CN112250682B - Aromatic heterocycle modified naphthalimide derivative and preparation method and application thereof - Google Patents

Aromatic heterocycle modified naphthalimide derivative and preparation method and application thereof Download PDF

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CN112250682B
CN112250682B CN202011204942.3A CN202011204942A CN112250682B CN 112250682 B CN112250682 B CN 112250682B CN 202011204942 A CN202011204942 A CN 202011204942A CN 112250682 B CN112250682 B CN 112250682B
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王玉霞
苌聪聪
代付军
谢松强
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Abstract

The invention discloses aThe aromatic heterocycle modified naphthalimide derivative has a structural general formula shown in the specification,

Description

Aromatic heterocycle modified naphthalimide derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to an aromatic heterocycle modified naphthalimide derivative, and a preparation method and application thereof.
Background
Cancer is the disease with the highest global mortality, and the "world cancer report" predicts that global cancer cases will reach 1900 million people by 2025. The cancer treatment is generally surgical treatment, radiotherapy, chemotherapy, or biological treatment. Currently, chemotherapy plays one of the most important roles in cancer treatment.
Naphthalimide compounds have wide biological activity, a plurality of naphthalimide derivatives have antitumor activity, and representative drugs of aminonaftifide, mitotaneamine and the like all enter clinical research stages, but are not successfully marketed due to bone marrow inhibition, dose limitation, blood toxicity and unpredictable toxic and side effects.
Aromatic heterocycles such as aminothiazoles and imidazopyridines have attracted much attention as structural fragments having physiological and pharmacological activities. Thiazole compounds widely exist in the natural world, and have different biological activities and low toxicity of human bodies, so that the thiazole compounds have wide application in the aspects of medicines and drug synthesis. Imidazopyridines are typical nitrogen-containing heterocyclic compounds that are widely found in natural products and pharmaceuticals. The imidazopyridine and the derivatives thereof are widely applied to the field of research and development of new drugs, and have good pharmacological activities of resisting cancer, resisting virus, relieving fever, relieving pain and the like. Currently, a variety of drugs containing an imidazopyridine skeleton have been clinically applied. As a medicine molecular structure framework with better biological activity, the fragment-containing medicine has abundant and diverse pharmacological activities, and particularly has remarkable efficacy in the aspect of tumor treatment. Therefore, the imidazopyridine skeleton structural unit is receiving more and more extensive attention and becomes a research hotspot of organic chemists and medicinal chemists.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide an aromatic heterocycle modified naphthalimide derivative which has better inhibitory activity on tumor cells.
The second object of the present invention is to provide a process for producing the microorganism.
The invention also aims to provide the application of the compound in preparing antitumor drugs.
One of the purposes of the invention is realized by adopting the following technical scheme:
an aromatic heterocycle modified naphthalimide derivative has a structural general formula I:
Figure BDA0002756689140000021
wherein R is an imidazopyridine group or an aminothiazole group, R2Is polyamine chain, amino, tertiary amino, hydroxyl, pyrrolidinyl or morpholinyl, X is an integer from 0 to 4, q is 1,2 or 3;
further, when R is imidazopyridine, the compound has the general structural formula I-1:
Figure BDA0002756689140000022
wherein R is2Is selected from
Figure BDA0002756689140000023
Any one of (1) or (2) and (2) is k.
Further, when R is aminothiazole, the compound has the general structural formula I-2:
Figure BDA0002756689140000024
wherein R is2Is selected from
Figure BDA0002756689140000025
Any one of (1) or (2) and (2) is k.
The second purpose of the invention is realized by the following technical scheme:
a method for synthesizing a compound represented by the general formula I-1, comprising the steps of:
Figure BDA0002756689140000026
(1) adding the compound 10 into a reaction container, and reacting with a dichloromethane solution of acetyl chloride by using aluminum trichloride as a catalyst to obtain a compound 11;
(2) refluxing the compound 11 obtained in the step (1) with potassium dichromate under the condition that acetic acid is used as a solvent to obtain a compound 12;
(3) stirring the compound 12 obtained in the step (2) in acetonitrile and NBS at normal temperature for 15min, and then carrying out reflux reaction with methylbenzenesulfonic acid to obtain a compound 13;
(4) stirring the compound 13 obtained in the step (3) and o-aminopyridine in tetrahydrofuran at normal temperature for 12h to obtain a compound 14;
(5) reacting the compound 14 obtained in the step (4) with a nitrogen-containing compound to obtain a compound 15 a-j;
(6) and (3) reacting the compound 15a-j obtained in the step (5) with 4M hydrochloric acid in absolute ethyl alcohol to obtain the aromatic heterocyclic modified naphthalimide derivative 16a-j with the structure of the general formula I-1.
