CN102731396B - Polyamine naphthalimide compounds and application of same in preparation of pharmaceutical preparation - Google Patents
Polyamine naphthalimide compounds and application of same in preparation of pharmaceutical preparation Download PDFInfo
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- CN102731396B CN102731396B CN201110337478.XA CN201110337478A CN102731396B CN 102731396 B CN102731396 B CN 102731396B CN 201110337478 A CN201110337478 A CN 201110337478A CN 102731396 B CN102731396 B CN 102731396B
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- 0 CCC(CN(C)CCN(C(c1cccc2c1c1ccc2*)=O)C1=O)=*C Chemical compound CCC(CN(C)CCN(C(c1cccc2c1c1ccc2*)=O)C1=O)=*C 0.000 description 1
Abstract
The invention discloses polyamine naphthalimide compounds. A preparation method for the compounds comprises the following steps: (a) weighing 4-bromo-1,8-naphthalenic anhydride and N, N-dimethyl ethylene diamine according to a mole ratio of 1: 1, mixing and heating 4-bromo-1,8-naphthalenic anhydride and N, N-dimethyl ethylene diamine, reacting for 8 to 10 h and then carrying out filtering and drying; and (b) weighing and adding intermediates obtained in step (a) and alicyclic amine into a glycol monomethyl ether solution, carrying out heating and a reaction for 8 to 12 h, evaporating the glycol monomethyl ether solution under reduced pressure, dissolving obtained solids with dichloromethane, separating an obtained solution with a silica gel column and carrying out elution with an eluant. The compounds provided in the invention have obvious inhibitory effects on the liver cancer cell Bel-7402, the leukemia cell HL-60, the human lung cancer cell A549, the human uterus cancer cell Hela and the like, and antineoplastic activity of a part of the compounds is superior to that of the commonly used antineoplastic drug cisplatin. Thus, application of the compounds in preparation of antineoplastic pharmaceutical preparations is brought forward for the first time in the invention; and particularly, application of the compounds in preparation of pharmaceutical preparations used for treating liver cancers, leukemia and uterus cancers is brought forward.
Description
Technical field
The present invention relates to new compound and uses thereof, specifically relate to polyamine compounds, with and application in useful in preparing drug formulations.
Background technology
The research of the antitumor drug taking DNA as target spot is the focus that people study always.Wherein naphthoyl imide compounds has caused the very big interest of people as the research of DNA intercalator and topoisomerase enzyme inhibitor, and entering at present the compound that the clinical II phase studies has amonafide, Mitonafide, elinafide and bisnafide etc.This compounds, by between intercalation of DNA molecule base pair, reaches the process that suppresses DNA and rna replicon, and can suppress the activity of topoisomerase II, thereby plays object (a) M.F. that suppresses tumor growth
, A.Ramos.Curr.Med.Chem.-Anti-Cancer Agents, 2001,1,237-255; B) Laurent Ingrassia, Florence Lefranc, Robert Kiss, and Tatjana Mijatovic.CurrentMedicinal Chemistry, 2009,16,1192-1213; C) Min Lv and Hui Xu.Current MedicinalChemistry, 2009,16,4797-4813.).
On the other hand, naphthoyl imide compounds has very strong cytolemma penetrativity and gene transfection effect, it is combined with the phosphate of DNA chain by electrostatic interaction, can strengthen targeting (a) the Otmane Boussif of drug molecule, FrankLezoialc ' h, Marla Antonietta Zanta, Mojgan Djavaheri Mergny, Daniel Scherman, Barbara Demeneix, Jean-Paul Behr.Proc.Natl.Acad.Sci.USA, 1995,92,7297-7301; B) Tae Gwan Park, Ji Hoon Jeong, Sung Wan Kim.Advanced Drug Delivery Reviews, 2006,58,467-486; C) Zhi-yong Tian, Song-qiang Xie, Zi-hou Mei, Jin Zhao, Wen-yuan Gao, Chao-jie Wang.Org.Biomol.Chem., 2009,7,4651-4660.).
Therefore, the urgent hope of people can obtain stronger, the active high naphthoyl imide compounds of multi-selection.
Summary of the invention
Object of the present invention is exactly for people provide more new naphthoyl imide compounds, and a kind of the application of invention compound in useful in preparing drug formulations is provided simultaneously.
