CN117362297A - Imidazopyrimidine modified naphthalimide-polyamine conjugate as well as preparation method and application thereof - Google Patents

Imidazopyrimidine modified naphthalimide-polyamine conjugate as well as preparation method and application thereof Download PDF

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CN117362297A
CN117362297A CN202311292921.5A CN202311292921A CN117362297A CN 117362297 A CN117362297 A CN 117362297A CN 202311292921 A CN202311292921 A CN 202311292921A CN 117362297 A CN117362297 A CN 117362297A
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imidazopyrimidine
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naphthalimide
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王玉霞
葛小领
王治华
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Henan University
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention belongs to the technical field of compound synthesis, and particularly relates to an imidazopyrimidine modified naphthalimide-polyamine conjugate, and a preparation method and application thereof. The imidazopyrimidine modified naphthalimide-polyamine conjugate is a compound shown in a formula I or pharmaceutically acceptable salt thereof:

Description

Imidazopyrimidine modified naphthalimide-polyamine conjugate as well as preparation method and application thereof
Technical Field
The invention belongs to the technical field of compound synthesis, and particularly relates to an imidazopyrimidine modified naphthalimide-polyamine conjugate, and a preparation method and application thereof.
Background
Imidazopyrimidines are important nitrogen-containing heterocyclic compounds having a variety of biological activities and are now being used effectively in the market as famciclovir (fasiplon), taniplon (taniplon) and divalpron (divaplon). Facetipran, tanipran Long Chang are useful in the treatment of acute and chronic schizophrenia as well as other various psychotic states with pronounced positive symptoms and pronounced negative symptoms, which are central nervous system drugs, antipsychotics or anxiolytics. Devapraon is a novel sedative hypnotic. There is no report on the development and preparation of antitumor drugs having an imidazopyrimidine structural fragment.
Naphthalimide compounds have wide physiological activities and strong cytotoxicity as antitumor agents, and a plurality of naphthalimide derivatives have been put into clinical researches, for example, typical representative compounds of amonafide and Mi Tuonai ammonia have been put into clinical researches, and amonafide has been put into clinical three-phase researches. In recent years, structural modification and modification of naphthalimide to improve the activity thereof are one of the research hot spots of naphthalimide compounds at present. Polyamine is a substance necessary for cell metabolism and growth, has physiological activity, can utilize polyamine transport channels on cell membranes to transport drugs into tumor cells in a targeting manner, has the function of a drug carrier, and can improve the targeting of the drugs.
However, there is no study on co-modification of an imidazopyrimidine structural fragment with naphthalimide or polyamine to exert an antitumor effect. Therefore, how to develop a novel medicament with better anti-tumor activity by utilizing the groups has important significance for developing anti-tumor medicaments and improving clinical treatment effects of tumors.
Disclosure of Invention
The first object of the present invention is to provide an imidazopyrimidine modified naphthalimide-polyamine conjugate, which adopts imidazopyrimidine to modify naphthalimide naphthalene ring and is conjugated with polyamine to form a new pharmacophore, and the compound has the characteristics of imidazopyrimidine compounds while maintaining the activity of naphthalimide compounds, and can improve the anti-tumor activity of the compounds on tumor cells.
The second object of the invention is to provide a preparation method of an imidazopyrimidine modified naphthalimide-polyamine conjugate, which has mild process conditions and is convenient for realizing structural modification of naphthalimide related drugs.
The third object of the invention is to provide an application of an imidazopyrimidine modified naphthalimide-polyamine conjugate in preparing antitumor drugs.
One of the purposes of the invention is realized by adopting the following technical scheme:
an imidazopyrimidine modified naphthalimide-polyamine conjugate which is a compound of formula I:
in the formula I, m is 1, 2 or 3; r is selected from -NH 2 One of them.
The imidazopyrimidine modified naphthalimide-polyamine conjugate provided by the invention firstly adopts the imidazopyrimidine group to carry out structural transformation and modification on the 6-position of the naphthalimide naphthalene ring to synthesize a new imidazopyrimidine modified naphthalimide pharmacophore, then the imidazopyrimidine modified naphthalimide-polyamine conjugate is conjugated with polyamine, and a class of imidazopyrimidine modified naphthalimide-polyamine conjugate is designed and synthesized. The imidazopyrimidine is an important condensed heterocycle, and the compound is widely focused by pharmaceutical chemists as an important pharmacophore structure skeleton because of a novel structure and a unique action mechanism, and a large number of researches show that the compound containing the heterocycle has better biological activity, such as disinsection, sterilization, weeding, antiviral and the like. The fused heterocyclic fragment is firstly introduced into naphthalimide-polyamine conjugate with wide physiological activity, and a compound with a novel structure is designed and synthesized, so that the compound has the characteristics of an imidazopyrimidine compound while keeping the activity of the naphthalimide compound, the biological activity of the original molecule is improved, and the antitumor activity of the target molecule is improved.
The invention is not particularly limited in the kind of pharmaceutically acceptable salts, and can be selected by those skilled in the art according to actual needs. Preferably, the pharmaceutically acceptable salt is one or more of hydrochloride, sulfate, maleate, phosphate, citrate, hydrobromide, acetate, benzenesulfonate, tartrate, carbonate, citrate, malate, methanesulfonate, stearate, valerate, nitrate.
The second purpose of the invention is realized by adopting the following technical scheme:
the preparation method of the imidazopyrimidine modified naphthalimide-polyamine conjugate comprises the following steps of:
step (1): the compound is preparedAnd CH (CH) 3 COCl reaction to give the compound->
Step (2): the compound is preparedOn CH 3 COOH and Na 2 Cr 2 O 7 Carrying out reaction to obtain the compound
Step (3): the compound is preparedWith N-bromosuccinimide in acetonitrile, followed by purification to give the compound +.>
Step (4): the compound is preparedAnd->Reacting in acetone at 40-60 deg.c for 5-7 hr to obtain the compound +.>
Step (5): the compound is preparedWith amine chain R' NH in absolute ethanol 2 Reacting and purifying to obtain the compound->
Step (6): the compound is preparedMixing the mixture with acid in absolute ethyl alcohol to perform stirring reaction to obtain pharmaceutically acceptable salt of the compound shown in the formula I;
when the target product is a compound shown in a formula I, the preparation method comprises the steps of neutralizing the compound shown in the formula I and obtained in the step (6) in addition to the steps (1) to (6) to obtain the compound shown in the formula I;
wherein the amine chain R' NH 2 Selected from the group consisting of One of them.