Preferably, the synthesis route of the partial nitrogen-containing compound (or Boc anhydride protection) is as follows:
Figure BDA0002756689140000031
a method for synthesizing a compound represented by the general formula I-2, comprising the steps of:
Figure BDA0002756689140000041
(1) adding the compound 10 into a reaction container, and reacting with a dichloromethane solution of acetyl chloride by using aluminum trichloride as a catalyst to obtain a compound 11;
(2) refluxing the compound 11 obtained in the step (1) with potassium dichromate under the condition that acetic acid is used as a solvent to obtain a compound 12;
(3) stirring the compound 12 obtained in the step (2) in acetonitrile and NBS at normal temperature for 15min, and then carrying out reflux reaction with methylbenzenesulfonic acid to obtain a compound 13;
(4) reacting the compound 13 obtained in the step (3) with thiourea to obtain a compound 17;
(5) reacting the compound 17 obtained in the step (4) with a nitrogen-containing compound to obtain compounds 18 a-h;
(6) and (3) reacting the compound 18a-h obtained in the step (5) with 4M hydrochloric acid in absolute ethyl alcohol to obtain the aromatic heterocyclic modified naphthalimide derivative 19a-h with the structure of the general formula I-2.
The invention also aims to provide the application of the aromatic heterocycle modified naphthalimide derivative in preparing antitumor drugs.
Further provides the application of the aromatic heterocycle modified naphthalimide derivative in preparing medicaments for treating human colon cancer, liver cancer and breast cancer.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides an aromatic heterocycle modified naphthalimide derivative which has a novel framework, high efficiency, low toxicity and good inhibitory activity on tumor cells. The invention also provides a preparation method of the compound, which takes naphthalimide as a raw material, introduces active groups of imidazopyridine and aminothiazole on a parent naphthalene ring respectively to synthesize a novel aromatic heterocycle modified naphthalimide pharmacophore, and modifies the naphthalimide pharmacophore by a polyamine chain, relating to the synthesis of an imidazopyridine and aminothiazole aromatic heterocycle modified naphthalimide derivative. The compound retains the antitumor activity of naphthalimide, has the characteristics of imidazopyridine and aminothiazole, improves the biological activity of the original molecule, and improves the antitumor activity of the target molecule. The invention also provides the application of the compound in preparing anti-tumor drugs, has certain inhibitory activity on human colon cancer cells, human liver cancer cells and human breast cancer cells, and shows good development potential.
Detailed Description
The present invention is further described below with reference to specific embodiments, and it should be noted that, without conflict, any combination between the embodiments or technical features described below may form a new embodiment.
Example 1
Synthesis of 6- [1- (imidazo [1,2-a ] pyridine) ] -2- {4- [4- (4-aminobutyl) -aminobutyl ] -aminobutyl } -1H-benzisoquinoline-1, 3(2H) -dione tetrahydrate salt (16a)
Figure BDA0002756689140000051
(1) 1.0g (6.5mmol) of Compound 10 was taken with anhydrous AlCl31.29g (9.7mmol) was placed in a 100mL round-bottom flask, dried dichloromethane was added as a reaction solvent, and after stirring at room temperature for 15min, 0.48mL (6.8mmol) of acetyl chloride in dichloromethane was slowly added dropwise under ice-bath conditions, and after completion of dropwise addition, reaction was carried out at room temperature for 30 min. After 2 hours, the mixture was poured into ice water, the organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and petroleum ether: separating and purifying the ethyl acetate with a 10:1 column to obtain a compound 11;
(2) 2.2g (7.5 mmo) was takenl) Compound 11, K from step (1)2Cr2O7·2H2And refluxing O6.6 g (22.0mmol) in 20mL of glacial acetic acid for 2h, cooling to room temperature, pouring into ice water, and performing suction filtration and water washing to obtain a compound 12.
(3) Taking 1.20g (5.0mmol) of the compound 12 obtained in the step (2), adding NBS 890mg (5.0mmol) into a 100mL round-bottom flask, adding a proper amount of acetonitrile serving as a reaction solvent, stirring at normal temperature for 15min, adding 1.90g (10.0mmol) of p-toluenesulfonic acid, refluxing for 5h, evaporating to dryness after the reaction of the reaction raw materials is finished, and separating and purifying by a silica gel column to obtain a light yellow solid product 13. The yield was 75.5%.
(4) 638mg (2.0mmol) of the compound 13 obtained in the step (3) and 188mg (2.0mmol) of o-aminopyridine are added into a 100mL round-bottom flask, tetrahydrofuran is used as a reaction solvent, the mixture is stirred at normal temperature for 12 hours, a yellow solid is continuously precipitated, the system is changed from a clear light yellow solution to a yellow turbid solution, and the product 14 is obtained as a yellow solid by suction filtration, wherein the yield is 50%.
(5) Putting 314mg (1.0mmol) of the compound 14 obtained in the step (4) into a 100mL round-bottom flask, adding 5a1.25mmol, taking a proper amount of ethanol as a reaction solvent, carrying out reflux reaction for 5h, after the reaction of the raw materials is finished, separating and purifying by a silica gel column to obtain a yellow solid compound 15a, wherein the yield is 86-98%.
(6) And (3) putting 1mmol of the compound 15 obtained in the step (5) into 2mL of absolute ethyl alcohol, dropwise adding 4M HCl ethanol solution into the mixture under ice-bath stirring, stirring the mixture at room temperature overnight until a large amount of solid appears, filtering the mixture, collecting the solid, washing the solid with redistilled absolute ethyl alcohol for three times, and drying the solid to obtain a compound 16 a. The yield was 47%.