Naphthoyl imide compounds provided by the present invention is a polyamine species naphthalimide compound, and its chemical structure of general formula is as follows:
Wherein
m=1,2,3 or 4
Above-claimed cpd (hereinafter to be referred as 4-position diamines naphthalimide compound), as m=1,2,3 or 4 time, R
1=quadrol base, propylene diamine base, butanediamine base or pentamethylene diamine base;
Its preparation method comprises the following steps
(a) according to molar part than 1: 1, take 4-bromo-1,8-naphthalene acid anhydride, N, N-dimethyl-ethylenediamine, by bromo-4-1,8-naphthalene acid anhydride, N, N-dimethyl-ethylenediamine is added in ethanol solution, is heated to 70-80 DEG C, keeps 1-3 hour, stopped reaction, reaction solution is chilled to room temperature, filters, be dried to obtain yellow solid intermediate N (N, N-dimethyl-1,3-the third diamino)-1,8-naphthalene acid anhydride;
(b) according to molar part than 1: 10, take above-mentioned intermediate, aliphatic amide, be added in ethylene glycol monomethyl ether solution, be heated to 100-150 DEG C, keep reaction 8～12 hours, stopped reaction, is chilled to room temperature, and decompression steams ethylene glycol monomethyl ether solution, the solids obtaining dissolves with methylene dichloride, solution separates through silicagel column, is that the volume ratio methylene chloride/methanol/triethylamine of 10: 1: 0.1 carries out wash-out with eluent, and eluate is 4-position diamines naphthalimide compound; Wherein said aliphatic amide is the one in quadrol, propylene diamine, butanediamine, pentamethylene diamine.
Another kind of polyamines naphthalimide compound provided by the present invention, its chemical structure of general formula is as follows:
Wherein
(n+2) HCl n=1,2 or 3
Above-claimed cpd is called for short 4-position polyamines naphthalimide compound, as n=1,2 or 3 time, and R
2the hydrochloride of=diethylenetriamine base, triethylene tetramine base or tetraethylene pentamine base;
Its preparation method comprises the following steps:
(a) according to molar part than 1: 1, take 4-bromo-1,8-naphthalene acid anhydride, N, N-dimethyl-ethylenediamine, by bromo-4-1,8-naphthalene acid anhydride, N, N-dimethyl-ethylenediamine is added in ethanol solution, is heated to 70-80 DEG C, keeps 1-3 hour, stopped reaction, reaction solution is chilled to room temperature, filters, be dried to obtain yellow solid intermediate N (N, N-dimethyl-1,3-the third diamino)-1,8-naphthalene acid anhydride;
(b) according to molar part than 1: 10, take above-mentioned intermediate, aliphatic amide, be added in ethylene glycol monomethyl ether solution, be heated to 100-150 DEG C, keep reaction 8～12 hours, stopped reaction, be chilled to room temperature, decompression steams ethylene glycol monomethyl ether solution, and residuum is without separation, the solution for continuous and the two tert.-butoxy formic anhydride (Boc that are 1/1 in methylene dichloride and methyl alcohol volume ratio
2o) reaction, obtained the amino intermediate of being protected by Boc, decompression steams solvent, crosses silicagel column and separates, eluent is the ethyl acetate/methanol of volume ratio 16/1, the intermediate obtaining and then react 2-12 hour under room temperature in the hydrochloric acid mixed solution (volume ratio 1/1) of ethanol and 6M, stopped reaction, adds ethanol, reaction solution turns lower centrifugal 15000, pour out supernatant liquid, repeatedly wash three times with ethanol, be dried to obtain 4-position polyamines naphthalimide compound; Wherein said aliphatic amide is a kind of hydrochloride in diethylenetriamine, triethylene tetramine, tetraethylene pentamine;
Above-mentioned 4-is bromo-1, and 8-naphthalene acid anhydride is the synthetic commercially available acquisition of raw material of the present invention.
Compound provided by the present invention has obvious restraining effect to liver cancer cell Bel-7402, leukemia cell HL-60, human lung cancer cell A549 and people's uterus carcinoma cell Hela etc., and the anti-tumor activity of part of compounds is better than antitumor common medicine cis-platinum.
Therefore the inventor proposes this compound first for the preparation of anti-tumor medicinal preparation.
Especially propose in the application of preparing in Hepatoma therapy pharmaceutical preparation; Application in preparation treatment leukemia medicament preparation; Application in preparation treatment uterus carcinoma pharmaceutical preparation.
4-of the present invention position diamines naphthalimide compound can with the mineral acid (example hydrochloric acid, sulfuric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid), organic acid (as acetic acid, propionic acid, citric acid, toxilic acid, oxysuccinic acid, tartrate, the methylsulfonic acid) salify that allow on physiology.
