CN105669657B - Naphthalimide-polyamines conjugate of benzopyran -4- ketone substitution and its preparation method and application - Google Patents

Naphthalimide-polyamines conjugate of benzopyran -4- ketone substitution and its preparation method and application Download PDF

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CN105669657B
CN105669657B CN201610101385.XA CN201610101385A CN105669657B CN 105669657 B CN105669657 B CN 105669657B CN 201610101385 A CN201610101385 A CN 201610101385A CN 105669657 B CN105669657 B CN 105669657B
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benzopyran
naphthalimide
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CN105669657A (en
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王超杰
王玉霞
谢松强
代付军
李骞
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Henan University
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

Naphthalimide polyamines conjugate the present invention relates to the substitution of 4 ketone of benzopyran and its preparation method and application, the naphthalimide polyamines conjugate has structure shown in following formula I.4 ketone naphthalimide polyamines conjugate of benzopyran provided by the invention is to HCT 116（Human colon cancer cell）、HepG2（Human liver cancer cell）、K562（The chronic marrow original leukaemia cell of people）、SMMC7721（Human liver cancer cell）Kinds of tumor cells proliferation all shows apparent inhibitory activity, while can also be used as targeting mitochondria fluorescence probe, can effectively inhibit the Lung metastases of tumour in vivo.I wherein a takes 0,1 or 2；M takes 1,2 or 3；N takes 1,2,3 or 4；R is H or CH3；R1For、、、、Or

Description

Naphthalimide-polyamines conjugate of benzopyran -4- ketone substitution and its preparation side Method and purposes
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of " naphthalimide-polyamines " containing benzopyran-4-one is sewed Close object and its preparation method and application.
Background technology
Polyamines is that a kind of have the function of the biological endogenous property small molecule of complex physiologic.Most eukaryocytes are on its cell membrane There are one polyamines movement systems, can adjust the concentration of intracellular polyamine on demand, these features based on polyamines cause it anti- It is interesting in the drug designs such as tumour and neuroprotection.And recent studies indicate that natural polyamines or synthetic polyamine have it is latent Power develops into a kind of targeting vector that can efficiently use the polyamine transport body on cell membrane.
Naphthoyl imide compounds are interesting as anti-tumor agent comprising salmosin in recent years, and a variety of naphthalimide derivatives once entered Clinical I phase and the experimental stage of II phases.But it has also been found that having serious central nervous system (NCS) toxicity, blood in clinical test The toxic side effects such as liquid toxicity and bone marrow suppression, and clinical activity is limited.
Flavone compound is a kind of compound with 2- phenyl chromone structures for being present in nature.Because its is low Malicious advantage, many natural or synthetic flavonoids such as rutin, Quercetin etc. have been enter into clinical I phase experiment, have centainly The effects that anticancer and reversing tumor drug resistance.
Invention content
The object of the present invention is to provide " naphthalimide-polyamines " conjugate of the one kind containing benzopyran-4-one and its preparations Method and purposes.
Based on above-mentioned purpose, the present invention adopts the following technical scheme that：
" naphthalimide-polyamines " conjugate of benzopyran -4- ketone substitution, the structural formula of the conjugate are as follows：
Wherein a takes 0,1 or 2；M takes 1,2 or 3；N takes 1,2,3 or 4；R is H or CH3；R1For
X takes 1,2 or 3.
The preparation method of " naphthalimide-polyamines " conjugate of above-mentioned benzopyran -4- ketone substitution, including walking as follows Suddenly：
First, compoundSynthesis
Can by following synthetic routes and step synthesis (its common structure can be purchased by market Buy),
(1) take 1,3- propane diamine or 1,4- butanediamine or piperazine (50mmol) be dissolved in 30mL 10v% triethylamine methanol it is molten Liquid, by 20mmol Boc under ice bath2The methanol solution 20mL of O (4.3g) is slowly dropped into above-mentioned solution, and drop, which finishes to be warmed to room temperature, to be stirred Mix 12h；Decompression steams solvent after completion of the reaction, and residue is first extracted with dichloromethane, then with saturation Na2CO3Solution washs, and receives Collect organic layer, anhydrous Na2SO4It is dry, it is concentrated to give compound 1 or compound 8；
(2) 4.50g (23.9mmol) compound 1 or compound 8 or morpholine or n-butylamine is taken to be dissolved in 100mL acetonitriles, adds nothing Aqueous carbonate potassium 4.5g (32mmol) after 15min is stirred at room temperature, is warming up to 45 DEG C, and 5.45 (20.4mmol) 3- bromines third are added portionwise Base phthalimide or 4- brombutyl phthalimides react 12h in 45 DEG C.Reaction terminates, and removes solvent under reduced pressure, Residue is first extracted with dichloromethane, and the Na of mass fraction 10% is used after extraction2CO3Aqueous solution washs, and collected organic layer is anhydrous Na2SO4It is dry, be concentrated under reduced pressure after in ethyl alcohol with a kind of two tert-butoxy formic acid anhydride reactants of 28.68mmol (6.194g) to raw material It has been reacted that, decompression steams solvent, the extraction of residue chloroform, washing；With volume ratio petroleum ether:Ethyl acetate=4:1 is purified by flash Product 2 and 6 or with volume ratio dichloromethane:Methanol=20:1 is purified by flash to obtain compound 9 and 11；
(3) 2.1g (4.3mmol) compound 2 or compound 6 or compound 9 or compound 11 are taken in 100mL absolute ethyl alcohols In, add hydrazine hydrate 1.27g (25mmol), 12h is stirred at room temperature, remove solvent under reduced pressure, residue is first extracted with dichloromethane, then is used The Na of mass fraction 10%2CO3Aqueous solution washs, collected organic layer, is concentrated to give compound 3 or compound 7 or compound 10 or changes Object 12 is closed, separation is not required to and is directly used in the next step.