1H NMR(300MHz,Deuterium Oxide)δ8.64(d,J＝6.0Hz,1H),8.37(s,1H),8.33-8.24(m,3H),7.95-7.88(m,1H),7.80(t,J＝9.0Hz,2H),7.67(t,J＝9.0Hz,1H),7.48-7.40(m,1H),3.95(s,2H),3.09-3.00(m,10H),1.84-1.58(m,12H).13C NMR(75MHz,Deuterium Oxide)δ:164.74,164.39,140.48,134.30,131.99,131.86,131.28,130.52,128.73,128.59,128.39,127.93,127.26,122.25,121.29,117.57,114.79,111.92,47.17,46.86,46.81,39.77,38.71,24.18,23.86,23.17,22.76,22.71,16.70.ESI-MS m/z:527.53[M-4HCl+1]+.Elemental analysis for C31H42Cl4N6O2·0.3CH3CH2OH·3.2H2O:C,51.02；H,6.80；N,11.30；Found:C,50.95；H,7.02；N,11.34.
Example 2
Synthesis of 6- [1- (imidazo [1,2-a ] pyridine) ] -2- [4- (4-aminobutyl) -aminobutyl ] -1H-benzisoquinoline-1, 3(2H) -dione trihydrochloride (16b)
Figure BDA0002756689140000061
The synthesis and purification were the same as in example 1 except that 3b was used in place of 5a in step (5). The yield was 52%.
1H NMR(300MHz,Deuterium Oxide)δ:8.60(d,J＝6.0Hz,1H),8.31(s,1H),8.24(dd,J＝12.0,6.0Hz,3H),7.96–7.84(m,1H),7.75(t,J＝7.5Hz,2H),7.63(t,J＝7.5Hz,1H),7.42(s,1H),3.95(t,J＝6.0Hz,2H),3.25–3.05(m,6H),2.06-2.16(m,2H),1.86–1.63(m,4H).13C NMR(75MHz,Deuterium Oxide)δ164.55,164.19,140.54,134.10,132.10,131.79,131.22,130.60,130.46,128.50,128.37,127.66,127.08,121.95,121.09,117.46,114.72,112.01,47.31,44.47,39.78,36.52,24.17,23.73,23.16.ESI-MS m/z:442.45[M-3HCl+1]+.Elemental analysis for C26H30Cl3N5O2·2.9H2O:C,51.78；H,5.98；N,11.61；Found:C,51.89；H,6.09；N,11.45.
Example 3
Synthesis of 6- [1- (imidazo [1,2-a ] pyridine) ] -2- [3- (3-aminopropyl) -aminopropyl ] -1H-benzisoquinoline-1, 3(2H) -dione trihydrochloride (16c)
Figure BDA0002756689140000062
The synthesis and purification were the same as in example 1 except that 3a was used in place of 5a in step (5). The yield was 59%.
1H NMR(300MHz,Deuterium Oxide)δ8.70(d,J＝6.0Hz,1H),8.43(s,1H),8.35-8.24(m,3H),8.03-7.94(m,1H),7.84(dd,J＝9.0,3.0Hz,2H),7.68(t,J＝9.0Hz,1H),7.50(t,J＝6.0Hz,1H),4.07(t,J＝7.5Hz,2H),3.22-3.13(m,6H),2.29-1.90(m,4H).13C NMR(75MHz,Deuterium Oxide)δ164.60,164.25,140.43,134.56,131.92,131.67,131.38,130.57,130.50,128.78,128.70,128.48,127.86,127.17,122.04,121.04,117.73,114.88,111.88,45.44,44.63,37.46,36.51,24.22,23.73.ESI-MS m/z:428.41[M-3HCl+1]+.Elemental analysis for C25H28Cl3N5O2·3.2H2O:C,50.51；H,5.83；N,11.78；Found:C,50.56；H,5.92；N,11.62.
Example 4
Synthesis of 6- [1- (imidazo [1,2-a ] pyridine) ] -2- (3-aminopropyl) -1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (16d)
Figure BDA0002756689140000071
The synthesis and purification were the same as in example 1 except that in step (5), propylenediamine was used instead of 5 a. The yield was 55%.
1H NMR(300MHz,Deuterium Oxide)δ8.67(d,J＝9.0Hz,1H),8.39(s,1H),8.32-8.20(m,3H),7.94(ddd,J＝9.0,6.0,3.0Hz,1H),7.88-7.77(m,2H),7.64(t,J＝9.0Hz,1H),7.47(t,J＝6.0Hz,1H),4.04(t,J＝7.5Hz,2H),3.08(t,J＝7.5Hz,2H),2.03(p,J＝6.0Hz,2H).13C NMR(75MHz,Deuterium Oxide)δ164.67,164.33,140.47,134.48,131.89,131.80,131.33,130.55,128.76,128.66,128.44,127.88,127.20,122.07,121.08,117.69,114.84,111.90,37.44,37.18,25.32.ESI-MS m/z:371.35[M-2HCl+1]+.Elemental analysis for C22H20Cl2N4O2·0.4CH3CH2OH:C,59.31；H,4.89；N,12.13；Found:C,59.44；H,5.01；N,12.14.