The preparation method of the imidazopyrimidine modified naphthalimide-polyamine conjugate has the advantages of mild process conditions, high product yield and capability of effectively preparing the imidazopyrimidineAnd pyrimidine modified naphthalimide-polyamine conjugates. Wherein, in the step (4), the invention uses bromoacetyl naphthalene anhydrideWith 2-aminopyrimidine->In the reaction for preparing the imidazopyrimidine by condensation, firstly, a conventional solvent THF in the prior art is adopted, and a conventional operation mode of stirring at room temperature is adopted, but no target compound is generated by TLC monitoring reaction; then the reaction time is prolonged to 3 hours, most of raw materials are still unreacted through TLC monitoring, and the yield of products is very low through column chromatography separation; the reaction temperature is gradually increased to reflux from room temperature, the reaction time is prolonged to overnight from 3 hours, but the yield is still lower than 30 percent, and the requirement cannot be met at all. Based on the above, the inventor of the invention replaces the solvent with acetone on the basis of a plurality of technical researches and repeated exploring tests, and adjusts the reaction temperature to 40-60 ℃ for reaction for 5-7 hours, and the inventor discovers that the adoption of the conditions can greatly improve the reaction yield, the product can be separated out in a precipitation form, and the product obtained by decompression and filtration can be directly used for the next reaction, thereby greatly simplifying the post-treatment flow of the reaction and having obvious technical advantages.
In order to improve the reaction efficiency and the yield of the target product, preferably, in the step (3), the compoundThe reaction molar ratio of the N-bromosuccinimide is 2:1.
Further, in the step (4), the compoundAnd->The reaction molar ratio of (2) is 1:1.
Preferably, in the step (6), the acid is one or more of hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, citric acid, hydrobromic acid, acetic acid, benzenesulfonic acid, tartaric acid, carbonic acid, citric acid, malic acid, methanesulfonic acid, stearic acid, valeric acid, and nitric acid. The target product is subjected to salt forming reaction to prepare pharmaceutically acceptable salt, so that the application dosage form of the medicine can be conveniently expanded.
More preferably, in step (6), the acid is hydrochloric acid having a concentration of 4 mol/L.
The third purpose of the invention is realized by adopting the following technical scheme:
use of an imidazopyrimidine modified naphthalimide-polyamine conjugate as described above in the preparation of an anti-tumour medicament.
Preferably, the antitumor drug is a drug that inhibits tumor cell activity.
Further, the tumor cells are one or more of Sun739 cells, MCF-7 cells, PC-12 cells and HepG2 cells.
The inhibition test of tumor cells proves that the imidazopyrimidine modified naphthalimide-polyamine conjugate with the structure shown in the formula I has obvious inhibition activity on proliferation of various tumor cells such as Sun739 (human liver cancer cells), MCF-7 (human breast cancer cells), PC-12 (rat adrenal chromaffin cell tumor cells) and HepG2 (human liver cancer cells), and has good application prospect in development of novel antitumor drugs and antitumor lead compounds.
Detailed Description
The technical scheme of the invention is further described below with reference to specific embodiments. It is to be understood that the following examples are merely illustrative of the present invention and are not intended to be limiting thereof. The reagents used in the examples below are all commercially available unless otherwise indicated.
In the following examples, the imidazopyrimidine modified naphthalimide-polyamine conjugates involved are compounds of formula I:
in the formula I, m is 1, 2 or3, a step of; r is selected from -NH 2 One of them.
Specifically, the imidazopyrimidine modified naphthalimide-polyamine conjugate provided in the following examples, specifically, the hydrochloride form of the compound shown in formula I, has the structural formula shown in formula ii:
in the formula II, m is 1, 2 or 3; r is selected from -NH 2 One of the following; 1, 2 or 3.
Since the antitumor activity of the compound is given by the inherent structure of the compound, whether the compound forms a salt or not and the type of the salt only change the solubility of the compound, and the intrinsic activity of the compound is not affected. Thus, in other embodiments, the quinoxaline modified naphthalimide-polyamine conjugate may also be directly a compound of formula I, or one or more of the sulfate, maleate, phosphate, citrate, hydrobromide, acetate, benzenesulfonate, tartrate, carbonate, citrate, malate, methanesulfonate, stearate, valerate, nitrate of a compound of formula I, which is capable of achieving a similar effect as the hydrochloride salt.
The preparation routes of the compounds of examples 1 to 10 below are as follows, by changing R' NH 2 The obtained compounds are sequentially named as compounds 19a to 19j, and the specific method comprises the following steps:
step (1): the compound is preparedAnd CH (CH) 3 COCl reaction to give the compound->
Step (2): the compound is preparedOn CH 3 COOH and Na 2 Cr 2 O 7 Carrying out reaction to obtain the compound
Step (3): the compound is preparedWith N-bromosuccinimide in acetonitrile, followed by purification to give the compound +.>
Step (4): the compound is preparedAnd->Reacting in acetone at 40-60 deg.c for 5-7 hr to obtain the compound +.>
Step (5): the compound is preparedWith amine chain R' NH in absolute ethanol 2 Reacting and purifying to obtain the compound->
Step (6): the compound is preparedMixing the mixture with hydrochloric acid in absolute ethyl alcohol to carry out stirring reaction, thus obtaining pharmaceutically acceptable hydrochloride of the compound shown in the formula I.
Wherein the amine chain R' NH 2 Selected from the group consisting of
One of them. Amine chain R' NH 2 The synthesis may be carried out by referring to the synthetic route and process in example 1 below, and the common structure thereof may be purchased from commercial sources.