(4) 8mmol compounds 3 are dissolved in 50mL acetonitriles, add Anhydrous potassium carbonate 2.25g (16mmol), 15min is stirred at room temperature Afterwards, 45 DEG C are warming up to, 2.14g (8mmol) N- (3- bromopropyls) phthalimide is added portionwise, reacts 12h in 45 DEG C. Reaction terminates, and removes solvent under reduced pressure, and residue is first extracted with dichloromethane, then with mass fraction 10%Na2CO3Solution washs, and receives Collect organic layer, anhydrous Na2SO4It is dry, it is concentrated under reduced pressure after anti-with two tert-butoxy formic anhydrides of 9.6mmol (2.07g) in ethyl alcohol Should, decompression steams solvent, the extraction of residue chloroform, washing, with volume ratio Shi You Mi ︰ ethyl acetate=4:1 is purified by flash to obtain production Object 4；Compound 4 is dissolved in 50mL absolute ethyl alcohols, adds hydrazine hydrate 1.27g (25mmol), is stirred overnight at room temperature, remove under reduced pressure molten Agent, residue are first extracted with dichloromethane, then the Na with mass fraction 10%2CO3Solution washs, collected organic layer, being concentrated to give Object 5 is closed, separation is not required to and is directly used in the next step.
2nd, the synthesis of target compound
(1) compound 13 and phosphorus oxychloride, n,N-Dimethylformamide are poured into water after reacting 3h in 90~95 DEG C, depressurize Filter to obtain compound 14；
(2) compound 14 in mass fraction 50%KOH solution withChinese red solid is made in reaction, this is solid Cyclization obtains compound 15 to body under concentrated sulfuric acid effect in dimethyl sulfoxide；
(3) compound 15 in glacial acetic acid liquid with potassium dichromate oxidation prepare compound 16；
(4) compound 16 flows back with compound 5 or 10 compound 12 of compound 7 or compound in absolute ethyl alcohol, product Column separating purification obtains compound 17；
(5) compound 17 is stirred overnight in absolute ethyl alcohol with 4M hydrochloric acid, and filtering absolute ethyl alcohol is washed up to target chemical combination Object 18.
The molar ratio of compound 16 and 10 compound 12 of compound 5 or compound 7 or compound is 1 ︰ 1 in step (4).
" naphthalimide-polyamines " conjugate of the benzopyran -4- ketone substitution is preparing antineoplastic object space The application in face.
" naphthalimide-polyamines " conjugate of the benzopyran -4- ketone substitution is preparing antitumor drug elder generation Lead the application in terms of compound.
It is described that " " naphthalimide-polyamines " conjugate of benzopyran -4- ketone substitution is preparing antitumor Lung metastases Application in terms of drug.
" naphthalimide-polyamines " conjugate of the benzopyran -4- ketone substitution is preparing mitochondria targeting The application of fluorescence probe.
Specific embodiment
Technical scheme of the present invention is described in further details below in conjunction with specific embodiment, but the protection model of the present invention It encloses and is not limited thereto.
