obtains target product by N-dimethyl-ethylenediamine (1.2mmol) reflux in ethanol (20mL).
Embodiment 17
6-(dimethylin-ethamine)-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (7a):
Compound (6) (174mg, 0.5mmol), N, N-dimethyl-ethylenediamine (2mmol) and K 2CO 3(reflux obtained target product through purification after 12 hours in ethylene glycol monomethyl ether (15mL) for 69mg, mixture 0.5mmol).
Yield 75%, yellow solid, mp 118-118.6 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.58 (d, 1H, J=7.2Hz) 8.46 (d, 1H, J=8.0Hz) 8.14 (d, 1H, J=8.4Hz) 7.62 (t, 1H, J=8.0Hz) 6.66 (d, 1H, J=8.8Hz) 6.3 (br, 1H) 4.32 (t, 2H, J=7.2Hz) 3.40-3.36 (m, 2H) 2.73 (t, 2H, J=6.0Hz) 2.65 (t, 2H, J=7.2Hz) 2.37 (s, and 6H) 2.34 (s, 6H); 13C NMR (400MHz CDCl 3) δ (ppm) 164.8,164.2,149.7,134.6,131.1,129.9,126.4,124.6,123.0,120.4,110.0,104.4,57.1,45.7,45.0,40.1,37.9; IR (KBr cm -1) 3274,2955,1677,1640; HRMS (EI) m/z (M+H) +Calcd for C 20H 27N 4O 2355.2134 found 355.2118.
Embodiment 18
6-(dimethylin-propylamine)-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (7b):
Synthetic method is with embodiment 17.
Yield 72%, yellow solid, mp 117-117.8 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.58-8.55 (m, 2H) 8.43 (d, 1H, J=8.0Hz) 8.00 (d, 1H, J=8.0Hz) 7.57 (t, 1H, J=7.6Hz) 6.58 (d, 1H, J=8.0Hz) 4.32 (t, 2H, J=7.2Hz) 3.48 (s, 2H) 2.67-2.63 (m, 4H) 2.42 (s, 6H) 2.37 (s, 6H) 1.97 (t, 2H, J=5.6Hz); 13C NMR (100MHz CDCl 3) δ (ppm) 164.9,164.2,150.9,134.9,131.0,130.0,126.7,124.4,122.9,120.7,109.1,103.4,59.6,57.1,44.8,37.8,24.2; IR (KBr cm -1) 3422,2948,1680,1639; HRMS (EI) m/z (M+H) +Calcd for C 21H 29N 4O 2369.2291 found 369.2281.
Embodiment 19
6-butylamine-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (7c):
Synthetic method is with embodiment 17.
Yield 60%, yellow solid, mp 105-106.7 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.55 (d, 1H, J=7.6Hz) 8.43 (d, 1H, J=8.0Hz) 8.07 (d, 1H, J=8.0Hz) 7.59 (t, 1H, J=8.0Hz) 6.69 (d, 1H, J=8.0Hz) 5.32 (br, 1H) 4.33 (t, 2H, J=7.2Hz) 3.43-3.38 (m, 2H) 2.69 (t, 2H, J=7.2Hz) 2.39 (s, 6H) 1.84-1.76 (m, 2H) 1.59-1.49 (m, 2H) 1.032 (t, 3H, J=7.6Hz); 13C NMR (100MHz CDCl 3) δ (ppm) 164.7,164.1,149.5,134.5,131.1,129.8,125.8,124.6,123.1,120.1,110.1,104.3,57.1,45.7,43.4,37.8,31.0,20.3,13.8; IR (KBr cm -1) 3291,2952,1683,1637; HRMS (EI) m/z (M+H) +Calcd for C 20H 26N 3O 2340.2025 found 340.2023.
Embodiment 20
6-[(thiophene-2-methyl]-amido]-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (7d):
Synthetic method is with embodiment 17.