Example 5
Synthesis of 6- [1- (imidazo [1,2-a ] pyridine) ] -2- (2-dimethylaminoethyl) -1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (16e)
Figure BDA0002756689140000072
The synthesis and purification were the same as in example 1 except that N, N-dimethylethylenediamine was used in place of 5a in step (5). The yield was 84%.
1H NMR(300MHz,Deuterium Oxide)δ8.71(d,J＝9.0Hz,1H),8.45(s,1H),8.39(s,1H),8.36(s,1H),8.34(s,1H),7.97(dd,J＝3.0,6.0,15.0Hz,1H),7.90-7.83(m,2H),7.72(t,J＝9.0Hz,1H),7.50(td,J＝6.0,3.0Hz,1H),4.42(t,J＝9.0Hz,2H),3.50(t,J＝6.0Hz,2H),3.02(s,6H).13C NMR(75MHz,Deuterium Oxide)δ164.77,164.44,140.52,134.58,132.17,131.79,131.74,130.91,130.83,128.97,128.73,128.51,128.22,127.47,122.06,121.03,117.75,114.95,111.93,55.24,43.33,35.43,ESI-MS m/z:385.34[M-2HCl+1]+.Elemental analysis for C23H22Cl2N4O2·1.2H2O:C,57.68；H,5.13；N,11.70；Found:C,57.83；H,5.16；N,11.56.
Example 6
Synthesis of 6- [1- (imidazo [1,2-a ] pyridine) ] -2- (2-dimethylaminopropyl) -1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (16f)
Figure BDA0002756689140000081
The synthesis and purification were the same as in example 1 except that N, N-dimethylpropylamine was used in place of 5a in step (5). The yield was 67%.
1H NMR(300MHz,Deuterium Oxide)δ8.67(d,J＝6.0Hz,1H),8.38(s,1H),8.32-8.11(m,3H),8.03-7.88(m,1H),7.80(dd,J＝9.0,3.0Hz,2H),7.61(t,J＝9.0Hz,1H),7.47(t,J＝6.0Hz,1H),4.01(s,2H),3.25(s,2H),2.91(s,6H),2.09(t,J＝7.5Hz,2H).13C NMR(75MHz,Deuterium Oxide)δ164.54,164.23,140.50,134.54,131.86,131.79,131.35,130.58,128.78,128.69,128.46,127.87,127.19,122.02,121.04,117.73,114.87,111.93,55.29,42.80,37.35,22.79.ESI-MS m/z:399.35[M-2HCl+1]+.Elemental analysis for C24H24Cl2N4O2·H2O:C,58.90；H,5.36；N,11.45；Found:C,58.98；H,5.58；N,11.42.
Example 7
Synthesis of 6- [1- (imidazo [1,2-a ] pyridine) ] -2- (3-diethylaminopropyl) -1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (16g)
Figure BDA0002756689140000082
The synthesis and purification were the same as in example 1 except that N, N-diethylpropanediamine was used in place of 5a in the step (5). The yield was 72%.
1H NMR(75MHz,Deuterium Oxide)δ8.68(d,J＝6.0Hz,1H),8.40(s,1H),8.33-8.19(m,3H),8.01-7.92(m,1H),7.87-7.78(m,2H),7.63(t,J＝7.5Hz,1H),7.51-7.46(m,1H),4.02(t,J＝6.0Hz,2H),3.30-3.22(m,6H),2.14-2.04(m,2H),1.30(t,J＝7.5Hz,6H).13C NMR(75MHz,Deuterium Oxide)δ164.41,164.10,140.49,134.46,131.77,131.32,130.59,130.53,128.73,128.64,128.41,127.80,127.13,121.93,120.96,117.67,114.83,111.91,49.23,47.33,37.55,22.11,8.12.ESI-MS m/z:427.39[M-2HCl+1]+.Elemental analysis for C26H28Cl2N4O2·3.5H2O:C,55.52；H,6.27；N,9.96；Found:C,55.56；H,6.07；N,9.85.
Example 8
Synthesis of 6- [1- (imidazo [1,2-a ] pyridine) ] -2- (3-pyrrolidinopropyl ] -1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (16H)
Figure BDA0002756689140000091
The synthesis and purification were the same as in example 1 except that in step (5), compound 9a was used instead of 5 a. The yield was 53%.