Embodiment 1
6- (2-4H-1- benzopyran-4-ones)-{ 2- [(2- dimethylaminos)-ethyl] } -1H- benzisoquinolines -1,3 (2H)-diketone } hydrochloride (18a) preparation：
(1) 1,3- propane diamine (50mmol) is taken to be dissolved in the triethylamine methanol solution of 30mL 10v%, by 4.3g under ice bath Boc2The methanol solution 20mL of O (20mmol) is slowly dropped into above-mentioned solution, and drop, which finishes, is warmed to room temperature stirring 12h；Subtract after completion of the reaction Pressure steams solvent, and residue is first extracted with dichloromethane, then with saturation Na2CO3Solution washs, collected organic layer, anhydrous Na2SO4 It is dry, it is concentrated to give compound 1；
(2) 4.50g (23.9mmol) compound 1 is taken to be dissolved in 100mL acetonitriles, adds Anhydrous potassium carbonate 4.5g (32mmol), room After temperature stirring 15min, 45 DEG C are warming up to, 5.45g (20.4mmol) N- (3- bromopropyls) phthalimide is added portionwise, in 45 DEG C of reaction 12h.Reaction terminates, and decompression steams solvent, and residue is first extracted with dichloromethane, then with mass fraction 10% Na2CO3Solution washs, collected organic layer, anhydrous Na2SO4It is dry, be concentrated under reduced pressure after in absolute ethyl alcohol with 28.68mmol (6.19g) two tert-butoxy formic acid anhydride reactant, decompression steam solvent, and the extraction of residue chloroform, washing, organic layer is through volume ratio stone Oily ether:Ethyl acetate=4:1 is purified by flash to obtain compound 2；
(3) 2.1g (4.3mmol) compound 2 is taken to add hydrazine hydrate 1.27g (25mmol), room temperature in 100mL absolute ethyl alcohols 12h is stirred, decompression steams solvent, and residue is first extracted with dichloromethane, then the Na with mass fraction 10%2CO3Solution washs, Collected organic layer is concentrated to give compound 3, is not required to separation and is directly used in the next step；
(4) 8mmol compounds 3 are dissolved in 50mL acetonitriles, add Anhydrous potassium carbonate 2.25g (16mmol), 15min is stirred at room temperature Afterwards, 45 DEG C are warming up to, 2.14g (8mmol) N- (3- bromopropyls) phthalimide is added portionwise, reacts 12h in 45 DEG C.Instead It should terminate, decompression steams solvent, and residue is first extracted with dichloromethane, then uses 10wt%Na2CO3Solution washs, and collects organic Layer, anhydrous Na2SO4It is dry, be concentrated under reduced pressure after in ethyl alcohol with two tert-butoxy formic acid anhydride reactants of 9.6mmol (2.07g), reaction After decompression steam solvent, the extraction of residue chloroform, washing, organic layer is through volume ratio Shi You Mi ︰ ethyl acetate=4:1 elution Isolate and purify to obtain product 4；Compound 4 adds hydrazine hydrate 1.27g (25mmol), 12h is stirred at room temperature, subtracts in 50mL absolute ethyl alcohols Pressure steams solvent, and residue is first extracted with dichloromethane, then the Na with mass fraction 10%2CO3Solution washs, collected organic layer, Compound 5 is concentrated to give, separation is not required to and is directly used in the next step；
(5) 9mmoL (1.38g) compound 13 is taken to be mixed with 1.35mL phosphorus oxychloride, N, N- bis- are slowly added by dropping funel Methylformamide 1.35mL is finished and is poured into 27mL ice water after reacting 3h with 90~95 DEG C, and stirring has a large amount of brown viscous solids Generation, decompression filter, and wash to obtain compound 14；
(6) 15mmol (2.04g) o-hydroxyacetophenone is taken to add 19mmoL (3.55g) compound 14, anhydrous second in flask Alcohol 11mL, under ice-water bath stirring, constant pressure addition drip adds mass fraction 50%KOH aqueous solution 12g, and reacts 5.5h in 52 DEG C, Reaction terminates to pour into ice water, with concentrated hydrochloric acid tune pH value to 3~4 or so, has a large amount of red flocculent precipitations to generate, and decompression filters, Collect to obtain Chinese red solid.
Exocarpium Citri Rubrum solid obtained by step is taken in 27mL dimethyl sulfoxides, low-grade fever dissolving adds in the 3.5mL concentrated sulfuric acids, 110 DEG C of stirrings After 20min, 1 iodine grain, the reaction was continued 5.5h are added in, reaction finishes, reaction solution is poured into ice water, and decompression filters to obtain compound 15。
(7) it takes in 7.5mmoL (2.25g) compound 15 and flask, adds in glacial acetic acid 18mL, potassium bichromate 6.8g, 90~ 100 DEG C of reaction 2h, then pour into ice water after natural cooling 0.5h, have a large amount of dirty-green flocculent deposits to generate, decompression filters, and obtains Compound 16.