Example 1
The structural formula of the imidazopyrimidine modified naphthalimide-polyamine conjugate provided in the embodiment is as follows:
the preparation method of the compound of the example 1 specifically comprises the following steps:
1. amine chain R' NH 2 Is synthesized by (a)
Amine chain R' NH 2 The synthetic route of (2) is as follows:
(1) 2.01g (15 mmol) of anhydrous potassium carbonate and 0.92g (10 mmol) of cyclopropylamine are placed in a flask containing 25mL of acetonitrile, stirred at room temperature for 15min and then heated to 45 ℃, and then 3-bromopropyl phthalimide 1.79 (8 mmol)) is added in portions and keptThe reaction was carried out for 12 hours at this temperature. Then concentrating under reduced pressure, extracting the residue with chloroform, and saturating with Na 2 CO 3 Washing with aqueous solution, collecting organic layer, anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain light yellow oily matter. The oil was stirred at room temperature overnight in a mixture of 30mL of methanol and 15mmol (3.27 g) of di-tert-butyl dicarbonate, the solvent was distilled off under reduced pressure, the residue was extracted with chloroform, washed with water and separated by column chromatography (eluent: V) Petroleum ether :V Acetic acid ethyl ester =4:1) to give compound 2;
(2) 1.00g (2.05 mmol) of Compound 2 was taken in 30mL of absolute ethanol, 0.52g (12.5 mmol) of hydrazine hydrate was added, stirred at room temperature for 12 hours, the solvent was distilled off under reduced pressure, and the residue was extracted with dichloromethane and then with Na in a mass fraction of 10% 2 CO 3 Washing with aqueous solution, collecting organic layer, concentrating to obtain compound 3, and directly using in the next reaction without separation;
(3) 2.01g (15 mmol) of anhydrous potassium carbonate and 1.96g (10 mmol) of Compound 3 in 25mL of acetonitrile were taken, stirred at room temperature for 15min, then heated to 45℃and then 1.79 (8 mmol) of 3-bromopropyl phthalimide was added in portions and the temperature was maintained for reaction for 12 hours. Then concentrating under reduced pressure, extracting the residue with chloroform, and saturating with Na 2 CO 3 Washing with aqueous solution, collecting organic layer, anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain light yellow oily substance. The oil was stirred at room temperature overnight in a mixture of 30mL of methanol and 15mmol (3.27 g) of di-tert-butyl dicarbonate, the solvent was distilled off under reduced pressure, the residue was extracted with chloroform, washed with water and separated by column chromatography (eluent: V) Petroleum ether :V Acetic acid ethyl ester =4:1) to give compound 4;
(4) 1.00g (2.05 mmol) of Compound 4 was taken in 30mL of absolute ethanol, 0.52g (12.5 mmol) of hydrazine hydrate was added, stirred at room temperature for 12h, the solvent was distilled off under reduced pressure, the residue was extracted with dichloromethane and then with Na in a mass fraction of 10% 2 CO 3 The organic layer was collected by washing with aqueous solution and concentrated to give compound 5, which was used directly in the next reaction without isolation.
(5) 2.01g (15 mmol) of anhydrous potassium carbonate and 1.96g (10 mmol) of Compound 5 in 25mL of acetonitrile are stirred at room temperature for 15min and then heated to 45℃before the addition of 3-bromopropyl o-ring in portionsPhthalimide 1.79 (8 mmol) and this temperature was maintained for reaction for 12h. Then concentrating under reduced pressure, extracting the residue with chloroform, and saturating with Na 2 CO 3 Washing with aqueous solution, collecting organic layer, anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain light yellow oily substance. The oily substance was stirred at room temperature overnight in a mixture of 30mL of methanol and 15mmol (3.27 g) of di-tert-butyl dicarbonate, the solvent was distilled off under reduced pressure, the residue was extracted with chloroform, washed with water and separated by column chromatography (eluent: V) Petroleum ether :V Acetic acid ethyl ester =4:1) to give compound 6;
(6) 1.00g (2.05 mmol) of Compound 6 in 30mL of absolute ethanol was taken, 0.52g (12.5 mmol) of hydrazine hydrate was added, stirred at room temperature for 12h, the solvent was distilled off under reduced pressure, the residue was extracted with dichloromethane and then with Na in a mass fraction of 10% 2 CO 3 Washing with aqueous solution, collecting organic layer, concentrating to obtain compound 7, and directly using in the next reaction without separation;
(7) 20mmol of 1, 3-propylene diamine is added into 12mL of mixed solution of triethylamine and methanol in the volume ratio of 1:10, and 8mmol of Boc is added dropwise under ice bath 2 O (1.76 g) in methanol 8mL, after the dropping, stirring at room temperature overnight, then concentrating under reduced pressure, extracting residues by chloroform, washing by 10% sodium carbonate aqueous solution, collecting an organic layer, drying, and evaporating under reduced pressure to remove a solvent to obtain a compound 9;
(8) 2.01g (15 mmol) of anhydrous potassium carbonate, 1.96g (10 mmol) of Compound 9 were placed in a flask containing 25mL of acetonitrile, stirred at room temperature for 15min, then heated to 45℃and then 1.79 (8 mmol) of 3-bromopropyl phthalimide was added in portions and the temperature was maintained for reaction for 12 hours. Concentrating under reduced pressure after the reaction is finished, extracting the residual substances in the flask with chloroform, and saturating Na 2 CO 3 Washing with aqueous solution, collecting organic layer, anhydrous Na 2 SO 4 Drying, filtering, concentrating under reduced pressure, stirring in a mixture of 30mL of methanol and 15mmol (3.27 g) of di-tert-butyl dicarbonate at room temperature overnight, evaporating the solvent under reduced pressure, extracting the residue with chloroform, washing with water, and separating by column chromatography (eluent: V) Petroleum ether :V Acetic acid ethyl ester =4:1) to give compound 10;
(9) 1.00g (2.05 mmol) of Compound 10 is taken in 30mL of absolute ethanol and hydratedHydrazine 0.52g (12.5 mmol), stirring at room temperature for 12h, evaporating the solvent under reduced pressure, extracting the residue with dichloromethane and then Na with mass fraction of 10% 2 CO 3 Washing with aqueous solution, collecting organic layer, concentrating to obtain compound 11, and directly using in the next reaction without separation;
(10) 2.01g (15 mmol) of anhydrous potassium carbonate, 1.96g (10 mmol) of Compound 11 were placed in a flask containing 25mL of acetonitrile, stirred at room temperature for 15min, then heated to 45℃and then 1.79 (8 mmol) of 3-bromopropyl phthalimide was added in portions and the temperature was maintained for reaction for 12 hours. Concentrating under reduced pressure after the reaction is finished, extracting the residual substances in the flask with chloroform, and saturating Na 2 CO 3 Washing with aqueous solution, collecting organic layer, anhydrous Na 2 SO 4 Drying, filtering, concentrating under reduced pressure, stirring in a mixture of 30mL of methanol and 15mmol (3.27 g) of di-tert-butyl dicarbonate at room temperature overnight, evaporating the solvent under reduced pressure, extracting the residue with chloroform, washing with water, and separating by column chromatography (eluent: V) Petroleum ether :V Acetic acid ethyl ester =4:1) to give compound 12;
(11) 1.00g (2.05 mmol) of the compound 12 is taken in 30mL of absolute ethanol, 0.52g (12.5 mmol) of hydrazine hydrate is added, the mixture is stirred for 12h at room temperature, the solvent is distilled off under reduced pressure, the residue is extracted with dichloromethane and then Na with the mass fraction of 10 percent is added 2 CO 3 The organic layer was collected by washing with aqueous solution and concentrated to give compound 13, which was used directly in the next reaction without isolation. Compound 13 is the amine chain R' NH of example 1 2 。
2. Synthesis of target Compound
The route is as follows:
(12) 6.48mmol (1 g) acenaphthene and 1.30g (8.72 mmol) anhydrous AlCl are taken 3 In a dry flask, adding 20mL of dry dichloromethane, stirring for 15min in an ice bath, slowly dripping a mixed solution of 6.80mmol (4.86 mL) of acetyl chloride and 5mL of dichloromethane, reacting for 2h at room temperature after the addition, pouring into ice water, extracting with dichloromethane, washing with water, collecting an organic layer, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and obtaining a residue silica gelColumn separation (eluent: V) Petroleum ether :V Acetic acid ethyl ester =6:1) to afford compound 14 as a brown solid, yield 62.32%;
(13) 1.96g (10.0 mmol) of compound 14 and 7.45g (25.0 mmol) of Na were taken 2 Cr 2 O 7 .2H 2 O is heated to reflux in 25mL of glacial acetic acid for reaction for 6h and cooled to room temperature, the reaction solution is poured into 50mL of ice water, reduced pressure suction filtration is carried out, water is washed to be neutral, and the compound 15 in a light yellow solid state is obtained after drying, and the yield is 81.57%;
(14) 1.20g (5.0 mmol) of the compound 15 and 0.88g (2.5 mmol) of N-bromosuccinimide (NBS) were taken in 25mL of acetonitrile, stirred at 25℃for 15min, 1.90g (10.0 mmol) of p-toluenesulfonic acid was added thereto, and after heating to reflux for 5 hours, the solvent was distilled off under reduced pressure, and the residue was separated by a silica gel column (eluent: V) Petroleum ether :V Acetic acid ethyl ester =5:1) to give compound 16 as a yellow solid in 77.41% yield;
(15) 5mmol (0.48 g) of 2-aminopyrimidine and 5mmol (1.59 g) of compound 16 are taken and reacted in 25mL of acetone at 50 ℃ under stirring for 6h, then the mixture is filtered under reduced pressure, washed by acetone, and the solid is collected and dried to obtain compound 17, and the compound 17 is directly used in the next reaction without purification.