As 4-of the present invention position diamines naphthalimide compound and hydrochloric acid reaction can be obtained to 4-position diamines naphthalimide hydrochloride.Its concrete preparation method is as follows:
It is in the dehydrated alcohol, 6M hydrochloric acid mixed solution of 1: 1 that 4-position diamines naphthalimide compound is dissolved in to volume ratio, under room temperature, react 2-12 hour, stopped reaction, add ethanol, reaction solution turns lower centrifugal 15000, pours out supernatant liquid, repeatedly washes three times with ethanol, or directly decompression steams solvent, be dried to obtain 4-position diamines naphthalimide compound hydrochloride;
The compounds of this invention can allow the carrier using to be evenly mixed with into various forms of pharmaceutical preparations with pharmacology.As taking the compounds of this invention as active ingredient, be prepared into oral liquid with water, sucrose, Sionit, fructose etc.; Also can lactose, glucose, sucrose, N.F,USP MANNITOL sugar etc. is vehicle, taking starch etc. as disintegrating agent, taking stearic acid, talcum powder etc. as lubricant, gelatin, polyvinyl alcohol are that bonding agent is prepared into tablet or capsule; Also can be prepared into injection liquid with the mixed carrier of physiological saline, glucose solution or salt solution and glucose composition.
Compound of the present invention is being prepared into after pharmaceutical preparation, can or adopt oral administration or adopt intravenous drip administration according to the different of formulation.Dosage is also had nothing in common with each other because formulation is different.Concerning grownup, 25～200mg every day is more suitable for oral medication.Intramuscular injection or intravenous injection medication 10～100mg every day are more suitable.
Brief description of the drawings
Fig. 1 is the anti-tumor activity trend variation diagram of compound of the present invention.
Fig. 2 is the anti-tumor activity trend variation diagram of 4-of the present invention position diamines naphthalimide compound.
In Fig. 1, Fig. 2 in X-coordinate 1,2,3,4,5,6,7 be representation compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7 respectively.
Embodiment
Embodiment 1:
Intermediate N (N, N-dimethyl-1,3-the third diamino)-1,8-naphthalene acid anhydride (hereinafter to be referred as M1) synthetic:
Under room temperature by bromo-4-1,8-naphthalene acid anhydride (5.0g, 18.1mmol), N, N-dimethyl-ethylenediamine (2mL, 18.2mmol) joins in 100 milliliters of dehydrated alcohols; Be heated to 70-80 DEG C, keep reaction 1-3 hour.Stopped reaction, cool to room temperature, pressure reducing and steaming ethanol, obtains faint yellow solid (M
1).
In order to obtain purer intermediate, can be by M
1dissolve with methylene dichloride, cross silicagel column, obtain product (M with the eluent of methylene chloride/methanol (volume ratio 20/1)
1) 4.8 grams, productive rate is 76%.
Prepared M
1chemical structural formula is:
Hydrogen nuclear magnetic resonance
1h NMR data are:
1h NMR (600MHz, CDCl
3) δ (ppm) 2.35 (s, 6H, CH
3), 2.66 (t, J=7.2Hz, 2H, CH
2), 4.33 (t, J=7.2Hz, 6H, CH
3), 7.85 (t, J=7.8Hz, 1H, Ph), 8.05 (d, J=8.4Hz, 1H, Ph), 8.42 (d, J=7.8Hz, 1H, Ph), 8.57 (d, J=8.4Hz, 1H, Ph), 8.66 (d, J=7.2Hz, 1H, Ph).