(8) 2mmoL (0.68g) compound 16 is taken in flask, adds in N, N- dimethyl-ethylenediamine 2mmol, is added in anhydrous Ethyl alcohol 20mL, is heated to reflux, TLC monitoring reactions, is depressurized after about 3h and steams solvent, volume ratio Shi You Mi ︰ ethyl acetate=2:1 It is purified by flash to obtain sterling 17.Take step gained compound 17 on 1mmol that in 10mL absolute ethyl alcohols, 4M HCl are added dropwise under ice bath stirring Ethyl alcohol (V4M hydrochloric acid:VEthyl alcohol=1:2) solution 0.5mL, drop finish, and 12h is stirred at room temperature and occurs to a large amount of solids, filters, collects solid, It is washed three times with the steamed absolute ethyl alcohol of weight, dry compound 18a yields：86%,1H NMR(400MHz,D2O)δ:7.98~ 8.05(m,3H,Ar-H)；7.62 (d, J=7.60Hz, 1H, Ar-H)；7.46 (t, J=7.88Hz, 1H, Ar-H)；7.24(d,J =6.80Hz, 1H, Ar-H)；7.19 (d, J=6.88Hz, 1H, Ar-H)；7.10 ((t, J=7.48Hz, 1H, Ar-H)；5.87 (s,1H,Ar-H)；4.43 (t, J=6.54Hz, 2H, 1 × N-CH2)；3.52 (t, J=6.62Hz, 2H, 1 × N-CH2)；3.13 (s,6H,2×CH3)；ESI-MI m/z:427.21[M+H-HCl]+.Anal.calcd for C26H23Cl1N2O4·1.45H2O: C 63.85%, H 5.34%, N 5.73%；Found C 63.90%, H 5.51%, N 5.48%.
Embodiment 2
6- (2-4H-1- benzopyran-4-ones) -2- [3- (3- aminopropyls)-aminopropyl] 1H- benzisoquinoline -1, 3 (2H) -one } dihydrochloride (18b) preparation：
Except N is replaced with 3a in (8) step, 2mL 4M HCl ethyl alcohol (V is added dropwise in N- dimethyl-ethylenediamines4M hydrochloric acid:VEthyl alcohol=1:2) Outside solution, other synthesizing progress methods are the same as embodiment 1.Yield：86%,1HNMR(400MHz,D2O)δ：8.15~8.26 (m, 3H,Ar-H)；7.82 (d, 1H, J=8.8Hz, Ar-H)；7.63~7.67 (m, 1H, Ar-H)；7.51~7.56 (m, 2H, Ar- H)；7.29 (t, J=7.78Hz, 1H, Ar-H), 7.12 (d, J=4.28Hz, 1H, Ar-H)；6.26(s,1H,Ar-H)；4.18 (t, J=6.96Hz, 2H, 1 × N-CH2)；3.21~3.26 (m, 4H, 2 × N-CH2)；3.15 (t, J=7.82Hz, 2H, 1 × N- CH2)；2.12~2.20 (m, 4H, 2 × CH2)；ESI-MS m/z:456.2[M+1–2HCl]+.Anal.calcd for C27H27Cl2N3O4·1.85H2O:C 57.73%, H 5.51%, N 7.48%；Found C 57.64%, H 5.50%, N 7.42%.
Embodiment 3
6- (2-4H-1- benzopyran-4-ones) -2- [3- (4- aminobutyls)-aminopropyl] 1H- benzisoquinoline -1, 3 (2H) -one } dihydrochloride (18c) preparation：
Except N is replaced with 3b in (8) step, 2mL 4M HCl ethanol solutions (V is added dropwise in N- dimethyl-ethylenediamines4M hydrochloric acid:VEthyl alcohol= 1:2) outside, other synthesizing progress methods are the same as embodiment 1.Yield：86%, white solid1H NMR(400MHz,D2O)δ：7.74 ~7.78 (m, 3H, Ar-H)；7.42 (t, 1H, J=3.70Hz, Ar-H)；7.26~7.29 (m, 2H, Ar-H)；7.05(s,2H, Ar-H)；6.74 (t, J=4.08Hz, 1H, Ar-H), 5.64 (d, 1H, J=4.68Hz, Ar-H)；3.98 (t, J=6.78Hz, 2H,1×N-CH2)；3.16~3.22 (m, 4H, 2 × N-CH2)；3.10 (1 × N-CH of t, 2H, J=7.12Hz2)；2.06(t, 1 × CH of 2H, J=7.02Hz2)；1.78-1.89(4H,2×CH2).ESI-MI m/z:470.21[M+H-2HCl]+ .Anal.calcd for C28H29Cl2N3O4·1.6H2O:C 58.87%, H 5.68%, N 7.36%；found C 58.97%, H 5.57%, N 7.45%.