(16) 2.0mmol (0.63 g) of Compound 17 in 20mL of ethanol was taken, and 2.5mmol of the amine chain R' NH prepared as described above was added 2 Reflux under heating for 5h, vacuum evaporating to remove solvent, and separating the residue with silica gel column (eluent: V) Dichloromethane (dichloromethane) :V Methanol =100:3) to afford compound 18;
(17) Dissolving 2mmol of the compound 18 obtained in the previous step in 10mL of redistilled absolute ethyl alcohol, slowly dropwise adding 4M hydrochloric acid ethanol solution, stirring at room temperature for 12h after adding until a large amount of solids are separated out, carrying out vacuum filtration, washing a filter cake with absolute ethyl alcohol, and drying the filter cake to obtain a compound 19a, namely the imidazopyrimidine modified naphthalimide-polyamine conjugate of the example 1.
The compound of example 1 was a pale yellow solid in 41.26% yield. The structural characterization result is: 1 H NMR(500MHz,D 2 O):δ(ppm)8.90(dd,J＝1.50Hz,6.65Hz,1H,Ar-H),8.73(dd,J＝1.65Hz,4.30Hz,1H,Ar-H),8.20(d,J＝8.50Hz,1H,Ar-H),8.06(t,J＝7.15Hz,2H,Ar-H),8.02(d,J＝7.55Hz,1H,Ar-H),7.61(d,J＝7.55Hz,1H,Ar-H),7.45(t,J＝7.85Hz,1H,Ar-H),7.36(q,J＝4.40Hz,6.65Hz,1H,Ar-H),4.15(d,J＝6.80Hz,2H,1×N-CH 2 ),3.29(t,J＝8.00Hz,2H,1×N-CH 2 ),3.18-3.24(m,8H,4×CH 2 ),2.76-2.80(m,1H,1×N-CH),2.15-2.18(m,4H,2×CH 2 ),2.05-2.09(m,2H,1×CH 2 ),0.88-0.94(m,4H,2×CH 2 ). 13 C NMR(125MHz,D 2 O):δ(ppm)164.5,164.2,155.7,145.3,136.8,136.4,132.7,131.9,131.6,130.6,128.4,128.0,127.5,126.9,121.0,120.5,113.0,112.4,45.5,44.9,44.7,44.7,44.6,37.5,30.1,24.3,22.7,22.8,3.0.ESI-MS m/z:526.31[M-3HCl+H] + .Elemental Analysis for C 30 H 38 Cl 3 N 7 O 2 :C 56.74％,H 6.03％,N 15.44％；found:C 57.01％,H 5.75％,N 15.75％.
example 2
The structural formula of the imidazopyrimidine modified naphthalimide-polyamine conjugate provided in the embodiment is as follows:
the preparation method of the compound of example 2 is basically the same as that of the steps (12) to (17) in example 1, and the difference between them is that: in step (16), use is made ofThe procedure of example 1 was followed except that the amine chain was replaced with the one in example 1. Wherein, the amine chain R' NH employed in example 2 2 The preparation of (2) was carried out according to the procedure of example 1.
The compound of example 2 was a brown solid in 50.39% yield. The structural characterization result is: 1 H NMR(500MHz,D 2 O):δ(ppm)9.15(dd,J＝1.60Hz,6.70Hz,1H,Ar-H),8.95(dd,J＝1.60Hz,4.40Hz,1H,Ar-H),8.35(s,1H,Ar-H),8.28(d,J＝8.45Hz,1H,Ar-H),8.15(dd,J＝2.80Hz,7.60Hz,2H,Ar-H),7.77(d,J＝7.55Hz,1H,Ar-H),7.60(q,J＝4.70Hz,11.60Hz,2H,Ar-H),4.15(d,J＝12.90Hz,2H,1×N-CH 2 ),3.99(t,J＝7.10Hz,2H,1×O-CH 2 ),3.84(t,J＝12.05Hz,2H,1×O-CH 2 ),3.59(d,J＝12.65Hz,2H,1×N-CH 2 ),3.33(t,J＝8.20Hz,2H,1×N-CH 2 ),3.22-3.28(m,2H,1×N-CH 2 ),3.20(q,J＝7.60Hz,15.90Hz,4H,2×N-CH 2 ),2.21-2.28(m 2H,1×CH 2 ),2.03-2.09(m 2H,1×CH 2 ). 13 C NMR(125MHz,D 2 O):δ(ppm)164.5,164.2,157.4,144.6,137.5,134.1,131.8,131.6,131.3,130.5,128.9,128.4,127.8,127.1,121.8,120.8,113.7,113.4,63.8,53.8,51.9,45.5,44.5,37.5,24.2.ESI-MS m/z:499.26[M+H] + .Elemental Analysis for C 28 H 32 Cl 2 N 6 O 3 :C 58.85％,H 5.64％,N 14.71；found:C59.14％,H 5.81％,N 14.38％.
example 3
The structural formula of the imidazopyrimidine modified naphthalimide-polyamine conjugate provided in the embodiment is as follows:
the preparation of the compound of example 3 was substantially the same as in steps (12) to (17) of example 1, except that: in step (16), use is made ofThe procedure of example 1 was followed except that the amine chain was replaced with the one in example 1. Wherein, the amine chain R' NH employed in example 3 2 The preparation of (2) was carried out according to the procedure of example 1.