Embodiment 2:
Synthesizing of N-(N, N-dimethyl-1,3-the third diamino)-4-quadrol base naphthalimide (compound 1):
Under room temperature by M
1(500mg, 1.4mmol), quadrol (864mg, 14mmol), triethylamine (1mL, 7.0mmol) joins in 20 milliliters of ethylene glycol monomethyl ether solutions and dissolves; Be heated to 100-150 DEG C, keep reaction 10 hours.Stopped reaction, cool to room temperature, pressure reducing and steaming ethylene glycol monomethyl ether, obtains yellow solid.Yellow solid is dissolved with methylene dichloride, separate through silicagel column, obtain 187 milligrams of products with the eluent of methylene chloride/methanol/triethylamine (volume ratio 10/1/0.02), productive rate is 40%, this dissolution of solid is (volume ratio 1/1) in the ethanol of 2mL and the hydrochloric acid soln of 6M, under room temperature, stir 2-12 hour, add 10mL ethanol, turn lower centrifugal 15000, pour out supernatant liquid, repeatedly wash 3 times, obtain N-(N, N-dimethyl-1,3-the third diamino)-4-quadrol base naphthalimide hydrochloride.Characterization data before this compound is protonated is as follows:
Yellow solid, m.p.174-175 DEG C;
Hydrogen nuclear magnetic resonance
1h NMR data
1H?NMR(600MHz，DMSO)δ(ppm)2.19(s，6H，CH
3)，2.45(t，J＝6.6Hz，2H，CH
2)，2.93(t，J＝6.0Hz，2H，CH
2)，3.41(t，J＝6.0Hz，2H，CH
2)，4.09(t，J＝6.6Hz，2H，CH
2)，6.73(d，J＝9.0Hz，1H，Ph)，7.61(t，J＝7.8Hz，1H，Ph)，8.18(d，J＝8.4Hz，1H，Ph)，8.36(d，J＝7.2Hz，1H，Ph)，8.69(d，J＝8.4Hz，1H，Ph)，
13C?NMR(150MHz，DMSO)δ37.64，41.80，45.81，45.97，57.13，104.27，108.08，120.61，122.20，124.64，129.20，129.84，131.10，134.66，151.25，163.33，164.20；MS(ESI)m/z：327.4[M+H]
+。
Embodiment 3:
Synthesizing of N-(N, N-dimethyl-1,3-the third diamino)-4-diethylenetriamine base naphthalimide (compound 2):
Under room temperature by M
1(500mg, 1.4mmol), diethylenetriamine (1.44g, 14mmol), triethylamine (1mL, 7.0mmol) joins in 20 milliliters of ethylene glycol monomethyl ether solutions; Be heated to 100-150 DEG C, keep reaction 8-12 hour.Stopped reaction, cool to room temperature, pressure reducing and steaming ethylene glycol monomethyl ether, obtaining yellow oily liquid is N-(N, N-dimethyl-1,3-the third diamino)-4-diethylenetriamine base naphthalimide.By yellow oily methylene chloride/methanol (volume ratio 1/1) dissolving for liquid, in reaction system, add N-(N, N-dimethyl-1, 3-the third diamino) two tert.-butoxy formic anhydrides of-5 times of molar weights of 4-diethylenetriamine base naphthalimide, under room temperature, react 0.5-2 hour, stopped reaction, decompression steams solvent, residuum is crossed silicagel column, obtain product with the eluent of ethyl acetate/methanol/(volume ratio 6/1), and then this product is dissolved in to (volume ratio 1/1) in the ethanol of 2mL and the hydrochloric acid soln of 6M, under room temperature, stir 2-12 hour, add 10mL ethanol, turn lower centrifugal 15000, pour out supernatant liquid, repeatedly wash 3 times, obtain yellow solid, be dried to obtain 288 milligrams of N-(N, N-dimethyl-1, 3-the third diamino)-4-diethylenetriamine base naphthalimide hydrochloride, two step productive rates are 40%.The characterization data of this compound is as follows:
Yellow solid, m.p.192-193 DEG C;
1h NMR (600MHz, D
2o) δ (ppm) 4.49 (s, 6H, CH
3), 4.87-4.94 (m, 4H, CH
2), 4.97-5.02 (m, 4H, CH
2), 5.29 (t, J=6.6Hz, 2H, CH
2), 5.72 (t, J=6.6Hz, 2H, CH
2), 7.97 (d, J=8.4Hz, 1H, Ph), 8.81 (t, J=8.4Hz, 1H, Ph) 9.26 (m, 1H, Ph), 9.41-9.42 (m, 2H, Ph),
13c NMR (150MHz, D
2o) δ 16.85,35.19,35.32,35.49,39.00,43.20,43.34,43.49,43.63,44.55,46.24,55.48,57.45,104.27,104.47,107.42,119.78,124.73,128.48,128.90,131.43,134.59,150.38,164.22,165.21; MALDI-MS:calcd for C
20h
27n
5o
2na, 392.2062[M+Na-4HCl]
+; Found 392.2073[M+Na-4HCl]
+.