1H NMR(300MHz,Deuterium Oxide)δ8.66(d,J＝6.0Hz,1H),8.38(s,1H),8.30-8.17(m,3H),8.00-7.87(m,1H),7.80(dd,J＝9.0,3.0Hz,2H),7.61(t,J＝9.0Hz,1H),7.46(t,J＝7.5Hz,1H),4.01(t,J＝7.5Hz,2H),3.70-3.63(m,2H),3.28(t,J＝9.0Hz,2H),3.11-3.02(m,2H),2.20-1.90(m,6H).13C NMR(75MHz,Deuterium Oxide)δ164.53,164.21,140.47,134.44,131.80,131.31,130.57,130.50,128.74,128.63,128.39,127.87,127.17,122.02,121.03,117.64,114.81,111.88,54.12,52.47,37.44,24.07,22.55.ESI-MS m/z:425.35(M-2HCl+1)+.Elemental analysis for C26H26Cl2N4O2·H2O:C,60.59；H,5.48；N,10.87；Found:C,60.54；H,5.66；N,10.77.
Example 9
Synthesis of 6- [1- (imidazo [1,2-a ] pyridine) ] -2- (3-morpholinopropyl) -1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (16i)
Figure BDA0002756689140000092
The synthesis and purification were the same as in example 1 except that compound 7 was used in place of 5a in step (5). The yield was 49%.
1H NMR(300MHz,Deuterium Oxide)δ8.54(d,J＝9.0Hz,1H),8.26(s,1H),8.18-8.03(m,3H),7.81(ddd,J＝9.0,6.0,3.0Hz,1H),7.69-7.66(m,2H),7.49(t,J＝9.0Hz,1H),7.35(t,J＝6.0Hz,1H),4.07-3.83(m,4H),3.71(t,J＝12.0Hz,2H),3.43(d,J＝12.0Hz,2H),3.24-2.95(m,4H),2.04-1.94(m,2H).13C NMR(75MHz,Deuterium Oxide)δ164.45,164.13,140.44,134.46,131.80,131.71,131.30,130.54,130.50,128.72,128.62,128.38,127.81,127.12,121.96,120.96,117.65,114.81,111.86,63.69,54.74,51.68,37.42,21.84.ESI-MS m/z:441.38(M-2HCl+1)+.Elemental analysis for C26H26Cl2N4O3·3.2H2O:C,54.68；H,5.72；N,9.81；Found:C,54.79；H,5.85；N,9.77.
Example 10
Synthesis of 6- [1- (imidazo [1,2-a ] pyridine) ] -2- (3-hydroxypropyl) -1H-benzisoquinoline-1, 3(2H) -dione (16i)
Figure BDA0002756689140000101
The synthesis and purification were the same as in example 1 except that 3-aminopropanol compound was used in place of 5a in step (5). The yield was 66%.
1H NMR(300MHz,DMSO-d6)δ9.41(d,J＝9.0Hz,1H),8.60-8.48(m,4H),8.16(d,J＝9.0Hz,1H),7.92-7.61(m,2H),7.34(s,1H),6.99(s,1H),4.55(s,1H),4.10(s,2H),3.40(s,2H),1.80(s,2H).13C NMR(75MHz,DMSO-d6)δ163.94,163.63,145.28,143.06,137.97,133.70,131.08,130.80,129.12,128.68,127.91,127.66,127.54,126.24,122.72,121.57,117.46,114.14,113.34,59.48,38.04,31.44.ESI-MS m/z:372.34[M+1]+.Elemental analysis for C22H17N3O3:C,71.15；H,4.61；N,11.31；Found:C,70.99；H,4.60；N,11.34.
Example 11
Synthesis of 6- [4- (2-aminothiazole) ] -2- {4- [4- (4-aminobutyl) -aminobutyl ] -aminobutyl } -1H-benzisoquinoline-1, 3(2H) -dione tetrahydrate salt (19a)
Figure BDA0002756689140000102
(1) The synthesis process of the step (3) is the same as that of example 1;
(4) taking 1.60mg (5.0mmol) of the compound 13 obtained in the step (3) and 380mg (5.0mmol) of thiourea into a 100mL round-bottom flask, adding a proper amount of acetonitrile as a reaction solvent, reacting at 55 ℃ for 6h to change the solution from the light yellow turbid solution into a yellow turbid solution, and performing suction filtration to obtain a yellow solid product 17 with the yield of 56%;
(5) putting 296mg (1.0mmol) of the compound 17 obtained in the step (4) into a 100mL round-bottom flask, adding 1.25mmol of amine chain 5a, adding a proper amount of DMF as a reaction solvent, carrying out reflux reaction for 5 hours, changing a yellow solution into an orange-red solution after the reaction of the raw materials is finished, evaporating the solvent to dryness, and separating and purifying by a silica gel column to obtain an orange-yellow solid compound 18a with the yield of 45-57%. 3.95(s,2H),3.09-3.00(m,10H),1.84-1.58(m,12H).
(6) Dissolving 18a (0.5mmol) obtained in the step (5) in a proper amount of ethanol, dropwise adding 4M hydrochloric acid ethanol solution under stirring, stirring at room temperature until a large amount of solid is separated out, performing suction filtration, washing a filter cake with anhydrous ether, and drying the filter cake to obtain a compound 19 a. Yield: 39 percent.