The compound of example 3 was a yellow solid in 60.53% yield. The structural characterization result is: 1 H NMR(500MHz,CDCl 3 ):δ(ppm)9.35(d,J＝6.70Hz,1H,Ar-H),8.66(dd,J＝1.60Hz,4.45Hz,1H,Ar-H),8.58-8.65(m,3H,Ar-H),8.06(d,J＝8.30Hz,1H,Ar-H),8.06(s,1H，Ar-H),8.02(s,1H,Ar-H),7.76(t,J1＝4.70Hz,1H,Ar-H),4.27(t,J＝6.25Hz,2H,1×N-CH 2 ),3.61(t,J＝6.85Hz,4H,2×O-CH 2 ),2.53(t,J＝7.05Hz,2H,1×N-CH 2 ),2.45(brs,4H,2×N-CH 2 ),1.95-1.98(m 2H,1×CH 2 ). 13 C NMR(125MHz,CDCl 3 ):δ(ppm)164.3,164.0,150.9,148.5,145.7,137.1,133.4,133.4,131.2,130.5,129.5,128.9,127.9,127.3,122.7,122.5,110.5,109.5,66.95,56.5,53.6,38.9,24.6.ESI-MS m/z:442.20[M+H] + .Elemental Analysis for C 25 H 23 N 5 O 3 :C 68.01％,H 5.25％,N 15.86％；found:C 67.72％,H 5.57％,N16.13％.
example 4
The structural formula of the imidazopyrimidine modified naphthalimide-polyamine conjugate provided in the embodiment is as follows:
the preparation method of the compound of example 4 is substantially the same as that of the steps (12) to (17) in example 1, and the difference is that: in step (16), use is made ofThe procedure of example 1 was followed except that the amine chain was replaced with the one in example 1. Wherein, the amine chain R' NH employed in example 4 2 The preparation of (2) was carried out according to the procedure of example 1.
The compound of example 4 was a yellow solid in 47.65% yield. The structural characterization result is: 1 H NMR(500MHz,D 2 O):δ(ppm)9.15(d,J＝5.05Hz,1H,Ar-H),8.97(s,1H,Ar-H),8.35(s,1H,Ar-H),8.24(d,J＝8.30Hz,1H,Ar-H),8.12(t,J＝8.15Hz,2H,Ar-H),7.74(d,1H,J＝7.40Hz,Ar-H),7.62(d,J＝3.62Hz,1H,Ar-H),7.54(t,J＝7.55Hz,1H,Ar-H),3.99(t,J＝6.03Hz,2H,1×N-CH 2 ),3.71(brs,8H,4×N-CH 2 ),3.46-3.48(m,2H,1×N-CH 2 ),2.16-2.18(m,2H,1×CH 2 ). 13 C NMR(125MHz,D 2 O):δ(ppm)164.3,163.9,157.5,144.6,137.5,133.9,131.7,131.5,131.1,130.5,128.8,128.3,127.7,126.9,121.6,120.7,113.7,113.4,54.9,48.5,40.7,37.4,22.1.ESI-MS m/z:440.123[M-2HCl+H] + .Elemental Analysis for C 25 H 26 Cl 2 N 6 O 2 :C 58.48,H 5.10,N 16.37；found:C 58.21％,H 4.75％,N 16.01％.
example 5
The structural formula of the imidazopyrimidine modified naphthalimide-polyamine conjugate provided in the embodiment is as follows:
the preparation of the compound of example 5 was substantially the same as in steps (12) to (17) of example 1, except that: in step (16), use is made ofThe procedure of example 1 was followed except that the amine chain was replaced with the one in example 1. Wherein, the amine chain R' NH employed in example 5 2 The preparation of (2) was carried out according to the procedure of example 1.
The compound of example 5 was a yellow solid in 69.58% yield. The structural characterization result is: 1 H NMR(500MHz,D 2 O):δ(ppm)9.08(dd,J＝1.60Hz,6.71Hz 1H,Ar-H),8.89(dd,J＝1.70Hz,4.40Hz,1H,Ar-H),8.26(s,1H,Ar-H),8.19(d,J＝8.24Hz,1H,Ar-H),8.05(t,J＝5.81Hz,2H,Ar-H),7.68(d,1H,J＝7.41Hz,Ar-H),7.54(q,J＝4.25Hz,6.45Hz 1H,Ar-H),7.47(t,J＝8.10Hz,1H,Ar-H),3.92(t,J＝6.24Hz,2H,1×N-CH 2 ),3.67-3.71(m,2H,1×N-CH 2 ),3.29(t,J＝7.71Hz,2H,1×N-CH 2 ),3.07-3.12(m,2H,1×N-CH 2 ),2.12-2.18(m,2H,1×CH 2 ),1.99-2.05(m,2H,1×CH 2 ). 13 C NMR(125MHz,D 2 O):δ(ppm)164.3,164.0,157.2,144.7,137.4,134.4,131.6,131.5,131.4,130.4,128.7,128.2,127.6,126.9,121.5,120.7,113.5,113.3,54.2,52.5,37.5,24.1,22.6.ESI-MS m/z:426.21[M+H] + .Elemental Analysis for C 25 H 24 ClN 5 O 2 :C 65.00％,H 5.24％,N 15.16％；found:C 65.23％,H 4.89％,N 15.41％.
example 6
The structural formula of the imidazopyrimidine modified naphthalimide-polyamine conjugate provided in the embodiment is as follows:
implementation of the embodimentsThe preparation method of the compound of example 6 is basically the same as that of the steps (12) to (17) in example 1, and the only difference is that: in step (16), use is made ofThe procedure of example 1 was followed except that the amine chain was replaced with the one in example 1. Wherein, the amine chain R' NH employed in example 6 2 The preparation of (2) was carried out according to the procedure of example 1.