Embodiment 4:
Synthesizing of N-(N, N-dimethyl-1,3-the third diamino)-4-diethylenetriamine base naphthalimide (compound 3):
Under room temperature by M
1(500mg, 1.4mmol), triethylene tetramine (2.04g, 14mmol), triethylamine (1mL, 7.0mmol) joins in 20 milliliters of ethylene glycol monomethyl ether solutions; Be heated to 100-150 DEG C, keep reaction 8-12 hour.Stopped reaction, cool to room temperature, pressure reducing and steaming ethylene glycol monomethyl ether, obtains yellow oily liquid.By yellow oily liquid N-(N, N-dimethyl-1, 3-the third diamino) methylene chloride/methanol (volume ratio 1/1) dissolving for naphthalimide of-4-diethylenetriamine base, in reaction system, add N-(N, N-dimethyl-1, 3-the third diamino) two tert.-butoxy formic anhydrides of-5 times of amounts of 4-diethylenetriamine base naphthalimide, under room temperature, react 0.5-2 hour, stopped reaction, decompression steams solvent, residuum is crossed silicagel column, obtain product with the eluent of ethyl acetate/methanol/(volume ratio 6/1), and then by this dissolution of solid (volume ratio 1/1) in the ethanol of 2mL and the hydrochloric acid soln of 6M, under room temperature, stir 2-12 hour, add 10mL ethanol, turn lower centrifugal 15000, pour out supernatant liquid, repeatedly wash 3 times, obtain yellow solid, be dried to obtain N-(N, N-dimethyl-1, 3-the third diamino) 291 milligrams of-4-diethylenetriamine base naphthalimide hydrochlorides, two step productive rates are 35%.The characterization data of this compound is as follows:
Brown color solid, m.p.192-193 DEG C;
1h NMR (600MHz, D
2o) δ (ppm) 2.93 (s, 6H, CH
3), 3.31-3.36 (m, 4H, CH
2), 3.41-3.46 (m, 4H, CH
2), 3.49-3.51 (m, 4H, CH
2), 3.77 (t, J=6.0Hz, 2H, CH
2), 4.23 (t, J=6.0Hz, 2H, CH
2), 6.47 (d, J=9.0Hz, 1H, Ph), 7.34 (t, J=8.4Hz, 1H, Ph), 7.78 (d, J=9.0Hz, 1H, Ph), 7.94-7.96 (m, 2H, Ph),
13c NMR (150MHz, D
2o) δ 34.79,35.25,35.32,35.49,39.03,43.32,43.43,43.49,43.50,44.62,44.66,46.41,50.36,50.73,52.73,55.63,104.48,107.69,119.69,120.03,124.80,128.71,128.97,131.54,134.69,150.48,164.47,165.44; MALDI-MS:calcd for C
22h
33n
6o
2, 413.2665[M+H-5HCl]
+; Found 413.2678[M+H-5HCl]
+.
Embodiment 5:
Synthesizing of N-(N, N-dimethyl-1,3-the third diamino)-4-diethylenetriamine base naphthalimide (compound 4):
Under room temperature by M
1(500mg, 1.4mmol), tetraethylene pentamine (2.65g, 14mmol), triethylamine (1mL, 7.0mmol) joins in 20 milliliters of ethylene glycol monomethyl ether solutions; Reaction system is heated to 100-150 DEG C, keeps reaction 8-12 hour.Stopped reaction, cool to room temperature, pressure reducing and steaming ethylene glycol monomethyl ether, obtaining yellow oily liquid is N-(N, N-dimethyl-1,3-the third diamino)-4-diethylenetriamine base naphthalimide.By yellow oily methylene chloride/methanol (volume ratio 1/1) dissolving for liquid, in reaction system, add N-(N, N-dimethyl-1, 3-the third diamino) two tert.-butoxy formic anhydrides of-5 times of amounts of 4-diethylenetriamine base naphthalimide, under room temperature, react 0.5-2 hour, stopped reaction, decompression steams solvent, residuum is crossed silicagel column, obtain product with the eluent of ethyl acetate/methanol/(volume ratio 6/1), and then by this dissolution of solid (volume ratio 1/1) in the ethanol of 2mL and the hydrochloric acid soln of 6M, under room temperature, stir 2-12 hour, add 10mL ethanol, turn lower centrifugal 15000, pour out supernatant liquid, repeatedly wash 3 times, obtain yellow solid, be dried to obtain N-(N, N-dimethyl-1, 3-the third diamino) 283 milligrams of-4-diethylenetriamine base naphthalimide hydrochlorides, two step productive rates are 30%.The characterization data of this compound is as follows:
Brown color solid, m.p.140-141 DEG C;
1h NMR (600MHz, D
2o) δ (ppm) 2.94 (s, 6H, CH
3), 3.47-3.31 (m, 16H, CH
2), 3.79 (t, J=6.0Hz, 2H, CH
2), 4.27 (t, J=6.0Hz, 2H, CH
2), 6.54 (d, J=9.0Hz, 1H, Ph), 7.39 (d, J=7.8Hz, 1H, Ph), 7.88 (d, J=9.0Hz, 1H, Ph), 8.04 (d, J=7.8Hz, 1H, Ph);
13c NMR (150MHz, D
2o): δ 30.32,35.33,35.59,39.10,43.50,43.69,43.78,43.85,44.69,46.42,55.78,104.61,107.92,119.89,120.29,124.96,128.95,129.07,131.72,134.89,150.62,164.71,165.66; MALDI-MS:calcd for C
24h
38n
7o
2, 456.3087[M+H-6HCl]
+; Found 456.3104[M+H-6HCl]
+.