Yield 54%, yellow solid, mp 162.4-164 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.56 (d, 2H, J=7.2Hz) 8.44 (d, 1H, J=8.0Hz) 8.09 (d, 1H, J=8.0Hz) 7.61 (t, 1H, J=7.6Hz) 7.31 (dd, 1H, J=0.8 and 4.8Hz), 7.14 (s, 1H) 7.05-7.03 (m, 1H) 6.80 (d, 1H, J=7.6Hz) 5.69 (t, 1H, J=4.8Hz) 4.79 (d, 2H, J=4.8Hz) 4.35 (t, 2H, J=7.2Hz) 2.73 (t, 2H, J=6.8Hz) 2.42 (s, 6H); 13C NMR (100MHz CDCl 3) δ (ppm) 164.6,164.0,148.6,140.0,134.3,131.2,129.7,127.3,126.3,126.0,125.6,125.0,123.1,120.4,111.2,105.0,57.0,45.6,43.0,37.6; IR (KBr cm -1) 3311,2348,1677,1647; HRMS (EI) m/z (M+H) +Calcd for C 21H 22N 2O 2S 380.1433, and found 380.1422.
Embodiment 21
The preparation of 6-morpholine-2-[2-(dimethylin) ethyl]-1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (7e):
Synthetic method is with embodiment 17.
Yield 70%, yellow solid, mp133.3-134.8 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.59 (d, 1H, J=7.2Hz) 8.54 (d, 1H, J=8.0Hz) 8.42 (d, 1H, J=7.6Hz) 7.71 (t, 1H, J=8.0Hz) 7.23 (d, 1H, J=8.0Hz) 4.33 (t, 2H, J=7.2Hz) 4.02 (t, 4H, J=4.4Hz) 3.27 (t.4H, J=4.4Hz) 2.68 (t, 2H, and J=6.8Hz) 2.38 (s, 6H); 13C NMR (100MHz CDCl 3) δ (ppm) 164.5,164.0,155.6,132.6,131.2,130.1,130.0,126.2,125.8,123.3,117.2,115.0,67.0,57.0,53.4,45.7,37.9; IR (KBr cm -1) 2977,1699,1651; HRMS (EI) m/z (M+H) +Calcd for C 20H 24N 3O 3354.1818 found 354.1824.
Embodiment 22
6-parathiazan-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (7f):
Synthetic method is with embodiment 17.
Yield 73%, yellow solid, mp 118.3-119.5 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.59 (d, 1H, J=7.6Hz) 8.52 (d, 1H, J=8.0Hz) 8.37 (d, 1H, J=8.0Hz) 7.71 (t, 1H, J=7.6Hz) 7.24 (d, 1H, J=8.0Hz) 4.33 (t, 2H, J=7.2Hz) 3.51 (t, 4H, J=4.0Hz) 2.97 (t, 4H, J=4.4Hz) 2.68 (t, 2H, and J=6.8Hz) 2.38 (s, 6H); 13C NMR (100MHz CDCl 3) δ (ppm) 164.5,164.0,156.8,132.5,131.2,130.0,129.9,126.6,125.9,123.3,117.2,116.0,56.9,55.6,45.6,37.8,28.2; IR (KBr cm -1) 3311,2963,1677,1647; HRMS (EI) m/z (M+H) +Calcd for C 20H 24N 3O 2S 370.1589, and found 370.1579.
Embodiment 23
6-piperidines-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (7g):
Synthetic method is with embodiment 17.
Yield 78%, yellow solid, mp 128-129.3 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.57d, 1H, J=7.2Hz) 8.49 (d, 1H, J=8.0Hz) 8.39 (d, 1H, J=8.0Hz) 7.67 (t, 1H, J=8.0Hz) 7.17 (d, 1H, J=8.0Hz) 4.32 (t, 2H, J=7.2Hz) 3.23 (s, 4H) 2.66 (t, 2H, J=7.2Hz) 2.37 (s, 6H) 1.90-1.86 (m, 4H) 1.74-1.72 (m, 2H); 13C NMR (100MHz CDCl 3) δ (ppm) 164.6,164.1,157.4,132.7,131.1,130.6,126.3,125.3,123.1,115.9,114.7,56.9,54.5,45.6,37.8,26.2,24.3; IR (KBr cm -1) 3370,2933,1691,1654; HRMS (EI) m/z (M+H) +Calcd for C 21H 26N 3O 2352.2025 found 352.2034.
Embodiment 24
6-(4 '-methyl-piperazine)-2-[2-(dimethylin) ethyl]-preparation of 1 hydrogen-benzo [de] isoquinoline 99.9-1,3 (2 hydrogen)-diketone (7h):
Synthetic method is with embodiment 17.