The compound of example 6 was a yellow solid in 80.23% yield. The structural characterization result is: 1 H NMR(500MHz,D 2 O):δ(ppm)9.15(d,J＝6.70Hz,1H,Ar-H),8.97(t,J＝1.85Hz,1H,Ar-H),8.38(s,1H,Ar-H),8.33(d,J＝8.45Hz,1H,Ar-H),8.22(t,J＝7.80Hz,2H,Ar-H),7.81(d,J＝7.55Hz,1H,Ar-H),7.60-7.64(m,2H,Ar-H),4.35(t,J＝6.00Hz,2H,1×N-CH 2 ),3.48(t,J＝6.15Hz,2H,1×N-CH 2 ),3.02(s,6H,2×N-CH 3 ). 13 C NMR(125MHz,D 2 O):δ(ppm)164.6,164.2,157.7,144.6,137.6,133.8,132.0,131.9,131.3,130.7,129.0,128.4,128.0,127.3,121.8,120.8,113.9,113.4,55.2,43.4,35.4.ESI-MS m/z:386.17[M-HCl+H] + .Elemental Analysis for C 22 H 20 ClN 5 O 2 :C 62.63％,H 4.78％,N16.60％；found:C 62.28％,H 5.02％,N 16.43％.
example 7
The structural formula of the imidazopyrimidine modified naphthalimide-polyamine conjugate provided in the embodiment is as follows:
the preparation method of the compound of example 7 is basically the same as that of steps (12) to (17) in example 1, and the difference between them is that: in step (16), use is made ofThe procedure of example 1 was followed except that the amine chain was replaced with the one in example 1. Wherein, the amine chain R' NH employed in example 7 2 The preparation of (2) was carried out according to the procedure of example 1.
Example 7 Compounds areBrown solid, yield 30.5%. The structural characterization result is: 1 H NMR(500MHz,D 2 O):δ(ppm)9.15(d,J＝6.60Hz,1H,Ar-H),8.95(d,J＝1.95Hz,1H,Ar-H),8.36(d,J＝4.45Hz,1H,Ar-H),8.30(t,J＝8.20Hz,1H,Ar-H),8.17(t,J＝6.25Hz,2H,Ar-H),7.79(t,1H,J＝6.05Hz,Ar-H),7.60(q,J＝8.05Hz,14.05Hz,2H,Ar-H),4.01(t,J＝6.40Hz,2H,1×CH 2 ),3.12-3.23(m,8H,4×CH 2 ),3.12(t,J＝7.45Hz,2H,1×CH 2 ),2.05-2.21(m,6H,3×CH 2 ). 13 C NMR(125MHz,D 2 O):δ(ppm)164.6,164.3,157.4,144.7,137.5,134.3,131.8,131.7,131.3,130.6,128.9,128.4,127.9,127.1,121.8,120.9,113.6,113.3,45.5,44.7,44.6,44.6,37.5,36.53,24.25,23.7,22.7.ESI-MS m/z:486.27[M-3HCl+H] + .Elemental Analysis forC 27 H 34 Cl 3 N 7 O 2 :C 54.51％,H 5.76％,N 16.48％；found:C54.28％,H 5.31％,N 16.19％.
example 8
The structural formula of the imidazopyrimidine modified naphthalimide-polyamine conjugate provided in the embodiment is as follows:
the preparation method of the compound of example 8 is basically the same as that of steps (12) to (17) in example 1, and the difference between them is that: in step (16), use is made ofThe procedure of example 1 was followed except that the amine chain was replaced with the one in example 1. Wherein, the amine chain R' NH employed in example 8 2 The preparation of (2) was carried out according to the procedure of example 1.
The compound of example 8 was a yellow solid in 47.86% yield. The structural characterization result is: 1 H NMR(500MHz,D 2 O):δ(ppm)9.08(dd,J1＝1.75Hz,6.75Hz,1H,Ar-H),8.94(dd,J＝1.75Hz,4.44Hz,1H,Ar-H),8.24(s,1H,Ar-H),8.19(d,J＝8.25Hz,1H,Ar-H),8.04(q,J＝7.35Hz,9.90Hz,2H,Ar-H),7.66(d,1H,J＝7.55Hz,Ar-H),7.54(q,J＝4.45Hz,6.70Hz,1H,Ar-H),7.49(t,J＝7.51Hz,1H,Ar-H),3.84(t,J＝7.20Hz,2H,1×N-CH 2 ),3.10-3.13(m,4H,2×N-CH 2 ),3.06(t,J＝6.45Hz,2H,1×N-CH 2 ),1.74-1.79(m,6H,3×CH 2 ),1.62-1.65(m,2H,1×CH 2 ). 13 C NMR(125MHz,D 2 O):δ(ppm)164.3,164.0,157.0,144.8,137.3,134.7,131.6,131.4,131.4,130.4,128.6,128.2,127.6,126.9,121.6,120.8,113.4,113.2,47.2,46.9,39.8,38.8,24.2,24.0,23.2,22.8.ESI-MS m/z:457.25[M-2HCl+H] + .Elemental Analysis for C 26 H 30 Cl 2 N 6 O 2 :C 58.98％,H 5.71％,N 15.87％；found:C58.65％,H 5.34％,N 16.02％.
example 9
The structural formula of the imidazopyrimidine modified naphthalimide-polyamine conjugate provided in the embodiment is as follows:
the preparation method of the compound of example 9 is substantially the same as that of the steps (12) to (17) in example 1, and the difference is that: in step (16), use is made ofThe procedure of example 1 was followed except that the amine chain was replaced with the one in example 1. Wherein, the amine chain R' NH employed in example 9 2 The preparation of (2) was carried out according to the procedure of example 1.
The compound of example 9 was a yellow solid in 45.58% yield. The structural characterization result is: 1 H NMR(500MHz,D 2 O):δ(ppm)9.14(d,J＝6.75Hz,1H,Ar-H),8.96-8.97(m,1H,Ar-H),8.36(s,1H,Ar-H),8.31(d,J＝8.40Hz,1H,Ar-H),8.19(d,J＝7.51Hz,2H,Ar-H),7.80(d,1H,J＝7.60Hz,Ar-H),7.59-7.63(m,2H,Ar-H),4.02(t,J＝6.70Hz,2H,1×N-CH 2 ),3.20(q,J＝8.35Hz,J＝16.05Hz,4H,2×N-CH 2 ),3.14(t,J＝7.85Hz,2H,1×N-CH 2 ),2.11-2.18(m,2H,1×CH 2 ),2.04-2.09(m,2H,1×CH 2 ). 13 C NMR(125MHz,D 2 O):δ(ppm)164.6,164.2,157.4,144.7,137.5,134.2,131.8,131.6,131.3,130.6,128.9,128.4,127.9,127.1,121.8,120.9,113.7,113.3,45.5,44.7,37.5,36.6,24.2,23.8.ESI-MS m/z:429.22[M-2HCl+H] + .Elemental Analysis for C 24 H 26 Cl 2 N 6 O 2 :C 57.49％,H 5.23％,N 16.76％；found:C 57.68％,H 5.49％,N 17.02％.
example 10
The structural formula of the imidazopyrimidine modified naphthalimide-polyamine conjugate provided in the embodiment is as follows:
the preparation method of the compound of example 10 is substantially the same as that of steps (12) to (17) in example 1, and the only difference is that: in step (16), use is made ofThe procedure of example 1 was followed except that the amine chain was replaced with the one in example 1. Wherein, the amine chain R' NH employed in example 10 2 The preparation of (2) was carried out according to the procedure of example 1.