Embodiment 6:
Synthesizing of N-(N, N-dimethyl-1,3-the third diamino)-4-propylene diamine base naphthalimide hydrochloride (compound 5):
Under room temperature by M
1(500mg, 1.4mmol), propylene diamine (1.04g, 14mmol), triethylamine (1mL, 7.0mmol) joins in 20 milliliters of ethylene glycol monomethyl ether solutions; Be heated to 100-150 DEG C, keep reaction 8-12 hour.Stopped reaction, cool to room temperature, pressure reducing and steaming ethylene glycol monomethyl ether, obtains yellow solid.Yellow solid is dissolved with methylene dichloride, cross silicagel column, obtain 300 milligrams of products with the eluent of methylene chloride/methanol/triethylamine (volume ratio 10/1/0.02), productive rate is 63%, this dissolution of solid is (volume ratio 1/1) in the ethanol of 2mL and the hydrochloric acid soln of 6M, under room temperature, stir 2-12 hour, add 10mL ethanol, turn lower centrifugal 15000, pour out supernatant liquid, repeatedly wash 3 times, obtain N-(N, N-dimethyl-1,3-the third diamino)-4-propylene diamine base naphthalimide hydrochloride.Characterization data before this compound is protonated is as follows:
Yellow oily liquid,
1h NMR (600MHz, CDOD) δ (ppm) 1.89-1.94 (m, 2H, CH
2), 2.33 (s, 6H, CH
3), 2.56 (t, J=7.2Hz, 2H, CH
2), 2.85 (t, J=7.2Hz, 2H, CH
2), 3.34 (t, J=7.2Hz, 2H, CH
2), 4.08 (t, J=7.2Hz, 2H, CH
2), 6.41 (d, J=9.0Hz, 1H, Ph), 7.28 (t, J=8.4Hz, 1H, Ph), 7.92 (d, J=8.4Hz, 1H, Ph), 8.06-8.08 (m, 2H, Ph),
13c NMR (150MHz, CDOD) δ 32.12,38.41,40.50,42.34,45.79,57.77,104.77,109.14,121.36,122.90,125.03,128.84,130.71,131.72,135.45,152.08,165.13,165.81; MS (ESI) m/z:341.3[M+H]
+.
Embodiment 7:
Synthesizing of N-(N, N-dimethyl-1,3-the third diamino)-4-butanediamine base naphthalimide hydrochloride (compound 6):
Under room temperature by M
1(500mg, 1.4mmol), butanediamine (1.23g, 14mmol), triethylamine (1mL, 7.0mmol), joins in 20 milliliters of ethylene glycol monomethyl ether solutions;
Reaction system is heated to 100-150 DEG C, keeps reaction 8-12 hour.Stopped reaction, cool to room temperature, pressure reducing and steaming ethylene glycol monomethyl ether, obtains yellow solid.Yellow solid is dissolved with methylene dichloride, cross silicagel column, obtain 287 milligrams of products with the eluent of methylene chloride/methanol/triethylamine (volume ratio 10/1/0.02), productive rate is 58%, this dissolution of solid is (volume ratio 1/1) in the ethanol of 2mL and the hydrochloric acid soln of 6M, under room temperature, stir 2-12 hour, add 10mL ethanol, turn lower centrifugal 15000, pour out supernatant liquid, repeatedly wash 3 times, obtain N-(N, N-dimethyl-1,3-the third diamino)-4-butanediamine base naphthalimide hydrochloride.Characterization data before this compound is protonated is as follows:
Yellow oily liquid,
1h NMR (600MHz, CDOD) δ (ppm) 1.46-1.51 (m, 2H, CH
2), 1.69-1.74 (m, 2H, CH
2), 2.18 (s, 6H, CH
3), 2.44 (t, J=7.2Hz, 2H, CH
2), 2.59 (t, J=6.6Hz, 2H, CH
2), 3.34 (t, J=6.6Hz, 2H, CH
2), 4.08 (t, J=7.2Hz, 2H, CH
2), 6.71 (d, J=9.0Hz, 1H, Ph), 7.63 (t, J=7.8Hz, 1H, Ph), 8.20 (d, J=8.4Hz, 1H, Ph), 8.37 (d, J=6.6Hz, 1H, Ph), 8.66 (d, J=8.4Hz, 1H, Ph)
13c NMR (150MHz, CDOD) δ 18.99,25.83,30.97,37.61,41.64,43.25,45.86,57.12,104.13,107.75,120.50,122.17,124.56,129.07,129.86,131.05,134.72,151.13,163.30,164.19; MS (ESI) m/z:355.3[M+H]
+.