1H NMR(300MHz,Deuterium Oxide)δ8.24–8.09(m,3H),7.68(d,J＝8.60Hz,1H),7.53(t,J＝7.24Hz,1H),7.03(s,1H),3.88(t,J＝7.5Hz,2H),3.22–2.98(m,6H),1.92–1.54(m,8H).13C NMR(75MHz,DMSO-d6)δ169.66,163.96,163.64,133.03,131.49,130.78,129.37,128.46,128.02,122.75,122.42,109.11,46.77,46.23,46.15,38.27,25.28,24.35,23.58,22.96,22.81.ESI-MS m/z:509.45[M-4HCl+1]+.Elemental analysis for C27H40Cl4N6O2S·2.8H2O:C,46.00；H,6.52；N,11.92；Found:C,45.81；H,6.28；N,11.71.
Example 12
Synthesis of 6- [4- (2-aminothiazole) ] -2- [4- (4-aminobutyl) -aminobutyl ] -1H-benzisoquinoline-1, 3(2H) -dione trihydrochloride (19b)
Figure BDA0002756689140000111
The synthesis and purification were carried out in the same manner as in example 11 except that in step (2), compound 3c was used instead of 5 a. Yield: 66 percent.
1H NMR(300MHz,Deuterium Oxide)δ8.26–8.08(m,3H),7.66(d,J＝9.0Hz,1H),7.52(t,J＝7.5Hz,1H),7.05(s,1H),3.88(t,J＝7.5Hz,2H),3.22–2.98(m,6H),1.92–1.54(m,8H).13C NMR(75MHz,Deuterium Oxide)δ170.50,164.61,164.29,135.70,132.81,131.59,130.48,128.08,127.98,127.07,121.67,120.92,108.98,47.16,46.84,39.75,38.76,24.18,23.90,23.16,22.74.ESI-MS m/z:438.42[M-3HCl+1]+.Elemental analysis for C23H30Cl3N5O2S·H2O:C,48.90；H,5.71；N,12.40；Found:C,48.93；H,5.88；N,12.37.
Example 13
Synthesis of 6- [4- (2-aminothiazole) ] -2- [3- (3-aminopropyl) -aminopropyl ] 1H-benzisoquinoline-1, 3(2H) -dione trihydrochloride (19c)
Figure BDA0002756689140000112
The synthesis and purification were carried out in the same manner as in example 11 except that in step (2), compound 3a was used instead of 5 a. Yield: 56 percent.
1H NMR(300MHz,Deuterium Oxide)δ8.41–8.26(m,3H),7.79(d,J＝7.5Hz,1H),7.69(t,J＝9.0Hz,1H),7.11(s,1H),4.10(t,J＝6.0Hz,2H),3.24–3.05(m,6H),2.19–1.95(m,2H).13C NMR(75MHz,DMSO-d6)δ170.06,164.00,163.69,134.75,132.51,131.57,130.62,129.30,128.77,128.32,122.92,122.76,45.24,44.15,37.69,36.39,24.88,23.95.ESI-MS m/z:410.37[M-3HCl+1]+.Elemental analysis for C21H26Cl3N5O2S·1.6H2O:C,46.05；H,5.37；N,12.79；Found:C,46.12；H,5.46；N,12.71.
Example 14
Synthesis of 6- [4- (2-aminothiazole) ] -2- [2- (2-dimethylamino) -ethyl ] 1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (19d)
Figure BDA0002756689140000121
The synthesis and purification were carried out in the same manner as in example 11 except that in the step (2), the compound N, N-dimethylethylenediamine was used in place of 5 a. Yield: 82 percent.
1H NMR(300MHz,Deuterium Oxide)δ8.31-8.18(m,3H),7.74(d,J＝6.0Hz,1H),7.59(t,J＝6.0Hz,1H),7.09(s,1H),4.36(t,J＝6.0Hz,2H),3.48(t,J＝6.0Hz,2H),3.02(s,6H).13C NMR(75MHz,Deuterium Oxide)δ170.54,164.77,164.44,135.23,135.11,133.05,131.98,130.85,128.41,128.23,128.11,127.36,121.62,120.80,109.07,55.24,43.34,35.39.ESI-MS m/z:367.32(M-2HCl+1)+.Elemental analysis for C19H20Cl2N4O2S·1.3H2O:C,49.31；H,4.92；N,12.11；Found:C,49.17；H,5.09；N,12.11.
Example 15
Synthesis of 6- [4- (2-aminothiazole) ] -2- [3- (3-diethylamino) -propyl ] 1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (19e)
Figure BDA0002756689140000122
The synthesis and purification were carried out in the same manner as in example 11 except that in the step (2), the compound N, N-diethylpropanediamine was used in place of 5 a. Yield: 79 percent.
1H NMR(300MHz,Deuterium Oxide)δ7.94(dd,J＝3.0,6.0Hz,2H),7.84(d,J＝9.0Hz,1H),7.50(d,J＝9.0Hz,1H),7.26(t,J＝9.0Hz,1H),6.93(s,1H),3.81(t,J＝6.0Hz,2H),3.22(m,6H),1.97(m,2H),1.26(t,J＝9.0Hz,6H).13C NMR(75MHz,Deuterium Oxide)δ170.33,163.92,163.70,135.01,132.49,131.22,130.40,127.81,127.71,127.51,126.64,121.03,120.30,109.32,49.16,47.29,37.49,22.03,8.15.ESI-MS m/z:409.34[M-2HCl+1]+.Elemental analysis for C22H26Cl2N4O2S·3.4H2O:C,48.69；H,6.09；N,10.32；Found:C,48.77；H,6.19；N,10.32.