The compound of example 10 was a yellow solid in 75.52% yield. The structural characterization result is: 1 H NMR(500MHz,D 2 O):δ(ppm)9.10(dd,J＝1.75Hz,6.75Hz,1H,Ar-H),8.92(dd,J＝1.80Hz,4.45Hz,1H,Ar-H),8.29(s,1H,Ar-H),8.24(d,J＝8.45Hz,1H,Ar-H),8.12(d,J＝7.50Hz,2H,Ar-H),7.72(d,1H,J＝7.60Hz,Ar-H),7.52-7.57(m,2H,Ar-H),3.99(t,J＝6.95Hz,2H,1×N-CH 2 ),3.10(t,J＝9.15Hz,2H,1×N-CH 2 ),1.99-2.05(m,2H,1×CH 2 ). 13 C NMR(125MHz,D 2 O):δ(ppm)164.5,164.2,157.2,144.7,137.4,134.5,131.4,131.6,131.4,130.5,128.8,128.3,127.7,127.0,121.7,120.8,113.5,113.3,37.5,37.3,25.3.ESI-MS m/z:372.16[M-HCl+H] + .Elemental Analysis for C 21 H 18 ClN 5 O 2 :C61.84％,H 4.45％,N 17.17％；found:C 62.11％,H 4.68％,N 17.43％.
comparative example 1
The naphthalimide-polyamine conjugates provided in this comparative example are structurally similar to the compound of example 9, except that the 6-position of the naphthalimide naphthalene ring is not structurally modified. The specific structural formula is as follows:
the compound of comparative example 1 was a pale yellow solid, 67.02% yield. The structural characterization result is: 1 H NMR(D 2 O,400MHz)δ:7.54(d,2H,J＝8.0Hz),7.49(d,2H,J＝7.2Hz),7.12(t,2H,J＝8.0Hz),3.53(t,2H,J＝7.2Hz),3.10～3.20(m,6H),2.07～2.15(m,2H),1.67～1.74(m,2H),1.47～1.52(m,2H)； 13 C NMR(D 2 O)δ:164.12,134.73,130.84,129.82,126.57,125.46,119.22,47.24,44.50,39.52,36.57,24.08,23.78,23.16；ESI-MS m/z:326.1[M+H-2HCl] + ；Anal.calcd.for C 18 H 23 Cl 2 N 3 O 2 :C 56.26,H 6.03,N10.93；found:C 56.52,H 6.28,N 10.073.
comparative example 2
The imidazopyridine modified naphthalimide-polyamine conjugates provided in this comparative example are structurally similar to the compound of example 3, except that the modified fragment at the 6-position of the naphthalimide naphthalene ring is different. The modified fragment adopted in the comparative example is imidazopyridine, and the specific structural formula is as follows:
the compound of comparative example 2 was a yellow solid in 49.02% yield. The structural characterization result is: 1 H NMR(300MHz,D 2 O):δ(ppm)8.54(d,J＝9.05Hz,1H,Ar-H),8.26(s,1H,Ar-H),8.18-8.03(m,3H,Ar-H),7.81(m,1H,Ar-H),7.69-7.66(m,2H,Ar-H),7.49(t,1H,J＝8.60Hz,Ar-H),7.35(t,1H,J＝6.10Hz,Ar-H),4.07-3.83(m,4H,2×CH 2 ),3.71(t,J＝7.15Hz,2H,1×CH 2 ),3.43(d,2H,J＝8.45Hz,1×CH 2 ),3.24-2.95(m,4H),2.04-1.94(m,2H). 13 C NMR(75MHz,D 2 O):δ(ppm)159.3,150.2,145.1,140.1,128.0,137.9,137.5,129.7,129.5,126.8,126.2,125.6,124.1,114.6,116.8,113.1,66.7,62.9,56.4,51.9,26.6.ESI-MS m/z:441.38[M-2HCl+H] + .Elemental Analysis for C 25 H 26 ClN 4 O 3 :C65.47％,H 5.28％,N11.75％；found:C 65.71％,H 4.99％,N 11.49％.
comparative example 3
The imidazopyridine modified naphthalimide-polyamine conjugates provided in this comparative example are structurally similar to the compound of example 9, except that: the modified fragment at the 6-position of the naphthalimide naphthalene ring is different. The structural formula of the comparative example compound is as follows:
the compound of comparative example 3 was a yellow solid in 51.34% yield. The structural characterization result is: 1 H NMR(300MHz,DMSO):δ(ppm)13.22(s,1H,Ar-H),9.75(d,1H,J＝8.02Hz,Ar-H),8.63(d,1H,J＝7.95Hz,Ar-H),8.58(d,1H,J＝7.81Hz,Ar-H),8.37(1H,J＝7.61Hz,Ar-H),7.99(dd,1H,J 1 ＝J 2 ＝8.14Hz,Ar-H),7.84(d,1H,J＝7.60Hz,Ar-H),7.66(d,1H,J＝7.58Hz,Ar-H),7.32(m,2H,Ar-H),4.16(t,2H,J＝8.05Hz,1×CH 2 ),3.01(q,J＝6.21Hz,J＝8.15Hz,4H,2×CH 2 ),2.89(t,J＝5.39Hz,2H,1×CH 2 ),2.09-2.15(m,2H,1×CH 2 ),2.03-2.07(m,2H,1×CH 2 ). 13 C NMR(75MHz,DMSO):δ(ppm)159.3,152.9,145.6,141.7,138.0,137.9,137.5,129.7,129.5,126.8,125.6,124.1,123.0,115.2,45.1,44.2,37.1,36.5,24.0,23.9.ESI-MS m/z:413.17[M-HCl+H] + .Elemental Analysis for C 25 H 27 Cl 2 N 5 O 2 :C 60.00％,H 5.44％,N14.00％；found:C 60.15％,H 5.70％,N 14.31％.
experimental example in vitro determination of tumor cell growth inhibition Activity
The imidazopyrimidine-modified naphthalimide-polyamine conjugates prepared in examples 1 to 10 of the present invention and the compounds prepared in comparative examples 1 to 3 were selected as subjects, and Sun739 (human liver cancer cell), MCF-7 (human breast cancer cell), PC-12 (rat adrenal chromaffin cell tumor cell) and HepG2 (human liver cancer cell) tumors in the logarithmic growth phase were taken, respectivelyCell lines were embedded in 96-well plates at 5000-8000 cells per well, 90. Mu.L/well. After 24h of incubation, 100, 300. Mu.M of the sample to be tested diluted with medium are added, each concentration having four multiplex wells, at 37℃with 5% CO 2 After 48h incubation, 50. Mu.L of MTT (thiazole blue) was added, incubation was continued for 4h, 100. Mu.L of DSMO was added to each well, and the absorbance A was measured at 570nm by a microplate reader with gentle shaking for 15 min. The inhibition rate of the test object on the growth of different tumor cells is calculated according to the following formula, and the experiment is repeated three times. The results are shown in Table 1. Tumor cell growth inhibition (%) = OD control-OD experiment)/(OD control-OD blank) ×100%.