Yield 72%, yellow solid, mp 162.4-163.7 ℃; 1H NMR (400MHz CDCl 3) δ (ppm) 8.58 (dd, 1H, J=0.8 and 7.2Hz) 8.51 (d, 1H, J=8.0Hz) 8.41 (d, 1H, J=0.8 and 8.0Hz) 7.69 (t, 1H, J=7.6Hz) 7.22 (d, 1H, J=8.0Hz) 4.36 (t, 2H, J=7.2Hz) 3.32 (t, 4H, J=4.4Hz) 2.76-2.72 (m, 6H) 2.45 (s, and 3H) 2.43 (s, 6H); 13C NMR (100MHz CDCl 3) δ (ppm) 164.5,164.0,156.0,132.7,131.2,130.3,130.0,126.2,125.6,123.2,116.6,115.0,56.8,55.1,52.9,46.1,45.5,37.6; IR (KBr cm -1) 3392,2985,1692,1652; HRMS (EI) m/z (M+H) +Calcd for C 21H 27N 4O 2367.2089 found 367.2090.
Embodiment 25
The extracorporeal suppression tumor cell growth activity is measured:
(microculture tetrozolium, MTT) reduction method is carried out inhibition test to P388D1 mouse lymph sample oncocyte and HeLa human cervical carcinoma cell with tetrazolium.
The concrete operations of tetrazolium (MTT) reduction method are: by different tumor growth rates, the tumor cell inoculation that some amount is in logarithmic phase is in 96 hole microtest plates, add soup 10 μ l/ holes 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 2After cultivating 24h under the condition, add MTT (Sigma) liquid 5mg/ml and prepare 20 μ l/ holes with physiological saline; After continue cultivating 4h, (the 50 μ l/ holes of 10% SDS-5% isopropylcarbinol-0.01mol/LHCl) are 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%.
Screening method: tetrazolium (microculture tetrozolium, MTT) reduction method
Cell strain: P388D1 mouse lymph sample oncocyte, HeLa human cervical carcinoma cell
Action time: 24h
External living survey result to compound is as follows:
Compound is to the inhibiting rate % of P388D1 and HeLa growth
Above compound has stronger anti-tumor activity.

Claims (2)

1, the naphthalimide compound of a class 5-position or 6-position replacement is characterized in that this compound has following general structure (1):
In a, (1) formula: R 1Be C 1~C 6Alkyl or by the substituted radical shown in (2) formula
In the formula (2): n=1~6, R 4, R 5Be selected from H, C 1~C 6A kind of or pyrrole ring in the alkyl;
In b, (1) formula, work as R 2During=H, R 3Be selected from following substituted radical or work as R 3During=H, R 2Also be selected from following substituted radical:
-NHR 6R wherein 6Be C 1~C 6The straight or branched alkyl, Contain C 1~C 6The substituted-phenyl of alkyl, halogen, amino, nitro, thiophene, pyrroles, cumarone, pyridine and contain C 1~C 6These heterocycles that alkyl, halogen, amino, nitro replace.
2, the antitumor application method of the naphthalimide compound that replaces according to the described class 5-position of claim 1 or 6-position, it is characterized in that described compound adopts the tetrazolium reduction method to the strain of HeLa human cervical carcinoma cell to the extracorporeal suppression tumor cell growth activity, P388D1 mouse lymph sample tumor cell strain is tested, method is by different tumor growth rates, the tumor cell inoculation that some amount is in logarithmic phase is in 96 hole microtest plates, cultivate and add soup 10 μ L/ holes after 24 hours, each concentration of each cell strain is all established three multiple holes, other establishes acellular withered hole, when having color, medicine to do the acellular withered hole of relative medicine concentration, tumour cell is at 37 ℃, cultivate after 24 hours under the 5%CO2 condition, add MTT (Sigma) liquid 5mg/mL and dispose 20 μ L/ holes with physiological saline, continue to cultivate after 4 hours, add three liquid (the 50 μ L/ holes of 10%SDS-5% isopropylcarbinol-0.01mol/LHCl), in CO2gas incubator, spend the night, survey the OD570 value with microplate reader then;
Calculate the growth inhibition ratio of tested medicine by following formula to tumour cell:
Tumor control rate=(control group OD value-treatment group OD value)/control group OD value * 100%.
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