Example 16
Synthesis of 6- [4- (2-aminothiazole) ] -2- [ 4-pyrrolidinyl) -butyl ] -1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (19f)
Figure BDA0002756689140000131
The synthesis and purification were carried out in the same manner as in example 11 except that in step (2), compound 9b was used instead of 5 a. Yield: and 43 percent.
1H NMR(300MHz,Deuterium Oxide)δ8.29–8.13(m,1H),8.12–8.01(m,2H),7.61(d,J＝9.0Hz,1H),7.47(t,J＝7.5Hz,1H),7.00(s,1H),3.86(t,J＝7.5Hz,2H),3.61-3.69(m,2H),3.32–3.20(m,2H),3.15–3.01(m,2H),2.17-2.08(m,2H),2.02-1.97(m,2H),1.86–1.72(m,2H),1.66-1.61(m,2H).13C NMR(75MHz,DMSO-d6)δ163.95,163.63,132.78,131.55,130.73,129.35,128.63,128.37,128.19,122.76,122.69,109.16,53.94,53.40,39.58,25.17,23.29,23.03.ESI-MS m/z:421.35[M-2HCl+1]+.Elemental analysis for C23H26Cl2N4O2S·2.4H2O:C,51.47；H,5.78；N,10.44；Found:C,51.50；H,5.80；N,10.32.
Example 17
Synthesis of 6- [4- (2-aminothiazole) ] -2- [3- (3-diethylamino) -propyl ] 1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (19g)
Figure BDA0002756689140000132
The synthesis and purification were carried out in the same manner as in example 11 except that in step (2), compound 7 was used instead of 5 a. Yield: and 43 percent.
1H NMR(300MHz,Deuterium Oxide)δ8.20(d,J＝9.0Hz,1H),8.13(dd,J＝7.5,6.0Hz,2H),7.64(d,J＝6.0Hz,1H),7.48(t,J＝9.0Hz,1H),6.98(s,1H),4.12(d,J＝12.0Hz,2H),4.00(t,J＝7.5Hz,2H),3.83(t,J＝12.0Hz,2H),3.55(d,J＝15.0Hz,2H),3.42–3.11(m,4H),2.11(p,J＝7.5Hz,2H).13C NMR(75MHz,Deuterium Oxide)δ170.35,164.72,164.43,137.79,134.17,131.97,131.53,130.62,128.11,127.80,127.68,127.17,121.17,120.71,109.30,63.73,54.79,51.71,37.39,21.89.ESI-MS m/z:423.33[M-2HCl+1]+.Elemental analysis for C22H24Cl2N4O3S·2.2H2O:C,49.39；H,5.35；N,10.47；Found:C,49.58；H,5.46；N,10.40.
Example 18
Synthesis of 6- [4- (2-aminothiazole) ] -2- [3- (3-diethylamino) -propyl ] 1H-benzisoquinoline-1, 3(2H) -dione hydrochloride (19H)
Figure BDA0002756689140000141
The synthesis and purification were the same as in example 11 except that 3-aminopropanol compound used in step (2) was used instead of 5 a. Yield: 65 percent.
1H NMR(300MHz,DMSO-d6)δ8.63(d,J＝9.0Hz,1H),8.51(t,J＝7.5Hz,2H),7.98(d,J＝6.0Hz,1H),7.89(t,J＝7.5Hz,1H),7.24(s,1H),4.09(dd,J＝9.0,6.0Hz,2H),3.49(t,J＝6.0Hz,2H),1.78(p,J＝6.0Hz,2H).13C NMR(75MHz,DMSO-d6)δ170.11,163.75,163.43,138.74,134.56,132.35,131.48,130.51,129.34,128.83,128.31,128.19,123.05,122.82,109.14,59.34,38.18,31.28.ESI-MS m/z:354.31[M-HCl+1]+.Elemental analysis for C18H16ClN3O3S·0.2CH3CH2OH, C, 55.38; h, 4.34; n, 10.53; found, C, 55.02; h, 4.43; n,10.66. test example 1
Evaluation of biological Activity
(1) The in vitro tumor cell growth inhibition activity of the compound is determined: the compounds prepared in examples 1-18 were selected, and three tumor cell lines, MDA-MB-231 (breast cancer cells), HCT-116 (human cancer cells), and HepG2 (human hepatoma cells) in logarithmic growth phase were embedded in 96-well plates at 90. mu.L/well with 8000 cells per well. After 24h incubation, samples of known concentration were added, four replicates per concentration for each cell line, at 37 ℃ and 5% CO2Culturing for 48h, adding MTT50 μ L, culturing for 4h, discarding supernatant, adding 100 μ L of DSMO into each well, shaking gently for 15min, and measuring absorbance A at 570nm with microplate reader. The inhibition rate of the test substance on the growth of tumor cells was calculated according to the formula (tumor cell growth inhibition rate (%) (OD control-OD experiment)/(OD control-OD blank) × 100%), and the experiment was repeated three times. The results are shown in Table 1.