Embodiment 8:
Synthesizing of N-(N, N-dimethyl-1,3-the third diamino)-4-pentamethylene diamine base naphthalimide hydrochloride (compound 7):
Under room temperature by M
1(500mg, 1.4mmol), pentamethylene diamine (1.43mg, 14mmol), triethylamine (1mL, 7.0mmol) joins in 20 milliliters of ethylene glycol monomethyl ether solutions; Reaction system is heated to 100-150 DEG C, keeps reaction 8-12 hour.Stopped reaction, cool to room temperature, pressure reducing and steaming ethylene glycol monomethyl ether, obtains yellow solid.Yellow solid is dissolved with methylene dichloride, cross silicagel column, obtain 335 milligrams of products with the eluent of methylene chloride/methanol/triethylamine (volume ratio 10/1/0.02), productive rate is 63%, and this dissolution of solid is (volume ratio 1/1) in the ethanol of 2mL and the hydrochloric acid soln of 6M, under room temperature, stirs 2-12 hour, decompression steams solvent, obtain yellow dope N-(N, N-dimethyl-1,3-the third diamino)-4-pentamethylene diamine base naphthalimide hydrochloride.Characterization data before this compound is protonated is as follows:
Yellow oily liquid,
1h NMR (600MHz, CDOD) δ (ppm) 1.41-1.45 (m, 4H, CH
2), 1.52-1.50 (m, 2H, CH
2), 1.72-1.70 (m, 2H, CH
2), 2.19 (s, 6H, CH
3), 2.61 (t, J=7.2Hz, 2H, CH
2), 2.65 (t, J=6.6Hz, 2H, CH
2), 3.38 (m, 2H, CH
2), 4.12 (t, J=7.2Hz, 2H, CH
2), 6.78 (d, J=8.4Hz, 1H, Ph), 7.67 (t, J=7.8Hz, 1H, Ph), 8.27 (d, J=8.4Hz, 1H, Ph), 8.43 (d, J=7.2Hz, 1H, Ph), 8.74 (d, J=9.0Hz, 1H, Ph)
13c NMR (150MHz, CDOD) δ 23.49,24.04,27.76,26.13,37.62,43.06,45.83,57.12,104.20,107.87,120.62,122.25,124.65,129.25,131.14,134.78,151.24,163.36,164.24; MS (ESI) m/z:369.2[M+H]
+.
Synthetic route in embodiment 1-8 gathers as follows:
Embodiment 9:
The antitumor activity of 4-position polyamines or diamines naphthalimide compound:
Test method:
Above-mentioned synthetic compound is by the anti-tumor activity test to four kinds of cell strains such as liver cancer cell Bel-7402, leukemia cell HL-60, human lung cancer cell A549 and people's uterus carcinoma cell Hela.
Described 4-position polyamines and diamines naphthalimide compound are configured to the liquid of different concns, by tetrazolium reduction method to Human hepatoma cell line Bel-7402, human leukemia cell line HL-60, human lung cancer cell A549 and human breast cancer cell Hela test, method is by different tumor growth rates, tumour cell by some amount in logarithmic phase is inoculated in 96 hole microtest plates with 90 μ L/ holes, after cultivating 24h, add the liquid 10 μ L/ holes that configure, to each cell strain, each concentration is four multiple holes, and the physiological saline solvent of establishing respective concentration contrasts, tumour cell is at 37 DEG C, 5%CO
2under condition, cultivate 48h, add MTT liquid 5mg/mL physiological saline and configure 20 μ L/ holes, continue to cultivate after 4h, every hole adds 100 μ L DMSO, fully after vibration, surveys OD by microplate reader
570value, calculate the inhibiting rate of the described compound containing triazole heterocyclic structure to growth of cancer cells by following formula:
Tumor control rate=(control group OD value-treatment group OD value)/control group OD value × 100%
And then, calculate IC by inhibiting rate
50value.
The results are shown in Table 1.