Embodiment 4
6- (2-4H-1- benzopyran-4-ones) -2- [(4- butyl)-aminobutyl] 1H- benzisoquinolines -1,3 (2H) - Ketone } dihydrochloride (18d) preparation：
Except compound 7 is used to replace N in (8) step, 1.0mL 4M HCl ethanol solutions are added dropwise in N- dimethyl-ethylenediamines (V4M hydrochloric acid:VEthyl alcohol=1:2) outside, other synthesizing progress methods are the same as embodiment 1.Yield：86%, white solid1HNMR(400MHz, D2O)δ：7.77~7.86 (m, 3H, Ar-H)；7.46 (d, 1H, J=7.28Hz, Ar-H)；7.35 (t, 2H, J=7.84Hz, Ar- H)；7.16 (d, J=6.76Hz, 1H, Ar-H)；7.07 (t, 1H, J=7.44Hz, Ar-H)；6.84 (d, J=7.72Hz, 1H, Ar-H)；5.83(s,1H,Ar-H)；3.89 (t, J=8.0Hz, 1 × N-CH2)；3.06~3.13 (m, 4H, 2 × N-CH2)；1.75 ~1.79 (m, 2H, 1 × CH2)；1.65~1.73 (m, 4H, 2 × CH2)；1.39~1.45 (m, 2H, 1 × CH2)；0.95(t,3H, J=7.36Hz, 1 × CH3).ESI-MI m/z:469.2[M+H-3HCl]+.Anal.calcd for C29H29Cl1N2O4· 0.6H2O:C 67.53%, H 5.90%, N 5.43%；Found C 67.36%, H 5.90%, N 5.49%.
Embodiment 5
6- (2-4H-1- benzopyran-4-ones) -2- [4- (4- aminobutyls)-aminobutyl] 1H- benzisoquinoline -1, 3 (2H) -one } dihydrochloride (18e) preparation：
Except N is replaced with compound 3d in (8) step, 2mL 4M HCl ethanol solutions are added dropwise in N- dimethyl-ethylenediamines (V4M hydrochloric acid:VEthyl alcohol=1:2) outside, other synthesizing progress methods are the same as embodiment 1.Yield：86%, white solid1HNMR(400MHz, D2O)δ：7.68~7.76 (m, 3H, Ar-H)；7.37 (d, 1H, J=8.0Hz, Ar-H)；7.20~7.30 (m, 2H, Ar-H)； 6.98-7.06(m,2H,Ar-H)；6.73 (d, J=8.0Hz, 1H, Ar-H), 5.71 (s, 1H, Ar-H)；3.83 (t, 2H, J= 6.0Hz,1×N-CH2)；3.04~3.12 (m, 6H, 3 × N-CH2)；；1.76-1.78(m,6H,3×CH2)；1.63-1.65(m, 2H,1×CH2)(ESI-MI m/z:484.2[M+H-2HCl]+.Anal.calcd for C29H31Cl2N3O4·3.35H2O:C 56.47%, H 6.16%, N 6.81%；Found C 56.86%, H 6.24%, N 6.43%.
Embodiment 6
6- (2-4H-1- benzopyran-4-ones)-{ 2- [3- (3- (3- aminopropyls) aminopropyl)-aminopropyl]-amine } 1H- benzisoquinolines -1,3 (2H) -one } tri hydrochloride (18f) preparation：
Except N is replaced with compound 5a in (8) step, 3mL 4M HCl ethanol solutions are added dropwise in N- dimethyl-ethylenediamines (V4M hydrochloric acid:VEthyl alcohol=1:2) outside, other synthesizing progress methods are the same as embodiment 1.Yield：86%,1H NMR(400MHz,D2O)δ： 7.98~8.06 (m, 3H, Ar-H)；7.65 (d, 1H, J=7.68Hz, Ar-H)；7.51 (t, 1H, J=7.92Hz, Ar-H)； 7.41-7.45(m,1H,Ar-H)；7.31 (d, J=7.72Hz, 1H, Ar-H), 7.19 (t, 1H, J=7.6Hz, Ar-H)；6.95 (d, 1H, J=8.32Hz, Ar-H)；6.00 (s, 1H, Ar-H)；4.10 (t, 2H, J=6.68Hz, 1 × N-CH2)；3.21~ 3.27(m,8H,4×N-CH2)；3.14 (t, 2H, J=7.86Hz, 1 × N-CH2)；2.09-2.25(m,6H,3×CH2).ESI- MI m/z:513.25[M+H-3HCl]+.Anal.calcd for C30H35Cl3N4O4·1.0H2O:C 56.30%, H 5.83%, N 8.75%；Found C 56.03%, H 5.84%, N 8.88%.