TABLE 1 growth inhibitory Activity of the Compounds on different tumor cells
Figure BDA0002756689140000142
Figure BDA0002756689140000151
As can be seen from Table 1, the two series of compounds of the aromatic heterocycle modified naphthalimide derivative provided by the invention have certain inhibitory activity on tumor cell strains HCT-116, HepG2 and MDA-MB-231. For example, the compounds 16a, 16c, 16e, 19a, 19c and the like have better inhibitory activities and higher inhibition rates on the three tumor cells, for example, the compound 16c has far higher inhibition rates on three tumor cell lines, namely HCT-116, HepG2 and MDA-MB-231 than the positive control aminonaftifine at low concentration (10 mu M) and high concentration (30 mu M). The inhibition rate of the compounds 16a, 16c and 16e provided by the invention on HepG2 and MDA-MB-231 tumor strains is higher than that of aminonaftifide at low concentration (10 mu M); the inhibition rate of the compounds 16b, 16c, 16d and 16e on three tumor cell lines HCT-116, HepG2 and MDA-MB-231 is higher than that of aminonaftifide at high concentration (30 mu M). The inhibition activity of the compound 19a on tumor cell lines MDA-MB-231 is higher than that of aminonaftifide at low concentration (10 mu M) and high concentration (30 mu M), and the inhibition rate of the compound 19c on three tumor cell lines of HCT-116, HepG2 and MDA-MB-231 is far higher than that of the positive control aminonaftifide at high concentration (30 mu M).
In conclusion, the aromatic heterocycle modified naphthalimide derivative provided by the invention has certain inhibitory activity on tumor cell strains HCT-116, HepG2 and MDA-MB-231, shows good development potential, can be further developed as a potential antitumor drug lead, and provides a new direction for development of antitumor drugs.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.

Claims (5)

1. An aromatic heterocycle modified naphthalimide derivative is characterized in that the structural general formula is I:
Figure FDA0003308908490000011
wherein R is an imidazopyridine group or an aminothiazole group, X is an integer of 0 to 4, and q is 1,2 or 3;
when R is imidazopyridine, the compound has the general structural formula I-1:
Figure FDA0003308908490000012
when R is aminothiazole, the compound has a structural general formula I-2:
Figure FDA0003308908490000013
wherein R is2Is selected from
Figure FDA0003308908490000014
Any one of (1) or (2) and (2) is k.
2. A process for the synthesis of compounds of formula i-1 according to claim 1, comprising the steps of:
Figure FDA0003308908490000015
(1) adding the compound 10 into a reaction container, and reacting with a dichloromethane solution of acetyl chloride by using aluminum trichloride as a catalyst to obtain a compound 11;
(2) refluxing the compound 11 obtained in the step (1) with potassium dichromate under the condition that acetic acid is used as a solvent to obtain a compound 12;
(3) stirring the compound 12 obtained in the step (2) in acetonitrile and NBS at normal temperature for 15min, and then carrying out reflux reaction with methylbenzenesulfonic acid to obtain a compound 13;
(4) stirring the compound 13 obtained in the step (3) and o-aminopyridine in tetrahydrofuran at normal temperature for 12h to obtain a compound 14;
(5) reacting the compound 14 obtained in the step (4) with a nitrogen-containing compound to obtain a compound 15 a-j;
(6) and (3) reacting the compound 15a-j obtained in the step (5) with 4M hydrochloric acid in absolute ethyl alcohol to obtain the aromatic heterocyclic modified naphthalimide derivative 16a-j with the structure of the general formula I-1.
3. A process for the synthesis of compounds of formula i-2 according to claim 1, comprising the steps of:
Figure FDA0003308908490000021
(1) adding the compound 10 into a reaction container, and reacting with a dichloromethane solution of acetyl chloride by using aluminum trichloride as a catalyst to obtain a compound 11;
(2) refluxing the compound 11 obtained in the step (1) with potassium dichromate under the condition that acetic acid is used as a solvent to obtain a compound 12;
(3) stirring the compound 12 obtained in the step (2) in acetonitrile and NBS at normal temperature for 15min, and then carrying out reflux reaction with methylbenzenesulfonic acid to obtain a compound 13;
(4) reacting the compound 13 obtained in the step (3) with thiourea to obtain a compound 17;
(5) reacting the compound 17 obtained in the step (4) with a nitrogen-containing compound to obtain compounds 18 a-h;
(6) reacting the compound 18a-h obtained in the step (5) with 4M hydrochloric acid in absolute ethyl alcohol to obtain the aromatic heterocyclic modified naphthalimide derivative 19a-h with the structure of the general formula I-2.
4. The use of the heteroaromatic modified naphthalimide derivative of claim 1 in the preparation of an anti-tumor medicament.
5. The use of the heteroaromatic modified naphthalimide derivative of claim 1, wherein the compound is used in the preparation of a medicament for the treatment of human colon, liver, and breast cancer.
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