The IC of the anti-tumor activity of table 1 compound to Bel-7402, HL-60, A549 and Hela
50value
Test-results:
The activity all with obvious inhibition tumor growth of described compound 1-7 to liver cancer cell Bel-7402, leukemia cell HL-60, human lung cancer cell A549 and tetra-kinds of cell strains of people's uterus carcinoma cell Hela.Be embodied in:
(1) above-claimed cpd 1-7 has certain selectivity to human lung cancer cell A549's cell, has good anti-tumor activity.From IC
50value can find out, compound 1,2,5,6,7 is all better than the activity of positive control cis-platinum; Therefore when for the preparation of anti-tumor medicinal preparation, compound 1,2,5,6,7 is preferred;
(2) above-claimed cpd 1-7 has restraining effect to leukemia cell HL-60;
(3) for human lung cancer cell A549 and people's uterus carcinoma cell Hela cell, the activity of compound 1,5,6 and 7 is better than compound 2,3 and 4;
(4) for liver cancer cell Bel-7402, the anti-tumor activity of compound 2,3 and 4 is along with increasing of ethyleneimine base is downward trend, (as shown in Figure 1); Therefore when for the preparation of Hepatoma therapy pharmaceutical preparation, compound 2,3 is more preferred;
(5) for human lung cancer cell A549 and people's uterus carcinoma cell Hela cell, the anti-tumor activity of compound 1,5,6 and 7 is the trend (as shown in Figure 2) of reduction along with the growth of carbochain; Therefore when for the preparation for the treatment of lung-cancer medicament preparation, compound 1,5 is more preferred;
(6) compound 1,5,6 and 7 has shown certain selectivity to human lung cancer cell A549 in four cell strains of test, and anti-tumor activity is lower than 4 μ M.
Embodiment 10:
N-(N, N-dimethyl-1,3-the third diamino)-4-quadrol base naphthalimide (compound 1) injection liquid:
Get N-(N, N-dimethyl-1,3-the third diamino)-4-quadrol base naphthalimide hydrochloride 5000mg, be dissolved in 500ml water, make the aqueous solution, regulate pH to 5.5～6.5, heating for dissolving, mix, be distributed into the injection liquid that 100mg/10ml/ props up, steam circulation sterilizing 30 minutes.
Embodiment 11:
N-(N, N-dimethyl-1,3-the third diamino)-4-diethylenetriamine base naphthalimide (compound 2) oral liquid:
By 50000mg N-(N, N-dimethyl-1,3-the third diamino)-4-diethylenetriamine base naphthalimide hydrochloride, be dissolved in 2000ml water, make the aqueous solution of 2.5% concentration, regulate pH to 5.5～6.5, heating for dissolving, mix, pack in 10ml medicine bottle, sealing, sterilization.
Embodiment 12:
N-(N, N-dimethyl-1,3-the third diamino)-4-diethylenetriamine base naphthalimide (compound 3) tablet:
Get 200g N-(N, N-dimethyl-1,3-the third diamino)-4-diethylenetriamine base naphthalimide hydrochloride, by known method for preparing tablet thereof, add starch, dextrin, magnesium stearate etc., be mixed and made into wet grain, machine punching press is in blocks, and every containing N-(N, N-dimethyl-1,3-the third diamino)-4-diethylenetriamine base naphthalimide 25mg.
Pharmaceutical dosage form of the present invention is also not limited to this completely, and it can be prepared into more formulation, as dripping pill, capsule, soft capsule, sustained-release preparation etc.
Claims (5)
1. a polyamine species naphthalimide compound, its chemical structure of general formula is as follows:
Wherein
。
Described in claim 1 compound in the application of preparing in anti-tumor medicinal preparation.
3. the application of compound in preparation treatment leukemia medicament preparation described in claim 1.
Described in claim 1 compound in the application of preparing in Hepatoma therapy pharmaceutical preparation.
5. the application of compound in preparation treatment uterus carcinoma pharmaceutical preparation described in claim 1.
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| CN101323591A (en) * | 2008-07-23 | 2008-12-17 | 大连理工大学 | 5- or 6-substited naphthoyl imines compounds and antineoplastic application |
| CN101786985A (en) * | 2010-02-05 | 2010-07-28 | 苏州大学 | Naphthalimide derivative and use thereof as fluorescent probe |
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| CN101786985A (en) * | 2010-02-05 | 2010-07-28 | 苏州大学 | Naphthalimide derivative and use thereof as fluorescent probe |
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| Title |
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| "Novel naphthalimide derivatives as potential apoptosis-inducing agents:Design, synthesis and biological evaluation";Aibin Wu,et al.;《European Journal of Medicinal Chemistry》;20090716;第44卷;第4674-4680页 * |
| AibinWu et al.."Novel naphthalimide derivatives as potential apoptosis-inducing agents:Design |
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| Medicinal Chemistry》.2008,第16卷第8440-8446页. * |
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