Embodiment 7
6- (2-4H-1- benzopyran-4-ones) -2- [(3- piperazinyls)-propyl] 1H- benzisoquinolines -1,3 (2H) - Ketone } dihydrochloride (18g) preparation：
Except N is replaced with compound 10a in (8) step, 1.5mL 4M HCl ethanol solutions are added dropwise in N- dimethyl-ethylenediamines (V4M hydrochloric acid:V Ethyl alcohol=1:2) outside, other synthesizing progress methods are the same as embodiment 1.Yield：86%, white solid1H NMR (400MHz,D2O)δ:7.61~7.85 (m, 3H, Ar-H)；7.29 (d, J=5.16Hz, 1H, Ar-H)；7.17~7.19 (m, 2H,Ar-H)；6.96(s,1H,Ar-H)；6.64 (d, J=6.32Hz, 1H, Ar-H), 6.84~6.87 (m, 1H, Ar-H)；5.55 (s,1H,Ar-H)；3.71~3.82 (t, J=10Hz, 5 × N-CH2)；3.40 (t, J=8.2Hz, 1H, 1 × N-CH2)；1.87~ 1.88(m,2H,1×CH2)；1.63~1.65 (m, 2H, 1 × CH2).ESI-MI m/z:468.19[M+H-2HCl]+ .Anal.calcd for C28H27Cl2N3O4·3.0H2O:C 56.57%, H 5.60%, N 7.07%；found C 56.65%, H 5.34%, N 7.03%.
Embodiment 8
6- (2-4H-1- benzopyran-4-ones) -2- [(4- piperazinyls)-butyl] 1H- benzisoquinolines -1,3 (2H) - Ketone }-dihydrochloride (18h) preparation：
Except N is replaced with compound 10b in (8) step, 1.5mL 4M HCl ethanol solutions are added dropwise in N- dimethyl-ethylenediamines (V4M hydrochloric acid:VEthyl alcohol=1:2) outside, other synthesizing progress methods are the same as embodiment 1.Yield：86%, white solid1HNMR(400MHz, D2O)δ：7.61~7.65 (m, 3H, Ar-H)；7.29 (d, 1H, J=5.16Hz, Ar-H)；7.18~7.20 (m, 2H, Ar-H)； 6.96(s,2H,Ar-H)；6.64 (d, J=6.32Hz, 1H, Ar-H), 5.55 (s, 1H, Ar-H)；3.70-3.82 (m, 8H, 4 × N-CH2)；3.39 (t, J=8.2Hz, 2H, 1 × N-CH2)；1.86-1.88(m,2H,1×CH2)；1.63-1.65(m,2H,1× CH2)(ESI-MI m/z:482.2[M+H-2HCl]+.Anal.calcd for C29H29Cl2N3O4·3.0H2O:C 57.24%, H 5.80%, N 6.91%；Found C 57.53%, H 5.64%, N 6.95%.
Embodiment 9
6- (2-4H-1- benzopyran-4-ones) -2- [(morpholinyl)-propyl] 1H- benzisoquinolines -1,3 (2H) - Ketone } hydrochloride (18i) preparation：
Except compound 12 being used to replace N in (8) step, outside N- dimethyl-ethylenediamines, other synthesizing progress methods are the same as implementing Example 1.Yield：86%, white solid1H NMR(400MHz,D2O)δ：7.85 (d, J=7.56Hz, 2H, Ar-H)；7.78(d,1H, J=7.12Hz, Ar-H)；7.49 (d, J=7.16Hz, 1H, Ar-H)；7.37~7.40 (m, 1H, Ar-H)；7.31 (t, 1H, J= 7.82Hz,Ar-H)；7.11~7.18 (m, 2H, Ar-H)；6.87 (d, J=8.28Hz, 1H, Ar-H)；5.66(s,1H,Ar-H)； 4.19 (t, J=5.82Hz, 1 × N-CH2)；4.04 (t, J=6.68Hz, 1 × N-CH2)；3.92 (t, 2H, J=5.38Hz, 2 × N-CH2)；3.62~3.67 (m, 2H, 1 × CH2)；3.38 (t, 2H, J=7.94Hz, 1 × CH2)；3.25~3.27 (m, 2H, 1 × CH2)；2.15~2.20 (m, 2H, 1 × CH2).(ESI-MI m/z:469.17[M+H-HCl]+.Anal.calcd for C28H25Cl1N2O5·1.85H2O:C 62.48%, H 5.37%, N 5.20%；Found C 62.41%, H 5.29%, N 5.17%.