Table 1 comparison of growth inhibitory Activity of example and comparative Compounds against tumor cells
From the inhibitory activity data in Table 1, it is understood that the compounds of examples 1 to 10 of the present invention have various degrees of inhibition on the growth of four tumor cells, sun739 (human liver cancer cell), MCF-7 (human breast cancer cell), PC-12 (rat adrenal pheochromocytoma cell) and HepG2 (human liver cancer cell), respectively. Wherein, the inhibition capability of the compounds of examples 1-10 on Sun739 tumor cell lines is superior to that of positive control amonafide at low concentration and high concentration; the compound of example 2 has 16 times higher inhibitory capacity on Sun739 tumor cell line than amonafide at a concentration of 10 μm; the compounds of examples 1 to 10 showed slightly weaker inhibition of the MCF-7 tumor cell strain than the positive control at a concentration of 10. Mu.M, but the activity at a high concentration of 30. Mu.M was comparable to that of the positive control except for example 3, and the remaining compounds were superior to the positive control; the inhibition ability of the compounds of examples 1 to 10 on PC-12 tumor cell lines at a concentration of 30 mu M is also better than that of the positive control; the inhibition ability of the compounds of examples 1 to 10 on HepG2 tumor cell lines at a concentration of 30. Mu.M was almost superior to that of the positive control, and examples 7, 8 and 9 were slightly weaker than the positive control; examples 1, 2 and 6 have better selectivity for both Sun739 and HepG2 tumor cell lines at low concentrations of 10 μm.
In addition, compared with the compounds provided in comparative examples 1-3, the compound obtained by adopting the imidazo pyrimidine to modify the 6-position of the naphthalene ring of naphthalimide also has stronger anti-tumor effect on tumor cells. The compound provided by the invention has more obvious inhibition activity on proliferation of various tumor cells in vitro, and the compound can effectively inhibit proliferation of tested tumor cell lines, has the potential of drug formation, and can provide a new structural choice for development of novel anti-tumor drugs.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other modifications without departing from the scope of the present invention should be equivalent, and are included in the scope of the present invention.

Claims (10)

1. An imidazopyrimidine modified naphthalimide-polyamine conjugate, characterized by being a compound represented by formula i:
in the formula I, m is 1, 2 or 3; r is selected from
One of them.
2. The imidazopyrimidine modified naphthalimide-polyamine conjugate according to claim 1, wherein the pharmaceutically acceptable salt is one or more of hydrochloride, sulfate, maleate, phosphate, citrate, hydrobromide, acetate, benzenesulfonate, tartrate, carbonate, citrate, malate, methanesulfonate, stearate, valerate, nitrate.
3. A process for the preparation of an imidazopyrimidine modified naphthalimide-polyamine conjugate according to claim 1, wherein when the target product is a pharmaceutically acceptable salt of a compound of formula i, the process comprises the steps of:
step (1): the compound is preparedAnd CH (CH) 3 COCl reaction to give the compound->
Step (2): the compound is preparedOn CH 3 COOH and Na 2 Cr 2 O 7 Carrying out reaction to obtain the compound
Step (3): the compound is preparedWith N-bromosuccinimide in acetonitrile, followed by purification to give the compound +.>
Step (4): the compound is preparedAnd->Reacting in acetone at 40-60 deg.c for 5-7 hr to obtain the compound +.>
Step (5): the compound is preparedWith amine chain R' NH in absolute ethanol 2 Reacting and purifying to obtain the compound->
Step (6): the compound is preparedMixing the mixture with acid in absolute ethyl alcohol to perform stirring reaction to obtain pharmaceutically acceptable salt of the compound shown in the formula I;
when the target product is a compound shown in a formula I, the preparation method comprises the steps of neutralizing the compound shown in the formula I obtained in the step (6) in addition to the steps (1) to (6) to obtain the compound shown in the formula I;
wherein the amine chain R' NH 2 Selected from the group consisting of Is a kind of the above-mentioned materials.
4. A process for the preparation of an imidazopyrimidine modified naphthalimide-polyamine conjugate according to claim 3, wherein in step (3) the compoundThe reaction molar ratio of the N-bromosuccinimide is 2:1.
5. A process for the preparation of an imidazopyrimidine modified naphthalimide-polyamine conjugate according to claim 3, wherein in step (4) the compoundAnd->The reaction molar ratio of (2) is 1:1.
6. The method of preparing an imidazopyrimidine modified naphthalimide-polyamine conjugate according to claim 3, wherein in step (6), the acid is one or more of hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, citric acid, hydrobromic acid, acetic acid, benzenesulfonic acid, tartaric acid, carbonic acid, citric acid, malic acid, methanesulfonic acid, stearic acid, valeric acid, nitric acid.
7. The method for preparing an imidazopyrimidine modified naphthalimide-polyamine conjugate according to claim 3 or 6, wherein in step (6), the acid is hydrochloric acid having a concentration of 4 mol/L.
8. Use of an imidazopyrimidine modified naphthalimide-polyamine conjugate according to claim 1 in the preparation of an antitumor drug.
9. Use of an imidazopyrimidine modified naphthalimide-polyamine conjugate according to claim 8 for the manufacture of an anti-tumor drug, wherein the anti-tumor drug is a drug that inhibits tumor cell activity.
10. Use of an imidazopyrimidine modified naphthalimide-polyamine conjugate according to claim 9 in the manufacture of an anti-tumour medicament, wherein the tumour cell is one or more of Sun739 cells, MCF-7 cells, PC-12 cells, hepG2 cells.
CN202311292921.5A 2023-10-08 2023-10-08 Imidazopyrimidine modified naphthalimide-polyamine conjugate as well as preparation method and application thereof Pending CN117362297A (en)

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