Embodiment 10
6- (2-4H-1- benzopyran-4-ones) -2- [(2- ethoxys)-ethyl] 1H- benzisoquinolines -1,3 (2H) - Ketone } hydrochloride (18j) preparation：
Except replacing N with compound beta-hydroxyethyl ethylenediamine in (8) step, outside N- dimethyl-ethylenediamines, other synthesis and carry Pure method is the same as embodiment 1.Yield：86%, white solid1H NMR(400MHz,D2O)δ:8.03~8.08 (m, 3H, Ar-H)； 7.65 (d, J=7.68Hz, 1H, Ar-H)；7.46~7.51 (m, 2H, Ar-H)；7.40 (d, J=7.88Hz, 1H, Ar-H)； 7.24 (t, J=7.58Hz, 1H, Ar-H)；7.04 ((d, J=8.36Hz, 1H, Ar-H)；5.97(s,1H,Ar-H)；4.42(t,J =6.26Hz, 2H, 1 × CH2)；3.89 (t, J=5.16Hz, 2H, 1 × CH2)；3.47 (t, J=6.26Hz, 2H, 1 × CH2)； 3.32 (t, J=5.12Hz, 2H, 1 × CH2).ESI-MI m/z:482.2[M+H-2HCl]+.Anal.calcd for C29H29Cl2N3O4·3.0H2O:C 57.24%, H 5.80%, N 6.91%；Found C 57.53%, H 5.64%, N 6.95%.
Embodiment 11
6- [2- (8- methyl) 4H-1- benzopyran-4-ones]-[2- (3- aminopropyls)] 1H- benzisoquinolines -1,3 (2H) -one } hydrochloride (18k) preparation：
It is other to synthesize and carry in addition to o-hydroxyacetophenone is replaced with compound 2- hydroxy-3-methyl acetophenones in (6) step Pure method is the same as embodiment 1.Yield:86%,1H NMR(400MHz,D2O)δ:7.98~8.05 (m, 3H, Ar-H)；7.62 (d, J= 7.60Hz,1H,Ar-H)；7.46 (t, J=7.88Hz, 1H, Ar-H)；7.24 (d, J=6.80Hz, 1H, Ar-H)；7.19(d,J =6.88Hz, 1H, Ar-H)；7.10 ((t, J=7.48Hz, 1H, Ar-H)；5.87(s,1H,Ar-H)；4.43 (t, J= 6.54Hz,2H,1×N-CH2)；3.52 (t, J=6.62Hz, 2H, 1 × N-CH2)；3.13(s,6H,2×CH3)；2.95(s,3H, 1×CH3)；ESI-MI m/z:427.21[M+H-HCl]+.Anal.calcd for C26H23Cl1N2O4·1.45H2O:C 63.85%, H 5.34%, N 5.73%；Found C 63.90%, H 5.51%, N 5.48%.
Embodiment 12
6- [2- (8- methyl) 4H-1- benzopyran-4-ones] -2- [2- (3- aminopropyls)] 1H- benzisoquinolines -1,3 (2H) -one } hydrochloride (18l) preparation：
Except o-hydroxyacetophenone is replaced with compound 2- hydroxy-3-methyl acetophenones in (6) step, Boc is used in (8) step The propane diamine of protection replaces N, and 1.0mL 4M HCl ethanol solutions (V is added dropwise in N- dimethyl-ethylenediamines4M hydrochloric acid:VEthyl alcohol=1:2) outside, Its synthesizing progress method is the same as embodiment 1.Yield:86%,1H NMR(400MHz,D2O)δ：7.97 (d, J=8.26Hz, 1H, Ar-H)；7.90 (d, 2H, J=7.66Hz, Ar-H)；7.57 (d, J=7.60Hz, 1H, Ar-H)；7.44 (t, J=10.86Hz, 1H,Ar-H)；7.15 (d, 1H, J=6.36Hz, Ar-H)；7.06 (d, J=6.92Hz, 1H, Ar-H)；7.00 (t, J= 7.44Hz,1H,Ar-H)；5.82(s,1H,Ar-H)；4.02 (t, J=6.98Hz, 1 × N-CH2)；3.16 (t, 2H, J= 7.32Hz,1×N-CH2)；2.04~2.12 (m, 2H, 1 × CH2)；1.65(s,3H,1×CH3).ESI-MI m/z:413.15[M +H-HCl]+.Anal.calcd for C25H21Cl1N2O4·0.5H2O:C 65.57%, H 4.84%, N 6.12%；found C 65.41%, H 6.29%, N 6.17%.
Biological evaluation：
(1) Compound ira vitro inhibits tumor cell growth activity to measure：
Compound prepared by selection example 1-12, HCT-116 (human cancer cell), the HepG2 in growth period of taking the logarithm respectively (human liver cancer cell), K562 (the chronic marrow original leukaemia cell of people), four kinds of tumor cell lines of SMMC7721 (human liver cancer cell) and QSG-7701 (Human normal hepatocyte) is embedded to 96 orifice plates, 90 μ L/ holes with every 5000-8000 cell in hole.After culture for 24 hours, add in 10th, 50,100,300,500 μM of sample, to each cell strain, each concentration is there are four multiple holes, at 37 DEG C, 5v%CO2Item After cultivating 48h under part, add 50 μ L (i.e. tetrazolium bromide) of MTT, continue to abandon supernatant after cultivating 4h, 100 μ L DSMO are added in per hole, gently 15min is vibrated, surveys its absorbance A value at 570nm wavelength with microplate reader.Measured object is calculated to different tumours by following formula In triplicate, and IC50 values are obtained by statistical software in the inhibiting rate of cell growth, experiment.It the results are shown in Table 1.
Growth of tumour cell inhibiting rate (%)=(OD controls-OD experiments)/(OD control-OD blank) × 100%
The growth inhibition of 1 each embodiment compound on tumor cell of table is lived
The compound of embodiment 1 to 12 is respectively to HCT-116 (human cancer cell), HepG2 (people it can be seen from 1 data of table Liver cancer cells), K562 (the chronic marrow original leukaemia cell of people), SMMC7721 (human liver cancer cell) four kinds of tumour cells cell toxicant Different degrees of effect is played in terms of effect causes compound to have selectivity.Most of embodiment compound is swollen to four kinds of tests Tumor cell strain has similar activity with positive control ammonia naphthalene Fitow；Wherein embodiment 10 is to the rejection ability of four kinds of tumor cell lines It is substantially better than positive control；2,5,12 compound of embodiment shows significantly lower than positive control QSG-7701 normal liver cells Toxicity, especially 5 compound of embodiment has tri- kinds of tumour cells of HCT-116, HepG2, SMMC7721 preferable selectivity, There are the potentiality of druggability substantially without toxicity to QSG-7701 normal liver cells simultaneously.
(2) compound measures the inhibition of mouse interior tumor Lung metastases：
The mouse H22 liver cancer cells of external exponential phase are taken, it is thin to 30 kunming mices injection H22 by intravenous injection Born of the same parents (5 × 106A/only), to ensure the tumour average production of all mouse before administration, it will cultivate 7 days, take after its inoculated tumour The mouse model being inoculated with after the 7th day is randomly divided into 3 groups (every group 10), and respectively physiological saline group, 5 groups of embodiment, the positive are right According to (ammonia naphthalene Fitow) group.Embodiment 5 (5mg/kg), ammonia naphthalene Fitow were injected respectively to mouse by tail vein injections at the 8th day (5mg/kg) and physiological saline (10mL/kg, negative control), and continue 7 days.Mouse was put to death with cervical dislocation in 15th day, The tubercle number of each lobe of the lung is counted with disecting microscope.Lung metastases inhibiting rate is calculated with following equation：Inhibiting rate (%)=(1- is treated The average Lung neoplasm number/negative control group of group is averaged Lung neoplasm number) × 100%.Experimental result is shown in Table 2.
2 embodiment of table, 5 compound inhibits mouse interior tumor Lung metastases activity
The compound provided in the present invention in vitro shows the proliferation of kinds of tumor cells compared to control drug ammonia naphthalene Fitow More obvious inhibitory activity and selectivity are shown, it is important that 12 compounds of synthesis compared with positive control ammonia naphthalene Fitow, The toxic side effect of normal liver cell QSG-7701 is substantially reduced.Wherein embodiment 5 there almost is not normal liver cell QSG-7701 There is any toxic side effect.And in vivo experiment, embodiment 5 is apparently higher than the rejection ability of mouse interior tumor Lung metastases pair According to drug ammonia naphthalene Fitow.Therefore it can be applied to the drug for preparing treatment metastases.It is carried out using laser co-focusing thin The fluorometric assay of intracellular, it was demonstrated that the compound has more than 95% registration with mitochondrial dye, so the compound It is positioned in cell mitochondrial, so Mitochondrially targeted property fluorescence probe can be used as, in vivo bioactivity shows such compound The Lung metastases of tumour can effectively be inhibited, be potential antitumor Lung metastases drug.
Above-described embodiment is the preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment Limitation, other any changes made without departing from the present invention should be equivalent substitute mode, are included in the guarantor of the present invention Within the scope of shield.

Claims (2)

1. naphthalimide-polyamines conjugate of benzopyran -4- ketone substitution is in terms of antitumor Lung metastases drug is prepared Using, which is characterized in that the structural formula of the conjugate is as follows：
Wherein a takes 0,1 or 2；M takes 1,2 or 3；N takes 1,2,3 or 4；R is H or CH3； R1For、、、、Or。
2. naphthalimide-polyamines conjugate of benzopyran -4- ketone substitution is preparing mitochondria targeting fluorescence probe Using, which is characterized in that the structural formula of the conjugate is as follows：
Wherein a takes 0,1 or 2；M takes 1,2 or 3；N takes 1,2,3 or 4；R is H or CH3； R1For、、、、Or。
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